RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 1 af 13

Baggrundsnotat for biologisk behandling af reumatoid artritis (RA)

Notatet vedlaeliggges som dokumentation for behandlingsvejledningen

Fagudvalget under Raringdet for Anvendelse af Dyr Sygehusmedicin RADS er et raringdgivende

udvalg som udarbejder udkast til behandlingsvejledning og baggrundsnotat for anvendelse af

medicin indenfor specifikke behandlingsomraringder Dokumenterne forelaeliggges RADS som

herefter traeligffer beslutning om indholdet af den endelige behandlingsvejledning og

baggrundsnotat Maringlgruppe Reumatologiske afdelinger

Laeliggemiddelkomiteacuteer

Sygehusapoteker

Udarbejdet af Fagudvalget for Biologisk Behandling af Reumatologiske lidelser under

Raringdet for Anvendelse af Dyr Sygehusmedicin

Godkendt af

RADS

30 januar 2014

Version 20

Dokument nr 147149

Dato Februar 2014

Baggrundsnotatet er i vaeligsentlig grad baseret paring kliniske retningslinjer udarbejdet af Dansk

Reumatologisk Selskab og GRADE

Patientgrundlag

Reumatoid artritis (RA) forekommer globalt men med geografisk og etnisk variation I

Danmark antages 07 af befolkningen svarende til 35000 at lide af RA (1) Der er ca 1600

nydiagnosticerede tilfaeliglde hvert aringr (2) og 3 ud af 4 patienter er kvinder Sygdommen kan

debutere i alle aldre men typisk i 4 til 6 dekade I Landspatientregisteret var der i 2011

registreret 22965 individer med RA I Dansk Reumatologisk Database (DANBIO) var der ved

udgangen af 2012 registreret 11688 patienter med RA hvoraf 4284 modtager biologisk

behandling Populationen af biologisk behandlede patienter er fra 2006 til 2012 oslashget med ca

500aringr (3) Ved analyse af DANBIO-registrerede biologiske behandlingsforloslashb fandt Hetland et

al (4) en praeligparatoverlevelse efter 12 mdr paring infliximab adalimumab og etanercept paring

henholdsvis 64 72 og 80 og efter 24 mdr 50 64 og 72 Ved baseline fik

76 tillige methotrexat Med baggrund i disse data kan det forventes at skoslashnsmaeligssigt 30

af behandlingsforloslashb med infliximab adalimumab eller etanercept vil blive afsluttet indenfor et

aringr enten ved skift til et andet biologisk praeligparat eller ved ophoslashr med biologisk behandling

Fagudvalget har ikke haft adgang til estimater for praeligparatoverlevelse for oslashvrige biologiske

laeliggemidler men skoslashnner at mindst 20 af alle RA-patienter med et biologisk

behandlingsforloslashb i DANBIO vil opleve skift til nyt biologisk laeliggemiddel indenfor et aringr hvilket

svarer til 857 patienter (4284 x 020aringr) Naeligrvaeligrende baggrundsnotat refererer saringledes til et

patientgrundlag som aringrligt tilfoslashres ca 500 nye biologisk behandlingsnaive patienter og hvor

aringrligt 857 biologisk behandlingserfarne patienter skiftes til andet biologisk praeligparat Frafaldet

af biologisk behandlede patienter pga doslashd eller medicinske omstaeligndigheder er ubetydeligt i

forhold til den samlede tilgang For nogle patienter vil biologisk monoterapi vaeligre eneste

mulige behandlingsprincip Fagudvalget skoslashnner at biologisk monoterapi vedroslashrer en ikke

ubetydelig og maringske tiltagende patientpopulation hvis stoslashrrelse ikke kan dokumenteres

naeligrmere

Baggrundsnotatet omfatter behandling med foslashlgende laeliggemidler i ATC nr orden

L04AA24 abatacept

L04AA29 tofacitinib

L04AB01 etanercept

L04AB02 infliximab

L04AB04 adalimumab

L04AB05 certolizumab

L04AB06 golimumab

L01XC02 rituximab

L04AC03 anakinra

L04AC07 tocilizumab

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 2 af 13

Patientantal

Fagudvalgets skoslashn pba tilgaeligngelige DANBIO data

Incidensaringr

Praeligvalens

Nye patienter (bionaive) 500 4280

Skifte patienter 850

Gennemsnitsvaeliggt for patienten med reumatoid artrit i biologisk behandling 739 kg

Laeliggemiddellevetid (Fagudvalgets skoslashn) 18 mdr

Patienter interventioner comparatorer og kritiske effektmaringl (PICO) for patienter

med reumatoid artritis (RA)

Foslashlgende patientpopulationer indgaringr i baggrundsnotatets arbejde

P1 Biologisk behandlingsnaive (BIO-naive) patienter som ikke responderer adaeligkvat paring

non-biologisk behandling herefter benaeligvnt DMARD-svigt

P2 Patienter som tidligere har vaeligret i behandling med et biologisk laeliggemiddel men ikke

laeligngere tolererer dette eller ikke oplever oslashnsket effekt herefter benaeligvnt DMARD

svigt BIO-svigt

P3 Biologisk behandlingsnaive patienter (BIO-naive) som ikke tolererer non-biologisk

behandling speciel methotrexat herefter benaeligvnt BIO-mono

P4 Patienter som tidligere har vaeligret i behandling med et biologisk laeliggemiddel men ikke

laeligngere tolererer dette eller ikke oplever oslashnsket effekt og som ikke tolererer non-

biologisk behandling speciel methotrexat herefter benaeligvnt BIO-mono svigt

For patientgrupperne vurderes foslashlgende interventioner

I1 etanercept + methotrexat

I2 infliximab 3 mgkg + methotrexat

I3 infliximab 6 mgkg + methotrexat

I4 adalimumab + methotrexat

I5 certolizumab + methotrexat

I6 golimumab + methotrexat

I7 abatacept + methotrexat

I8 tofacitinib + methotrexat

I9 rituximab + methotrexat

I10 anakinra + methotrexat

I11 tocilizumab + methotrexat

I12 adalimumab

I13 certolizumab

I14 etanercept

I16 tocilizumab

Comparator er foslashlgende

C1 DMARD (methotrexat)

C2 Placebo

C3 etanercept + methotrexat

C4 infliximab 3 mgkg + methotrexat

C5 infliximab 6 mgkg + methotrexat

C6 adalimumab + methotrexat

C7 certolizumab + methotrexat

C8 golimumab + methotrexat

C9 abatacept + methotrexat

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 3 af 13

C10 tofacitinib + methotrexat

C11 rituximab + methotrexat

C12 anakinra + methotrexat

C13 tocilizumab + methotrexat

C14 adalimumab

C15 certolizumab

C16 etanercept

C17 tocilizumab

Outcome

O1 ACR50 (ACR50 response)

O2 Total Sharp Score

O3 Frafald pga bivirkninger

O4 Alvorlige bivirkninger (SAE)

Behandlingskriterier

Beslutning om behandling med biologiske antireumatika traeligffes ved en ekspertvurdering (se

nedenfor) af patientens diagnose sygdomsstatus og behandlingserfaring Biologisk behandling

kan tilbydes saringfremt foslashlgende 4 delkriterier alle er til stede

1 Aktuel og vedvarende (gt 3 mdr) moderat eller hoslashj sygdomsaktivitet ( DAS28crp ge 32

eller gt 51) dokumenteret ved mindst 2 paring hinanden foslashlgende konsultationer

2 Ekspertvurderet inflammatorisk aktiv og derved forventet reversibel sygdom

3 Behandlingserfaring med mindst 2 non-biologiske antireumatika i relevant dosering og

indtil steady state (3-4 maringneder for hvert praeligparat eller 3-4 maringneder ved kombinations-

behandling) Non-biologiske antireumatika kan anvendes sekventielt eller i kombination

Farmakoterapi med non-biologiske antireumatika er beskrevet i Dansk Reumatologisk

Selskabs Kliniske Retningslinje for RA (4) Biologisk behandling kombineres som

hovedregel med non-biologisk behandling primaeligrt methotrexat i hoslashjest tolererede dosis

dog minimum 15 mguge

Ved intolerans for peroral methotrexat kan subkutan behandling med methotrexat

forsoslashges ogeller der gives oslashget folinsyretilskud (max 10 mguge) Hvis der fortsat er

intolerans for methotrexat kan anden DMARD overvejes feks leflunomid eller

salazopyrin foslashr biologisk monoterapi accepteres

4 Temporaeligr behandling med glukokortikoid systemisk eller som intraartikulaeligr injektion

afproslashvet (5)

Ovennaeligvnte delkriterier kan fraviges i foslashlgende situationer

a Serielle roslashntgenoptagelser viser signifikant aktuel og klinisk betydende progressiv erosiv

sygdom uanset DAS28crp vaeligrdi (delkriterium 1 fraviges men ikke 2 3 og 4) Det

afgoslashres ved ekspertvurdering om den observerede roslashntgenologiske progression er

signifikant og klinisk betydende Serielle roslashntgenoptagelser af haelignder og foslashdder boslashr

udfoslashres ved ordination og 1 aringr efter en paringbegyndt ny behandling

Serielle roslashntgenoptagelser som er udfoslashrt med flere aringrs mellemrum og under forskellige

behandlingsregimer og som viser erosiv progression kan ikke isoleret set begrunde

biologisk behandling

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 4 af 13

b Kontinuerlig (adskillige maringneder) systemisk brug af glukokortikoid aeligkvipotent med ge75

mg prednisolondoslashgn hos patient som opfylder delkriterium 2 3 og 4 men ikke

noslashdvendigvis delkriterium 1 og hvor biologisk behandling forventes at nedbringeophoslashre

forbrug af glukokortikoid

Kriterier for farmakologisk behandling af RA er beskrevet indgaringende i Dansk Reumatologisk

Selskabs Kliniske Retningslinje for diagnostik behandling og monitorering af reumatoid artritis

(5)

Diagnosen Stilles klinisk og refererer til ACR-EULAR-2010 klassifikationskriterier for RA (5)

Patienter som historisk opfylder 1987 klassifikationskriterier for RA (6) opfylder tillige 2010

kriterier

Sygdomsaktivitet DAS28 DANBIO Sygdomsaktivitet behandling med antireumatika og

effekten og eventuelle bivirkninger af denne dokumenteres i DANBIO (7) Registrering af

behandlingsforloslashb i DANBIO er obligatorisk for alle patienter med RA uanset type af

behandling Sygdomsaktiviteten vurderes klinisk og understoslashttes af parakliniske fund Disease

Activity Score (DAS28crp) (8) er et valideret og internationalt anerkendt maringl for sygdoms-

aktivitet ved RA som anvendes obligatorisk og indrapporteres til DANBIO Kliniske studier har

vist at anvendelse af DAS28crp under saeligrlige forudsaeligtninger (treat-to-target) bedrer

prognosen ved reumatoid artritis DAS28crp er vejledende ved initieringmonitorering

dosisjusteringseponeringskift af antireumatisk behandling DAS28crp aflaeligses paring en skala fra

09-94 og inddeles arbitraeligrt i foslashlgende intervaller Remission (DAS28crp lt 26) lav (26 -

32) moderat (32 - 51) og hoslashj (gt 51) sygdomsaktivitet Rationel brug af DAS28crp i praksis

er beskrevet i DRS-klinisk retningslinje (4) Patienter med identiske DAS28crp vaeligrdier kan

praeligsentere sig klinisk vidt forskelligt og den enkelte patient kan have en DAS28crp vurderet

hoslashj sygdomsaktivitet i fravaeligr af inflammation udtrykt ved ledhaeligvelse paringvirket biokemi og

billeddiagnostiske (UL og MR) tegn til sygdomsaktivitet DAS28crp er ikke designet til

registrering af ekstraartikulaeligr sygdomsaktivitet eller billed-diagnostisk dokumenteret

inflammation og progression af ledskade Da DAS28crp saringledes hverken er et eksakt eller

udtoslashmmende estimat af sygdomsaktivitet men dog et valideret monitoreringsvaeligrktoslashj ved

reumatoid artritis boslashr der ved planlaeliggning af den enkelte patients behandlingsbehov tillige

indgaring en ekspertvurdering (se nedenfor)

Behandlingsmaringl Defineres ved stabil lav (low-DAS) eller ingen (remission) sygdomsaktivitet

og tillige roslashntgenologisk non-progression Behandlingsmaringlet kan desuden vaeligre at reducere et

eventuelt laeligngerevarende prednisolonbehov til le 75 mgdoslashgn eller tilsvarende forbrug af

andet glukokortikoid Behandlingsmaringlet ekspertvurderes tillige

Ekspertvurdering En ekspertvurdering er obligatorisk ved biologiske behandlingsforloslashb og

kan med fordel indgaring ved non-biologisk behandling En ekspert er i denne sammenhaeligng en

speciallaeligge i reumatologi som praktiserer og har stor erfaring med brug af biologiske

laeliggemidler En ekspertvurdering er tillige en konferenceaktivitet i et fagligt miljoslash med

deltagelse af flere reumatologer og hvor biologisk behandling er daglig rutine

Ekspertvurderingen tager udgangspunkt i den enkelte patients sygehistorie prognostiske

risikoprofil behandlingserfaring radiografiske data og aktuelle symptomer og tegn paring

sygdomsaktivitet herunder DAS28crp Givet disse oplysninger ekspertvurderes det om den

paringgaeligldende patient er inflammatorisk aktiv og derved kan forventes at respondere paring

biologisk behandling og om denne forventes tolereret Ekspertvurdering skal foreligge ved

ordination dosisjustering seponering og skift af biologisk behandling

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 5 af 13

Valg af mulige 1 linje og efterfoslashlgende biologiske laeliggemidler

Fagudvalget har valgt at gennemfoslashre en komparativ evaluering med brug af direkte og

indirekte data af effekt og sikkerhed af biologiske antireumatika Til dette formaringl er primaeligrt

benyttet GRADE-metodikken appliceret paring metaanalyse af datamateriale modtaget fra

laeliggemiddelproducenterne systematisk soslashgning af litteratur og sekundaeligrt publicerede meta-

analyser (10-11) registerdata (12) og Cochrane-reviews (13) Foslashlgende indikatorer er valgt

for effektmaringl

Klinisk effekt belyst ved et opnaringet American College of Rheumatology 50 respons

(ACR50-respons) (PICO 1)

Effekt paring opbremsning i udvikling af strukturel ledskade opgjort som Total Sharp

ScoreGenant-Sharp-ScoreHeijde-Sharp-Score (TSS) (PICO 2)

Praeligparaternes sikkerhed er belyst ved

Forekomst af alvorlige bivirkninger (Serious Adverse Events - SAEs) (PICO 4)

Ophoslashr med projektmedicin pga bivirkninger (Adverse Events - AE) (PICO 3 + 4)

I fagudvalgets bedoslashmmelse af praeligparaternes sikkerhed er tillige udvist et forsigtighedsprincip

idet praeligparater for hvilke der eksisterer et vaeligsentligt og mangearingrigt klinisk erfarings-

grundlag alt andet lige vurderes mere sikre end nyligt registrerede praeligparater med

begraelignset erfaring og nye virkningsmekanismer

Meta-analyse af 1 linje biologiske laeliggemidler er baseret paring klinisk kontrollerede

laeliggemiddelforsoslashg (RCTs) som sammenligner et biologisk laeliggemiddel i kombination med et

DMARD (Methotrexat) versus placebo + DMARD i patientpopulationer som har oplevet svigt af

non-biologisk behandling (DMARD-svigt)

Fagudvalgets indstillinger til biologisk praeligparatvalg for specifikke patient-

populationer

P1 BIO-naive syntetisk DMARD-svigt

P2 BIO-svigt syntetisk DMARD-svigt

P3 BIO-MONO

P4 BIO-MONO-svigt

Valg af biologisk 1 linje praeligparat til bio-naive patienter med DMARD-svigt(P1)

Effekt

Klinisk effekt ACR50-respons (O1) I alt 38 RCTs er fordelt paring alle 9 biologiske

antireumatika indgaringr i analysen Alle praeligparater opnaringr bedre effekt end placebo (=DMARDs)

Overordnet er der signifikante undergruppeforskelle hvilket indikerer en forskel praeligparaterne

imellem (Figur 1) Fagudvalget tilskriver primaeligrt denne forskel en svagere effekt af anakinra

Efter korrektion for anakinra kan der saringledes ikke paringvises signifikant forskellige ACR50

effektmaringl mellem de oslashvrige 8 praeligparater For infliximab 3 mgkg8 uge finder fagudvalget

dog ringere effekt end ved dosering svarende til 6 mgkg8 uge (moderat kvalitetsevidens)

Radiografisk effekt TSS (O2) Effekt belyst ved opbremsning i udvikling af strukturel

ledskadeTSS Analysen vanskeliggoslashres ved at metoden anvendt for opgoslashrelse af TSS ikke er

ens paring tvaeligrs af studierne I alt 12 RCTs indgaringr For golimumab + MTX finder fagudvalget ved

metaanalyse effekt paring linje med placebo + MTX (Figur 2) For rituximab har fagudvalget ikke

roslashntgenologiske data for patientgruppen syntetisk DMARD-svigt For alle oslashvrige biologiske

laeliggemidler finder fagudvalget signifikant bedre effekt end ved behandling med placebo (MTX)

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 6 af 13

Med forbehold for golimumab og rituximab finder fagudvalget ikke signifikant forskelle

praeligparaterne imellem hvad angaringr radiografisk effekt

Sikkerhed

Ophoslashr med projektmedicin pga bivirkninger (withdrawals due to AEs)(O3) Analysen

baseres paring i alt 38 RCTs (Figur 3) For anakinra certolizumab tocilizumab og infliximab 3

mgkg forekommer behandlingsophoslashr pga bivirkninger signifikant hyppigere end for placebo

(MTX) For oslashvrige praeligparater finder fagudvalget ingen signifikant forskel mellem placebo og

biologisk behandling

Alvorlige bivirkninger (SAEs) (O4) Analysen baseres paring 38 RCTs (Figur 4) Behandling

med certolizumab og tocilizumab viste signifikant flere SAEs end placebo (MTX) For oslashvrige

praeligparater var forekomsten af SAEs paring linje med placebo

Med det formaringl at afklare om denne beskrevne oslashgede risiko var klinisk betydningsfuld foretog

fagudvalget to ekstra meta-analytiske tiltag

1 Samtlige biologiske laeliggemidler vs placebo paring tvaeligrs af sygdoms kategorier (RA SpA

AS) blev kombineret for at oslashge den statistiske styrke (Figur 5) de inkluderede studier var de

blev benyttet i den oslashvrige RADS proces Certolizumab fremstod herved som et biologisk

laeliggemiddel med en saeligrlig risiko-profil

2 Fagudvalget vurderede at denne forskel kunne vaeligre betydningsfuld Paring denne baggrund

blev der udfoslashrt en rdquonetvaeligrks meta-analyserdquo der muliggjorde at alle laeliggemidler kunne

sammenlignes direkte paring baggrund af indirekte data Som en konsekvens af disse data

vurderede fagudvalget at samtlige alvorlige bivirkninger fra de inkluderede studier skulle

gennemgarings af eacuten reumatolog for at sikre sig at der var tale om egentlige risici snarere end en

statistisk tilfaeligldighed Statistisk blev der sideloslashbende benyttet flere modeller Disse

sandsynliggjorde at certolizumab og tocilizumab fremstod som havende flere alvorlige

bivirkninger pga saringkaldte adaptive trial designs I et saringdant design kan den almindelige

rsquoIntention-to-treatrsquo population give fejlvisende konklusioner Det blev vurderet for baringde

certolizumab og tocilizumab at dette studiedesign havde foraringrsaget dette statistiske signal ved

at lade flere af deres rdquoplacebo patienterrdquo paringbegynde en aktiv-behandling inden afslutningen paring

rsquoIntention-to-treatrsquo perioden

Efter at fagudvalget noslashje havde vurderet hver enkelt alvorlig bivirkning for samtlige patienter i

alle studierne blev konklusionen at der sandsynligvis var tale om rdquoet statistisk artefaktrdquo pga

de rsquoadaptive trial designsrsquo idet det samme klare billede ikke kunne genfindes paring individ

niveau

Fagudvalgets indstilling til 1 linje praeligparatvalg for patienter karakteriseret ved

syntetisk DMARD-svigt (P1) Tofacitinib fravaeliglges generelt pga manglende godkendelse

hos EMA Anakinra fravaeliglges pga ugunstige data for klinisk effekt Golimumab fravaeliglges pga

tvivlsom dokumentation for effekt paring radiografiske effektmaringl Rituximab er godkendt til

behandling efter svigt af DMARDs inkl biologiske laeliggemidler og kan derfor ikke anvendes som

1 linje Infliximab 3 mgkg8 uge viser utilfredsstillende data for sikkerhed belyst ved

behandlingsophoslashr pga bivirkninger Tocilizumab fravaeliglges med reference til foslashrnaeligvnte

forsigtighedsprincip og idet der ikke foreligger et head-to-head studie som kan dokumentere

hvorvidt dette laeliggemiddel er ligevaeligrdigt med TNF-alfa haeligmmende behandling

Herefter kan uprioriteret ligestilles abatacept SCIV adalimumab certolizumab etanercept og

infliximab 6 mgkg8 uge som 1 linjebehandling

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 7 af 13

Fagudvalgets indstilling til 2 3 og foslashlgende linje biologisk praeligparatvalg for

patienter karakteriseret ved syntetisk DMARD-svigt BIO-svigt (P2) Som naeligvnt under

punktet rsquopatientgrundlagrsquo er der her tale om en stor og voksende patientgruppe karakteriseret

ved manglende eller aftagende effekt ogeller intolerans overfor et eller flere biologiske

laeliggemidler Registerstudier viser her at sandsynligheden for respons er omvendt proportional

med antallet af tidligere afproslashvede biologiske laeliggemidler Effekt og sikkerhed af nyt biologisk

laeliggemiddel + DMARD efter svigt af tidligere biologisk laeliggemiddel (primaeligrt TNF-alfa

haeligmmere) er dokumenteret for abatacept golimumab rituximab tocilizumab (og tofacitinib)

(O1234) For alle praeligparater fandtes et gunstigt forhold mellem effekt (ACR50 ndash O1) og

sikkerhed (SAEsndash O4) og behandlingsophoslashr pga bivirkninger (O3) For golimumab gaeliglder

saeligrskilt at nye radiografiske data praeligsenteret efter RADS 2012 laeliggemiddel-

rekommandationen nu tillader indplacering af dette laeliggemiddel som mulig 2 linjebehandling

uden dog at kvalificere til 1 linje prioritet

Fagudvalget indstiller herefter i uprioriteret raeligkkefoslashlge abatacept SCIV adalimumab

certolizumab etanercept golimumab infliximab 6 mgkg8 uge rituximab og tocilizumab

som mulige 2 3 og foslashlgende linje praeligparater

Patientprofiler Biologisk behandling af patienter med tidligere malign diagnose er med faring

undtagelser forbeholdt rituximab Fravaeligr af IgM-RF i serum er associeret med et daringrligere

behandlingsrespons af rituximab end ved +IgM-RF Betydningen af IgM-RF for respons ved

andre biologiske laeliggemidler er ikke naeligrmere belyst

Fagudvalgets indstilling til monoterapi med biologisk laeliggemiddel (P3 P4) I lighed med

DRS fastslaringr fagudvalget at biologisk behandling boslashr forudgarings af afproslashvet sekventiel eller

kombineret behandling med mindst 2 non-biologiske DMARDs (hvori MTX indgaringr) +

glukokortikoid I denne kontekst vil biologisk monoterapi vaeligre relevant hos patienten med

paringgaringende moderat eller hoslashj sygdomsaktivitet og dokumenteret intoleranskontraindikation

overfor MTX + yderligere afproslashvede non-biologiske DMARDs Foslashlgende biologiske laeliggemidler

kan anvendes som monoterapi (i henhold til SPCs og PROmedicindk) adalimumab

etanercept certolizumab og tocilizumab Kombinationsbehandling med MTX og

etanerceptadalimumab har vist sig mere effektiv end monoterapi med

etanerceptadalimumab En tilsvarende synergimekanisme er ikke vist for tocilizumab + MTX I

et nyligt offentliggjort rdquoHead-to-Headrdquo komparativt studie fandtes monoterapi med tocilizumab

signifikant mere effektivt (ACR50 ndash O1) og lige saring sikkert som adalimumab

Fagudvalget indstiller derfor tocilizumab som eneste 1 linje biologiske laeliggemiddel ved

DMARD-intolerante patienter (P3)

Som 2 linje (P4) kan adalimumab etanercept og certolizumab anvendes som monoterapi efter

svigtintolerans af tocilizumab og forudsat observeret intolerans kontraindikation overfor

syntetiske DMARDs

Praeligparatoverlevelse Studier baseret paring registerdata finder kortere praeligparatoverlevelse for

infliximab end for andre TNF-alfa haeligmmere (12) En eventuel betydning af dosisoslashgning for

praeligparatoverlevelse af infliximab er ikke afklaret

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 8 af 13

Doseringstabel Initial behandling Vedligeholdelsesbehandling

abatacept

subkutant regime

(forfyldt sproslashjtepen

initialdosis IV)

Intravenoslashst

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

uge 0

Subkutan injektion med 125 mg

ugentligt

Foslashrste injektion samme dag som

initialdosis

abatacept

intravenoslashst regime

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

uge 0 2 og 4

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

hver 4 uge

etanercept

subkutant regime

(forfyldt sproslashjtepen)

50 mg 50 mg hver uge

infliximab

intravenoslashst regime

3 mgkg legemsvaeliggt uge 0 og 2

45 mgkg uge 6

6 mgkg uge 12 og 20

6 mgkg legemsvaeliggt hver 8 uge

dosistitrering ved behov

adalimumab

subkutant regime

(forfyldt sproslashjtepen)

40 mg 40 mg hver 2 uge

certolizumab

subkutant regime

(forfyldt sproslashjtepen)

400 mg uge 0 2 4 200 mg hver 2 uge

eller

400 mg hver 4 uge

golimumab

subkutant regime

(forfyldt sproslashjtepen)

50 mg 50 mg om maringneden paring den

samme dag hver maringned som

initialdosis

rituximab

intravenoslashst regime

1000 mg uge 0 2 Regimet gentages hver 6 til 12

maringned

tocilizumab

intravenoslashst regime

8 mgkg legemsvaeliggt dog hoslashjst

800 mg

8 mgkg legemsvaeliggt dog hoslashjst

800 mg hver 4 uge

Vurdering af behandlingseffekt

Til vurdering af effekt anbefales primaeligrt brugt aeligndringer i DAS-score og opnaringelse af LDAS

eller DAS remission og radiologisk non-progression

Dokumentation af sygdomsstatus behandling effekt og eventuelle bivirkninger

Alle patientforloslashb rapporteres til den kliniske database DANBIO Dokumentation sikres foslashr

behandling ved behandlingsstart og herefter til tiden 3 6 12 mdr Yderligere kontrol

afhaelignger af graden af sygdomskontrol dog som minimum hver 6 mdr

Dosisreduktion

Der er ikke sikker evidens for at dosis kan reduceres i vaeligsentligt omfang i forhold til dosis

givet i registreringsstudierne men dette er ikke systematisk undersoslashgt

Seponeringskriterier

Seponering gennemfoslashres ved

1) Uacceptable bivirkninger og manglende effekt som anfoslashrt under skiftekriterier

2) Oslashnske om konception eller ved konstateret graviditet Generelt anbefales optimal

sygdomskontrol op til og under graviditet adalimumab etanercept og infliximab kan

anvendes frem til konstateret graviditet oslashvrige biologiske praeligparater seponeres forud

for (karenstid ndash se DANBIO patientvejledninger herom) konception

3) Kritisk komorbiditet (i henhold til produktresumeer infektion svaeligr hjerteinsufficiens

demyeliniserende lidelser cancer mm)

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 9 af 13

Skiftekriterier

Opnaringr patienten ved en given biologisk behandling ikke det definerede behandlingsmaringl inden

4 maringneder (lav sygdomsaktivitet + radiografisk non-progression + reduktion i et eventuelt

hoslashjt forbrug af glukokortikoid) kan patienten skifte til en ny biologisk behandling

Maringling af laeliggemiddelkoncentrationer og neutraliserende laeliggemiddelantistoffer

kan i plasma belyse aringrsagen til behandlingssvigt dog savnes her stoslashrre prospektive kliniske

studier Fagudvalget finder det praeligmaturt at inddrage saringdanne analyser rutinemaeligssigt i

klinisk praksis

Screening og sikkerhed

Patienterne boslashr inden behandlingsstart screenes for latent tuberkulose kronisk viral

hepatitis og andre kroniske infektioner Foslashr og under biologisk behandling foretages

regelmaeligssig klinisk og paraklinisk kontrol som beskrevet i DRS-vejledning

Undtagelse for valg af 1 linje

Afdelinger som ikke raringder over de ressourcer som indgaringr i behandling af patienter med

intravenoslashst administreret laeliggemiddel kan garing videre til naeligstfoslashlgende linje med subkutan

administration

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 10 af 13

KOMBINATIONSBEHANDLING (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter og patienter som skal skifte biologisk behandling i

kombination med methotrexat (P1)

med angivelse af behandlingsmaringl for 1 linje i

De angivne estimater viser den forventede variation som vil forekomme

afhaeligngig af den endelige rangordning

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje

abatacept (subkutant eller intravenoslashst regime) etanercept

infliximab (6mgkg hver 8 uge) adalimumab certolizumab

Ved subkutan formulering

som 1 linje paring baggrund af

laeliggemiddelpris

1 linje 1 valg

80 paring subkutan formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet af laeliggemidlerne)

Ved IV formulering som 1 linje paring

baggrund af laeliggemiddelpris

1 linje 1 valg

50 paring IV formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet IV laeliggemiddel)

1 linje 2 valg

30 paring subkutan formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet subkutant laeliggemiddel)

Behandlingskaskade ved skift af biologisk behandling i kombination med methotrexat

samt nye patienter i kombination med methotrexat som ikke kan behandles efter 1 linje

(P2)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje ved svigt efter

abatacept i 1 linje

Ved laeliggemiddel-

rekommandationen

anfoslashres eacutet af laeliggemidlerne

paring baggrund af den

opnaringede laeliggemiddelpris

etanercept

infliximab (6mgkg hver 8 uge)

adalimumab

certolizumab

golimumab

(Hvis infliximab anfoslashres paring baggrund af den opnaringede laeliggemiddelpris

anfoslashres tillige det subkutane laeliggemiddel som har tilbudt den naeligst

mest fordelagtige laeliggemiddelpris)

2 linje ved svigt efter

TNF-haeligmmer i 1 linje

samt efterfoslashlgende linjer

uprioriteret

Der anvendes hoslashjst 2 TNF-

haeligmmere i det samlede

behandlingsforloslashb

Ved laeliggemiddel-

rekommandationen

vurderes laeliggemidlerne i

raeligkkefoslashlge paring baggrund

af den opnaringede

laeliggemiddelpris

Valg af laeliggemiddel tages

paring baggrund af faglige kriterier

abatacept (subkutan eller intravenoslashst regime)

etanercept Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

infliximab (6mgkg hver 8 uge)

Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

adalimumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

certolizumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

golimumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

rituximab anvendes isaeligr ved positiv reumafaktorCCP eller tidligere

cancer

Anvendes saeligdvanligvis ikke til patienter med svaeligr erosiv sygdom

tocilizumab Anvendes saeligdvanligvis ikke til patienter med leversygdom

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 11 af 13

MONOTERAPI (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter i monoterapi (P3)

med angivelse af behandlingsmaringl for 1 linje i

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje 80 tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Behandlingskaskade for skifte patienter i monoterapi

samt nye patienter som ikke kan behandles efter 1 linje (P4)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje uprioriteret

Ved laeliggemiddel-rekommandationen

anfoslashres laeliggemidlerne i raeligkkefoslashlge

paring baggrund af den opnaringede

laeliggemiddelpris

etanercept

adalimumab

certolizumab

tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Efterlevelsesmaringl

Der vil aringrligt kunne blive foretaget udtraeligk fra DANBIO vedroslashrende anvendelsen af biologisk

medicin paring de reumatologiske afdelinger i Danmark fordelt paring de enkelte laeliggemidler Dette

gaeliglder baringde det praeligvalente forbrug og ordination af 1 linje biologisk behandling

Det forventede samlede nationale efterlevelsesmaringl for 1 linje laeliggemiddel er paring 80 af

patienterne for nye patienter

Bilag

1 GRADE metode og materialer

2 GRADE Forest Plots RA

3 GRADE Evidens profil RA

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 12 af 13

Referencer

1 Sorensen K Rheumatoid Arthritis in Denmark Two Population Studies Dan Med Bull

197320(3)86-93

2 Symmonds DM Barrett EM Bankhead CR Scott DI Silman AJ The Occurrence of

Rheumatoid Arthritis in the United Kingdom Results from the Norfolk Arthritis Register

Br J Rheumatol 199433735-739

3 Danbio Aringrsrapport for 2012httpsdanbio-onlinedkformidling

4 Hetland MH Christensen IJ Tarp U et al Direct comparison of treatment responses

remission rates and drug adherence in patients with Rheumatoid Arthritis treated with

Adalimumab Etanercept or Infliximab ArthritisRheum 2010 62 22-32

5 Dansk Reumatologisk Selskabs Kliniske Retningslinje for Diagnostik Behandling og

Monitorering af Reumatoid Artritis

httpwwwdanskreumatologiskselskabdkimagesrokquickcartpdf_filesRheumatoid_Ar

thritis_Kliniske_Vejledningdrs_kliniske_retningslinje_for_rapdf

6 Aletaha D Neogi T Silman AJ et al Ann Rheum Dis 2010 69 1580-1588 2010

Rheumatoid arthritis classification criteria an American College of

RheumatologyEuropean League Against Rheumatism collaborative initiative

7 Arnett FC Edworthy SM Bloch DA McShane DJ Fries FJ Cooper NS et al The American

Rheumatism 1987 revised criteria for the classification of rheumatoid arthritis Arthritis

rheum 198831315-324

8 Danbio Dansk Reumatologisk Database httpwwwdanbio-onlinedk

9 J Fransen PLCM van Riel The Disease Activity Score and the EULAR response criteria

Clin Exp Rheumatol 2005 23 (Suppl 39)S93-S99

10 The GRADE Working Group httpwwwgradeworkinggrouporgindexhtm

11 Kristensen LE Jakobsen AK Bartels EM Geborek P Bliddal H Saxne T et al The number

needed to treat for secondndashgeneration biologics when treating established rheumatoid

arthritis a systematic quantitative review of randomized controlled trials Scand J

Rheumatol 2011 Jan40(1)1-7

12 Kristensen LE Christensen R Bliddal H Geborek P Danneskiold-Samsoslashe B Saxne T The

number needed to treat for adalimumab etanercept and infliximab based on ACR50

response in three randomizec controlled trials on established rheumatoid arthritis a

systematic literature review Scand J Rheumatol 2007 Nov-Dec36(6)411-7

13 Hetland ML Christensen IJ Tarp U Dreyer L Hansen A Hansen IT Kollerup G Linde L

Lindegaard HM Poulsen UE Schlemmer A Jensen DV Jensen S Hostenkamp G

Ostergaard M Direct comparison of treatment responses remission rates and drug

adherence in patients with rheumatoid arthritis treated with adalimumab etanercept or

infliximab Results from eight years of surveillance of clinical practice in the nationwide

Danish DANBIO registry Arthritis Rheum 2010 Jan62(1)22-32

14 Singh JA Christensen R Wells GA Suarez-Almazor ME Buchbinder R Lopez-Olivo MA et

al Biologics for rheumatoid arthritis an overview of Cochrane reviews Sao paulo Med J

2010128(5)309-310

15 Grijalva CG Chen L Delzell E et al Initiation of tumor necrosis factor-G antagonists and

the risk of hospitalization for infection in patients with autoimmune diseases JAMA 2011

Dec 7306(21)2331-9

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 2 af 13

Patientantal

Fagudvalgets skoslashn pba tilgaeligngelige DANBIO data

Incidensaringr

Praeligvalens

Nye patienter (bionaive) 500 4280

Skifte patienter 850

Gennemsnitsvaeliggt for patienten med reumatoid artrit i biologisk behandling 739 kg

Laeliggemiddellevetid (Fagudvalgets skoslashn) 18 mdr

Patienter interventioner comparatorer og kritiske effektmaringl (PICO) for patienter

med reumatoid artritis (RA)

Foslashlgende patientpopulationer indgaringr i baggrundsnotatets arbejde

P1 Biologisk behandlingsnaive (BIO-naive) patienter som ikke responderer adaeligkvat paring

non-biologisk behandling herefter benaeligvnt DMARD-svigt

P2 Patienter som tidligere har vaeligret i behandling med et biologisk laeliggemiddel men ikke

laeligngere tolererer dette eller ikke oplever oslashnsket effekt herefter benaeligvnt DMARD

svigt BIO-svigt

P3 Biologisk behandlingsnaive patienter (BIO-naive) som ikke tolererer non-biologisk

behandling speciel methotrexat herefter benaeligvnt BIO-mono

P4 Patienter som tidligere har vaeligret i behandling med et biologisk laeliggemiddel men ikke

laeligngere tolererer dette eller ikke oplever oslashnsket effekt og som ikke tolererer non-

biologisk behandling speciel methotrexat herefter benaeligvnt BIO-mono svigt

For patientgrupperne vurderes foslashlgende interventioner

I1 etanercept + methotrexat

I2 infliximab 3 mgkg + methotrexat

I3 infliximab 6 mgkg + methotrexat

I4 adalimumab + methotrexat

I5 certolizumab + methotrexat

I6 golimumab + methotrexat

I7 abatacept + methotrexat

I8 tofacitinib + methotrexat

I9 rituximab + methotrexat

I10 anakinra + methotrexat

I11 tocilizumab + methotrexat

I12 adalimumab

I13 certolizumab

I14 etanercept

I16 tocilizumab

Comparator er foslashlgende

C1 DMARD (methotrexat)

C2 Placebo

C3 etanercept + methotrexat

C4 infliximab 3 mgkg + methotrexat

C5 infliximab 6 mgkg + methotrexat

C6 adalimumab + methotrexat

C7 certolizumab + methotrexat

C8 golimumab + methotrexat

C9 abatacept + methotrexat

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 3 af 13

C10 tofacitinib + methotrexat

C11 rituximab + methotrexat

C12 anakinra + methotrexat

C13 tocilizumab + methotrexat

C14 adalimumab

C15 certolizumab

C16 etanercept

C17 tocilizumab

Outcome

O1 ACR50 (ACR50 response)

O2 Total Sharp Score

O3 Frafald pga bivirkninger

O4 Alvorlige bivirkninger (SAE)

Behandlingskriterier

Beslutning om behandling med biologiske antireumatika traeligffes ved en ekspertvurdering (se

nedenfor) af patientens diagnose sygdomsstatus og behandlingserfaring Biologisk behandling

kan tilbydes saringfremt foslashlgende 4 delkriterier alle er til stede

1 Aktuel og vedvarende (gt 3 mdr) moderat eller hoslashj sygdomsaktivitet ( DAS28crp ge 32

eller gt 51) dokumenteret ved mindst 2 paring hinanden foslashlgende konsultationer

2 Ekspertvurderet inflammatorisk aktiv og derved forventet reversibel sygdom

3 Behandlingserfaring med mindst 2 non-biologiske antireumatika i relevant dosering og

indtil steady state (3-4 maringneder for hvert praeligparat eller 3-4 maringneder ved kombinations-

behandling) Non-biologiske antireumatika kan anvendes sekventielt eller i kombination

Farmakoterapi med non-biologiske antireumatika er beskrevet i Dansk Reumatologisk

Selskabs Kliniske Retningslinje for RA (4) Biologisk behandling kombineres som

hovedregel med non-biologisk behandling primaeligrt methotrexat i hoslashjest tolererede dosis

dog minimum 15 mguge

Ved intolerans for peroral methotrexat kan subkutan behandling med methotrexat

forsoslashges ogeller der gives oslashget folinsyretilskud (max 10 mguge) Hvis der fortsat er

intolerans for methotrexat kan anden DMARD overvejes feks leflunomid eller

salazopyrin foslashr biologisk monoterapi accepteres

4 Temporaeligr behandling med glukokortikoid systemisk eller som intraartikulaeligr injektion

afproslashvet (5)

Ovennaeligvnte delkriterier kan fraviges i foslashlgende situationer

a Serielle roslashntgenoptagelser viser signifikant aktuel og klinisk betydende progressiv erosiv

sygdom uanset DAS28crp vaeligrdi (delkriterium 1 fraviges men ikke 2 3 og 4) Det

afgoslashres ved ekspertvurdering om den observerede roslashntgenologiske progression er

signifikant og klinisk betydende Serielle roslashntgenoptagelser af haelignder og foslashdder boslashr

udfoslashres ved ordination og 1 aringr efter en paringbegyndt ny behandling

Serielle roslashntgenoptagelser som er udfoslashrt med flere aringrs mellemrum og under forskellige

behandlingsregimer og som viser erosiv progression kan ikke isoleret set begrunde

biologisk behandling

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 4 af 13

b Kontinuerlig (adskillige maringneder) systemisk brug af glukokortikoid aeligkvipotent med ge75

mg prednisolondoslashgn hos patient som opfylder delkriterium 2 3 og 4 men ikke

noslashdvendigvis delkriterium 1 og hvor biologisk behandling forventes at nedbringeophoslashre

forbrug af glukokortikoid

Kriterier for farmakologisk behandling af RA er beskrevet indgaringende i Dansk Reumatologisk

Selskabs Kliniske Retningslinje for diagnostik behandling og monitorering af reumatoid artritis

(5)

Diagnosen Stilles klinisk og refererer til ACR-EULAR-2010 klassifikationskriterier for RA (5)

Patienter som historisk opfylder 1987 klassifikationskriterier for RA (6) opfylder tillige 2010

kriterier

Sygdomsaktivitet DAS28 DANBIO Sygdomsaktivitet behandling med antireumatika og

effekten og eventuelle bivirkninger af denne dokumenteres i DANBIO (7) Registrering af

behandlingsforloslashb i DANBIO er obligatorisk for alle patienter med RA uanset type af

behandling Sygdomsaktiviteten vurderes klinisk og understoslashttes af parakliniske fund Disease

Activity Score (DAS28crp) (8) er et valideret og internationalt anerkendt maringl for sygdoms-

aktivitet ved RA som anvendes obligatorisk og indrapporteres til DANBIO Kliniske studier har

vist at anvendelse af DAS28crp under saeligrlige forudsaeligtninger (treat-to-target) bedrer

prognosen ved reumatoid artritis DAS28crp er vejledende ved initieringmonitorering

dosisjusteringseponeringskift af antireumatisk behandling DAS28crp aflaeligses paring en skala fra

09-94 og inddeles arbitraeligrt i foslashlgende intervaller Remission (DAS28crp lt 26) lav (26 -

32) moderat (32 - 51) og hoslashj (gt 51) sygdomsaktivitet Rationel brug af DAS28crp i praksis

er beskrevet i DRS-klinisk retningslinje (4) Patienter med identiske DAS28crp vaeligrdier kan

praeligsentere sig klinisk vidt forskelligt og den enkelte patient kan have en DAS28crp vurderet

hoslashj sygdomsaktivitet i fravaeligr af inflammation udtrykt ved ledhaeligvelse paringvirket biokemi og

billeddiagnostiske (UL og MR) tegn til sygdomsaktivitet DAS28crp er ikke designet til

registrering af ekstraartikulaeligr sygdomsaktivitet eller billed-diagnostisk dokumenteret

inflammation og progression af ledskade Da DAS28crp saringledes hverken er et eksakt eller

udtoslashmmende estimat af sygdomsaktivitet men dog et valideret monitoreringsvaeligrktoslashj ved

reumatoid artritis boslashr der ved planlaeliggning af den enkelte patients behandlingsbehov tillige

indgaring en ekspertvurdering (se nedenfor)

Behandlingsmaringl Defineres ved stabil lav (low-DAS) eller ingen (remission) sygdomsaktivitet

og tillige roslashntgenologisk non-progression Behandlingsmaringlet kan desuden vaeligre at reducere et

eventuelt laeligngerevarende prednisolonbehov til le 75 mgdoslashgn eller tilsvarende forbrug af

andet glukokortikoid Behandlingsmaringlet ekspertvurderes tillige

Ekspertvurdering En ekspertvurdering er obligatorisk ved biologiske behandlingsforloslashb og

kan med fordel indgaring ved non-biologisk behandling En ekspert er i denne sammenhaeligng en

speciallaeligge i reumatologi som praktiserer og har stor erfaring med brug af biologiske

laeliggemidler En ekspertvurdering er tillige en konferenceaktivitet i et fagligt miljoslash med

deltagelse af flere reumatologer og hvor biologisk behandling er daglig rutine

Ekspertvurderingen tager udgangspunkt i den enkelte patients sygehistorie prognostiske

risikoprofil behandlingserfaring radiografiske data og aktuelle symptomer og tegn paring

sygdomsaktivitet herunder DAS28crp Givet disse oplysninger ekspertvurderes det om den

paringgaeligldende patient er inflammatorisk aktiv og derved kan forventes at respondere paring

biologisk behandling og om denne forventes tolereret Ekspertvurdering skal foreligge ved

ordination dosisjustering seponering og skift af biologisk behandling

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 5 af 13

Valg af mulige 1 linje og efterfoslashlgende biologiske laeliggemidler

Fagudvalget har valgt at gennemfoslashre en komparativ evaluering med brug af direkte og

indirekte data af effekt og sikkerhed af biologiske antireumatika Til dette formaringl er primaeligrt

benyttet GRADE-metodikken appliceret paring metaanalyse af datamateriale modtaget fra

laeliggemiddelproducenterne systematisk soslashgning af litteratur og sekundaeligrt publicerede meta-

analyser (10-11) registerdata (12) og Cochrane-reviews (13) Foslashlgende indikatorer er valgt

for effektmaringl

Klinisk effekt belyst ved et opnaringet American College of Rheumatology 50 respons

(ACR50-respons) (PICO 1)

Effekt paring opbremsning i udvikling af strukturel ledskade opgjort som Total Sharp

ScoreGenant-Sharp-ScoreHeijde-Sharp-Score (TSS) (PICO 2)

Praeligparaternes sikkerhed er belyst ved

Forekomst af alvorlige bivirkninger (Serious Adverse Events - SAEs) (PICO 4)

Ophoslashr med projektmedicin pga bivirkninger (Adverse Events - AE) (PICO 3 + 4)

I fagudvalgets bedoslashmmelse af praeligparaternes sikkerhed er tillige udvist et forsigtighedsprincip

idet praeligparater for hvilke der eksisterer et vaeligsentligt og mangearingrigt klinisk erfarings-

grundlag alt andet lige vurderes mere sikre end nyligt registrerede praeligparater med

begraelignset erfaring og nye virkningsmekanismer

Meta-analyse af 1 linje biologiske laeliggemidler er baseret paring klinisk kontrollerede

laeliggemiddelforsoslashg (RCTs) som sammenligner et biologisk laeliggemiddel i kombination med et

DMARD (Methotrexat) versus placebo + DMARD i patientpopulationer som har oplevet svigt af

non-biologisk behandling (DMARD-svigt)

Fagudvalgets indstillinger til biologisk praeligparatvalg for specifikke patient-

populationer

P1 BIO-naive syntetisk DMARD-svigt

P2 BIO-svigt syntetisk DMARD-svigt

P3 BIO-MONO

P4 BIO-MONO-svigt

Valg af biologisk 1 linje praeligparat til bio-naive patienter med DMARD-svigt(P1)

Effekt

Klinisk effekt ACR50-respons (O1) I alt 38 RCTs er fordelt paring alle 9 biologiske

antireumatika indgaringr i analysen Alle praeligparater opnaringr bedre effekt end placebo (=DMARDs)

Overordnet er der signifikante undergruppeforskelle hvilket indikerer en forskel praeligparaterne

imellem (Figur 1) Fagudvalget tilskriver primaeligrt denne forskel en svagere effekt af anakinra

Efter korrektion for anakinra kan der saringledes ikke paringvises signifikant forskellige ACR50

effektmaringl mellem de oslashvrige 8 praeligparater For infliximab 3 mgkg8 uge finder fagudvalget

dog ringere effekt end ved dosering svarende til 6 mgkg8 uge (moderat kvalitetsevidens)

Radiografisk effekt TSS (O2) Effekt belyst ved opbremsning i udvikling af strukturel

ledskadeTSS Analysen vanskeliggoslashres ved at metoden anvendt for opgoslashrelse af TSS ikke er

ens paring tvaeligrs af studierne I alt 12 RCTs indgaringr For golimumab + MTX finder fagudvalget ved

metaanalyse effekt paring linje med placebo + MTX (Figur 2) For rituximab har fagudvalget ikke

roslashntgenologiske data for patientgruppen syntetisk DMARD-svigt For alle oslashvrige biologiske

laeliggemidler finder fagudvalget signifikant bedre effekt end ved behandling med placebo (MTX)

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 6 af 13

Med forbehold for golimumab og rituximab finder fagudvalget ikke signifikant forskelle

praeligparaterne imellem hvad angaringr radiografisk effekt

Sikkerhed

Ophoslashr med projektmedicin pga bivirkninger (withdrawals due to AEs)(O3) Analysen

baseres paring i alt 38 RCTs (Figur 3) For anakinra certolizumab tocilizumab og infliximab 3

mgkg forekommer behandlingsophoslashr pga bivirkninger signifikant hyppigere end for placebo

(MTX) For oslashvrige praeligparater finder fagudvalget ingen signifikant forskel mellem placebo og

biologisk behandling

Alvorlige bivirkninger (SAEs) (O4) Analysen baseres paring 38 RCTs (Figur 4) Behandling

med certolizumab og tocilizumab viste signifikant flere SAEs end placebo (MTX) For oslashvrige

praeligparater var forekomsten af SAEs paring linje med placebo

Med det formaringl at afklare om denne beskrevne oslashgede risiko var klinisk betydningsfuld foretog

fagudvalget to ekstra meta-analytiske tiltag

1 Samtlige biologiske laeliggemidler vs placebo paring tvaeligrs af sygdoms kategorier (RA SpA

AS) blev kombineret for at oslashge den statistiske styrke (Figur 5) de inkluderede studier var de

blev benyttet i den oslashvrige RADS proces Certolizumab fremstod herved som et biologisk

laeliggemiddel med en saeligrlig risiko-profil

2 Fagudvalget vurderede at denne forskel kunne vaeligre betydningsfuld Paring denne baggrund

blev der udfoslashrt en rdquonetvaeligrks meta-analyserdquo der muliggjorde at alle laeliggemidler kunne

sammenlignes direkte paring baggrund af indirekte data Som en konsekvens af disse data

vurderede fagudvalget at samtlige alvorlige bivirkninger fra de inkluderede studier skulle

gennemgarings af eacuten reumatolog for at sikre sig at der var tale om egentlige risici snarere end en

statistisk tilfaeligldighed Statistisk blev der sideloslashbende benyttet flere modeller Disse

sandsynliggjorde at certolizumab og tocilizumab fremstod som havende flere alvorlige

bivirkninger pga saringkaldte adaptive trial designs I et saringdant design kan den almindelige

rsquoIntention-to-treatrsquo population give fejlvisende konklusioner Det blev vurderet for baringde

certolizumab og tocilizumab at dette studiedesign havde foraringrsaget dette statistiske signal ved

at lade flere af deres rdquoplacebo patienterrdquo paringbegynde en aktiv-behandling inden afslutningen paring

rsquoIntention-to-treatrsquo perioden

Efter at fagudvalget noslashje havde vurderet hver enkelt alvorlig bivirkning for samtlige patienter i

alle studierne blev konklusionen at der sandsynligvis var tale om rdquoet statistisk artefaktrdquo pga

de rsquoadaptive trial designsrsquo idet det samme klare billede ikke kunne genfindes paring individ

niveau

Fagudvalgets indstilling til 1 linje praeligparatvalg for patienter karakteriseret ved

syntetisk DMARD-svigt (P1) Tofacitinib fravaeliglges generelt pga manglende godkendelse

hos EMA Anakinra fravaeliglges pga ugunstige data for klinisk effekt Golimumab fravaeliglges pga

tvivlsom dokumentation for effekt paring radiografiske effektmaringl Rituximab er godkendt til

behandling efter svigt af DMARDs inkl biologiske laeliggemidler og kan derfor ikke anvendes som

1 linje Infliximab 3 mgkg8 uge viser utilfredsstillende data for sikkerhed belyst ved

behandlingsophoslashr pga bivirkninger Tocilizumab fravaeliglges med reference til foslashrnaeligvnte

forsigtighedsprincip og idet der ikke foreligger et head-to-head studie som kan dokumentere

hvorvidt dette laeliggemiddel er ligevaeligrdigt med TNF-alfa haeligmmende behandling

Herefter kan uprioriteret ligestilles abatacept SCIV adalimumab certolizumab etanercept og

infliximab 6 mgkg8 uge som 1 linjebehandling

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 7 af 13

Fagudvalgets indstilling til 2 3 og foslashlgende linje biologisk praeligparatvalg for

patienter karakteriseret ved syntetisk DMARD-svigt BIO-svigt (P2) Som naeligvnt under

punktet rsquopatientgrundlagrsquo er der her tale om en stor og voksende patientgruppe karakteriseret

ved manglende eller aftagende effekt ogeller intolerans overfor et eller flere biologiske

laeliggemidler Registerstudier viser her at sandsynligheden for respons er omvendt proportional

med antallet af tidligere afproslashvede biologiske laeliggemidler Effekt og sikkerhed af nyt biologisk

laeliggemiddel + DMARD efter svigt af tidligere biologisk laeliggemiddel (primaeligrt TNF-alfa

haeligmmere) er dokumenteret for abatacept golimumab rituximab tocilizumab (og tofacitinib)

(O1234) For alle praeligparater fandtes et gunstigt forhold mellem effekt (ACR50 ndash O1) og

sikkerhed (SAEsndash O4) og behandlingsophoslashr pga bivirkninger (O3) For golimumab gaeliglder

saeligrskilt at nye radiografiske data praeligsenteret efter RADS 2012 laeliggemiddel-

rekommandationen nu tillader indplacering af dette laeliggemiddel som mulig 2 linjebehandling

uden dog at kvalificere til 1 linje prioritet

Fagudvalget indstiller herefter i uprioriteret raeligkkefoslashlge abatacept SCIV adalimumab

certolizumab etanercept golimumab infliximab 6 mgkg8 uge rituximab og tocilizumab

som mulige 2 3 og foslashlgende linje praeligparater

Patientprofiler Biologisk behandling af patienter med tidligere malign diagnose er med faring

undtagelser forbeholdt rituximab Fravaeligr af IgM-RF i serum er associeret med et daringrligere

behandlingsrespons af rituximab end ved +IgM-RF Betydningen af IgM-RF for respons ved

andre biologiske laeliggemidler er ikke naeligrmere belyst

Fagudvalgets indstilling til monoterapi med biologisk laeliggemiddel (P3 P4) I lighed med

DRS fastslaringr fagudvalget at biologisk behandling boslashr forudgarings af afproslashvet sekventiel eller

kombineret behandling med mindst 2 non-biologiske DMARDs (hvori MTX indgaringr) +

glukokortikoid I denne kontekst vil biologisk monoterapi vaeligre relevant hos patienten med

paringgaringende moderat eller hoslashj sygdomsaktivitet og dokumenteret intoleranskontraindikation

overfor MTX + yderligere afproslashvede non-biologiske DMARDs Foslashlgende biologiske laeliggemidler

kan anvendes som monoterapi (i henhold til SPCs og PROmedicindk) adalimumab

etanercept certolizumab og tocilizumab Kombinationsbehandling med MTX og

etanerceptadalimumab har vist sig mere effektiv end monoterapi med

etanerceptadalimumab En tilsvarende synergimekanisme er ikke vist for tocilizumab + MTX I

et nyligt offentliggjort rdquoHead-to-Headrdquo komparativt studie fandtes monoterapi med tocilizumab

signifikant mere effektivt (ACR50 ndash O1) og lige saring sikkert som adalimumab

Fagudvalget indstiller derfor tocilizumab som eneste 1 linje biologiske laeliggemiddel ved

DMARD-intolerante patienter (P3)

Som 2 linje (P4) kan adalimumab etanercept og certolizumab anvendes som monoterapi efter

svigtintolerans af tocilizumab og forudsat observeret intolerans kontraindikation overfor

syntetiske DMARDs

Praeligparatoverlevelse Studier baseret paring registerdata finder kortere praeligparatoverlevelse for

infliximab end for andre TNF-alfa haeligmmere (12) En eventuel betydning af dosisoslashgning for

praeligparatoverlevelse af infliximab er ikke afklaret

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 8 af 13

Doseringstabel Initial behandling Vedligeholdelsesbehandling

abatacept

subkutant regime

(forfyldt sproslashjtepen

initialdosis IV)

Intravenoslashst

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

uge 0

Subkutan injektion med 125 mg

ugentligt

Foslashrste injektion samme dag som

initialdosis

abatacept

intravenoslashst regime

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

uge 0 2 og 4

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

hver 4 uge

etanercept

subkutant regime

(forfyldt sproslashjtepen)

50 mg 50 mg hver uge

infliximab

intravenoslashst regime

3 mgkg legemsvaeliggt uge 0 og 2

45 mgkg uge 6

6 mgkg uge 12 og 20

6 mgkg legemsvaeliggt hver 8 uge

dosistitrering ved behov

adalimumab

subkutant regime

(forfyldt sproslashjtepen)

40 mg 40 mg hver 2 uge

certolizumab

subkutant regime

(forfyldt sproslashjtepen)

400 mg uge 0 2 4 200 mg hver 2 uge

eller

400 mg hver 4 uge

golimumab

subkutant regime

(forfyldt sproslashjtepen)

50 mg 50 mg om maringneden paring den

samme dag hver maringned som

initialdosis

rituximab

intravenoslashst regime

1000 mg uge 0 2 Regimet gentages hver 6 til 12

maringned

tocilizumab

intravenoslashst regime

8 mgkg legemsvaeliggt dog hoslashjst

800 mg

8 mgkg legemsvaeliggt dog hoslashjst

800 mg hver 4 uge

Vurdering af behandlingseffekt

Til vurdering af effekt anbefales primaeligrt brugt aeligndringer i DAS-score og opnaringelse af LDAS

eller DAS remission og radiologisk non-progression

Dokumentation af sygdomsstatus behandling effekt og eventuelle bivirkninger

Alle patientforloslashb rapporteres til den kliniske database DANBIO Dokumentation sikres foslashr

behandling ved behandlingsstart og herefter til tiden 3 6 12 mdr Yderligere kontrol

afhaelignger af graden af sygdomskontrol dog som minimum hver 6 mdr

Dosisreduktion

Der er ikke sikker evidens for at dosis kan reduceres i vaeligsentligt omfang i forhold til dosis

givet i registreringsstudierne men dette er ikke systematisk undersoslashgt

Seponeringskriterier

Seponering gennemfoslashres ved

1) Uacceptable bivirkninger og manglende effekt som anfoslashrt under skiftekriterier

2) Oslashnske om konception eller ved konstateret graviditet Generelt anbefales optimal

sygdomskontrol op til og under graviditet adalimumab etanercept og infliximab kan

anvendes frem til konstateret graviditet oslashvrige biologiske praeligparater seponeres forud

for (karenstid ndash se DANBIO patientvejledninger herom) konception

3) Kritisk komorbiditet (i henhold til produktresumeer infektion svaeligr hjerteinsufficiens

demyeliniserende lidelser cancer mm)

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 9 af 13

Skiftekriterier

Opnaringr patienten ved en given biologisk behandling ikke det definerede behandlingsmaringl inden

4 maringneder (lav sygdomsaktivitet + radiografisk non-progression + reduktion i et eventuelt

hoslashjt forbrug af glukokortikoid) kan patienten skifte til en ny biologisk behandling

Maringling af laeliggemiddelkoncentrationer og neutraliserende laeliggemiddelantistoffer

kan i plasma belyse aringrsagen til behandlingssvigt dog savnes her stoslashrre prospektive kliniske

studier Fagudvalget finder det praeligmaturt at inddrage saringdanne analyser rutinemaeligssigt i

klinisk praksis

Screening og sikkerhed

Patienterne boslashr inden behandlingsstart screenes for latent tuberkulose kronisk viral

hepatitis og andre kroniske infektioner Foslashr og under biologisk behandling foretages

regelmaeligssig klinisk og paraklinisk kontrol som beskrevet i DRS-vejledning

Undtagelse for valg af 1 linje

Afdelinger som ikke raringder over de ressourcer som indgaringr i behandling af patienter med

intravenoslashst administreret laeliggemiddel kan garing videre til naeligstfoslashlgende linje med subkutan

administration

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 10 af 13

KOMBINATIONSBEHANDLING (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter og patienter som skal skifte biologisk behandling i

kombination med methotrexat (P1)

med angivelse af behandlingsmaringl for 1 linje i

De angivne estimater viser den forventede variation som vil forekomme

afhaeligngig af den endelige rangordning

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje

abatacept (subkutant eller intravenoslashst regime) etanercept

infliximab (6mgkg hver 8 uge) adalimumab certolizumab

Ved subkutan formulering

som 1 linje paring baggrund af

laeliggemiddelpris

1 linje 1 valg

80 paring subkutan formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet af laeliggemidlerne)

Ved IV formulering som 1 linje paring

baggrund af laeliggemiddelpris

1 linje 1 valg

50 paring IV formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet IV laeliggemiddel)

1 linje 2 valg

30 paring subkutan formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet subkutant laeliggemiddel)

Behandlingskaskade ved skift af biologisk behandling i kombination med methotrexat

samt nye patienter i kombination med methotrexat som ikke kan behandles efter 1 linje

(P2)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje ved svigt efter

abatacept i 1 linje

Ved laeliggemiddel-

rekommandationen

anfoslashres eacutet af laeliggemidlerne

paring baggrund af den

opnaringede laeliggemiddelpris

etanercept

infliximab (6mgkg hver 8 uge)

adalimumab

certolizumab

golimumab

(Hvis infliximab anfoslashres paring baggrund af den opnaringede laeliggemiddelpris

anfoslashres tillige det subkutane laeliggemiddel som har tilbudt den naeligst

mest fordelagtige laeliggemiddelpris)

2 linje ved svigt efter

TNF-haeligmmer i 1 linje

samt efterfoslashlgende linjer

uprioriteret

Der anvendes hoslashjst 2 TNF-

haeligmmere i det samlede

behandlingsforloslashb

Ved laeliggemiddel-

rekommandationen

vurderes laeliggemidlerne i

raeligkkefoslashlge paring baggrund

af den opnaringede

laeliggemiddelpris

Valg af laeliggemiddel tages

paring baggrund af faglige kriterier

abatacept (subkutan eller intravenoslashst regime)

etanercept Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

infliximab (6mgkg hver 8 uge)

Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

adalimumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

certolizumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

golimumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

rituximab anvendes isaeligr ved positiv reumafaktorCCP eller tidligere

cancer

Anvendes saeligdvanligvis ikke til patienter med svaeligr erosiv sygdom

tocilizumab Anvendes saeligdvanligvis ikke til patienter med leversygdom

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 11 af 13

MONOTERAPI (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter i monoterapi (P3)

med angivelse af behandlingsmaringl for 1 linje i

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje 80 tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Behandlingskaskade for skifte patienter i monoterapi

samt nye patienter som ikke kan behandles efter 1 linje (P4)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje uprioriteret

Ved laeliggemiddel-rekommandationen

anfoslashres laeliggemidlerne i raeligkkefoslashlge

paring baggrund af den opnaringede

laeliggemiddelpris

etanercept

adalimumab

certolizumab

tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Efterlevelsesmaringl

Der vil aringrligt kunne blive foretaget udtraeligk fra DANBIO vedroslashrende anvendelsen af biologisk

medicin paring de reumatologiske afdelinger i Danmark fordelt paring de enkelte laeliggemidler Dette

gaeliglder baringde det praeligvalente forbrug og ordination af 1 linje biologisk behandling

Det forventede samlede nationale efterlevelsesmaringl for 1 linje laeliggemiddel er paring 80 af

patienterne for nye patienter

Bilag

1 GRADE metode og materialer

2 GRADE Forest Plots RA

3 GRADE Evidens profil RA

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 12 af 13

Referencer

1 Sorensen K Rheumatoid Arthritis in Denmark Two Population Studies Dan Med Bull

197320(3)86-93

2 Symmonds DM Barrett EM Bankhead CR Scott DI Silman AJ The Occurrence of

Rheumatoid Arthritis in the United Kingdom Results from the Norfolk Arthritis Register

Br J Rheumatol 199433735-739

3 Danbio Aringrsrapport for 2012httpsdanbio-onlinedkformidling

4 Hetland MH Christensen IJ Tarp U et al Direct comparison of treatment responses

remission rates and drug adherence in patients with Rheumatoid Arthritis treated with

Adalimumab Etanercept or Infliximab ArthritisRheum 2010 62 22-32

5 Dansk Reumatologisk Selskabs Kliniske Retningslinje for Diagnostik Behandling og

Monitorering af Reumatoid Artritis

httpwwwdanskreumatologiskselskabdkimagesrokquickcartpdf_filesRheumatoid_Ar

thritis_Kliniske_Vejledningdrs_kliniske_retningslinje_for_rapdf

6 Aletaha D Neogi T Silman AJ et al Ann Rheum Dis 2010 69 1580-1588 2010

Rheumatoid arthritis classification criteria an American College of

RheumatologyEuropean League Against Rheumatism collaborative initiative

7 Arnett FC Edworthy SM Bloch DA McShane DJ Fries FJ Cooper NS et al The American

Rheumatism 1987 revised criteria for the classification of rheumatoid arthritis Arthritis

rheum 198831315-324

8 Danbio Dansk Reumatologisk Database httpwwwdanbio-onlinedk

9 J Fransen PLCM van Riel The Disease Activity Score and the EULAR response criteria

Clin Exp Rheumatol 2005 23 (Suppl 39)S93-S99

10 The GRADE Working Group httpwwwgradeworkinggrouporgindexhtm

11 Kristensen LE Jakobsen AK Bartels EM Geborek P Bliddal H Saxne T et al The number

needed to treat for secondndashgeneration biologics when treating established rheumatoid

arthritis a systematic quantitative review of randomized controlled trials Scand J

Rheumatol 2011 Jan40(1)1-7

12 Kristensen LE Christensen R Bliddal H Geborek P Danneskiold-Samsoslashe B Saxne T The

number needed to treat for adalimumab etanercept and infliximab based on ACR50

response in three randomizec controlled trials on established rheumatoid arthritis a

systematic literature review Scand J Rheumatol 2007 Nov-Dec36(6)411-7

13 Hetland ML Christensen IJ Tarp U Dreyer L Hansen A Hansen IT Kollerup G Linde L

Lindegaard HM Poulsen UE Schlemmer A Jensen DV Jensen S Hostenkamp G

Ostergaard M Direct comparison of treatment responses remission rates and drug

adherence in patients with rheumatoid arthritis treated with adalimumab etanercept or

infliximab Results from eight years of surveillance of clinical practice in the nationwide

Danish DANBIO registry Arthritis Rheum 2010 Jan62(1)22-32

14 Singh JA Christensen R Wells GA Suarez-Almazor ME Buchbinder R Lopez-Olivo MA et

al Biologics for rheumatoid arthritis an overview of Cochrane reviews Sao paulo Med J

2010128(5)309-310

15 Grijalva CG Chen L Delzell E et al Initiation of tumor necrosis factor-G antagonists and

the risk of hospitalization for infection in patients with autoimmune diseases JAMA 2011

Dec 7306(21)2331-9

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 3 af 13

C10 tofacitinib + methotrexat

C11 rituximab + methotrexat

C12 anakinra + methotrexat

C13 tocilizumab + methotrexat

C14 adalimumab

C15 certolizumab

C16 etanercept

C17 tocilizumab

Outcome

O1 ACR50 (ACR50 response)

O2 Total Sharp Score

O3 Frafald pga bivirkninger

O4 Alvorlige bivirkninger (SAE)

Behandlingskriterier

Beslutning om behandling med biologiske antireumatika traeligffes ved en ekspertvurdering (se

nedenfor) af patientens diagnose sygdomsstatus og behandlingserfaring Biologisk behandling

kan tilbydes saringfremt foslashlgende 4 delkriterier alle er til stede

1 Aktuel og vedvarende (gt 3 mdr) moderat eller hoslashj sygdomsaktivitet ( DAS28crp ge 32

eller gt 51) dokumenteret ved mindst 2 paring hinanden foslashlgende konsultationer

2 Ekspertvurderet inflammatorisk aktiv og derved forventet reversibel sygdom

3 Behandlingserfaring med mindst 2 non-biologiske antireumatika i relevant dosering og

indtil steady state (3-4 maringneder for hvert praeligparat eller 3-4 maringneder ved kombinations-

behandling) Non-biologiske antireumatika kan anvendes sekventielt eller i kombination

Farmakoterapi med non-biologiske antireumatika er beskrevet i Dansk Reumatologisk

Selskabs Kliniske Retningslinje for RA (4) Biologisk behandling kombineres som

hovedregel med non-biologisk behandling primaeligrt methotrexat i hoslashjest tolererede dosis

dog minimum 15 mguge

Ved intolerans for peroral methotrexat kan subkutan behandling med methotrexat

forsoslashges ogeller der gives oslashget folinsyretilskud (max 10 mguge) Hvis der fortsat er

intolerans for methotrexat kan anden DMARD overvejes feks leflunomid eller

salazopyrin foslashr biologisk monoterapi accepteres

4 Temporaeligr behandling med glukokortikoid systemisk eller som intraartikulaeligr injektion

afproslashvet (5)

Ovennaeligvnte delkriterier kan fraviges i foslashlgende situationer

a Serielle roslashntgenoptagelser viser signifikant aktuel og klinisk betydende progressiv erosiv

sygdom uanset DAS28crp vaeligrdi (delkriterium 1 fraviges men ikke 2 3 og 4) Det

afgoslashres ved ekspertvurdering om den observerede roslashntgenologiske progression er

signifikant og klinisk betydende Serielle roslashntgenoptagelser af haelignder og foslashdder boslashr

udfoslashres ved ordination og 1 aringr efter en paringbegyndt ny behandling

Serielle roslashntgenoptagelser som er udfoslashrt med flere aringrs mellemrum og under forskellige

behandlingsregimer og som viser erosiv progression kan ikke isoleret set begrunde

biologisk behandling

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 4 af 13

b Kontinuerlig (adskillige maringneder) systemisk brug af glukokortikoid aeligkvipotent med ge75

mg prednisolondoslashgn hos patient som opfylder delkriterium 2 3 og 4 men ikke

noslashdvendigvis delkriterium 1 og hvor biologisk behandling forventes at nedbringeophoslashre

forbrug af glukokortikoid

Kriterier for farmakologisk behandling af RA er beskrevet indgaringende i Dansk Reumatologisk

Selskabs Kliniske Retningslinje for diagnostik behandling og monitorering af reumatoid artritis

(5)

Diagnosen Stilles klinisk og refererer til ACR-EULAR-2010 klassifikationskriterier for RA (5)

Patienter som historisk opfylder 1987 klassifikationskriterier for RA (6) opfylder tillige 2010

kriterier

Sygdomsaktivitet DAS28 DANBIO Sygdomsaktivitet behandling med antireumatika og

effekten og eventuelle bivirkninger af denne dokumenteres i DANBIO (7) Registrering af

behandlingsforloslashb i DANBIO er obligatorisk for alle patienter med RA uanset type af

behandling Sygdomsaktiviteten vurderes klinisk og understoslashttes af parakliniske fund Disease

Activity Score (DAS28crp) (8) er et valideret og internationalt anerkendt maringl for sygdoms-

aktivitet ved RA som anvendes obligatorisk og indrapporteres til DANBIO Kliniske studier har

vist at anvendelse af DAS28crp under saeligrlige forudsaeligtninger (treat-to-target) bedrer

prognosen ved reumatoid artritis DAS28crp er vejledende ved initieringmonitorering

dosisjusteringseponeringskift af antireumatisk behandling DAS28crp aflaeligses paring en skala fra

09-94 og inddeles arbitraeligrt i foslashlgende intervaller Remission (DAS28crp lt 26) lav (26 -

32) moderat (32 - 51) og hoslashj (gt 51) sygdomsaktivitet Rationel brug af DAS28crp i praksis

er beskrevet i DRS-klinisk retningslinje (4) Patienter med identiske DAS28crp vaeligrdier kan

praeligsentere sig klinisk vidt forskelligt og den enkelte patient kan have en DAS28crp vurderet

hoslashj sygdomsaktivitet i fravaeligr af inflammation udtrykt ved ledhaeligvelse paringvirket biokemi og

billeddiagnostiske (UL og MR) tegn til sygdomsaktivitet DAS28crp er ikke designet til

registrering af ekstraartikulaeligr sygdomsaktivitet eller billed-diagnostisk dokumenteret

inflammation og progression af ledskade Da DAS28crp saringledes hverken er et eksakt eller

udtoslashmmende estimat af sygdomsaktivitet men dog et valideret monitoreringsvaeligrktoslashj ved

reumatoid artritis boslashr der ved planlaeliggning af den enkelte patients behandlingsbehov tillige

indgaring en ekspertvurdering (se nedenfor)

Behandlingsmaringl Defineres ved stabil lav (low-DAS) eller ingen (remission) sygdomsaktivitet

og tillige roslashntgenologisk non-progression Behandlingsmaringlet kan desuden vaeligre at reducere et

eventuelt laeligngerevarende prednisolonbehov til le 75 mgdoslashgn eller tilsvarende forbrug af

andet glukokortikoid Behandlingsmaringlet ekspertvurderes tillige

Ekspertvurdering En ekspertvurdering er obligatorisk ved biologiske behandlingsforloslashb og

kan med fordel indgaring ved non-biologisk behandling En ekspert er i denne sammenhaeligng en

speciallaeligge i reumatologi som praktiserer og har stor erfaring med brug af biologiske

laeliggemidler En ekspertvurdering er tillige en konferenceaktivitet i et fagligt miljoslash med

deltagelse af flere reumatologer og hvor biologisk behandling er daglig rutine

Ekspertvurderingen tager udgangspunkt i den enkelte patients sygehistorie prognostiske

risikoprofil behandlingserfaring radiografiske data og aktuelle symptomer og tegn paring

sygdomsaktivitet herunder DAS28crp Givet disse oplysninger ekspertvurderes det om den

paringgaeligldende patient er inflammatorisk aktiv og derved kan forventes at respondere paring

biologisk behandling og om denne forventes tolereret Ekspertvurdering skal foreligge ved

ordination dosisjustering seponering og skift af biologisk behandling

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 5 af 13

Valg af mulige 1 linje og efterfoslashlgende biologiske laeliggemidler

Fagudvalget har valgt at gennemfoslashre en komparativ evaluering med brug af direkte og

indirekte data af effekt og sikkerhed af biologiske antireumatika Til dette formaringl er primaeligrt

benyttet GRADE-metodikken appliceret paring metaanalyse af datamateriale modtaget fra

laeliggemiddelproducenterne systematisk soslashgning af litteratur og sekundaeligrt publicerede meta-

analyser (10-11) registerdata (12) og Cochrane-reviews (13) Foslashlgende indikatorer er valgt

for effektmaringl

Klinisk effekt belyst ved et opnaringet American College of Rheumatology 50 respons

(ACR50-respons) (PICO 1)

Effekt paring opbremsning i udvikling af strukturel ledskade opgjort som Total Sharp

ScoreGenant-Sharp-ScoreHeijde-Sharp-Score (TSS) (PICO 2)

Praeligparaternes sikkerhed er belyst ved

Forekomst af alvorlige bivirkninger (Serious Adverse Events - SAEs) (PICO 4)

Ophoslashr med projektmedicin pga bivirkninger (Adverse Events - AE) (PICO 3 + 4)

I fagudvalgets bedoslashmmelse af praeligparaternes sikkerhed er tillige udvist et forsigtighedsprincip

idet praeligparater for hvilke der eksisterer et vaeligsentligt og mangearingrigt klinisk erfarings-

grundlag alt andet lige vurderes mere sikre end nyligt registrerede praeligparater med

begraelignset erfaring og nye virkningsmekanismer

Meta-analyse af 1 linje biologiske laeliggemidler er baseret paring klinisk kontrollerede

laeliggemiddelforsoslashg (RCTs) som sammenligner et biologisk laeliggemiddel i kombination med et

DMARD (Methotrexat) versus placebo + DMARD i patientpopulationer som har oplevet svigt af

non-biologisk behandling (DMARD-svigt)

Fagudvalgets indstillinger til biologisk praeligparatvalg for specifikke patient-

populationer

P1 BIO-naive syntetisk DMARD-svigt

P2 BIO-svigt syntetisk DMARD-svigt

P3 BIO-MONO

P4 BIO-MONO-svigt

Valg af biologisk 1 linje praeligparat til bio-naive patienter med DMARD-svigt(P1)

Effekt

Klinisk effekt ACR50-respons (O1) I alt 38 RCTs er fordelt paring alle 9 biologiske

antireumatika indgaringr i analysen Alle praeligparater opnaringr bedre effekt end placebo (=DMARDs)

Overordnet er der signifikante undergruppeforskelle hvilket indikerer en forskel praeligparaterne

imellem (Figur 1) Fagudvalget tilskriver primaeligrt denne forskel en svagere effekt af anakinra

Efter korrektion for anakinra kan der saringledes ikke paringvises signifikant forskellige ACR50

effektmaringl mellem de oslashvrige 8 praeligparater For infliximab 3 mgkg8 uge finder fagudvalget

dog ringere effekt end ved dosering svarende til 6 mgkg8 uge (moderat kvalitetsevidens)

Radiografisk effekt TSS (O2) Effekt belyst ved opbremsning i udvikling af strukturel

ledskadeTSS Analysen vanskeliggoslashres ved at metoden anvendt for opgoslashrelse af TSS ikke er

ens paring tvaeligrs af studierne I alt 12 RCTs indgaringr For golimumab + MTX finder fagudvalget ved

metaanalyse effekt paring linje med placebo + MTX (Figur 2) For rituximab har fagudvalget ikke

roslashntgenologiske data for patientgruppen syntetisk DMARD-svigt For alle oslashvrige biologiske

laeliggemidler finder fagudvalget signifikant bedre effekt end ved behandling med placebo (MTX)

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 6 af 13

Med forbehold for golimumab og rituximab finder fagudvalget ikke signifikant forskelle

praeligparaterne imellem hvad angaringr radiografisk effekt

Sikkerhed

Ophoslashr med projektmedicin pga bivirkninger (withdrawals due to AEs)(O3) Analysen

baseres paring i alt 38 RCTs (Figur 3) For anakinra certolizumab tocilizumab og infliximab 3

mgkg forekommer behandlingsophoslashr pga bivirkninger signifikant hyppigere end for placebo

(MTX) For oslashvrige praeligparater finder fagudvalget ingen signifikant forskel mellem placebo og

biologisk behandling

Alvorlige bivirkninger (SAEs) (O4) Analysen baseres paring 38 RCTs (Figur 4) Behandling

med certolizumab og tocilizumab viste signifikant flere SAEs end placebo (MTX) For oslashvrige

praeligparater var forekomsten af SAEs paring linje med placebo

Med det formaringl at afklare om denne beskrevne oslashgede risiko var klinisk betydningsfuld foretog

fagudvalget to ekstra meta-analytiske tiltag

1 Samtlige biologiske laeliggemidler vs placebo paring tvaeligrs af sygdoms kategorier (RA SpA

AS) blev kombineret for at oslashge den statistiske styrke (Figur 5) de inkluderede studier var de

blev benyttet i den oslashvrige RADS proces Certolizumab fremstod herved som et biologisk

laeliggemiddel med en saeligrlig risiko-profil

2 Fagudvalget vurderede at denne forskel kunne vaeligre betydningsfuld Paring denne baggrund

blev der udfoslashrt en rdquonetvaeligrks meta-analyserdquo der muliggjorde at alle laeliggemidler kunne

sammenlignes direkte paring baggrund af indirekte data Som en konsekvens af disse data

vurderede fagudvalget at samtlige alvorlige bivirkninger fra de inkluderede studier skulle

gennemgarings af eacuten reumatolog for at sikre sig at der var tale om egentlige risici snarere end en

statistisk tilfaeligldighed Statistisk blev der sideloslashbende benyttet flere modeller Disse

sandsynliggjorde at certolizumab og tocilizumab fremstod som havende flere alvorlige

bivirkninger pga saringkaldte adaptive trial designs I et saringdant design kan den almindelige

rsquoIntention-to-treatrsquo population give fejlvisende konklusioner Det blev vurderet for baringde

certolizumab og tocilizumab at dette studiedesign havde foraringrsaget dette statistiske signal ved

at lade flere af deres rdquoplacebo patienterrdquo paringbegynde en aktiv-behandling inden afslutningen paring

rsquoIntention-to-treatrsquo perioden

Efter at fagudvalget noslashje havde vurderet hver enkelt alvorlig bivirkning for samtlige patienter i

alle studierne blev konklusionen at der sandsynligvis var tale om rdquoet statistisk artefaktrdquo pga

de rsquoadaptive trial designsrsquo idet det samme klare billede ikke kunne genfindes paring individ

niveau

Fagudvalgets indstilling til 1 linje praeligparatvalg for patienter karakteriseret ved

syntetisk DMARD-svigt (P1) Tofacitinib fravaeliglges generelt pga manglende godkendelse

hos EMA Anakinra fravaeliglges pga ugunstige data for klinisk effekt Golimumab fravaeliglges pga

tvivlsom dokumentation for effekt paring radiografiske effektmaringl Rituximab er godkendt til

behandling efter svigt af DMARDs inkl biologiske laeliggemidler og kan derfor ikke anvendes som

1 linje Infliximab 3 mgkg8 uge viser utilfredsstillende data for sikkerhed belyst ved

behandlingsophoslashr pga bivirkninger Tocilizumab fravaeliglges med reference til foslashrnaeligvnte

forsigtighedsprincip og idet der ikke foreligger et head-to-head studie som kan dokumentere

hvorvidt dette laeliggemiddel er ligevaeligrdigt med TNF-alfa haeligmmende behandling

Herefter kan uprioriteret ligestilles abatacept SCIV adalimumab certolizumab etanercept og

infliximab 6 mgkg8 uge som 1 linjebehandling

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 7 af 13

Fagudvalgets indstilling til 2 3 og foslashlgende linje biologisk praeligparatvalg for

patienter karakteriseret ved syntetisk DMARD-svigt BIO-svigt (P2) Som naeligvnt under

punktet rsquopatientgrundlagrsquo er der her tale om en stor og voksende patientgruppe karakteriseret

ved manglende eller aftagende effekt ogeller intolerans overfor et eller flere biologiske

laeliggemidler Registerstudier viser her at sandsynligheden for respons er omvendt proportional

med antallet af tidligere afproslashvede biologiske laeliggemidler Effekt og sikkerhed af nyt biologisk

laeliggemiddel + DMARD efter svigt af tidligere biologisk laeliggemiddel (primaeligrt TNF-alfa

haeligmmere) er dokumenteret for abatacept golimumab rituximab tocilizumab (og tofacitinib)

(O1234) For alle praeligparater fandtes et gunstigt forhold mellem effekt (ACR50 ndash O1) og

sikkerhed (SAEsndash O4) og behandlingsophoslashr pga bivirkninger (O3) For golimumab gaeliglder

saeligrskilt at nye radiografiske data praeligsenteret efter RADS 2012 laeliggemiddel-

rekommandationen nu tillader indplacering af dette laeliggemiddel som mulig 2 linjebehandling

uden dog at kvalificere til 1 linje prioritet

Fagudvalget indstiller herefter i uprioriteret raeligkkefoslashlge abatacept SCIV adalimumab

certolizumab etanercept golimumab infliximab 6 mgkg8 uge rituximab og tocilizumab

som mulige 2 3 og foslashlgende linje praeligparater

Patientprofiler Biologisk behandling af patienter med tidligere malign diagnose er med faring

undtagelser forbeholdt rituximab Fravaeligr af IgM-RF i serum er associeret med et daringrligere

behandlingsrespons af rituximab end ved +IgM-RF Betydningen af IgM-RF for respons ved

andre biologiske laeliggemidler er ikke naeligrmere belyst

Fagudvalgets indstilling til monoterapi med biologisk laeliggemiddel (P3 P4) I lighed med

DRS fastslaringr fagudvalget at biologisk behandling boslashr forudgarings af afproslashvet sekventiel eller

kombineret behandling med mindst 2 non-biologiske DMARDs (hvori MTX indgaringr) +

glukokortikoid I denne kontekst vil biologisk monoterapi vaeligre relevant hos patienten med

paringgaringende moderat eller hoslashj sygdomsaktivitet og dokumenteret intoleranskontraindikation

overfor MTX + yderligere afproslashvede non-biologiske DMARDs Foslashlgende biologiske laeliggemidler

kan anvendes som monoterapi (i henhold til SPCs og PROmedicindk) adalimumab

etanercept certolizumab og tocilizumab Kombinationsbehandling med MTX og

etanerceptadalimumab har vist sig mere effektiv end monoterapi med

etanerceptadalimumab En tilsvarende synergimekanisme er ikke vist for tocilizumab + MTX I

et nyligt offentliggjort rdquoHead-to-Headrdquo komparativt studie fandtes monoterapi med tocilizumab

signifikant mere effektivt (ACR50 ndash O1) og lige saring sikkert som adalimumab

Fagudvalget indstiller derfor tocilizumab som eneste 1 linje biologiske laeliggemiddel ved

DMARD-intolerante patienter (P3)

Som 2 linje (P4) kan adalimumab etanercept og certolizumab anvendes som monoterapi efter

svigtintolerans af tocilizumab og forudsat observeret intolerans kontraindikation overfor

syntetiske DMARDs

Praeligparatoverlevelse Studier baseret paring registerdata finder kortere praeligparatoverlevelse for

infliximab end for andre TNF-alfa haeligmmere (12) En eventuel betydning af dosisoslashgning for

praeligparatoverlevelse af infliximab er ikke afklaret

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 8 af 13

Doseringstabel Initial behandling Vedligeholdelsesbehandling

abatacept

subkutant regime

(forfyldt sproslashjtepen

initialdosis IV)

Intravenoslashst

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

uge 0

Subkutan injektion med 125 mg

ugentligt

Foslashrste injektion samme dag som

initialdosis

abatacept

intravenoslashst regime

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

uge 0 2 og 4

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

hver 4 uge

etanercept

subkutant regime

(forfyldt sproslashjtepen)

50 mg 50 mg hver uge

infliximab

intravenoslashst regime

3 mgkg legemsvaeliggt uge 0 og 2

45 mgkg uge 6

6 mgkg uge 12 og 20

6 mgkg legemsvaeliggt hver 8 uge

dosistitrering ved behov

adalimumab

subkutant regime

(forfyldt sproslashjtepen)

40 mg 40 mg hver 2 uge

certolizumab

subkutant regime

(forfyldt sproslashjtepen)

400 mg uge 0 2 4 200 mg hver 2 uge

eller

400 mg hver 4 uge

golimumab

subkutant regime

(forfyldt sproslashjtepen)

50 mg 50 mg om maringneden paring den

samme dag hver maringned som

initialdosis

rituximab

intravenoslashst regime

1000 mg uge 0 2 Regimet gentages hver 6 til 12

maringned

tocilizumab

intravenoslashst regime

8 mgkg legemsvaeliggt dog hoslashjst

800 mg

8 mgkg legemsvaeliggt dog hoslashjst

800 mg hver 4 uge

Vurdering af behandlingseffekt

Til vurdering af effekt anbefales primaeligrt brugt aeligndringer i DAS-score og opnaringelse af LDAS

eller DAS remission og radiologisk non-progression

Dokumentation af sygdomsstatus behandling effekt og eventuelle bivirkninger

Alle patientforloslashb rapporteres til den kliniske database DANBIO Dokumentation sikres foslashr

behandling ved behandlingsstart og herefter til tiden 3 6 12 mdr Yderligere kontrol

afhaelignger af graden af sygdomskontrol dog som minimum hver 6 mdr

Dosisreduktion

Der er ikke sikker evidens for at dosis kan reduceres i vaeligsentligt omfang i forhold til dosis

givet i registreringsstudierne men dette er ikke systematisk undersoslashgt

Seponeringskriterier

Seponering gennemfoslashres ved

1) Uacceptable bivirkninger og manglende effekt som anfoslashrt under skiftekriterier

2) Oslashnske om konception eller ved konstateret graviditet Generelt anbefales optimal

sygdomskontrol op til og under graviditet adalimumab etanercept og infliximab kan

anvendes frem til konstateret graviditet oslashvrige biologiske praeligparater seponeres forud

for (karenstid ndash se DANBIO patientvejledninger herom) konception

3) Kritisk komorbiditet (i henhold til produktresumeer infektion svaeligr hjerteinsufficiens

demyeliniserende lidelser cancer mm)

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 9 af 13

Skiftekriterier

Opnaringr patienten ved en given biologisk behandling ikke det definerede behandlingsmaringl inden

4 maringneder (lav sygdomsaktivitet + radiografisk non-progression + reduktion i et eventuelt

hoslashjt forbrug af glukokortikoid) kan patienten skifte til en ny biologisk behandling

Maringling af laeliggemiddelkoncentrationer og neutraliserende laeliggemiddelantistoffer

kan i plasma belyse aringrsagen til behandlingssvigt dog savnes her stoslashrre prospektive kliniske

studier Fagudvalget finder det praeligmaturt at inddrage saringdanne analyser rutinemaeligssigt i

klinisk praksis

Screening og sikkerhed

Patienterne boslashr inden behandlingsstart screenes for latent tuberkulose kronisk viral

hepatitis og andre kroniske infektioner Foslashr og under biologisk behandling foretages

regelmaeligssig klinisk og paraklinisk kontrol som beskrevet i DRS-vejledning

Undtagelse for valg af 1 linje

Afdelinger som ikke raringder over de ressourcer som indgaringr i behandling af patienter med

intravenoslashst administreret laeliggemiddel kan garing videre til naeligstfoslashlgende linje med subkutan

administration

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 10 af 13

KOMBINATIONSBEHANDLING (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter og patienter som skal skifte biologisk behandling i

kombination med methotrexat (P1)

med angivelse af behandlingsmaringl for 1 linje i

De angivne estimater viser den forventede variation som vil forekomme

afhaeligngig af den endelige rangordning

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje

abatacept (subkutant eller intravenoslashst regime) etanercept

infliximab (6mgkg hver 8 uge) adalimumab certolizumab

Ved subkutan formulering

som 1 linje paring baggrund af

laeliggemiddelpris

1 linje 1 valg

80 paring subkutan formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet af laeliggemidlerne)

Ved IV formulering som 1 linje paring

baggrund af laeliggemiddelpris

1 linje 1 valg

50 paring IV formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet IV laeliggemiddel)

1 linje 2 valg

30 paring subkutan formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet subkutant laeliggemiddel)

Behandlingskaskade ved skift af biologisk behandling i kombination med methotrexat

samt nye patienter i kombination med methotrexat som ikke kan behandles efter 1 linje

(P2)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje ved svigt efter

abatacept i 1 linje

Ved laeliggemiddel-

rekommandationen

anfoslashres eacutet af laeliggemidlerne

paring baggrund af den

opnaringede laeliggemiddelpris

etanercept

infliximab (6mgkg hver 8 uge)

adalimumab

certolizumab

golimumab

(Hvis infliximab anfoslashres paring baggrund af den opnaringede laeliggemiddelpris

anfoslashres tillige det subkutane laeliggemiddel som har tilbudt den naeligst

mest fordelagtige laeliggemiddelpris)

2 linje ved svigt efter

TNF-haeligmmer i 1 linje

samt efterfoslashlgende linjer

uprioriteret

Der anvendes hoslashjst 2 TNF-

haeligmmere i det samlede

behandlingsforloslashb

Ved laeliggemiddel-

rekommandationen

vurderes laeliggemidlerne i

raeligkkefoslashlge paring baggrund

af den opnaringede

laeliggemiddelpris

Valg af laeliggemiddel tages

paring baggrund af faglige kriterier

abatacept (subkutan eller intravenoslashst regime)

etanercept Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

infliximab (6mgkg hver 8 uge)

Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

adalimumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

certolizumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

golimumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

rituximab anvendes isaeligr ved positiv reumafaktorCCP eller tidligere

cancer

Anvendes saeligdvanligvis ikke til patienter med svaeligr erosiv sygdom

tocilizumab Anvendes saeligdvanligvis ikke til patienter med leversygdom

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 11 af 13

MONOTERAPI (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter i monoterapi (P3)

med angivelse af behandlingsmaringl for 1 linje i

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje 80 tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Behandlingskaskade for skifte patienter i monoterapi

samt nye patienter som ikke kan behandles efter 1 linje (P4)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje uprioriteret

Ved laeliggemiddel-rekommandationen

anfoslashres laeliggemidlerne i raeligkkefoslashlge

paring baggrund af den opnaringede

laeliggemiddelpris

etanercept

adalimumab

certolizumab

tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Efterlevelsesmaringl

Der vil aringrligt kunne blive foretaget udtraeligk fra DANBIO vedroslashrende anvendelsen af biologisk

medicin paring de reumatologiske afdelinger i Danmark fordelt paring de enkelte laeliggemidler Dette

gaeliglder baringde det praeligvalente forbrug og ordination af 1 linje biologisk behandling

Det forventede samlede nationale efterlevelsesmaringl for 1 linje laeliggemiddel er paring 80 af

patienterne for nye patienter

Bilag

1 GRADE metode og materialer

2 GRADE Forest Plots RA

3 GRADE Evidens profil RA

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 12 af 13

Referencer

1 Sorensen K Rheumatoid Arthritis in Denmark Two Population Studies Dan Med Bull

197320(3)86-93

2 Symmonds DM Barrett EM Bankhead CR Scott DI Silman AJ The Occurrence of

Rheumatoid Arthritis in the United Kingdom Results from the Norfolk Arthritis Register

Br J Rheumatol 199433735-739

3 Danbio Aringrsrapport for 2012httpsdanbio-onlinedkformidling

4 Hetland MH Christensen IJ Tarp U et al Direct comparison of treatment responses

remission rates and drug adherence in patients with Rheumatoid Arthritis treated with

Adalimumab Etanercept or Infliximab ArthritisRheum 2010 62 22-32

5 Dansk Reumatologisk Selskabs Kliniske Retningslinje for Diagnostik Behandling og

Monitorering af Reumatoid Artritis

httpwwwdanskreumatologiskselskabdkimagesrokquickcartpdf_filesRheumatoid_Ar

thritis_Kliniske_Vejledningdrs_kliniske_retningslinje_for_rapdf

6 Aletaha D Neogi T Silman AJ et al Ann Rheum Dis 2010 69 1580-1588 2010

Rheumatoid arthritis classification criteria an American College of

RheumatologyEuropean League Against Rheumatism collaborative initiative

7 Arnett FC Edworthy SM Bloch DA McShane DJ Fries FJ Cooper NS et al The American

Rheumatism 1987 revised criteria for the classification of rheumatoid arthritis Arthritis

rheum 198831315-324

8 Danbio Dansk Reumatologisk Database httpwwwdanbio-onlinedk

9 J Fransen PLCM van Riel The Disease Activity Score and the EULAR response criteria

Clin Exp Rheumatol 2005 23 (Suppl 39)S93-S99

10 The GRADE Working Group httpwwwgradeworkinggrouporgindexhtm

11 Kristensen LE Jakobsen AK Bartels EM Geborek P Bliddal H Saxne T et al The number

needed to treat for secondndashgeneration biologics when treating established rheumatoid

arthritis a systematic quantitative review of randomized controlled trials Scand J

Rheumatol 2011 Jan40(1)1-7

12 Kristensen LE Christensen R Bliddal H Geborek P Danneskiold-Samsoslashe B Saxne T The

number needed to treat for adalimumab etanercept and infliximab based on ACR50

response in three randomizec controlled trials on established rheumatoid arthritis a

systematic literature review Scand J Rheumatol 2007 Nov-Dec36(6)411-7

13 Hetland ML Christensen IJ Tarp U Dreyer L Hansen A Hansen IT Kollerup G Linde L

Lindegaard HM Poulsen UE Schlemmer A Jensen DV Jensen S Hostenkamp G

Ostergaard M Direct comparison of treatment responses remission rates and drug

adherence in patients with rheumatoid arthritis treated with adalimumab etanercept or

infliximab Results from eight years of surveillance of clinical practice in the nationwide

Danish DANBIO registry Arthritis Rheum 2010 Jan62(1)22-32

14 Singh JA Christensen R Wells GA Suarez-Almazor ME Buchbinder R Lopez-Olivo MA et

al Biologics for rheumatoid arthritis an overview of Cochrane reviews Sao paulo Med J

2010128(5)309-310

15 Grijalva CG Chen L Delzell E et al Initiation of tumor necrosis factor-G antagonists and

the risk of hospitalization for infection in patients with autoimmune diseases JAMA 2011

Dec 7306(21)2331-9

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 4 af 13

b Kontinuerlig (adskillige maringneder) systemisk brug af glukokortikoid aeligkvipotent med ge75

mg prednisolondoslashgn hos patient som opfylder delkriterium 2 3 og 4 men ikke

noslashdvendigvis delkriterium 1 og hvor biologisk behandling forventes at nedbringeophoslashre

forbrug af glukokortikoid

Kriterier for farmakologisk behandling af RA er beskrevet indgaringende i Dansk Reumatologisk

Selskabs Kliniske Retningslinje for diagnostik behandling og monitorering af reumatoid artritis

(5)

Diagnosen Stilles klinisk og refererer til ACR-EULAR-2010 klassifikationskriterier for RA (5)

Patienter som historisk opfylder 1987 klassifikationskriterier for RA (6) opfylder tillige 2010

kriterier

Sygdomsaktivitet DAS28 DANBIO Sygdomsaktivitet behandling med antireumatika og

effekten og eventuelle bivirkninger af denne dokumenteres i DANBIO (7) Registrering af

behandlingsforloslashb i DANBIO er obligatorisk for alle patienter med RA uanset type af

behandling Sygdomsaktiviteten vurderes klinisk og understoslashttes af parakliniske fund Disease

Activity Score (DAS28crp) (8) er et valideret og internationalt anerkendt maringl for sygdoms-

aktivitet ved RA som anvendes obligatorisk og indrapporteres til DANBIO Kliniske studier har

vist at anvendelse af DAS28crp under saeligrlige forudsaeligtninger (treat-to-target) bedrer

prognosen ved reumatoid artritis DAS28crp er vejledende ved initieringmonitorering

dosisjusteringseponeringskift af antireumatisk behandling DAS28crp aflaeligses paring en skala fra

09-94 og inddeles arbitraeligrt i foslashlgende intervaller Remission (DAS28crp lt 26) lav (26 -

32) moderat (32 - 51) og hoslashj (gt 51) sygdomsaktivitet Rationel brug af DAS28crp i praksis

er beskrevet i DRS-klinisk retningslinje (4) Patienter med identiske DAS28crp vaeligrdier kan

praeligsentere sig klinisk vidt forskelligt og den enkelte patient kan have en DAS28crp vurderet

hoslashj sygdomsaktivitet i fravaeligr af inflammation udtrykt ved ledhaeligvelse paringvirket biokemi og

billeddiagnostiske (UL og MR) tegn til sygdomsaktivitet DAS28crp er ikke designet til

registrering af ekstraartikulaeligr sygdomsaktivitet eller billed-diagnostisk dokumenteret

inflammation og progression af ledskade Da DAS28crp saringledes hverken er et eksakt eller

udtoslashmmende estimat af sygdomsaktivitet men dog et valideret monitoreringsvaeligrktoslashj ved

reumatoid artritis boslashr der ved planlaeliggning af den enkelte patients behandlingsbehov tillige

indgaring en ekspertvurdering (se nedenfor)

Behandlingsmaringl Defineres ved stabil lav (low-DAS) eller ingen (remission) sygdomsaktivitet

og tillige roslashntgenologisk non-progression Behandlingsmaringlet kan desuden vaeligre at reducere et

eventuelt laeligngerevarende prednisolonbehov til le 75 mgdoslashgn eller tilsvarende forbrug af

andet glukokortikoid Behandlingsmaringlet ekspertvurderes tillige

Ekspertvurdering En ekspertvurdering er obligatorisk ved biologiske behandlingsforloslashb og

kan med fordel indgaring ved non-biologisk behandling En ekspert er i denne sammenhaeligng en

speciallaeligge i reumatologi som praktiserer og har stor erfaring med brug af biologiske

laeliggemidler En ekspertvurdering er tillige en konferenceaktivitet i et fagligt miljoslash med

deltagelse af flere reumatologer og hvor biologisk behandling er daglig rutine

Ekspertvurderingen tager udgangspunkt i den enkelte patients sygehistorie prognostiske

risikoprofil behandlingserfaring radiografiske data og aktuelle symptomer og tegn paring

sygdomsaktivitet herunder DAS28crp Givet disse oplysninger ekspertvurderes det om den

paringgaeligldende patient er inflammatorisk aktiv og derved kan forventes at respondere paring

biologisk behandling og om denne forventes tolereret Ekspertvurdering skal foreligge ved

ordination dosisjustering seponering og skift af biologisk behandling

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 5 af 13

Valg af mulige 1 linje og efterfoslashlgende biologiske laeliggemidler

Fagudvalget har valgt at gennemfoslashre en komparativ evaluering med brug af direkte og

indirekte data af effekt og sikkerhed af biologiske antireumatika Til dette formaringl er primaeligrt

benyttet GRADE-metodikken appliceret paring metaanalyse af datamateriale modtaget fra

laeliggemiddelproducenterne systematisk soslashgning af litteratur og sekundaeligrt publicerede meta-

analyser (10-11) registerdata (12) og Cochrane-reviews (13) Foslashlgende indikatorer er valgt

for effektmaringl

Klinisk effekt belyst ved et opnaringet American College of Rheumatology 50 respons

(ACR50-respons) (PICO 1)

Effekt paring opbremsning i udvikling af strukturel ledskade opgjort som Total Sharp

ScoreGenant-Sharp-ScoreHeijde-Sharp-Score (TSS) (PICO 2)

Praeligparaternes sikkerhed er belyst ved

Forekomst af alvorlige bivirkninger (Serious Adverse Events - SAEs) (PICO 4)

Ophoslashr med projektmedicin pga bivirkninger (Adverse Events - AE) (PICO 3 + 4)

I fagudvalgets bedoslashmmelse af praeligparaternes sikkerhed er tillige udvist et forsigtighedsprincip

idet praeligparater for hvilke der eksisterer et vaeligsentligt og mangearingrigt klinisk erfarings-

grundlag alt andet lige vurderes mere sikre end nyligt registrerede praeligparater med

begraelignset erfaring og nye virkningsmekanismer

Meta-analyse af 1 linje biologiske laeliggemidler er baseret paring klinisk kontrollerede

laeliggemiddelforsoslashg (RCTs) som sammenligner et biologisk laeliggemiddel i kombination med et

DMARD (Methotrexat) versus placebo + DMARD i patientpopulationer som har oplevet svigt af

non-biologisk behandling (DMARD-svigt)

Fagudvalgets indstillinger til biologisk praeligparatvalg for specifikke patient-

populationer

P1 BIO-naive syntetisk DMARD-svigt

P2 BIO-svigt syntetisk DMARD-svigt

P3 BIO-MONO

P4 BIO-MONO-svigt

Valg af biologisk 1 linje praeligparat til bio-naive patienter med DMARD-svigt(P1)

Effekt

Klinisk effekt ACR50-respons (O1) I alt 38 RCTs er fordelt paring alle 9 biologiske

antireumatika indgaringr i analysen Alle praeligparater opnaringr bedre effekt end placebo (=DMARDs)

Overordnet er der signifikante undergruppeforskelle hvilket indikerer en forskel praeligparaterne

imellem (Figur 1) Fagudvalget tilskriver primaeligrt denne forskel en svagere effekt af anakinra

Efter korrektion for anakinra kan der saringledes ikke paringvises signifikant forskellige ACR50

effektmaringl mellem de oslashvrige 8 praeligparater For infliximab 3 mgkg8 uge finder fagudvalget

dog ringere effekt end ved dosering svarende til 6 mgkg8 uge (moderat kvalitetsevidens)

Radiografisk effekt TSS (O2) Effekt belyst ved opbremsning i udvikling af strukturel

ledskadeTSS Analysen vanskeliggoslashres ved at metoden anvendt for opgoslashrelse af TSS ikke er

ens paring tvaeligrs af studierne I alt 12 RCTs indgaringr For golimumab + MTX finder fagudvalget ved

metaanalyse effekt paring linje med placebo + MTX (Figur 2) For rituximab har fagudvalget ikke

roslashntgenologiske data for patientgruppen syntetisk DMARD-svigt For alle oslashvrige biologiske

laeliggemidler finder fagudvalget signifikant bedre effekt end ved behandling med placebo (MTX)

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 6 af 13

Med forbehold for golimumab og rituximab finder fagudvalget ikke signifikant forskelle

praeligparaterne imellem hvad angaringr radiografisk effekt

Sikkerhed

Ophoslashr med projektmedicin pga bivirkninger (withdrawals due to AEs)(O3) Analysen

baseres paring i alt 38 RCTs (Figur 3) For anakinra certolizumab tocilizumab og infliximab 3

mgkg forekommer behandlingsophoslashr pga bivirkninger signifikant hyppigere end for placebo

(MTX) For oslashvrige praeligparater finder fagudvalget ingen signifikant forskel mellem placebo og

biologisk behandling

Alvorlige bivirkninger (SAEs) (O4) Analysen baseres paring 38 RCTs (Figur 4) Behandling

med certolizumab og tocilizumab viste signifikant flere SAEs end placebo (MTX) For oslashvrige

praeligparater var forekomsten af SAEs paring linje med placebo

Med det formaringl at afklare om denne beskrevne oslashgede risiko var klinisk betydningsfuld foretog

fagudvalget to ekstra meta-analytiske tiltag

1 Samtlige biologiske laeliggemidler vs placebo paring tvaeligrs af sygdoms kategorier (RA SpA

AS) blev kombineret for at oslashge den statistiske styrke (Figur 5) de inkluderede studier var de

blev benyttet i den oslashvrige RADS proces Certolizumab fremstod herved som et biologisk

laeliggemiddel med en saeligrlig risiko-profil

2 Fagudvalget vurderede at denne forskel kunne vaeligre betydningsfuld Paring denne baggrund

blev der udfoslashrt en rdquonetvaeligrks meta-analyserdquo der muliggjorde at alle laeliggemidler kunne

sammenlignes direkte paring baggrund af indirekte data Som en konsekvens af disse data

vurderede fagudvalget at samtlige alvorlige bivirkninger fra de inkluderede studier skulle

gennemgarings af eacuten reumatolog for at sikre sig at der var tale om egentlige risici snarere end en

statistisk tilfaeligldighed Statistisk blev der sideloslashbende benyttet flere modeller Disse

sandsynliggjorde at certolizumab og tocilizumab fremstod som havende flere alvorlige

bivirkninger pga saringkaldte adaptive trial designs I et saringdant design kan den almindelige

rsquoIntention-to-treatrsquo population give fejlvisende konklusioner Det blev vurderet for baringde

certolizumab og tocilizumab at dette studiedesign havde foraringrsaget dette statistiske signal ved

at lade flere af deres rdquoplacebo patienterrdquo paringbegynde en aktiv-behandling inden afslutningen paring

rsquoIntention-to-treatrsquo perioden

Efter at fagudvalget noslashje havde vurderet hver enkelt alvorlig bivirkning for samtlige patienter i

alle studierne blev konklusionen at der sandsynligvis var tale om rdquoet statistisk artefaktrdquo pga

de rsquoadaptive trial designsrsquo idet det samme klare billede ikke kunne genfindes paring individ

niveau

Fagudvalgets indstilling til 1 linje praeligparatvalg for patienter karakteriseret ved

syntetisk DMARD-svigt (P1) Tofacitinib fravaeliglges generelt pga manglende godkendelse

hos EMA Anakinra fravaeliglges pga ugunstige data for klinisk effekt Golimumab fravaeliglges pga

tvivlsom dokumentation for effekt paring radiografiske effektmaringl Rituximab er godkendt til

behandling efter svigt af DMARDs inkl biologiske laeliggemidler og kan derfor ikke anvendes som

1 linje Infliximab 3 mgkg8 uge viser utilfredsstillende data for sikkerhed belyst ved

behandlingsophoslashr pga bivirkninger Tocilizumab fravaeliglges med reference til foslashrnaeligvnte

forsigtighedsprincip og idet der ikke foreligger et head-to-head studie som kan dokumentere

hvorvidt dette laeliggemiddel er ligevaeligrdigt med TNF-alfa haeligmmende behandling

Herefter kan uprioriteret ligestilles abatacept SCIV adalimumab certolizumab etanercept og

infliximab 6 mgkg8 uge som 1 linjebehandling

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 7 af 13

Fagudvalgets indstilling til 2 3 og foslashlgende linje biologisk praeligparatvalg for

patienter karakteriseret ved syntetisk DMARD-svigt BIO-svigt (P2) Som naeligvnt under

punktet rsquopatientgrundlagrsquo er der her tale om en stor og voksende patientgruppe karakteriseret

ved manglende eller aftagende effekt ogeller intolerans overfor et eller flere biologiske

laeliggemidler Registerstudier viser her at sandsynligheden for respons er omvendt proportional

med antallet af tidligere afproslashvede biologiske laeliggemidler Effekt og sikkerhed af nyt biologisk

laeliggemiddel + DMARD efter svigt af tidligere biologisk laeliggemiddel (primaeligrt TNF-alfa

haeligmmere) er dokumenteret for abatacept golimumab rituximab tocilizumab (og tofacitinib)

(O1234) For alle praeligparater fandtes et gunstigt forhold mellem effekt (ACR50 ndash O1) og

sikkerhed (SAEsndash O4) og behandlingsophoslashr pga bivirkninger (O3) For golimumab gaeliglder

saeligrskilt at nye radiografiske data praeligsenteret efter RADS 2012 laeliggemiddel-

rekommandationen nu tillader indplacering af dette laeliggemiddel som mulig 2 linjebehandling

uden dog at kvalificere til 1 linje prioritet

Fagudvalget indstiller herefter i uprioriteret raeligkkefoslashlge abatacept SCIV adalimumab

certolizumab etanercept golimumab infliximab 6 mgkg8 uge rituximab og tocilizumab

som mulige 2 3 og foslashlgende linje praeligparater

Patientprofiler Biologisk behandling af patienter med tidligere malign diagnose er med faring

undtagelser forbeholdt rituximab Fravaeligr af IgM-RF i serum er associeret med et daringrligere

behandlingsrespons af rituximab end ved +IgM-RF Betydningen af IgM-RF for respons ved

andre biologiske laeliggemidler er ikke naeligrmere belyst

Fagudvalgets indstilling til monoterapi med biologisk laeliggemiddel (P3 P4) I lighed med

DRS fastslaringr fagudvalget at biologisk behandling boslashr forudgarings af afproslashvet sekventiel eller

kombineret behandling med mindst 2 non-biologiske DMARDs (hvori MTX indgaringr) +

glukokortikoid I denne kontekst vil biologisk monoterapi vaeligre relevant hos patienten med

paringgaringende moderat eller hoslashj sygdomsaktivitet og dokumenteret intoleranskontraindikation

overfor MTX + yderligere afproslashvede non-biologiske DMARDs Foslashlgende biologiske laeliggemidler

kan anvendes som monoterapi (i henhold til SPCs og PROmedicindk) adalimumab

etanercept certolizumab og tocilizumab Kombinationsbehandling med MTX og

etanerceptadalimumab har vist sig mere effektiv end monoterapi med

etanerceptadalimumab En tilsvarende synergimekanisme er ikke vist for tocilizumab + MTX I

et nyligt offentliggjort rdquoHead-to-Headrdquo komparativt studie fandtes monoterapi med tocilizumab

signifikant mere effektivt (ACR50 ndash O1) og lige saring sikkert som adalimumab

Fagudvalget indstiller derfor tocilizumab som eneste 1 linje biologiske laeliggemiddel ved

DMARD-intolerante patienter (P3)

Som 2 linje (P4) kan adalimumab etanercept og certolizumab anvendes som monoterapi efter

svigtintolerans af tocilizumab og forudsat observeret intolerans kontraindikation overfor

syntetiske DMARDs

Praeligparatoverlevelse Studier baseret paring registerdata finder kortere praeligparatoverlevelse for

infliximab end for andre TNF-alfa haeligmmere (12) En eventuel betydning af dosisoslashgning for

praeligparatoverlevelse af infliximab er ikke afklaret

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 8 af 13

Doseringstabel Initial behandling Vedligeholdelsesbehandling

abatacept

subkutant regime

(forfyldt sproslashjtepen

initialdosis IV)

Intravenoslashst

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

uge 0

Subkutan injektion med 125 mg

ugentligt

Foslashrste injektion samme dag som

initialdosis

abatacept

intravenoslashst regime

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

uge 0 2 og 4

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

hver 4 uge

etanercept

subkutant regime

(forfyldt sproslashjtepen)

50 mg 50 mg hver uge

infliximab

intravenoslashst regime

3 mgkg legemsvaeliggt uge 0 og 2

45 mgkg uge 6

6 mgkg uge 12 og 20

6 mgkg legemsvaeliggt hver 8 uge

dosistitrering ved behov

adalimumab

subkutant regime

(forfyldt sproslashjtepen)

40 mg 40 mg hver 2 uge

certolizumab

subkutant regime

(forfyldt sproslashjtepen)

400 mg uge 0 2 4 200 mg hver 2 uge

eller

400 mg hver 4 uge

golimumab

subkutant regime

(forfyldt sproslashjtepen)

50 mg 50 mg om maringneden paring den

samme dag hver maringned som

initialdosis

rituximab

intravenoslashst regime

1000 mg uge 0 2 Regimet gentages hver 6 til 12

maringned

tocilizumab

intravenoslashst regime

8 mgkg legemsvaeliggt dog hoslashjst

800 mg

8 mgkg legemsvaeliggt dog hoslashjst

800 mg hver 4 uge

Vurdering af behandlingseffekt

Til vurdering af effekt anbefales primaeligrt brugt aeligndringer i DAS-score og opnaringelse af LDAS

eller DAS remission og radiologisk non-progression

Dokumentation af sygdomsstatus behandling effekt og eventuelle bivirkninger

Alle patientforloslashb rapporteres til den kliniske database DANBIO Dokumentation sikres foslashr

behandling ved behandlingsstart og herefter til tiden 3 6 12 mdr Yderligere kontrol

afhaelignger af graden af sygdomskontrol dog som minimum hver 6 mdr

Dosisreduktion

Der er ikke sikker evidens for at dosis kan reduceres i vaeligsentligt omfang i forhold til dosis

givet i registreringsstudierne men dette er ikke systematisk undersoslashgt

Seponeringskriterier

Seponering gennemfoslashres ved

1) Uacceptable bivirkninger og manglende effekt som anfoslashrt under skiftekriterier

2) Oslashnske om konception eller ved konstateret graviditet Generelt anbefales optimal

sygdomskontrol op til og under graviditet adalimumab etanercept og infliximab kan

anvendes frem til konstateret graviditet oslashvrige biologiske praeligparater seponeres forud

for (karenstid ndash se DANBIO patientvejledninger herom) konception

3) Kritisk komorbiditet (i henhold til produktresumeer infektion svaeligr hjerteinsufficiens

demyeliniserende lidelser cancer mm)

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 9 af 13

Skiftekriterier

Opnaringr patienten ved en given biologisk behandling ikke det definerede behandlingsmaringl inden

4 maringneder (lav sygdomsaktivitet + radiografisk non-progression + reduktion i et eventuelt

hoslashjt forbrug af glukokortikoid) kan patienten skifte til en ny biologisk behandling

Maringling af laeliggemiddelkoncentrationer og neutraliserende laeliggemiddelantistoffer

kan i plasma belyse aringrsagen til behandlingssvigt dog savnes her stoslashrre prospektive kliniske

studier Fagudvalget finder det praeligmaturt at inddrage saringdanne analyser rutinemaeligssigt i

klinisk praksis

Screening og sikkerhed

Patienterne boslashr inden behandlingsstart screenes for latent tuberkulose kronisk viral

hepatitis og andre kroniske infektioner Foslashr og under biologisk behandling foretages

regelmaeligssig klinisk og paraklinisk kontrol som beskrevet i DRS-vejledning

Undtagelse for valg af 1 linje

Afdelinger som ikke raringder over de ressourcer som indgaringr i behandling af patienter med

intravenoslashst administreret laeliggemiddel kan garing videre til naeligstfoslashlgende linje med subkutan

administration

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 10 af 13

KOMBINATIONSBEHANDLING (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter og patienter som skal skifte biologisk behandling i

kombination med methotrexat (P1)

med angivelse af behandlingsmaringl for 1 linje i

De angivne estimater viser den forventede variation som vil forekomme

afhaeligngig af den endelige rangordning

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje

abatacept (subkutant eller intravenoslashst regime) etanercept

infliximab (6mgkg hver 8 uge) adalimumab certolizumab

Ved subkutan formulering

som 1 linje paring baggrund af

laeliggemiddelpris

1 linje 1 valg

80 paring subkutan formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet af laeliggemidlerne)

Ved IV formulering som 1 linje paring

baggrund af laeliggemiddelpris

1 linje 1 valg

50 paring IV formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet IV laeliggemiddel)

1 linje 2 valg

30 paring subkutan formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet subkutant laeliggemiddel)

Behandlingskaskade ved skift af biologisk behandling i kombination med methotrexat

samt nye patienter i kombination med methotrexat som ikke kan behandles efter 1 linje

(P2)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje ved svigt efter

abatacept i 1 linje

Ved laeliggemiddel-

rekommandationen

anfoslashres eacutet af laeliggemidlerne

paring baggrund af den

opnaringede laeliggemiddelpris

etanercept

infliximab (6mgkg hver 8 uge)

adalimumab

certolizumab

golimumab

(Hvis infliximab anfoslashres paring baggrund af den opnaringede laeliggemiddelpris

anfoslashres tillige det subkutane laeliggemiddel som har tilbudt den naeligst

mest fordelagtige laeliggemiddelpris)

2 linje ved svigt efter

TNF-haeligmmer i 1 linje

samt efterfoslashlgende linjer

uprioriteret

Der anvendes hoslashjst 2 TNF-

haeligmmere i det samlede

behandlingsforloslashb

Ved laeliggemiddel-

rekommandationen

vurderes laeliggemidlerne i

raeligkkefoslashlge paring baggrund

af den opnaringede

laeliggemiddelpris

Valg af laeliggemiddel tages

paring baggrund af faglige kriterier

abatacept (subkutan eller intravenoslashst regime)

etanercept Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

infliximab (6mgkg hver 8 uge)

Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

adalimumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

certolizumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

golimumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

rituximab anvendes isaeligr ved positiv reumafaktorCCP eller tidligere

cancer

Anvendes saeligdvanligvis ikke til patienter med svaeligr erosiv sygdom

tocilizumab Anvendes saeligdvanligvis ikke til patienter med leversygdom

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 11 af 13

MONOTERAPI (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter i monoterapi (P3)

med angivelse af behandlingsmaringl for 1 linje i

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje 80 tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Behandlingskaskade for skifte patienter i monoterapi

samt nye patienter som ikke kan behandles efter 1 linje (P4)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje uprioriteret

Ved laeliggemiddel-rekommandationen

anfoslashres laeliggemidlerne i raeligkkefoslashlge

paring baggrund af den opnaringede

laeliggemiddelpris

etanercept

adalimumab

certolizumab

tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Efterlevelsesmaringl

Der vil aringrligt kunne blive foretaget udtraeligk fra DANBIO vedroslashrende anvendelsen af biologisk

medicin paring de reumatologiske afdelinger i Danmark fordelt paring de enkelte laeliggemidler Dette

gaeliglder baringde det praeligvalente forbrug og ordination af 1 linje biologisk behandling

Det forventede samlede nationale efterlevelsesmaringl for 1 linje laeliggemiddel er paring 80 af

patienterne for nye patienter

Bilag

1 GRADE metode og materialer

2 GRADE Forest Plots RA

3 GRADE Evidens profil RA

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 12 af 13

Referencer

1 Sorensen K Rheumatoid Arthritis in Denmark Two Population Studies Dan Med Bull

197320(3)86-93

2 Symmonds DM Barrett EM Bankhead CR Scott DI Silman AJ The Occurrence of

Rheumatoid Arthritis in the United Kingdom Results from the Norfolk Arthritis Register

Br J Rheumatol 199433735-739

3 Danbio Aringrsrapport for 2012httpsdanbio-onlinedkformidling

4 Hetland MH Christensen IJ Tarp U et al Direct comparison of treatment responses

remission rates and drug adherence in patients with Rheumatoid Arthritis treated with

Adalimumab Etanercept or Infliximab ArthritisRheum 2010 62 22-32

5 Dansk Reumatologisk Selskabs Kliniske Retningslinje for Diagnostik Behandling og

Monitorering af Reumatoid Artritis

httpwwwdanskreumatologiskselskabdkimagesrokquickcartpdf_filesRheumatoid_Ar

thritis_Kliniske_Vejledningdrs_kliniske_retningslinje_for_rapdf

6 Aletaha D Neogi T Silman AJ et al Ann Rheum Dis 2010 69 1580-1588 2010

Rheumatoid arthritis classification criteria an American College of

RheumatologyEuropean League Against Rheumatism collaborative initiative

7 Arnett FC Edworthy SM Bloch DA McShane DJ Fries FJ Cooper NS et al The American

Rheumatism 1987 revised criteria for the classification of rheumatoid arthritis Arthritis

rheum 198831315-324

8 Danbio Dansk Reumatologisk Database httpwwwdanbio-onlinedk

9 J Fransen PLCM van Riel The Disease Activity Score and the EULAR response criteria

Clin Exp Rheumatol 2005 23 (Suppl 39)S93-S99

10 The GRADE Working Group httpwwwgradeworkinggrouporgindexhtm

11 Kristensen LE Jakobsen AK Bartels EM Geborek P Bliddal H Saxne T et al The number

needed to treat for secondndashgeneration biologics when treating established rheumatoid

arthritis a systematic quantitative review of randomized controlled trials Scand J

Rheumatol 2011 Jan40(1)1-7

12 Kristensen LE Christensen R Bliddal H Geborek P Danneskiold-Samsoslashe B Saxne T The

number needed to treat for adalimumab etanercept and infliximab based on ACR50

response in three randomizec controlled trials on established rheumatoid arthritis a

systematic literature review Scand J Rheumatol 2007 Nov-Dec36(6)411-7

13 Hetland ML Christensen IJ Tarp U Dreyer L Hansen A Hansen IT Kollerup G Linde L

Lindegaard HM Poulsen UE Schlemmer A Jensen DV Jensen S Hostenkamp G

Ostergaard M Direct comparison of treatment responses remission rates and drug

adherence in patients with rheumatoid arthritis treated with adalimumab etanercept or

infliximab Results from eight years of surveillance of clinical practice in the nationwide

Danish DANBIO registry Arthritis Rheum 2010 Jan62(1)22-32

14 Singh JA Christensen R Wells GA Suarez-Almazor ME Buchbinder R Lopez-Olivo MA et

al Biologics for rheumatoid arthritis an overview of Cochrane reviews Sao paulo Med J

2010128(5)309-310

15 Grijalva CG Chen L Delzell E et al Initiation of tumor necrosis factor-G antagonists and

the risk of hospitalization for infection in patients with autoimmune diseases JAMA 2011

Dec 7306(21)2331-9

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 5 af 13

Valg af mulige 1 linje og efterfoslashlgende biologiske laeliggemidler

Fagudvalget har valgt at gennemfoslashre en komparativ evaluering med brug af direkte og

indirekte data af effekt og sikkerhed af biologiske antireumatika Til dette formaringl er primaeligrt

benyttet GRADE-metodikken appliceret paring metaanalyse af datamateriale modtaget fra

laeliggemiddelproducenterne systematisk soslashgning af litteratur og sekundaeligrt publicerede meta-

analyser (10-11) registerdata (12) og Cochrane-reviews (13) Foslashlgende indikatorer er valgt

for effektmaringl

Klinisk effekt belyst ved et opnaringet American College of Rheumatology 50 respons

(ACR50-respons) (PICO 1)

Effekt paring opbremsning i udvikling af strukturel ledskade opgjort som Total Sharp

ScoreGenant-Sharp-ScoreHeijde-Sharp-Score (TSS) (PICO 2)

Praeligparaternes sikkerhed er belyst ved

Forekomst af alvorlige bivirkninger (Serious Adverse Events - SAEs) (PICO 4)

Ophoslashr med projektmedicin pga bivirkninger (Adverse Events - AE) (PICO 3 + 4)

I fagudvalgets bedoslashmmelse af praeligparaternes sikkerhed er tillige udvist et forsigtighedsprincip

idet praeligparater for hvilke der eksisterer et vaeligsentligt og mangearingrigt klinisk erfarings-

grundlag alt andet lige vurderes mere sikre end nyligt registrerede praeligparater med

begraelignset erfaring og nye virkningsmekanismer

Meta-analyse af 1 linje biologiske laeliggemidler er baseret paring klinisk kontrollerede

laeliggemiddelforsoslashg (RCTs) som sammenligner et biologisk laeliggemiddel i kombination med et

DMARD (Methotrexat) versus placebo + DMARD i patientpopulationer som har oplevet svigt af

non-biologisk behandling (DMARD-svigt)

Fagudvalgets indstillinger til biologisk praeligparatvalg for specifikke patient-

populationer

P1 BIO-naive syntetisk DMARD-svigt

P2 BIO-svigt syntetisk DMARD-svigt

P3 BIO-MONO

P4 BIO-MONO-svigt

Valg af biologisk 1 linje praeligparat til bio-naive patienter med DMARD-svigt(P1)

Effekt

Klinisk effekt ACR50-respons (O1) I alt 38 RCTs er fordelt paring alle 9 biologiske

antireumatika indgaringr i analysen Alle praeligparater opnaringr bedre effekt end placebo (=DMARDs)

Overordnet er der signifikante undergruppeforskelle hvilket indikerer en forskel praeligparaterne

imellem (Figur 1) Fagudvalget tilskriver primaeligrt denne forskel en svagere effekt af anakinra

Efter korrektion for anakinra kan der saringledes ikke paringvises signifikant forskellige ACR50

effektmaringl mellem de oslashvrige 8 praeligparater For infliximab 3 mgkg8 uge finder fagudvalget

dog ringere effekt end ved dosering svarende til 6 mgkg8 uge (moderat kvalitetsevidens)

Radiografisk effekt TSS (O2) Effekt belyst ved opbremsning i udvikling af strukturel

ledskadeTSS Analysen vanskeliggoslashres ved at metoden anvendt for opgoslashrelse af TSS ikke er

ens paring tvaeligrs af studierne I alt 12 RCTs indgaringr For golimumab + MTX finder fagudvalget ved

metaanalyse effekt paring linje med placebo + MTX (Figur 2) For rituximab har fagudvalget ikke

roslashntgenologiske data for patientgruppen syntetisk DMARD-svigt For alle oslashvrige biologiske

laeliggemidler finder fagudvalget signifikant bedre effekt end ved behandling med placebo (MTX)

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 6 af 13

Med forbehold for golimumab og rituximab finder fagudvalget ikke signifikant forskelle

praeligparaterne imellem hvad angaringr radiografisk effekt

Sikkerhed

Ophoslashr med projektmedicin pga bivirkninger (withdrawals due to AEs)(O3) Analysen

baseres paring i alt 38 RCTs (Figur 3) For anakinra certolizumab tocilizumab og infliximab 3

mgkg forekommer behandlingsophoslashr pga bivirkninger signifikant hyppigere end for placebo

(MTX) For oslashvrige praeligparater finder fagudvalget ingen signifikant forskel mellem placebo og

biologisk behandling

Alvorlige bivirkninger (SAEs) (O4) Analysen baseres paring 38 RCTs (Figur 4) Behandling

med certolizumab og tocilizumab viste signifikant flere SAEs end placebo (MTX) For oslashvrige

praeligparater var forekomsten af SAEs paring linje med placebo

Med det formaringl at afklare om denne beskrevne oslashgede risiko var klinisk betydningsfuld foretog

fagudvalget to ekstra meta-analytiske tiltag

1 Samtlige biologiske laeliggemidler vs placebo paring tvaeligrs af sygdoms kategorier (RA SpA

AS) blev kombineret for at oslashge den statistiske styrke (Figur 5) de inkluderede studier var de

blev benyttet i den oslashvrige RADS proces Certolizumab fremstod herved som et biologisk

laeliggemiddel med en saeligrlig risiko-profil

2 Fagudvalget vurderede at denne forskel kunne vaeligre betydningsfuld Paring denne baggrund

blev der udfoslashrt en rdquonetvaeligrks meta-analyserdquo der muliggjorde at alle laeliggemidler kunne

sammenlignes direkte paring baggrund af indirekte data Som en konsekvens af disse data

vurderede fagudvalget at samtlige alvorlige bivirkninger fra de inkluderede studier skulle

gennemgarings af eacuten reumatolog for at sikre sig at der var tale om egentlige risici snarere end en

statistisk tilfaeligldighed Statistisk blev der sideloslashbende benyttet flere modeller Disse

sandsynliggjorde at certolizumab og tocilizumab fremstod som havende flere alvorlige

bivirkninger pga saringkaldte adaptive trial designs I et saringdant design kan den almindelige

rsquoIntention-to-treatrsquo population give fejlvisende konklusioner Det blev vurderet for baringde

certolizumab og tocilizumab at dette studiedesign havde foraringrsaget dette statistiske signal ved

at lade flere af deres rdquoplacebo patienterrdquo paringbegynde en aktiv-behandling inden afslutningen paring

rsquoIntention-to-treatrsquo perioden

Efter at fagudvalget noslashje havde vurderet hver enkelt alvorlig bivirkning for samtlige patienter i

alle studierne blev konklusionen at der sandsynligvis var tale om rdquoet statistisk artefaktrdquo pga

de rsquoadaptive trial designsrsquo idet det samme klare billede ikke kunne genfindes paring individ

niveau

Fagudvalgets indstilling til 1 linje praeligparatvalg for patienter karakteriseret ved

syntetisk DMARD-svigt (P1) Tofacitinib fravaeliglges generelt pga manglende godkendelse

hos EMA Anakinra fravaeliglges pga ugunstige data for klinisk effekt Golimumab fravaeliglges pga

tvivlsom dokumentation for effekt paring radiografiske effektmaringl Rituximab er godkendt til

behandling efter svigt af DMARDs inkl biologiske laeliggemidler og kan derfor ikke anvendes som

1 linje Infliximab 3 mgkg8 uge viser utilfredsstillende data for sikkerhed belyst ved

behandlingsophoslashr pga bivirkninger Tocilizumab fravaeliglges med reference til foslashrnaeligvnte

forsigtighedsprincip og idet der ikke foreligger et head-to-head studie som kan dokumentere

hvorvidt dette laeliggemiddel er ligevaeligrdigt med TNF-alfa haeligmmende behandling

Herefter kan uprioriteret ligestilles abatacept SCIV adalimumab certolizumab etanercept og

infliximab 6 mgkg8 uge som 1 linjebehandling

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 7 af 13

Fagudvalgets indstilling til 2 3 og foslashlgende linje biologisk praeligparatvalg for

patienter karakteriseret ved syntetisk DMARD-svigt BIO-svigt (P2) Som naeligvnt under

punktet rsquopatientgrundlagrsquo er der her tale om en stor og voksende patientgruppe karakteriseret

ved manglende eller aftagende effekt ogeller intolerans overfor et eller flere biologiske

laeliggemidler Registerstudier viser her at sandsynligheden for respons er omvendt proportional

med antallet af tidligere afproslashvede biologiske laeliggemidler Effekt og sikkerhed af nyt biologisk

laeliggemiddel + DMARD efter svigt af tidligere biologisk laeliggemiddel (primaeligrt TNF-alfa

haeligmmere) er dokumenteret for abatacept golimumab rituximab tocilizumab (og tofacitinib)

(O1234) For alle praeligparater fandtes et gunstigt forhold mellem effekt (ACR50 ndash O1) og

sikkerhed (SAEsndash O4) og behandlingsophoslashr pga bivirkninger (O3) For golimumab gaeliglder

saeligrskilt at nye radiografiske data praeligsenteret efter RADS 2012 laeliggemiddel-

rekommandationen nu tillader indplacering af dette laeliggemiddel som mulig 2 linjebehandling

uden dog at kvalificere til 1 linje prioritet

Fagudvalget indstiller herefter i uprioriteret raeligkkefoslashlge abatacept SCIV adalimumab

certolizumab etanercept golimumab infliximab 6 mgkg8 uge rituximab og tocilizumab

som mulige 2 3 og foslashlgende linje praeligparater

Patientprofiler Biologisk behandling af patienter med tidligere malign diagnose er med faring

undtagelser forbeholdt rituximab Fravaeligr af IgM-RF i serum er associeret med et daringrligere

behandlingsrespons af rituximab end ved +IgM-RF Betydningen af IgM-RF for respons ved

andre biologiske laeliggemidler er ikke naeligrmere belyst

Fagudvalgets indstilling til monoterapi med biologisk laeliggemiddel (P3 P4) I lighed med

DRS fastslaringr fagudvalget at biologisk behandling boslashr forudgarings af afproslashvet sekventiel eller

kombineret behandling med mindst 2 non-biologiske DMARDs (hvori MTX indgaringr) +

glukokortikoid I denne kontekst vil biologisk monoterapi vaeligre relevant hos patienten med

paringgaringende moderat eller hoslashj sygdomsaktivitet og dokumenteret intoleranskontraindikation

overfor MTX + yderligere afproslashvede non-biologiske DMARDs Foslashlgende biologiske laeliggemidler

kan anvendes som monoterapi (i henhold til SPCs og PROmedicindk) adalimumab

etanercept certolizumab og tocilizumab Kombinationsbehandling med MTX og

etanerceptadalimumab har vist sig mere effektiv end monoterapi med

etanerceptadalimumab En tilsvarende synergimekanisme er ikke vist for tocilizumab + MTX I

et nyligt offentliggjort rdquoHead-to-Headrdquo komparativt studie fandtes monoterapi med tocilizumab

signifikant mere effektivt (ACR50 ndash O1) og lige saring sikkert som adalimumab

Fagudvalget indstiller derfor tocilizumab som eneste 1 linje biologiske laeliggemiddel ved

DMARD-intolerante patienter (P3)

Som 2 linje (P4) kan adalimumab etanercept og certolizumab anvendes som monoterapi efter

svigtintolerans af tocilizumab og forudsat observeret intolerans kontraindikation overfor

syntetiske DMARDs

Praeligparatoverlevelse Studier baseret paring registerdata finder kortere praeligparatoverlevelse for

infliximab end for andre TNF-alfa haeligmmere (12) En eventuel betydning af dosisoslashgning for

praeligparatoverlevelse af infliximab er ikke afklaret

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 8 af 13

Doseringstabel Initial behandling Vedligeholdelsesbehandling

abatacept

subkutant regime

(forfyldt sproslashjtepen

initialdosis IV)

Intravenoslashst

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

uge 0

Subkutan injektion med 125 mg

ugentligt

Foslashrste injektion samme dag som

initialdosis

abatacept

intravenoslashst regime

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

uge 0 2 og 4

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

hver 4 uge

etanercept

subkutant regime

(forfyldt sproslashjtepen)

50 mg 50 mg hver uge

infliximab

intravenoslashst regime

3 mgkg legemsvaeliggt uge 0 og 2

45 mgkg uge 6

6 mgkg uge 12 og 20

6 mgkg legemsvaeliggt hver 8 uge

dosistitrering ved behov

adalimumab

subkutant regime

(forfyldt sproslashjtepen)

40 mg 40 mg hver 2 uge

certolizumab

subkutant regime

(forfyldt sproslashjtepen)

400 mg uge 0 2 4 200 mg hver 2 uge

eller

400 mg hver 4 uge

golimumab

subkutant regime

(forfyldt sproslashjtepen)

50 mg 50 mg om maringneden paring den

samme dag hver maringned som

initialdosis

rituximab

intravenoslashst regime

1000 mg uge 0 2 Regimet gentages hver 6 til 12

maringned

tocilizumab

intravenoslashst regime

8 mgkg legemsvaeliggt dog hoslashjst

800 mg

8 mgkg legemsvaeliggt dog hoslashjst

800 mg hver 4 uge

Vurdering af behandlingseffekt

Til vurdering af effekt anbefales primaeligrt brugt aeligndringer i DAS-score og opnaringelse af LDAS

eller DAS remission og radiologisk non-progression

Dokumentation af sygdomsstatus behandling effekt og eventuelle bivirkninger

Alle patientforloslashb rapporteres til den kliniske database DANBIO Dokumentation sikres foslashr

behandling ved behandlingsstart og herefter til tiden 3 6 12 mdr Yderligere kontrol

afhaelignger af graden af sygdomskontrol dog som minimum hver 6 mdr

Dosisreduktion

Der er ikke sikker evidens for at dosis kan reduceres i vaeligsentligt omfang i forhold til dosis

givet i registreringsstudierne men dette er ikke systematisk undersoslashgt

Seponeringskriterier

Seponering gennemfoslashres ved

1) Uacceptable bivirkninger og manglende effekt som anfoslashrt under skiftekriterier

2) Oslashnske om konception eller ved konstateret graviditet Generelt anbefales optimal

sygdomskontrol op til og under graviditet adalimumab etanercept og infliximab kan

anvendes frem til konstateret graviditet oslashvrige biologiske praeligparater seponeres forud

for (karenstid ndash se DANBIO patientvejledninger herom) konception

3) Kritisk komorbiditet (i henhold til produktresumeer infektion svaeligr hjerteinsufficiens

demyeliniserende lidelser cancer mm)

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 9 af 13

Skiftekriterier

Opnaringr patienten ved en given biologisk behandling ikke det definerede behandlingsmaringl inden

4 maringneder (lav sygdomsaktivitet + radiografisk non-progression + reduktion i et eventuelt

hoslashjt forbrug af glukokortikoid) kan patienten skifte til en ny biologisk behandling

Maringling af laeliggemiddelkoncentrationer og neutraliserende laeliggemiddelantistoffer

kan i plasma belyse aringrsagen til behandlingssvigt dog savnes her stoslashrre prospektive kliniske

studier Fagudvalget finder det praeligmaturt at inddrage saringdanne analyser rutinemaeligssigt i

klinisk praksis

Screening og sikkerhed

Patienterne boslashr inden behandlingsstart screenes for latent tuberkulose kronisk viral

hepatitis og andre kroniske infektioner Foslashr og under biologisk behandling foretages

regelmaeligssig klinisk og paraklinisk kontrol som beskrevet i DRS-vejledning

Undtagelse for valg af 1 linje

Afdelinger som ikke raringder over de ressourcer som indgaringr i behandling af patienter med

intravenoslashst administreret laeliggemiddel kan garing videre til naeligstfoslashlgende linje med subkutan

administration

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 10 af 13

KOMBINATIONSBEHANDLING (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter og patienter som skal skifte biologisk behandling i

kombination med methotrexat (P1)

med angivelse af behandlingsmaringl for 1 linje i

De angivne estimater viser den forventede variation som vil forekomme

afhaeligngig af den endelige rangordning

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje

abatacept (subkutant eller intravenoslashst regime) etanercept

infliximab (6mgkg hver 8 uge) adalimumab certolizumab

Ved subkutan formulering

som 1 linje paring baggrund af

laeliggemiddelpris

1 linje 1 valg

80 paring subkutan formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet af laeliggemidlerne)

Ved IV formulering som 1 linje paring

baggrund af laeliggemiddelpris

1 linje 1 valg

50 paring IV formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet IV laeliggemiddel)

1 linje 2 valg

30 paring subkutan formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet subkutant laeliggemiddel)

Behandlingskaskade ved skift af biologisk behandling i kombination med methotrexat

samt nye patienter i kombination med methotrexat som ikke kan behandles efter 1 linje

(P2)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje ved svigt efter

abatacept i 1 linje

Ved laeliggemiddel-

rekommandationen

anfoslashres eacutet af laeliggemidlerne

paring baggrund af den

opnaringede laeliggemiddelpris

etanercept

infliximab (6mgkg hver 8 uge)

adalimumab

certolizumab

golimumab

(Hvis infliximab anfoslashres paring baggrund af den opnaringede laeliggemiddelpris

anfoslashres tillige det subkutane laeliggemiddel som har tilbudt den naeligst

mest fordelagtige laeliggemiddelpris)

2 linje ved svigt efter

TNF-haeligmmer i 1 linje

samt efterfoslashlgende linjer

uprioriteret

Der anvendes hoslashjst 2 TNF-

haeligmmere i det samlede

behandlingsforloslashb

Ved laeliggemiddel-

rekommandationen

vurderes laeliggemidlerne i

raeligkkefoslashlge paring baggrund

af den opnaringede

laeliggemiddelpris

Valg af laeliggemiddel tages

paring baggrund af faglige kriterier

abatacept (subkutan eller intravenoslashst regime)

etanercept Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

infliximab (6mgkg hver 8 uge)

Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

adalimumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

certolizumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

golimumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

rituximab anvendes isaeligr ved positiv reumafaktorCCP eller tidligere

cancer

Anvendes saeligdvanligvis ikke til patienter med svaeligr erosiv sygdom

tocilizumab Anvendes saeligdvanligvis ikke til patienter med leversygdom

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 11 af 13

MONOTERAPI (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter i monoterapi (P3)

med angivelse af behandlingsmaringl for 1 linje i

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje 80 tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Behandlingskaskade for skifte patienter i monoterapi

samt nye patienter som ikke kan behandles efter 1 linje (P4)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje uprioriteret

Ved laeliggemiddel-rekommandationen

anfoslashres laeliggemidlerne i raeligkkefoslashlge

paring baggrund af den opnaringede

laeliggemiddelpris

etanercept

adalimumab

certolizumab

tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Efterlevelsesmaringl

Der vil aringrligt kunne blive foretaget udtraeligk fra DANBIO vedroslashrende anvendelsen af biologisk

medicin paring de reumatologiske afdelinger i Danmark fordelt paring de enkelte laeliggemidler Dette

gaeliglder baringde det praeligvalente forbrug og ordination af 1 linje biologisk behandling

Det forventede samlede nationale efterlevelsesmaringl for 1 linje laeliggemiddel er paring 80 af

patienterne for nye patienter

Bilag

1 GRADE metode og materialer

2 GRADE Forest Plots RA

3 GRADE Evidens profil RA

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 12 af 13

Referencer

1 Sorensen K Rheumatoid Arthritis in Denmark Two Population Studies Dan Med Bull

197320(3)86-93

2 Symmonds DM Barrett EM Bankhead CR Scott DI Silman AJ The Occurrence of

Rheumatoid Arthritis in the United Kingdom Results from the Norfolk Arthritis Register

Br J Rheumatol 199433735-739

3 Danbio Aringrsrapport for 2012httpsdanbio-onlinedkformidling

4 Hetland MH Christensen IJ Tarp U et al Direct comparison of treatment responses

remission rates and drug adherence in patients with Rheumatoid Arthritis treated with

Adalimumab Etanercept or Infliximab ArthritisRheum 2010 62 22-32

5 Dansk Reumatologisk Selskabs Kliniske Retningslinje for Diagnostik Behandling og

Monitorering af Reumatoid Artritis

httpwwwdanskreumatologiskselskabdkimagesrokquickcartpdf_filesRheumatoid_Ar

thritis_Kliniske_Vejledningdrs_kliniske_retningslinje_for_rapdf

6 Aletaha D Neogi T Silman AJ et al Ann Rheum Dis 2010 69 1580-1588 2010

Rheumatoid arthritis classification criteria an American College of

RheumatologyEuropean League Against Rheumatism collaborative initiative

7 Arnett FC Edworthy SM Bloch DA McShane DJ Fries FJ Cooper NS et al The American

Rheumatism 1987 revised criteria for the classification of rheumatoid arthritis Arthritis

rheum 198831315-324

8 Danbio Dansk Reumatologisk Database httpwwwdanbio-onlinedk

9 J Fransen PLCM van Riel The Disease Activity Score and the EULAR response criteria

Clin Exp Rheumatol 2005 23 (Suppl 39)S93-S99

10 The GRADE Working Group httpwwwgradeworkinggrouporgindexhtm

11 Kristensen LE Jakobsen AK Bartels EM Geborek P Bliddal H Saxne T et al The number

needed to treat for secondndashgeneration biologics when treating established rheumatoid

arthritis a systematic quantitative review of randomized controlled trials Scand J

Rheumatol 2011 Jan40(1)1-7

12 Kristensen LE Christensen R Bliddal H Geborek P Danneskiold-Samsoslashe B Saxne T The

number needed to treat for adalimumab etanercept and infliximab based on ACR50

response in three randomizec controlled trials on established rheumatoid arthritis a

systematic literature review Scand J Rheumatol 2007 Nov-Dec36(6)411-7

13 Hetland ML Christensen IJ Tarp U Dreyer L Hansen A Hansen IT Kollerup G Linde L

Lindegaard HM Poulsen UE Schlemmer A Jensen DV Jensen S Hostenkamp G

Ostergaard M Direct comparison of treatment responses remission rates and drug

adherence in patients with rheumatoid arthritis treated with adalimumab etanercept or

infliximab Results from eight years of surveillance of clinical practice in the nationwide

Danish DANBIO registry Arthritis Rheum 2010 Jan62(1)22-32

14 Singh JA Christensen R Wells GA Suarez-Almazor ME Buchbinder R Lopez-Olivo MA et

al Biologics for rheumatoid arthritis an overview of Cochrane reviews Sao paulo Med J

2010128(5)309-310

15 Grijalva CG Chen L Delzell E et al Initiation of tumor necrosis factor-G antagonists and

the risk of hospitalization for infection in patients with autoimmune diseases JAMA 2011

Dec 7306(21)2331-9

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 6 af 13

Med forbehold for golimumab og rituximab finder fagudvalget ikke signifikant forskelle

praeligparaterne imellem hvad angaringr radiografisk effekt

Sikkerhed

Ophoslashr med projektmedicin pga bivirkninger (withdrawals due to AEs)(O3) Analysen

baseres paring i alt 38 RCTs (Figur 3) For anakinra certolizumab tocilizumab og infliximab 3

mgkg forekommer behandlingsophoslashr pga bivirkninger signifikant hyppigere end for placebo

(MTX) For oslashvrige praeligparater finder fagudvalget ingen signifikant forskel mellem placebo og

biologisk behandling

Alvorlige bivirkninger (SAEs) (O4) Analysen baseres paring 38 RCTs (Figur 4) Behandling

med certolizumab og tocilizumab viste signifikant flere SAEs end placebo (MTX) For oslashvrige

praeligparater var forekomsten af SAEs paring linje med placebo

Med det formaringl at afklare om denne beskrevne oslashgede risiko var klinisk betydningsfuld foretog

fagudvalget to ekstra meta-analytiske tiltag

1 Samtlige biologiske laeliggemidler vs placebo paring tvaeligrs af sygdoms kategorier (RA SpA

AS) blev kombineret for at oslashge den statistiske styrke (Figur 5) de inkluderede studier var de

blev benyttet i den oslashvrige RADS proces Certolizumab fremstod herved som et biologisk

laeliggemiddel med en saeligrlig risiko-profil

2 Fagudvalget vurderede at denne forskel kunne vaeligre betydningsfuld Paring denne baggrund

blev der udfoslashrt en rdquonetvaeligrks meta-analyserdquo der muliggjorde at alle laeliggemidler kunne

sammenlignes direkte paring baggrund af indirekte data Som en konsekvens af disse data

vurderede fagudvalget at samtlige alvorlige bivirkninger fra de inkluderede studier skulle

gennemgarings af eacuten reumatolog for at sikre sig at der var tale om egentlige risici snarere end en

statistisk tilfaeligldighed Statistisk blev der sideloslashbende benyttet flere modeller Disse

sandsynliggjorde at certolizumab og tocilizumab fremstod som havende flere alvorlige

bivirkninger pga saringkaldte adaptive trial designs I et saringdant design kan den almindelige

rsquoIntention-to-treatrsquo population give fejlvisende konklusioner Det blev vurderet for baringde

certolizumab og tocilizumab at dette studiedesign havde foraringrsaget dette statistiske signal ved

at lade flere af deres rdquoplacebo patienterrdquo paringbegynde en aktiv-behandling inden afslutningen paring

rsquoIntention-to-treatrsquo perioden

Efter at fagudvalget noslashje havde vurderet hver enkelt alvorlig bivirkning for samtlige patienter i

alle studierne blev konklusionen at der sandsynligvis var tale om rdquoet statistisk artefaktrdquo pga

de rsquoadaptive trial designsrsquo idet det samme klare billede ikke kunne genfindes paring individ

niveau

Fagudvalgets indstilling til 1 linje praeligparatvalg for patienter karakteriseret ved

syntetisk DMARD-svigt (P1) Tofacitinib fravaeliglges generelt pga manglende godkendelse

hos EMA Anakinra fravaeliglges pga ugunstige data for klinisk effekt Golimumab fravaeliglges pga

tvivlsom dokumentation for effekt paring radiografiske effektmaringl Rituximab er godkendt til

behandling efter svigt af DMARDs inkl biologiske laeliggemidler og kan derfor ikke anvendes som

1 linje Infliximab 3 mgkg8 uge viser utilfredsstillende data for sikkerhed belyst ved

behandlingsophoslashr pga bivirkninger Tocilizumab fravaeliglges med reference til foslashrnaeligvnte

forsigtighedsprincip og idet der ikke foreligger et head-to-head studie som kan dokumentere

hvorvidt dette laeliggemiddel er ligevaeligrdigt med TNF-alfa haeligmmende behandling

Herefter kan uprioriteret ligestilles abatacept SCIV adalimumab certolizumab etanercept og

infliximab 6 mgkg8 uge som 1 linjebehandling

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 7 af 13

Fagudvalgets indstilling til 2 3 og foslashlgende linje biologisk praeligparatvalg for

patienter karakteriseret ved syntetisk DMARD-svigt BIO-svigt (P2) Som naeligvnt under

punktet rsquopatientgrundlagrsquo er der her tale om en stor og voksende patientgruppe karakteriseret

ved manglende eller aftagende effekt ogeller intolerans overfor et eller flere biologiske

laeliggemidler Registerstudier viser her at sandsynligheden for respons er omvendt proportional

med antallet af tidligere afproslashvede biologiske laeliggemidler Effekt og sikkerhed af nyt biologisk

laeliggemiddel + DMARD efter svigt af tidligere biologisk laeliggemiddel (primaeligrt TNF-alfa

haeligmmere) er dokumenteret for abatacept golimumab rituximab tocilizumab (og tofacitinib)

(O1234) For alle praeligparater fandtes et gunstigt forhold mellem effekt (ACR50 ndash O1) og

sikkerhed (SAEsndash O4) og behandlingsophoslashr pga bivirkninger (O3) For golimumab gaeliglder

saeligrskilt at nye radiografiske data praeligsenteret efter RADS 2012 laeliggemiddel-

rekommandationen nu tillader indplacering af dette laeliggemiddel som mulig 2 linjebehandling

uden dog at kvalificere til 1 linje prioritet

Fagudvalget indstiller herefter i uprioriteret raeligkkefoslashlge abatacept SCIV adalimumab

certolizumab etanercept golimumab infliximab 6 mgkg8 uge rituximab og tocilizumab

som mulige 2 3 og foslashlgende linje praeligparater

Patientprofiler Biologisk behandling af patienter med tidligere malign diagnose er med faring

undtagelser forbeholdt rituximab Fravaeligr af IgM-RF i serum er associeret med et daringrligere

behandlingsrespons af rituximab end ved +IgM-RF Betydningen af IgM-RF for respons ved

andre biologiske laeliggemidler er ikke naeligrmere belyst

Fagudvalgets indstilling til monoterapi med biologisk laeliggemiddel (P3 P4) I lighed med

DRS fastslaringr fagudvalget at biologisk behandling boslashr forudgarings af afproslashvet sekventiel eller

kombineret behandling med mindst 2 non-biologiske DMARDs (hvori MTX indgaringr) +

glukokortikoid I denne kontekst vil biologisk monoterapi vaeligre relevant hos patienten med

paringgaringende moderat eller hoslashj sygdomsaktivitet og dokumenteret intoleranskontraindikation

overfor MTX + yderligere afproslashvede non-biologiske DMARDs Foslashlgende biologiske laeliggemidler

kan anvendes som monoterapi (i henhold til SPCs og PROmedicindk) adalimumab

etanercept certolizumab og tocilizumab Kombinationsbehandling med MTX og

etanerceptadalimumab har vist sig mere effektiv end monoterapi med

etanerceptadalimumab En tilsvarende synergimekanisme er ikke vist for tocilizumab + MTX I

et nyligt offentliggjort rdquoHead-to-Headrdquo komparativt studie fandtes monoterapi med tocilizumab

signifikant mere effektivt (ACR50 ndash O1) og lige saring sikkert som adalimumab

Fagudvalget indstiller derfor tocilizumab som eneste 1 linje biologiske laeliggemiddel ved

DMARD-intolerante patienter (P3)

Som 2 linje (P4) kan adalimumab etanercept og certolizumab anvendes som monoterapi efter

svigtintolerans af tocilizumab og forudsat observeret intolerans kontraindikation overfor

syntetiske DMARDs

Praeligparatoverlevelse Studier baseret paring registerdata finder kortere praeligparatoverlevelse for

infliximab end for andre TNF-alfa haeligmmere (12) En eventuel betydning af dosisoslashgning for

praeligparatoverlevelse af infliximab er ikke afklaret

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 8 af 13

Doseringstabel Initial behandling Vedligeholdelsesbehandling

abatacept

subkutant regime

(forfyldt sproslashjtepen

initialdosis IV)

Intravenoslashst

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

uge 0

Subkutan injektion med 125 mg

ugentligt

Foslashrste injektion samme dag som

initialdosis

abatacept

intravenoslashst regime

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

uge 0 2 og 4

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

hver 4 uge

etanercept

subkutant regime

(forfyldt sproslashjtepen)

50 mg 50 mg hver uge

infliximab

intravenoslashst regime

3 mgkg legemsvaeliggt uge 0 og 2

45 mgkg uge 6

6 mgkg uge 12 og 20

6 mgkg legemsvaeliggt hver 8 uge

dosistitrering ved behov

adalimumab

subkutant regime

(forfyldt sproslashjtepen)

40 mg 40 mg hver 2 uge

certolizumab

subkutant regime

(forfyldt sproslashjtepen)

400 mg uge 0 2 4 200 mg hver 2 uge

eller

400 mg hver 4 uge

golimumab

subkutant regime

(forfyldt sproslashjtepen)

50 mg 50 mg om maringneden paring den

samme dag hver maringned som

initialdosis

rituximab

intravenoslashst regime

1000 mg uge 0 2 Regimet gentages hver 6 til 12

maringned

tocilizumab

intravenoslashst regime

8 mgkg legemsvaeliggt dog hoslashjst

800 mg

8 mgkg legemsvaeliggt dog hoslashjst

800 mg hver 4 uge

Vurdering af behandlingseffekt

Til vurdering af effekt anbefales primaeligrt brugt aeligndringer i DAS-score og opnaringelse af LDAS

eller DAS remission og radiologisk non-progression

Dokumentation af sygdomsstatus behandling effekt og eventuelle bivirkninger

Alle patientforloslashb rapporteres til den kliniske database DANBIO Dokumentation sikres foslashr

behandling ved behandlingsstart og herefter til tiden 3 6 12 mdr Yderligere kontrol

afhaelignger af graden af sygdomskontrol dog som minimum hver 6 mdr

Dosisreduktion

Der er ikke sikker evidens for at dosis kan reduceres i vaeligsentligt omfang i forhold til dosis

givet i registreringsstudierne men dette er ikke systematisk undersoslashgt

Seponeringskriterier

Seponering gennemfoslashres ved

1) Uacceptable bivirkninger og manglende effekt som anfoslashrt under skiftekriterier

2) Oslashnske om konception eller ved konstateret graviditet Generelt anbefales optimal

sygdomskontrol op til og under graviditet adalimumab etanercept og infliximab kan

anvendes frem til konstateret graviditet oslashvrige biologiske praeligparater seponeres forud

for (karenstid ndash se DANBIO patientvejledninger herom) konception

3) Kritisk komorbiditet (i henhold til produktresumeer infektion svaeligr hjerteinsufficiens

demyeliniserende lidelser cancer mm)

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 9 af 13

Skiftekriterier

Opnaringr patienten ved en given biologisk behandling ikke det definerede behandlingsmaringl inden

4 maringneder (lav sygdomsaktivitet + radiografisk non-progression + reduktion i et eventuelt

hoslashjt forbrug af glukokortikoid) kan patienten skifte til en ny biologisk behandling

Maringling af laeliggemiddelkoncentrationer og neutraliserende laeliggemiddelantistoffer

kan i plasma belyse aringrsagen til behandlingssvigt dog savnes her stoslashrre prospektive kliniske

studier Fagudvalget finder det praeligmaturt at inddrage saringdanne analyser rutinemaeligssigt i

klinisk praksis

Screening og sikkerhed

Patienterne boslashr inden behandlingsstart screenes for latent tuberkulose kronisk viral

hepatitis og andre kroniske infektioner Foslashr og under biologisk behandling foretages

regelmaeligssig klinisk og paraklinisk kontrol som beskrevet i DRS-vejledning

Undtagelse for valg af 1 linje

Afdelinger som ikke raringder over de ressourcer som indgaringr i behandling af patienter med

intravenoslashst administreret laeliggemiddel kan garing videre til naeligstfoslashlgende linje med subkutan

administration

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 10 af 13

KOMBINATIONSBEHANDLING (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter og patienter som skal skifte biologisk behandling i

kombination med methotrexat (P1)

med angivelse af behandlingsmaringl for 1 linje i

De angivne estimater viser den forventede variation som vil forekomme

afhaeligngig af den endelige rangordning

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje

abatacept (subkutant eller intravenoslashst regime) etanercept

infliximab (6mgkg hver 8 uge) adalimumab certolizumab

Ved subkutan formulering

som 1 linje paring baggrund af

laeliggemiddelpris

1 linje 1 valg

80 paring subkutan formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet af laeliggemidlerne)

Ved IV formulering som 1 linje paring

baggrund af laeliggemiddelpris

1 linje 1 valg

50 paring IV formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet IV laeliggemiddel)

1 linje 2 valg

30 paring subkutan formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet subkutant laeliggemiddel)

Behandlingskaskade ved skift af biologisk behandling i kombination med methotrexat

samt nye patienter i kombination med methotrexat som ikke kan behandles efter 1 linje

(P2)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje ved svigt efter

abatacept i 1 linje

Ved laeliggemiddel-

rekommandationen

anfoslashres eacutet af laeliggemidlerne

paring baggrund af den

opnaringede laeliggemiddelpris

etanercept

infliximab (6mgkg hver 8 uge)

adalimumab

certolizumab

golimumab

(Hvis infliximab anfoslashres paring baggrund af den opnaringede laeliggemiddelpris

anfoslashres tillige det subkutane laeliggemiddel som har tilbudt den naeligst

mest fordelagtige laeliggemiddelpris)

2 linje ved svigt efter

TNF-haeligmmer i 1 linje

samt efterfoslashlgende linjer

uprioriteret

Der anvendes hoslashjst 2 TNF-

haeligmmere i det samlede

behandlingsforloslashb

Ved laeliggemiddel-

rekommandationen

vurderes laeliggemidlerne i

raeligkkefoslashlge paring baggrund

af den opnaringede

laeliggemiddelpris

Valg af laeliggemiddel tages

paring baggrund af faglige kriterier

abatacept (subkutan eller intravenoslashst regime)

etanercept Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

infliximab (6mgkg hver 8 uge)

Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

adalimumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

certolizumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

golimumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

rituximab anvendes isaeligr ved positiv reumafaktorCCP eller tidligere

cancer

Anvendes saeligdvanligvis ikke til patienter med svaeligr erosiv sygdom

tocilizumab Anvendes saeligdvanligvis ikke til patienter med leversygdom

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 11 af 13

MONOTERAPI (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter i monoterapi (P3)

med angivelse af behandlingsmaringl for 1 linje i

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje 80 tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Behandlingskaskade for skifte patienter i monoterapi

samt nye patienter som ikke kan behandles efter 1 linje (P4)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje uprioriteret

Ved laeliggemiddel-rekommandationen

anfoslashres laeliggemidlerne i raeligkkefoslashlge

paring baggrund af den opnaringede

laeliggemiddelpris

etanercept

adalimumab

certolizumab

tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Efterlevelsesmaringl

Der vil aringrligt kunne blive foretaget udtraeligk fra DANBIO vedroslashrende anvendelsen af biologisk

medicin paring de reumatologiske afdelinger i Danmark fordelt paring de enkelte laeliggemidler Dette

gaeliglder baringde det praeligvalente forbrug og ordination af 1 linje biologisk behandling

Det forventede samlede nationale efterlevelsesmaringl for 1 linje laeliggemiddel er paring 80 af

patienterne for nye patienter

Bilag

1 GRADE metode og materialer

2 GRADE Forest Plots RA

3 GRADE Evidens profil RA

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 12 af 13

Referencer

1 Sorensen K Rheumatoid Arthritis in Denmark Two Population Studies Dan Med Bull

197320(3)86-93

2 Symmonds DM Barrett EM Bankhead CR Scott DI Silman AJ The Occurrence of

Rheumatoid Arthritis in the United Kingdom Results from the Norfolk Arthritis Register

Br J Rheumatol 199433735-739

3 Danbio Aringrsrapport for 2012httpsdanbio-onlinedkformidling

4 Hetland MH Christensen IJ Tarp U et al Direct comparison of treatment responses

remission rates and drug adherence in patients with Rheumatoid Arthritis treated with

Adalimumab Etanercept or Infliximab ArthritisRheum 2010 62 22-32

5 Dansk Reumatologisk Selskabs Kliniske Retningslinje for Diagnostik Behandling og

Monitorering af Reumatoid Artritis

httpwwwdanskreumatologiskselskabdkimagesrokquickcartpdf_filesRheumatoid_Ar

thritis_Kliniske_Vejledningdrs_kliniske_retningslinje_for_rapdf

6 Aletaha D Neogi T Silman AJ et al Ann Rheum Dis 2010 69 1580-1588 2010

Rheumatoid arthritis classification criteria an American College of

RheumatologyEuropean League Against Rheumatism collaborative initiative

7 Arnett FC Edworthy SM Bloch DA McShane DJ Fries FJ Cooper NS et al The American

Rheumatism 1987 revised criteria for the classification of rheumatoid arthritis Arthritis

rheum 198831315-324

8 Danbio Dansk Reumatologisk Database httpwwwdanbio-onlinedk

9 J Fransen PLCM van Riel The Disease Activity Score and the EULAR response criteria

Clin Exp Rheumatol 2005 23 (Suppl 39)S93-S99

10 The GRADE Working Group httpwwwgradeworkinggrouporgindexhtm

11 Kristensen LE Jakobsen AK Bartels EM Geborek P Bliddal H Saxne T et al The number

needed to treat for secondndashgeneration biologics when treating established rheumatoid

arthritis a systematic quantitative review of randomized controlled trials Scand J

Rheumatol 2011 Jan40(1)1-7

12 Kristensen LE Christensen R Bliddal H Geborek P Danneskiold-Samsoslashe B Saxne T The

number needed to treat for adalimumab etanercept and infliximab based on ACR50

response in three randomizec controlled trials on established rheumatoid arthritis a

systematic literature review Scand J Rheumatol 2007 Nov-Dec36(6)411-7

13 Hetland ML Christensen IJ Tarp U Dreyer L Hansen A Hansen IT Kollerup G Linde L

Lindegaard HM Poulsen UE Schlemmer A Jensen DV Jensen S Hostenkamp G

Ostergaard M Direct comparison of treatment responses remission rates and drug

adherence in patients with rheumatoid arthritis treated with adalimumab etanercept or

infliximab Results from eight years of surveillance of clinical practice in the nationwide

Danish DANBIO registry Arthritis Rheum 2010 Jan62(1)22-32

14 Singh JA Christensen R Wells GA Suarez-Almazor ME Buchbinder R Lopez-Olivo MA et

al Biologics for rheumatoid arthritis an overview of Cochrane reviews Sao paulo Med J

2010128(5)309-310

15 Grijalva CG Chen L Delzell E et al Initiation of tumor necrosis factor-G antagonists and

the risk of hospitalization for infection in patients with autoimmune diseases JAMA 2011

Dec 7306(21)2331-9

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 7 af 13

Fagudvalgets indstilling til 2 3 og foslashlgende linje biologisk praeligparatvalg for

patienter karakteriseret ved syntetisk DMARD-svigt BIO-svigt (P2) Som naeligvnt under

punktet rsquopatientgrundlagrsquo er der her tale om en stor og voksende patientgruppe karakteriseret

ved manglende eller aftagende effekt ogeller intolerans overfor et eller flere biologiske

laeliggemidler Registerstudier viser her at sandsynligheden for respons er omvendt proportional

med antallet af tidligere afproslashvede biologiske laeliggemidler Effekt og sikkerhed af nyt biologisk

laeliggemiddel + DMARD efter svigt af tidligere biologisk laeliggemiddel (primaeligrt TNF-alfa

haeligmmere) er dokumenteret for abatacept golimumab rituximab tocilizumab (og tofacitinib)

(O1234) For alle praeligparater fandtes et gunstigt forhold mellem effekt (ACR50 ndash O1) og

sikkerhed (SAEsndash O4) og behandlingsophoslashr pga bivirkninger (O3) For golimumab gaeliglder

saeligrskilt at nye radiografiske data praeligsenteret efter RADS 2012 laeliggemiddel-

rekommandationen nu tillader indplacering af dette laeliggemiddel som mulig 2 linjebehandling

uden dog at kvalificere til 1 linje prioritet

Fagudvalget indstiller herefter i uprioriteret raeligkkefoslashlge abatacept SCIV adalimumab

certolizumab etanercept golimumab infliximab 6 mgkg8 uge rituximab og tocilizumab

som mulige 2 3 og foslashlgende linje praeligparater

Patientprofiler Biologisk behandling af patienter med tidligere malign diagnose er med faring

undtagelser forbeholdt rituximab Fravaeligr af IgM-RF i serum er associeret med et daringrligere

behandlingsrespons af rituximab end ved +IgM-RF Betydningen af IgM-RF for respons ved

andre biologiske laeliggemidler er ikke naeligrmere belyst

Fagudvalgets indstilling til monoterapi med biologisk laeliggemiddel (P3 P4) I lighed med

DRS fastslaringr fagudvalget at biologisk behandling boslashr forudgarings af afproslashvet sekventiel eller

kombineret behandling med mindst 2 non-biologiske DMARDs (hvori MTX indgaringr) +

glukokortikoid I denne kontekst vil biologisk monoterapi vaeligre relevant hos patienten med

paringgaringende moderat eller hoslashj sygdomsaktivitet og dokumenteret intoleranskontraindikation

overfor MTX + yderligere afproslashvede non-biologiske DMARDs Foslashlgende biologiske laeliggemidler

kan anvendes som monoterapi (i henhold til SPCs og PROmedicindk) adalimumab

etanercept certolizumab og tocilizumab Kombinationsbehandling med MTX og

etanerceptadalimumab har vist sig mere effektiv end monoterapi med

etanerceptadalimumab En tilsvarende synergimekanisme er ikke vist for tocilizumab + MTX I

et nyligt offentliggjort rdquoHead-to-Headrdquo komparativt studie fandtes monoterapi med tocilizumab

signifikant mere effektivt (ACR50 ndash O1) og lige saring sikkert som adalimumab

Fagudvalget indstiller derfor tocilizumab som eneste 1 linje biologiske laeliggemiddel ved

DMARD-intolerante patienter (P3)

Som 2 linje (P4) kan adalimumab etanercept og certolizumab anvendes som monoterapi efter

svigtintolerans af tocilizumab og forudsat observeret intolerans kontraindikation overfor

syntetiske DMARDs

Praeligparatoverlevelse Studier baseret paring registerdata finder kortere praeligparatoverlevelse for

infliximab end for andre TNF-alfa haeligmmere (12) En eventuel betydning af dosisoslashgning for

praeligparatoverlevelse af infliximab er ikke afklaret

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 8 af 13

Doseringstabel Initial behandling Vedligeholdelsesbehandling

abatacept

subkutant regime

(forfyldt sproslashjtepen

initialdosis IV)

Intravenoslashst

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

uge 0

Subkutan injektion med 125 mg

ugentligt

Foslashrste injektion samme dag som

initialdosis

abatacept

intravenoslashst regime

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

uge 0 2 og 4

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

hver 4 uge

etanercept

subkutant regime

(forfyldt sproslashjtepen)

50 mg 50 mg hver uge

infliximab

intravenoslashst regime

3 mgkg legemsvaeliggt uge 0 og 2

45 mgkg uge 6

6 mgkg uge 12 og 20

6 mgkg legemsvaeliggt hver 8 uge

dosistitrering ved behov

adalimumab

subkutant regime

(forfyldt sproslashjtepen)

40 mg 40 mg hver 2 uge

certolizumab

subkutant regime

(forfyldt sproslashjtepen)

400 mg uge 0 2 4 200 mg hver 2 uge

eller

400 mg hver 4 uge

golimumab

subkutant regime

(forfyldt sproslashjtepen)

50 mg 50 mg om maringneden paring den

samme dag hver maringned som

initialdosis

rituximab

intravenoslashst regime

1000 mg uge 0 2 Regimet gentages hver 6 til 12

maringned

tocilizumab

intravenoslashst regime

8 mgkg legemsvaeliggt dog hoslashjst

800 mg

8 mgkg legemsvaeliggt dog hoslashjst

800 mg hver 4 uge

Vurdering af behandlingseffekt

Til vurdering af effekt anbefales primaeligrt brugt aeligndringer i DAS-score og opnaringelse af LDAS

eller DAS remission og radiologisk non-progression

Dokumentation af sygdomsstatus behandling effekt og eventuelle bivirkninger

Alle patientforloslashb rapporteres til den kliniske database DANBIO Dokumentation sikres foslashr

behandling ved behandlingsstart og herefter til tiden 3 6 12 mdr Yderligere kontrol

afhaelignger af graden af sygdomskontrol dog som minimum hver 6 mdr

Dosisreduktion

Der er ikke sikker evidens for at dosis kan reduceres i vaeligsentligt omfang i forhold til dosis

givet i registreringsstudierne men dette er ikke systematisk undersoslashgt

Seponeringskriterier

Seponering gennemfoslashres ved

1) Uacceptable bivirkninger og manglende effekt som anfoslashrt under skiftekriterier

2) Oslashnske om konception eller ved konstateret graviditet Generelt anbefales optimal

sygdomskontrol op til og under graviditet adalimumab etanercept og infliximab kan

anvendes frem til konstateret graviditet oslashvrige biologiske praeligparater seponeres forud

for (karenstid ndash se DANBIO patientvejledninger herom) konception

3) Kritisk komorbiditet (i henhold til produktresumeer infektion svaeligr hjerteinsufficiens

demyeliniserende lidelser cancer mm)

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 9 af 13

Skiftekriterier

Opnaringr patienten ved en given biologisk behandling ikke det definerede behandlingsmaringl inden

4 maringneder (lav sygdomsaktivitet + radiografisk non-progression + reduktion i et eventuelt

hoslashjt forbrug af glukokortikoid) kan patienten skifte til en ny biologisk behandling

Maringling af laeliggemiddelkoncentrationer og neutraliserende laeliggemiddelantistoffer

kan i plasma belyse aringrsagen til behandlingssvigt dog savnes her stoslashrre prospektive kliniske

studier Fagudvalget finder det praeligmaturt at inddrage saringdanne analyser rutinemaeligssigt i

klinisk praksis

Screening og sikkerhed

Patienterne boslashr inden behandlingsstart screenes for latent tuberkulose kronisk viral

hepatitis og andre kroniske infektioner Foslashr og under biologisk behandling foretages

regelmaeligssig klinisk og paraklinisk kontrol som beskrevet i DRS-vejledning

Undtagelse for valg af 1 linje

Afdelinger som ikke raringder over de ressourcer som indgaringr i behandling af patienter med

intravenoslashst administreret laeliggemiddel kan garing videre til naeligstfoslashlgende linje med subkutan

administration

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 10 af 13

KOMBINATIONSBEHANDLING (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter og patienter som skal skifte biologisk behandling i

kombination med methotrexat (P1)

med angivelse af behandlingsmaringl for 1 linje i

De angivne estimater viser den forventede variation som vil forekomme

afhaeligngig af den endelige rangordning

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje

abatacept (subkutant eller intravenoslashst regime) etanercept

infliximab (6mgkg hver 8 uge) adalimumab certolizumab

Ved subkutan formulering

som 1 linje paring baggrund af

laeliggemiddelpris

1 linje 1 valg

80 paring subkutan formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet af laeliggemidlerne)

Ved IV formulering som 1 linje paring

baggrund af laeliggemiddelpris

1 linje 1 valg

50 paring IV formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet IV laeliggemiddel)

1 linje 2 valg

30 paring subkutan formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet subkutant laeliggemiddel)

Behandlingskaskade ved skift af biologisk behandling i kombination med methotrexat

samt nye patienter i kombination med methotrexat som ikke kan behandles efter 1 linje

(P2)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje ved svigt efter

abatacept i 1 linje

Ved laeliggemiddel-

rekommandationen

anfoslashres eacutet af laeliggemidlerne

paring baggrund af den

opnaringede laeliggemiddelpris

etanercept

infliximab (6mgkg hver 8 uge)

adalimumab

certolizumab

golimumab

(Hvis infliximab anfoslashres paring baggrund af den opnaringede laeliggemiddelpris

anfoslashres tillige det subkutane laeliggemiddel som har tilbudt den naeligst

mest fordelagtige laeliggemiddelpris)

2 linje ved svigt efter

TNF-haeligmmer i 1 linje

samt efterfoslashlgende linjer

uprioriteret

Der anvendes hoslashjst 2 TNF-

haeligmmere i det samlede

behandlingsforloslashb

Ved laeliggemiddel-

rekommandationen

vurderes laeliggemidlerne i

raeligkkefoslashlge paring baggrund

af den opnaringede

laeliggemiddelpris

Valg af laeliggemiddel tages

paring baggrund af faglige kriterier

abatacept (subkutan eller intravenoslashst regime)

etanercept Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

infliximab (6mgkg hver 8 uge)

Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

adalimumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

certolizumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

golimumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

rituximab anvendes isaeligr ved positiv reumafaktorCCP eller tidligere

cancer

Anvendes saeligdvanligvis ikke til patienter med svaeligr erosiv sygdom

tocilizumab Anvendes saeligdvanligvis ikke til patienter med leversygdom

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 11 af 13

MONOTERAPI (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter i monoterapi (P3)

med angivelse af behandlingsmaringl for 1 linje i

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje 80 tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Behandlingskaskade for skifte patienter i monoterapi

samt nye patienter som ikke kan behandles efter 1 linje (P4)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje uprioriteret

Ved laeliggemiddel-rekommandationen

anfoslashres laeliggemidlerne i raeligkkefoslashlge

paring baggrund af den opnaringede

laeliggemiddelpris

etanercept

adalimumab

certolizumab

tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Efterlevelsesmaringl

Der vil aringrligt kunne blive foretaget udtraeligk fra DANBIO vedroslashrende anvendelsen af biologisk

medicin paring de reumatologiske afdelinger i Danmark fordelt paring de enkelte laeliggemidler Dette

gaeliglder baringde det praeligvalente forbrug og ordination af 1 linje biologisk behandling

Det forventede samlede nationale efterlevelsesmaringl for 1 linje laeliggemiddel er paring 80 af

patienterne for nye patienter

Bilag

1 GRADE metode og materialer

2 GRADE Forest Plots RA

3 GRADE Evidens profil RA

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 12 af 13

Referencer

1 Sorensen K Rheumatoid Arthritis in Denmark Two Population Studies Dan Med Bull

197320(3)86-93

2 Symmonds DM Barrett EM Bankhead CR Scott DI Silman AJ The Occurrence of

Rheumatoid Arthritis in the United Kingdom Results from the Norfolk Arthritis Register

Br J Rheumatol 199433735-739

3 Danbio Aringrsrapport for 2012httpsdanbio-onlinedkformidling

4 Hetland MH Christensen IJ Tarp U et al Direct comparison of treatment responses

remission rates and drug adherence in patients with Rheumatoid Arthritis treated with

Adalimumab Etanercept or Infliximab ArthritisRheum 2010 62 22-32

5 Dansk Reumatologisk Selskabs Kliniske Retningslinje for Diagnostik Behandling og

Monitorering af Reumatoid Artritis

httpwwwdanskreumatologiskselskabdkimagesrokquickcartpdf_filesRheumatoid_Ar

thritis_Kliniske_Vejledningdrs_kliniske_retningslinje_for_rapdf

6 Aletaha D Neogi T Silman AJ et al Ann Rheum Dis 2010 69 1580-1588 2010

Rheumatoid arthritis classification criteria an American College of

RheumatologyEuropean League Against Rheumatism collaborative initiative

7 Arnett FC Edworthy SM Bloch DA McShane DJ Fries FJ Cooper NS et al The American

Rheumatism 1987 revised criteria for the classification of rheumatoid arthritis Arthritis

rheum 198831315-324

8 Danbio Dansk Reumatologisk Database httpwwwdanbio-onlinedk

9 J Fransen PLCM van Riel The Disease Activity Score and the EULAR response criteria

Clin Exp Rheumatol 2005 23 (Suppl 39)S93-S99

10 The GRADE Working Group httpwwwgradeworkinggrouporgindexhtm

11 Kristensen LE Jakobsen AK Bartels EM Geborek P Bliddal H Saxne T et al The number

needed to treat for secondndashgeneration biologics when treating established rheumatoid

arthritis a systematic quantitative review of randomized controlled trials Scand J

Rheumatol 2011 Jan40(1)1-7

12 Kristensen LE Christensen R Bliddal H Geborek P Danneskiold-Samsoslashe B Saxne T The

number needed to treat for adalimumab etanercept and infliximab based on ACR50

response in three randomizec controlled trials on established rheumatoid arthritis a

systematic literature review Scand J Rheumatol 2007 Nov-Dec36(6)411-7

13 Hetland ML Christensen IJ Tarp U Dreyer L Hansen A Hansen IT Kollerup G Linde L

Lindegaard HM Poulsen UE Schlemmer A Jensen DV Jensen S Hostenkamp G

Ostergaard M Direct comparison of treatment responses remission rates and drug

adherence in patients with rheumatoid arthritis treated with adalimumab etanercept or

infliximab Results from eight years of surveillance of clinical practice in the nationwide

Danish DANBIO registry Arthritis Rheum 2010 Jan62(1)22-32

14 Singh JA Christensen R Wells GA Suarez-Almazor ME Buchbinder R Lopez-Olivo MA et

al Biologics for rheumatoid arthritis an overview of Cochrane reviews Sao paulo Med J

2010128(5)309-310

15 Grijalva CG Chen L Delzell E et al Initiation of tumor necrosis factor-G antagonists and

the risk of hospitalization for infection in patients with autoimmune diseases JAMA 2011

Dec 7306(21)2331-9

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 8 af 13

Doseringstabel Initial behandling Vedligeholdelsesbehandling

abatacept

subkutant regime

(forfyldt sproslashjtepen

initialdosis IV)

Intravenoslashst

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

uge 0

Subkutan injektion med 125 mg

ugentligt

Foslashrste injektion samme dag som

initialdosis

abatacept

intravenoslashst regime

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

uge 0 2 og 4

500 mg til pt le 60 kg

750 mg til pt gt 60 lt 100 kg

1000 mg til pt gt 100 kg

hver 4 uge

etanercept

subkutant regime

(forfyldt sproslashjtepen)

50 mg 50 mg hver uge

infliximab

intravenoslashst regime

3 mgkg legemsvaeliggt uge 0 og 2

45 mgkg uge 6

6 mgkg uge 12 og 20

6 mgkg legemsvaeliggt hver 8 uge

dosistitrering ved behov

adalimumab

subkutant regime

(forfyldt sproslashjtepen)

40 mg 40 mg hver 2 uge

certolizumab

subkutant regime

(forfyldt sproslashjtepen)

400 mg uge 0 2 4 200 mg hver 2 uge

eller

400 mg hver 4 uge

golimumab

subkutant regime

(forfyldt sproslashjtepen)

50 mg 50 mg om maringneden paring den

samme dag hver maringned som

initialdosis

rituximab

intravenoslashst regime

1000 mg uge 0 2 Regimet gentages hver 6 til 12

maringned

tocilizumab

intravenoslashst regime

8 mgkg legemsvaeliggt dog hoslashjst

800 mg

8 mgkg legemsvaeliggt dog hoslashjst

800 mg hver 4 uge

Vurdering af behandlingseffekt

Til vurdering af effekt anbefales primaeligrt brugt aeligndringer i DAS-score og opnaringelse af LDAS

eller DAS remission og radiologisk non-progression

Dokumentation af sygdomsstatus behandling effekt og eventuelle bivirkninger

Alle patientforloslashb rapporteres til den kliniske database DANBIO Dokumentation sikres foslashr

behandling ved behandlingsstart og herefter til tiden 3 6 12 mdr Yderligere kontrol

afhaelignger af graden af sygdomskontrol dog som minimum hver 6 mdr

Dosisreduktion

Der er ikke sikker evidens for at dosis kan reduceres i vaeligsentligt omfang i forhold til dosis

givet i registreringsstudierne men dette er ikke systematisk undersoslashgt

Seponeringskriterier

Seponering gennemfoslashres ved

1) Uacceptable bivirkninger og manglende effekt som anfoslashrt under skiftekriterier

2) Oslashnske om konception eller ved konstateret graviditet Generelt anbefales optimal

sygdomskontrol op til og under graviditet adalimumab etanercept og infliximab kan

anvendes frem til konstateret graviditet oslashvrige biologiske praeligparater seponeres forud

for (karenstid ndash se DANBIO patientvejledninger herom) konception

3) Kritisk komorbiditet (i henhold til produktresumeer infektion svaeligr hjerteinsufficiens

demyeliniserende lidelser cancer mm)

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 9 af 13

Skiftekriterier

Opnaringr patienten ved en given biologisk behandling ikke det definerede behandlingsmaringl inden

4 maringneder (lav sygdomsaktivitet + radiografisk non-progression + reduktion i et eventuelt

hoslashjt forbrug af glukokortikoid) kan patienten skifte til en ny biologisk behandling

Maringling af laeliggemiddelkoncentrationer og neutraliserende laeliggemiddelantistoffer

kan i plasma belyse aringrsagen til behandlingssvigt dog savnes her stoslashrre prospektive kliniske

studier Fagudvalget finder det praeligmaturt at inddrage saringdanne analyser rutinemaeligssigt i

klinisk praksis

Screening og sikkerhed

Patienterne boslashr inden behandlingsstart screenes for latent tuberkulose kronisk viral

hepatitis og andre kroniske infektioner Foslashr og under biologisk behandling foretages

regelmaeligssig klinisk og paraklinisk kontrol som beskrevet i DRS-vejledning

Undtagelse for valg af 1 linje

Afdelinger som ikke raringder over de ressourcer som indgaringr i behandling af patienter med

intravenoslashst administreret laeliggemiddel kan garing videre til naeligstfoslashlgende linje med subkutan

administration

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 10 af 13

KOMBINATIONSBEHANDLING (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter og patienter som skal skifte biologisk behandling i

kombination med methotrexat (P1)

med angivelse af behandlingsmaringl for 1 linje i

De angivne estimater viser den forventede variation som vil forekomme

afhaeligngig af den endelige rangordning

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje

abatacept (subkutant eller intravenoslashst regime) etanercept

infliximab (6mgkg hver 8 uge) adalimumab certolizumab

Ved subkutan formulering

som 1 linje paring baggrund af

laeliggemiddelpris

1 linje 1 valg

80 paring subkutan formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet af laeliggemidlerne)

Ved IV formulering som 1 linje paring

baggrund af laeliggemiddelpris

1 linje 1 valg

50 paring IV formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet IV laeliggemiddel)

1 linje 2 valg

30 paring subkutan formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet subkutant laeliggemiddel)

Behandlingskaskade ved skift af biologisk behandling i kombination med methotrexat

samt nye patienter i kombination med methotrexat som ikke kan behandles efter 1 linje

(P2)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje ved svigt efter

abatacept i 1 linje

Ved laeliggemiddel-

rekommandationen

anfoslashres eacutet af laeliggemidlerne

paring baggrund af den

opnaringede laeliggemiddelpris

etanercept

infliximab (6mgkg hver 8 uge)

adalimumab

certolizumab

golimumab

(Hvis infliximab anfoslashres paring baggrund af den opnaringede laeliggemiddelpris

anfoslashres tillige det subkutane laeliggemiddel som har tilbudt den naeligst

mest fordelagtige laeliggemiddelpris)

2 linje ved svigt efter

TNF-haeligmmer i 1 linje

samt efterfoslashlgende linjer

uprioriteret

Der anvendes hoslashjst 2 TNF-

haeligmmere i det samlede

behandlingsforloslashb

Ved laeliggemiddel-

rekommandationen

vurderes laeliggemidlerne i

raeligkkefoslashlge paring baggrund

af den opnaringede

laeliggemiddelpris

Valg af laeliggemiddel tages

paring baggrund af faglige kriterier

abatacept (subkutan eller intravenoslashst regime)

etanercept Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

infliximab (6mgkg hver 8 uge)

Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

adalimumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

certolizumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

golimumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

rituximab anvendes isaeligr ved positiv reumafaktorCCP eller tidligere

cancer

Anvendes saeligdvanligvis ikke til patienter med svaeligr erosiv sygdom

tocilizumab Anvendes saeligdvanligvis ikke til patienter med leversygdom

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 11 af 13

MONOTERAPI (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter i monoterapi (P3)

med angivelse af behandlingsmaringl for 1 linje i

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje 80 tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Behandlingskaskade for skifte patienter i monoterapi

samt nye patienter som ikke kan behandles efter 1 linje (P4)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje uprioriteret

Ved laeliggemiddel-rekommandationen

anfoslashres laeliggemidlerne i raeligkkefoslashlge

paring baggrund af den opnaringede

laeliggemiddelpris

etanercept

adalimumab

certolizumab

tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Efterlevelsesmaringl

Der vil aringrligt kunne blive foretaget udtraeligk fra DANBIO vedroslashrende anvendelsen af biologisk

medicin paring de reumatologiske afdelinger i Danmark fordelt paring de enkelte laeliggemidler Dette

gaeliglder baringde det praeligvalente forbrug og ordination af 1 linje biologisk behandling

Det forventede samlede nationale efterlevelsesmaringl for 1 linje laeliggemiddel er paring 80 af

patienterne for nye patienter

Bilag

1 GRADE metode og materialer

2 GRADE Forest Plots RA

3 GRADE Evidens profil RA

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 12 af 13

Referencer

1 Sorensen K Rheumatoid Arthritis in Denmark Two Population Studies Dan Med Bull

197320(3)86-93

2 Symmonds DM Barrett EM Bankhead CR Scott DI Silman AJ The Occurrence of

Rheumatoid Arthritis in the United Kingdom Results from the Norfolk Arthritis Register

Br J Rheumatol 199433735-739

3 Danbio Aringrsrapport for 2012httpsdanbio-onlinedkformidling

4 Hetland MH Christensen IJ Tarp U et al Direct comparison of treatment responses

remission rates and drug adherence in patients with Rheumatoid Arthritis treated with

Adalimumab Etanercept or Infliximab ArthritisRheum 2010 62 22-32

5 Dansk Reumatologisk Selskabs Kliniske Retningslinje for Diagnostik Behandling og

Monitorering af Reumatoid Artritis

httpwwwdanskreumatologiskselskabdkimagesrokquickcartpdf_filesRheumatoid_Ar

thritis_Kliniske_Vejledningdrs_kliniske_retningslinje_for_rapdf

6 Aletaha D Neogi T Silman AJ et al Ann Rheum Dis 2010 69 1580-1588 2010

Rheumatoid arthritis classification criteria an American College of

RheumatologyEuropean League Against Rheumatism collaborative initiative

7 Arnett FC Edworthy SM Bloch DA McShane DJ Fries FJ Cooper NS et al The American

Rheumatism 1987 revised criteria for the classification of rheumatoid arthritis Arthritis

rheum 198831315-324

8 Danbio Dansk Reumatologisk Database httpwwwdanbio-onlinedk

9 J Fransen PLCM van Riel The Disease Activity Score and the EULAR response criteria

Clin Exp Rheumatol 2005 23 (Suppl 39)S93-S99

10 The GRADE Working Group httpwwwgradeworkinggrouporgindexhtm

11 Kristensen LE Jakobsen AK Bartels EM Geborek P Bliddal H Saxne T et al The number

needed to treat for secondndashgeneration biologics when treating established rheumatoid

arthritis a systematic quantitative review of randomized controlled trials Scand J

Rheumatol 2011 Jan40(1)1-7

12 Kristensen LE Christensen R Bliddal H Geborek P Danneskiold-Samsoslashe B Saxne T The

number needed to treat for adalimumab etanercept and infliximab based on ACR50

response in three randomizec controlled trials on established rheumatoid arthritis a

systematic literature review Scand J Rheumatol 2007 Nov-Dec36(6)411-7

13 Hetland ML Christensen IJ Tarp U Dreyer L Hansen A Hansen IT Kollerup G Linde L

Lindegaard HM Poulsen UE Schlemmer A Jensen DV Jensen S Hostenkamp G

Ostergaard M Direct comparison of treatment responses remission rates and drug

adherence in patients with rheumatoid arthritis treated with adalimumab etanercept or

infliximab Results from eight years of surveillance of clinical practice in the nationwide

Danish DANBIO registry Arthritis Rheum 2010 Jan62(1)22-32

14 Singh JA Christensen R Wells GA Suarez-Almazor ME Buchbinder R Lopez-Olivo MA et

al Biologics for rheumatoid arthritis an overview of Cochrane reviews Sao paulo Med J

2010128(5)309-310

15 Grijalva CG Chen L Delzell E et al Initiation of tumor necrosis factor-G antagonists and

the risk of hospitalization for infection in patients with autoimmune diseases JAMA 2011

Dec 7306(21)2331-9

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 9 af 13

Skiftekriterier

Opnaringr patienten ved en given biologisk behandling ikke det definerede behandlingsmaringl inden

4 maringneder (lav sygdomsaktivitet + radiografisk non-progression + reduktion i et eventuelt

hoslashjt forbrug af glukokortikoid) kan patienten skifte til en ny biologisk behandling

Maringling af laeliggemiddelkoncentrationer og neutraliserende laeliggemiddelantistoffer

kan i plasma belyse aringrsagen til behandlingssvigt dog savnes her stoslashrre prospektive kliniske

studier Fagudvalget finder det praeligmaturt at inddrage saringdanne analyser rutinemaeligssigt i

klinisk praksis

Screening og sikkerhed

Patienterne boslashr inden behandlingsstart screenes for latent tuberkulose kronisk viral

hepatitis og andre kroniske infektioner Foslashr og under biologisk behandling foretages

regelmaeligssig klinisk og paraklinisk kontrol som beskrevet i DRS-vejledning

Undtagelse for valg af 1 linje

Afdelinger som ikke raringder over de ressourcer som indgaringr i behandling af patienter med

intravenoslashst administreret laeliggemiddel kan garing videre til naeligstfoslashlgende linje med subkutan

administration

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 10 af 13

KOMBINATIONSBEHANDLING (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter og patienter som skal skifte biologisk behandling i

kombination med methotrexat (P1)

med angivelse af behandlingsmaringl for 1 linje i

De angivne estimater viser den forventede variation som vil forekomme

afhaeligngig af den endelige rangordning

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje

abatacept (subkutant eller intravenoslashst regime) etanercept

infliximab (6mgkg hver 8 uge) adalimumab certolizumab

Ved subkutan formulering

som 1 linje paring baggrund af

laeliggemiddelpris

1 linje 1 valg

80 paring subkutan formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet af laeliggemidlerne)

Ved IV formulering som 1 linje paring

baggrund af laeliggemiddelpris

1 linje 1 valg

50 paring IV formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet IV laeliggemiddel)

1 linje 2 valg

30 paring subkutan formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet subkutant laeliggemiddel)

Behandlingskaskade ved skift af biologisk behandling i kombination med methotrexat

samt nye patienter i kombination med methotrexat som ikke kan behandles efter 1 linje

(P2)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje ved svigt efter

abatacept i 1 linje

Ved laeliggemiddel-

rekommandationen

anfoslashres eacutet af laeliggemidlerne

paring baggrund af den

opnaringede laeliggemiddelpris

etanercept

infliximab (6mgkg hver 8 uge)

adalimumab

certolizumab

golimumab

(Hvis infliximab anfoslashres paring baggrund af den opnaringede laeliggemiddelpris

anfoslashres tillige det subkutane laeliggemiddel som har tilbudt den naeligst

mest fordelagtige laeliggemiddelpris)

2 linje ved svigt efter

TNF-haeligmmer i 1 linje

samt efterfoslashlgende linjer

uprioriteret

Der anvendes hoslashjst 2 TNF-

haeligmmere i det samlede

behandlingsforloslashb

Ved laeliggemiddel-

rekommandationen

vurderes laeliggemidlerne i

raeligkkefoslashlge paring baggrund

af den opnaringede

laeliggemiddelpris

Valg af laeliggemiddel tages

paring baggrund af faglige kriterier

abatacept (subkutan eller intravenoslashst regime)

etanercept Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

infliximab (6mgkg hver 8 uge)

Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

adalimumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

certolizumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

golimumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

rituximab anvendes isaeligr ved positiv reumafaktorCCP eller tidligere

cancer

Anvendes saeligdvanligvis ikke til patienter med svaeligr erosiv sygdom

tocilizumab Anvendes saeligdvanligvis ikke til patienter med leversygdom

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 11 af 13

MONOTERAPI (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter i monoterapi (P3)

med angivelse af behandlingsmaringl for 1 linje i

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje 80 tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Behandlingskaskade for skifte patienter i monoterapi

samt nye patienter som ikke kan behandles efter 1 linje (P4)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje uprioriteret

Ved laeliggemiddel-rekommandationen

anfoslashres laeliggemidlerne i raeligkkefoslashlge

paring baggrund af den opnaringede

laeliggemiddelpris

etanercept

adalimumab

certolizumab

tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Efterlevelsesmaringl

Der vil aringrligt kunne blive foretaget udtraeligk fra DANBIO vedroslashrende anvendelsen af biologisk

medicin paring de reumatologiske afdelinger i Danmark fordelt paring de enkelte laeliggemidler Dette

gaeliglder baringde det praeligvalente forbrug og ordination af 1 linje biologisk behandling

Det forventede samlede nationale efterlevelsesmaringl for 1 linje laeliggemiddel er paring 80 af

patienterne for nye patienter

Bilag

1 GRADE metode og materialer

2 GRADE Forest Plots RA

3 GRADE Evidens profil RA

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 12 af 13

Referencer

1 Sorensen K Rheumatoid Arthritis in Denmark Two Population Studies Dan Med Bull

197320(3)86-93

2 Symmonds DM Barrett EM Bankhead CR Scott DI Silman AJ The Occurrence of

Rheumatoid Arthritis in the United Kingdom Results from the Norfolk Arthritis Register

Br J Rheumatol 199433735-739

3 Danbio Aringrsrapport for 2012httpsdanbio-onlinedkformidling

4 Hetland MH Christensen IJ Tarp U et al Direct comparison of treatment responses

remission rates and drug adherence in patients with Rheumatoid Arthritis treated with

Adalimumab Etanercept or Infliximab ArthritisRheum 2010 62 22-32

5 Dansk Reumatologisk Selskabs Kliniske Retningslinje for Diagnostik Behandling og

Monitorering af Reumatoid Artritis

httpwwwdanskreumatologiskselskabdkimagesrokquickcartpdf_filesRheumatoid_Ar

thritis_Kliniske_Vejledningdrs_kliniske_retningslinje_for_rapdf

6 Aletaha D Neogi T Silman AJ et al Ann Rheum Dis 2010 69 1580-1588 2010

Rheumatoid arthritis classification criteria an American College of

RheumatologyEuropean League Against Rheumatism collaborative initiative

7 Arnett FC Edworthy SM Bloch DA McShane DJ Fries FJ Cooper NS et al The American

Rheumatism 1987 revised criteria for the classification of rheumatoid arthritis Arthritis

rheum 198831315-324

8 Danbio Dansk Reumatologisk Database httpwwwdanbio-onlinedk

9 J Fransen PLCM van Riel The Disease Activity Score and the EULAR response criteria

Clin Exp Rheumatol 2005 23 (Suppl 39)S93-S99

10 The GRADE Working Group httpwwwgradeworkinggrouporgindexhtm

11 Kristensen LE Jakobsen AK Bartels EM Geborek P Bliddal H Saxne T et al The number

needed to treat for secondndashgeneration biologics when treating established rheumatoid

arthritis a systematic quantitative review of randomized controlled trials Scand J

Rheumatol 2011 Jan40(1)1-7

12 Kristensen LE Christensen R Bliddal H Geborek P Danneskiold-Samsoslashe B Saxne T The

number needed to treat for adalimumab etanercept and infliximab based on ACR50

response in three randomizec controlled trials on established rheumatoid arthritis a

systematic literature review Scand J Rheumatol 2007 Nov-Dec36(6)411-7

13 Hetland ML Christensen IJ Tarp U Dreyer L Hansen A Hansen IT Kollerup G Linde L

Lindegaard HM Poulsen UE Schlemmer A Jensen DV Jensen S Hostenkamp G

Ostergaard M Direct comparison of treatment responses remission rates and drug

adherence in patients with rheumatoid arthritis treated with adalimumab etanercept or

infliximab Results from eight years of surveillance of clinical practice in the nationwide

Danish DANBIO registry Arthritis Rheum 2010 Jan62(1)22-32

14 Singh JA Christensen R Wells GA Suarez-Almazor ME Buchbinder R Lopez-Olivo MA et

al Biologics for rheumatoid arthritis an overview of Cochrane reviews Sao paulo Med J

2010128(5)309-310

15 Grijalva CG Chen L Delzell E et al Initiation of tumor necrosis factor-G antagonists and

the risk of hospitalization for infection in patients with autoimmune diseases JAMA 2011

Dec 7306(21)2331-9

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 10 af 13

KOMBINATIONSBEHANDLING (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter og patienter som skal skifte biologisk behandling i

kombination med methotrexat (P1)

med angivelse af behandlingsmaringl for 1 linje i

De angivne estimater viser den forventede variation som vil forekomme

afhaeligngig af den endelige rangordning

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje

abatacept (subkutant eller intravenoslashst regime) etanercept

infliximab (6mgkg hver 8 uge) adalimumab certolizumab

Ved subkutan formulering

som 1 linje paring baggrund af

laeliggemiddelpris

1 linje 1 valg

80 paring subkutan formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet af laeliggemidlerne)

Ved IV formulering som 1 linje paring

baggrund af laeliggemiddelpris

1 linje 1 valg

50 paring IV formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet IV laeliggemiddel)

1 linje 2 valg

30 paring subkutan formulering (Ved laeliggemiddelrekommandationen anfoslashres eacutet subkutant laeliggemiddel)

Behandlingskaskade ved skift af biologisk behandling i kombination med methotrexat

samt nye patienter i kombination med methotrexat som ikke kan behandles efter 1 linje

(P2)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje ved svigt efter

abatacept i 1 linje

Ved laeliggemiddel-

rekommandationen

anfoslashres eacutet af laeliggemidlerne

paring baggrund af den

opnaringede laeliggemiddelpris

etanercept

infliximab (6mgkg hver 8 uge)

adalimumab

certolizumab

golimumab

(Hvis infliximab anfoslashres paring baggrund af den opnaringede laeliggemiddelpris

anfoslashres tillige det subkutane laeliggemiddel som har tilbudt den naeligst

mest fordelagtige laeliggemiddelpris)

2 linje ved svigt efter

TNF-haeligmmer i 1 linje

samt efterfoslashlgende linjer

uprioriteret

Der anvendes hoslashjst 2 TNF-

haeligmmere i det samlede

behandlingsforloslashb

Ved laeliggemiddel-

rekommandationen

vurderes laeliggemidlerne i

raeligkkefoslashlge paring baggrund

af den opnaringede

laeliggemiddelpris

Valg af laeliggemiddel tages

paring baggrund af faglige kriterier

abatacept (subkutan eller intravenoslashst regime)

etanercept Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

infliximab (6mgkg hver 8 uge)

Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

adalimumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

certolizumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

golimumab Der anbefales hoslashjst behandling med 2 TNF-haeligmmere

Anvendes saeligdvanligvis ikke ved primaeligr svigt af TNF-haeligmmer

rituximab anvendes isaeligr ved positiv reumafaktorCCP eller tidligere

cancer

Anvendes saeligdvanligvis ikke til patienter med svaeligr erosiv sygdom

tocilizumab Anvendes saeligdvanligvis ikke til patienter med leversygdom

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 11 af 13

MONOTERAPI (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter i monoterapi (P3)

med angivelse af behandlingsmaringl for 1 linje i

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje 80 tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Behandlingskaskade for skifte patienter i monoterapi

samt nye patienter som ikke kan behandles efter 1 linje (P4)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje uprioriteret

Ved laeliggemiddel-rekommandationen

anfoslashres laeliggemidlerne i raeligkkefoslashlge

paring baggrund af den opnaringede

laeliggemiddelpris

etanercept

adalimumab

certolizumab

tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Efterlevelsesmaringl

Der vil aringrligt kunne blive foretaget udtraeligk fra DANBIO vedroslashrende anvendelsen af biologisk

medicin paring de reumatologiske afdelinger i Danmark fordelt paring de enkelte laeliggemidler Dette

gaeliglder baringde det praeligvalente forbrug og ordination af 1 linje biologisk behandling

Det forventede samlede nationale efterlevelsesmaringl for 1 linje laeliggemiddel er paring 80 af

patienterne for nye patienter

Bilag

1 GRADE metode og materialer

2 GRADE Forest Plots RA

3 GRADE Evidens profil RA

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 12 af 13

Referencer

1 Sorensen K Rheumatoid Arthritis in Denmark Two Population Studies Dan Med Bull

197320(3)86-93

2 Symmonds DM Barrett EM Bankhead CR Scott DI Silman AJ The Occurrence of

Rheumatoid Arthritis in the United Kingdom Results from the Norfolk Arthritis Register

Br J Rheumatol 199433735-739

3 Danbio Aringrsrapport for 2012httpsdanbio-onlinedkformidling

4 Hetland MH Christensen IJ Tarp U et al Direct comparison of treatment responses

remission rates and drug adherence in patients with Rheumatoid Arthritis treated with

Adalimumab Etanercept or Infliximab ArthritisRheum 2010 62 22-32

5 Dansk Reumatologisk Selskabs Kliniske Retningslinje for Diagnostik Behandling og

Monitorering af Reumatoid Artritis

httpwwwdanskreumatologiskselskabdkimagesrokquickcartpdf_filesRheumatoid_Ar

thritis_Kliniske_Vejledningdrs_kliniske_retningslinje_for_rapdf

6 Aletaha D Neogi T Silman AJ et al Ann Rheum Dis 2010 69 1580-1588 2010

Rheumatoid arthritis classification criteria an American College of

RheumatologyEuropean League Against Rheumatism collaborative initiative

7 Arnett FC Edworthy SM Bloch DA McShane DJ Fries FJ Cooper NS et al The American

Rheumatism 1987 revised criteria for the classification of rheumatoid arthritis Arthritis

rheum 198831315-324

8 Danbio Dansk Reumatologisk Database httpwwwdanbio-onlinedk

9 J Fransen PLCM van Riel The Disease Activity Score and the EULAR response criteria

Clin Exp Rheumatol 2005 23 (Suppl 39)S93-S99

10 The GRADE Working Group httpwwwgradeworkinggrouporgindexhtm

11 Kristensen LE Jakobsen AK Bartels EM Geborek P Bliddal H Saxne T et al The number

needed to treat for secondndashgeneration biologics when treating established rheumatoid

arthritis a systematic quantitative review of randomized controlled trials Scand J

Rheumatol 2011 Jan40(1)1-7

12 Kristensen LE Christensen R Bliddal H Geborek P Danneskiold-Samsoslashe B Saxne T The

number needed to treat for adalimumab etanercept and infliximab based on ACR50

response in three randomizec controlled trials on established rheumatoid arthritis a

systematic literature review Scand J Rheumatol 2007 Nov-Dec36(6)411-7

13 Hetland ML Christensen IJ Tarp U Dreyer L Hansen A Hansen IT Kollerup G Linde L

Lindegaard HM Poulsen UE Schlemmer A Jensen DV Jensen S Hostenkamp G

Ostergaard M Direct comparison of treatment responses remission rates and drug

adherence in patients with rheumatoid arthritis treated with adalimumab etanercept or

infliximab Results from eight years of surveillance of clinical practice in the nationwide

Danish DANBIO registry Arthritis Rheum 2010 Jan62(1)22-32

14 Singh JA Christensen R Wells GA Suarez-Almazor ME Buchbinder R Lopez-Olivo MA et

al Biologics for rheumatoid arthritis an overview of Cochrane reviews Sao paulo Med J

2010128(5)309-310

15 Grijalva CG Chen L Delzell E et al Initiation of tumor necrosis factor-G antagonists and

the risk of hospitalization for infection in patients with autoimmune diseases JAMA 2011

Dec 7306(21)2331-9

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 11 af 13

MONOTERAPI (Laeliggemidlerne er angivet i ATC-nr orden)

Behandlingskaskade for nye patienter i monoterapi (P3)

med angivelse af behandlingsmaringl for 1 linje i

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

1 linje 80 tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Behandlingskaskade for skifte patienter i monoterapi

samt nye patienter som ikke kan behandles efter 1 linje (P4)

Ved valget skal tages hensyn til de tilstedevaeligrende ressourcer

herunder fysiske rammer i den behandlende afdeling

2 linje uprioriteret

Ved laeliggemiddel-rekommandationen

anfoslashres laeliggemidlerne i raeligkkefoslashlge

paring baggrund af den opnaringede

laeliggemiddelpris

etanercept

adalimumab

certolizumab

tocilizumab (anvendes saeligdvanligvis ikke til patienter

med leversygdom)

Efterlevelsesmaringl

Der vil aringrligt kunne blive foretaget udtraeligk fra DANBIO vedroslashrende anvendelsen af biologisk

medicin paring de reumatologiske afdelinger i Danmark fordelt paring de enkelte laeliggemidler Dette

gaeliglder baringde det praeligvalente forbrug og ordination af 1 linje biologisk behandling

Det forventede samlede nationale efterlevelsesmaringl for 1 linje laeliggemiddel er paring 80 af

patienterne for nye patienter

Bilag

1 GRADE metode og materialer

2 GRADE Forest Plots RA

3 GRADE Evidens profil RA

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 12 af 13

Referencer

1 Sorensen K Rheumatoid Arthritis in Denmark Two Population Studies Dan Med Bull

197320(3)86-93

2 Symmonds DM Barrett EM Bankhead CR Scott DI Silman AJ The Occurrence of

Rheumatoid Arthritis in the United Kingdom Results from the Norfolk Arthritis Register

Br J Rheumatol 199433735-739

3 Danbio Aringrsrapport for 2012httpsdanbio-onlinedkformidling

4 Hetland MH Christensen IJ Tarp U et al Direct comparison of treatment responses

remission rates and drug adherence in patients with Rheumatoid Arthritis treated with

Adalimumab Etanercept or Infliximab ArthritisRheum 2010 62 22-32

5 Dansk Reumatologisk Selskabs Kliniske Retningslinje for Diagnostik Behandling og

Monitorering af Reumatoid Artritis

httpwwwdanskreumatologiskselskabdkimagesrokquickcartpdf_filesRheumatoid_Ar

thritis_Kliniske_Vejledningdrs_kliniske_retningslinje_for_rapdf

6 Aletaha D Neogi T Silman AJ et al Ann Rheum Dis 2010 69 1580-1588 2010

Rheumatoid arthritis classification criteria an American College of

RheumatologyEuropean League Against Rheumatism collaborative initiative

7 Arnett FC Edworthy SM Bloch DA McShane DJ Fries FJ Cooper NS et al The American

Rheumatism 1987 revised criteria for the classification of rheumatoid arthritis Arthritis

rheum 198831315-324

8 Danbio Dansk Reumatologisk Database httpwwwdanbio-onlinedk

9 J Fransen PLCM van Riel The Disease Activity Score and the EULAR response criteria

Clin Exp Rheumatol 2005 23 (Suppl 39)S93-S99

10 The GRADE Working Group httpwwwgradeworkinggrouporgindexhtm

11 Kristensen LE Jakobsen AK Bartels EM Geborek P Bliddal H Saxne T et al The number

needed to treat for secondndashgeneration biologics when treating established rheumatoid

arthritis a systematic quantitative review of randomized controlled trials Scand J

Rheumatol 2011 Jan40(1)1-7

12 Kristensen LE Christensen R Bliddal H Geborek P Danneskiold-Samsoslashe B Saxne T The

number needed to treat for adalimumab etanercept and infliximab based on ACR50

response in three randomizec controlled trials on established rheumatoid arthritis a

systematic literature review Scand J Rheumatol 2007 Nov-Dec36(6)411-7

13 Hetland ML Christensen IJ Tarp U Dreyer L Hansen A Hansen IT Kollerup G Linde L

Lindegaard HM Poulsen UE Schlemmer A Jensen DV Jensen S Hostenkamp G

Ostergaard M Direct comparison of treatment responses remission rates and drug

adherence in patients with rheumatoid arthritis treated with adalimumab etanercept or

infliximab Results from eight years of surveillance of clinical practice in the nationwide

Danish DANBIO registry Arthritis Rheum 2010 Jan62(1)22-32

14 Singh JA Christensen R Wells GA Suarez-Almazor ME Buchbinder R Lopez-Olivo MA et

al Biologics for rheumatoid arthritis an overview of Cochrane reviews Sao paulo Med J

2010128(5)309-310

15 Grijalva CG Chen L Delzell E et al Initiation of tumor necrosis factor-G antagonists and

the risk of hospitalization for infection in patients with autoimmune diseases JAMA 2011

Dec 7306(21)2331-9

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 12 af 13

Referencer

1 Sorensen K Rheumatoid Arthritis in Denmark Two Population Studies Dan Med Bull

197320(3)86-93

2 Symmonds DM Barrett EM Bankhead CR Scott DI Silman AJ The Occurrence of

Rheumatoid Arthritis in the United Kingdom Results from the Norfolk Arthritis Register

Br J Rheumatol 199433735-739

3 Danbio Aringrsrapport for 2012httpsdanbio-onlinedkformidling

4 Hetland MH Christensen IJ Tarp U et al Direct comparison of treatment responses

remission rates and drug adherence in patients with Rheumatoid Arthritis treated with

Adalimumab Etanercept or Infliximab ArthritisRheum 2010 62 22-32

5 Dansk Reumatologisk Selskabs Kliniske Retningslinje for Diagnostik Behandling og

Monitorering af Reumatoid Artritis

httpwwwdanskreumatologiskselskabdkimagesrokquickcartpdf_filesRheumatoid_Ar

thritis_Kliniske_Vejledningdrs_kliniske_retningslinje_for_rapdf

6 Aletaha D Neogi T Silman AJ et al Ann Rheum Dis 2010 69 1580-1588 2010

Rheumatoid arthritis classification criteria an American College of

RheumatologyEuropean League Against Rheumatism collaborative initiative

7 Arnett FC Edworthy SM Bloch DA McShane DJ Fries FJ Cooper NS et al The American

Rheumatism 1987 revised criteria for the classification of rheumatoid arthritis Arthritis

rheum 198831315-324

8 Danbio Dansk Reumatologisk Database httpwwwdanbio-onlinedk

9 J Fransen PLCM van Riel The Disease Activity Score and the EULAR response criteria

Clin Exp Rheumatol 2005 23 (Suppl 39)S93-S99

10 The GRADE Working Group httpwwwgradeworkinggrouporgindexhtm

11 Kristensen LE Jakobsen AK Bartels EM Geborek P Bliddal H Saxne T et al The number

needed to treat for secondndashgeneration biologics when treating established rheumatoid

arthritis a systematic quantitative review of randomized controlled trials Scand J

Rheumatol 2011 Jan40(1)1-7

12 Kristensen LE Christensen R Bliddal H Geborek P Danneskiold-Samsoslashe B Saxne T The

number needed to treat for adalimumab etanercept and infliximab based on ACR50

response in three randomizec controlled trials on established rheumatoid arthritis a

systematic literature review Scand J Rheumatol 2007 Nov-Dec36(6)411-7

13 Hetland ML Christensen IJ Tarp U Dreyer L Hansen A Hansen IT Kollerup G Linde L

Lindegaard HM Poulsen UE Schlemmer A Jensen DV Jensen S Hostenkamp G

Ostergaard M Direct comparison of treatment responses remission rates and drug

adherence in patients with rheumatoid arthritis treated with adalimumab etanercept or

infliximab Results from eight years of surveillance of clinical practice in the nationwide

Danish DANBIO registry Arthritis Rheum 2010 Jan62(1)22-32

14 Singh JA Christensen R Wells GA Suarez-Almazor ME Buchbinder R Lopez-Olivo MA et

al Biologics for rheumatoid arthritis an overview of Cochrane reviews Sao paulo Med J

2010128(5)309-310

15 Grijalva CG Chen L Delzell E et al Initiation of tumor necrosis factor-G antagonists and

the risk of hospitalization for infection in patients with autoimmune diseases JAMA 2011

Dec 7306(21)2331-9

RADS Fagudvalg Biologisk Behandling af Reumatoid Artritis Baggrundsnotat Side 13 af 13

Fagudvalgs

sammensaeligtning

Formand Ulrik Tarp Ledende overlaeligge lektor drmed

Dansk Medicinsk Selskab og Dansk Reumatologisk Selskab

Naeligstformand Lis Smedegaard Andersen phd

speciallaeligge i intern medicin og reumatologi

Dansk Reumatologisk Selskab

Vivian Kjaeligr Hansen Ledende overlaeligge

Region Nordjylland

Tove Lorenzen Specialeansvarlig overlaeligge

Region Midtjylland

Hanne Merete Lindegaard Overlaeligge phd

Region Syddanmark

Michael Bo Stoltenberg Overlaeligge phd

Region Sjaeliglland

Hanne Slott Jensen Ledende overlaeligge dr med

Region Hovedstaden

Birgitte Brock Overlaeligge lektor phd

Dansk Selskab for Klinisk Farmakologi

Camilla Munk Mikkelsen Farmaceut

Dansk Selskab for Sygehusapoteksledelse

Dorte Vendelbo Jensen Overlaeligge

DANBIO

Karsten Heller Asmussen Overlaeligge phd

Inviteret af formanden

Troels Herlin Overlaeligge professor drmed

Inviteret af formanden

Robin Christensen Cand scient PhD Lektor i medicinsk

statistik

Inviteret af formanden

AEligndringslog

Version Dato AEligndring

10 Maj 2012

20 Februar 2014 2 vurdering Noslashje gennemgang af SAE for specielt certolizumab og tocilizumab Behandlingskaskaden er opdelt i rdquoKombinationsbehandlingrdquo og rdquoMonoterapirdquo Golimumab indgaringr som 2 linje i kombinationsbehandling

Litteraturudvaeliglgelse ekstraktion af data og evidenssyntese

Litteraturudvaeliglgelse og ekstraktion af data Udarbejdelsen af kliniske behandlingsvejledninger boslashr altid tage udgangspunkt

i et eller flere specifikke kliniske sposlashrgsmaringl som definerer den relevante population (eng Population) klinisk relevant sammenligningsgrundlag (eng

Comparator) og vaeligsentlige effektmaringl (eng Outcomes) Dette saringkaldte rsquoPICOrsquo format (population intervention comparatorcomparison outcome) danner

grundstenen for fagudvalgenes faciliterede diskussion om den mest

hensigtsmaeligssige behandling svarende til kommissorierne I kommissorierne for de tre RADS fagudvalg for biologisk behandling

(eng Intervention) af hhv dermatologiske gastroenterologiske og reumatologiske lidelser er angivet at behandlingsvejledningerne skal

indeholde kriterier for initiering og seponering af biologisk behandling Udover en systematisk oversigt (eng Systematic review) af alle de publicerede

artikler der kunne benyttes til at underbygge de givne sposlashrgsmaringl blev de respektive partnere fra industrien spurgt om at goslashre opmaeligrksom paring

undersoslashgelser af netop deres produkt og evt indlevere data data skulle vaeligre at betragte som peer reviewede saringledes at loslashdigheden var blevet vurderet

efter gaeligldende videnskabelige retningslinjer Der blev foretaget en systematisk gennemgang af samtlige randomiserede

studier samt data ekstraktion til database udviklet til formaringlet (Microsoft Excelreg)

Datasyntese For at skabe et generaliseret billede af effekt og bivirkning for hvert af de

eksisterende biologiske laeliggemidler blev der foretaget metaanalyse eller tilsvarende transparent praeligsentationsform for samtlige studier der kunne

besvare et specifikt PICO sposlashrgsmaringl De effektmaringl der blev inkluderet var - bortset fra roslashntgenaeligndringer ved reumatoid atrit - alle binaeligre (janej) hvilket

har en klar fordel naringr data efterfoslashlgende skal fortolkes og formidles Baseret paring de tilgaeligngelige data for hvor mange patienter der responderede (eller havde

en bivirkning) paring behandling blev den absolutte gruppeforskel udregnet som forskellen i proportionen der responderer paring biologisk hhv kontrol behandling

(eng Risk Difference) Hver af disse foslashlges ogsaring af de tilsvarende 95 sikkerhedsgraelignser (eng 95 Confidence Intervals) Ifoslashlge gaeligldende

Bilag 1 GRADE metoder og materialer

statistiske konventioner gaeliglder at hvis 95 sikkerhedsgraelignserne ikke overlapper rdquonul-linjenrdquo er det paringgaeligldende datapunkt at betragte som

statistisk signifikant forskelligt fra kontrolgruppen (Plt005) I meta-analyseplottet (kaldet et rdquoforest plotrdquo) er der for hvert af de

enkelte biologiske laeliggemidler en enkeltstaringende metaanalyse kaldet rsquoSubtotalrsquo hvilket benyttes til at vurdere det enkelte praeligparats specifikke statistiske

forhold Fortolkningen af den absolutte gruppeforskel er hvor mange flere der responderer paring det gaeligldende praeligparat end paring den tilsvarende kontrol

behandling dvs hvis man har en Risk Difference paring 0250 kan man

multiplicere dette med 1000 og udlede kausalt at 250 ekstra patienter vil have saeligrlig gavn af behandlingen - en behandlingseffekt der ikke kan opnarings

paring den konventionelle (kontrol) behandling En anden maringde at benytte Risk Difference paring vil vaeligre at udregne

rsquoNumber Needed to Treatrsquo (NNT) hvilket er et indeks for hvor mange der skal saeligttes i behandling med det biologiske laeliggemiddel foslashr eacuten patient faringr en

klinisk gevinst af interventionen i det naeligvnte eksempel ville en NNT vaeligre 4 patienter der skal saeligttes i behandling for at eacuten har en saeligrlig fordel af det

biologiske laeliggemiddel (NNT=10250=4) Det sidste der uddrages af forest plottet er hvorvidt de forskellige

studier er ensartede (homogene) hvis studie resultaterne ikke er ensartede beskrives inkonsistensen ved det saringkaldte I2 index Et I2 under 25 er ikke af

betydning I2 stoslashrre 50 er vanskelligt at fortolke da metaanalysen ikke umiddelbart er baseret paring undersoslashgelser der er egnet til at blive slaringet

sammen I det tilfaeliglde at inkonsistensen var hoslashj vurderede fagudvalget

hvorvidt inkonsistensen ville goslashre konklusionen problematisk - foraringrsaget af enkelte studier med et saeligrpraeligget resultat For at implementere dette forhold

var metaanalysen baseret paring den mest almindelige metode Overordnet vurderes det at studierne og praeligparaterne der indgaringr er rdquoforskelligerdquo hvorfor

det antages at de enkelte studier repraeligsenterer noget unikt Metaanalyserne er baseret paring en analyse model kaldet rsquorandom effects modelrsquo

Litteraturudvaeliglgelse ekstraktion af data og evidenssyntese

Litteraturudvaeliglgelse og ekstraktion af data Udarbejdelsen af kliniske behandlingsvejledninger boslashr altid tage udgangspunkt

i et eller flere specifikke kliniske sposlashrgsmaringl som definerer den relevante population (eng Population) klinisk relevant sammenligningsgrundlag (eng

Comparator) og vaeligsentlige effektmaringl (eng Outcomes) Dette saringkaldte rsquoPICOrsquo format (population intervention comparatorcomparison outcome) danner

grundstenen for fagudvalgenes faciliterede diskussion om den mest

hensigtsmaeligssige behandling svarende til kommissorierne I kommissorierne for de tre RADS fagudvalg for biologisk behandling

(eng Intervention) af hhv dermatologiske gastroenterologiske og reumatologiske lidelser er angivet at behandlingsvejledningerne skal

indeholde kriterier for initiering og seponering af biologisk behandling Udover en systematisk oversigt (eng Systematic review) af alle de publicerede

artikler der kunne benyttes til at underbygge de givne sposlashrgsmaringl blev de respektive partnere fra industrien spurgt om at goslashre opmaeligrksom paring

undersoslashgelser af netop deres produkt og evt indlevere data data skulle vaeligre at betragte som peer reviewede saringledes at loslashdigheden var blevet vurderet

efter gaeligldende videnskabelige retningslinjer Der blev foretaget en systematisk gennemgang af samtlige randomiserede

studier samt data ekstraktion til database udviklet til formaringlet (Microsoft Excelreg)

Datasyntese For at skabe et generaliseret billede af effekt og bivirkning for hvert af de

eksisterende biologiske laeliggemidler blev der foretaget metaanalyse eller tilsvarende transparent praeligsentationsform for samtlige studier der kunne

besvare et specifikt PICO sposlashrgsmaringl De effektmaringl der blev inkluderet var - bortset fra roslashntgenaeligndringer ved reumatoid atrit - alle binaeligre (janej) hvilket

har en klar fordel naringr data efterfoslashlgende skal fortolkes og formidles Baseret paring de tilgaeligngelige data for hvor mange patienter der responderede (eller havde

en bivirkning) paring behandling blev den absolutte gruppeforskel udregnet som forskellen i proportionen der responderer paring biologisk hhv kontrol behandling

(eng Risk Difference) Hver af disse foslashlges ogsaring af de tilsvarende 95 sikkerhedsgraelignser (eng 95 Confidence Intervals) Ifoslashlge gaeligldende

Bilag 1 GRADE metoder og materialer

statistiske konventioner gaeliglder at hvis 95 sikkerhedsgraelignserne ikke overlapper rdquonul-linjenrdquo er det paringgaeligldende datapunkt at betragte som

statistisk signifikant forskelligt fra kontrolgruppen (Plt005) I meta-analyseplottet (kaldet et rdquoforest plotrdquo) er der for hvert af de

enkelte biologiske laeliggemidler en enkeltstaringende metaanalyse kaldet rsquoSubtotalrsquo hvilket benyttes til at vurdere det enkelte praeligparats specifikke statistiske

forhold Fortolkningen af den absolutte gruppeforskel er hvor mange flere der responderer paring det gaeligldende praeligparat end paring den tilsvarende kontrol

behandling dvs hvis man har en Risk Difference paring 0250 kan man

multiplicere dette med 1000 og udlede kausalt at 250 ekstra patienter vil have saeligrlig gavn af behandlingen - en behandlingseffekt der ikke kan opnarings

paring den konventionelle (kontrol) behandling En anden maringde at benytte Risk Difference paring vil vaeligre at udregne

rsquoNumber Needed to Treatrsquo (NNT) hvilket er et indeks for hvor mange der skal saeligttes i behandling med det biologiske laeliggemiddel foslashr eacuten patient faringr en

klinisk gevinst af interventionen i det naeligvnte eksempel ville en NNT vaeligre 4 patienter der skal saeligttes i behandling for at eacuten har en saeligrlig fordel af det

biologiske laeliggemiddel (NNT=10250=4) Det sidste der uddrages af forest plottet er hvorvidt de forskellige

studier er ensartede (homogene) hvis studie resultaterne ikke er ensartede beskrives inkonsistensen ved det saringkaldte I2 index Et I2 under 25 er ikke af

betydning I2 stoslashrre 50 er vanskelligt at fortolke da metaanalysen ikke umiddelbart er baseret paring undersoslashgelser der er egnet til at blive slaringet

sammen I det tilfaeliglde at inkonsistensen var hoslashj vurderede fagudvalget

hvorvidt inkonsistensen ville goslashre konklusionen problematisk - foraringrsaget af enkelte studier med et saeligrpraeligget resultat For at implementere dette forhold

var metaanalysen baseret paring den mest almindelige metode Overordnet vurderes det at studierne og praeligparaterne der indgaringr er rdquoforskelligerdquo hvorfor

det antages at de enkelte studier repraeligsenterer noget unikt Metaanalyserne er baseret paring en analyse model kaldet rsquorandom effects modelrsquo

statistiske konventioner gaeliglder at hvis 95 sikkerhedsgraelignserne ikke overlapper rdquonul-linjenrdquo er det paringgaeligldende datapunkt at betragte som

statistisk signifikant forskelligt fra kontrolgruppen (Plt005) I meta-analyseplottet (kaldet et rdquoforest plotrdquo) er der for hvert af de

enkelte biologiske laeliggemidler en enkeltstaringende metaanalyse kaldet rsquoSubtotalrsquo hvilket benyttes til at vurdere det enkelte praeligparats specifikke statistiske

forhold Fortolkningen af den absolutte gruppeforskel er hvor mange flere der responderer paring det gaeligldende praeligparat end paring den tilsvarende kontrol

behandling dvs hvis man har en Risk Difference paring 0250 kan man

multiplicere dette med 1000 og udlede kausalt at 250 ekstra patienter vil have saeligrlig gavn af behandlingen - en behandlingseffekt der ikke kan opnarings

paring den konventionelle (kontrol) behandling En anden maringde at benytte Risk Difference paring vil vaeligre at udregne

rsquoNumber Needed to Treatrsquo (NNT) hvilket er et indeks for hvor mange der skal saeligttes i behandling med det biologiske laeliggemiddel foslashr eacuten patient faringr en

klinisk gevinst af interventionen i det naeligvnte eksempel ville en NNT vaeligre 4 patienter der skal saeligttes i behandling for at eacuten har en saeligrlig fordel af det

biologiske laeliggemiddel (NNT=10250=4) Det sidste der uddrages af forest plottet er hvorvidt de forskellige

studier er ensartede (homogene) hvis studie resultaterne ikke er ensartede beskrives inkonsistensen ved det saringkaldte I2 index Et I2 under 25 er ikke af

betydning I2 stoslashrre 50 er vanskelligt at fortolke da metaanalysen ikke umiddelbart er baseret paring undersoslashgelser der er egnet til at blive slaringet

sammen I det tilfaeliglde at inkonsistensen var hoslashj vurderede fagudvalget

hvorvidt inkonsistensen ville goslashre konklusionen problematisk - foraringrsaget af enkelte studier med et saeligrpraeligget resultat For at implementere dette forhold

var metaanalysen baseret paring den mest almindelige metode Overordnet vurderes det at studierne og praeligparaterne der indgaringr er rdquoforskelligerdquo hvorfor

det antages at de enkelte studier repraeligsenterer noget unikt Metaanalyserne er baseret paring en analyse model kaldet rsquorandom effects modelrsquo

SJEN0153

Tekstboks

1) Biologic+DMARD vs DMARD [DMARD failure] ACR50 respons

SJEN0153

Tekstboks

2) Biologic+DMARD vs DMARD [DMARD failure] Total Sharp Score

SJEN0153

Tekstboks

3) Biologic+DMARD vs DMARD [DMARD failure] Frafald (drop-out) pga bivirkninger

SJEN0153

Tekstboks

4) Biologic+DMARD vs DMARD [DMARD failure] Alvorlige bivirkninger (SAEs)

SJEN0153

Tekstboks

5) Biologic vs Placebo [DMARD failure+Naiumlve og Biologic failure] Alvorlige bivirkninger (SAEs)

SJEN0153

Tekstboks

6) Biologic+DMARD vs Biologic+DMARD [DMARD failure] ACR50 respons

SJEN0153

Tekstboks

7) Biologic+DMARD vs Biologic+DMARD [DMARD failure] Total Sharp Score

SJEN0153

Tekstboks

8) Biologic+DMARD vs Biologic+DMARD [DMARD failure] Frafald (drop-out) pga bivirkninger

SJEN0153

Tekstboks

9) Biologic+DMARD vs Biologic+DMARD [DMARD failure] Alvorlige bivirkninger (SAEs)

SJEN0153

Tekstboks

10) Bio mono vs placebo [DMARD failure] ACR50 respons

SJEN0153

Tekstboks

11) Bio mono vs placebo [DMARD failure] Frafald (drop-out) pga bivirkninger

SJEN0153

Tekstboks

12) Bio mono vs placebo [DMARD failure] Alvorlige bivirkninger (SAEs)

SJEN0153

Tekstboks

13) Bio mono vs Bio mono [DMARD failure] ACR50 response

SJEN0153

Tekstboks

14) Bio mono vs Bio mono [DMARD failure] Frafald (drop-out) pga bivirkninger

SJEN0153

Tekstboks

15) Bio mono vs Bio mono [DMARD failure] Alvorlige bivirkninger (SAEs)

SJEN0153

Tekstboks

16) Biologic+DMARD vs DMARD [Biologic failure] ACR50 respons

SJEN0153

Tekstboks

17) Biologic+DMARD vs DMARD [Biologic failure] Frafald (drop-out) pga bivirkninger

SJEN0153

Tekstboks

18) Biologic+DMARD vs DMARD [Biologic failure] Alvorlige bivirkninger (SAEs)

Question Should Biologic+DMARD vs DMARD be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect

Quality Importance No of

studies Design

Risk of bias

Inconsistency Indirectness Imprecision Other

considerations Biologic+DMARD DMARD

Relative (95 CI)

Absolute

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Abatacept_10mgkg4

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 344756 (455)

89509 (175)

RR 254 (18 to 356)

276 more per 1000 (from 200

more to 352 more)

HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Adalimumab_40mg2

7 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 4201182 (355)

95837 (114)

RR 304 (236 to

391)

256 more per 1000 (from 176

more to 333 more)

HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Anakinra_100mgd

1 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 43250 (172)

20251 (8)

RR 216 (131 to

356)

92 more per 1000 (from 35 more to

150 more)

HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Certolizumab_200 mg2

6 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 5421791 (303)

67831 (81)

RR 369 (264 to

516)

228 more per 1000 (from 153

more to 303 more)

HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Etanercept_50mg1

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 267686 (389)

105340 (309)

RR 348 (14 to 864)

300 more per 1000 (from 152

more to 449 more)

HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Golimumab_50mg4

3 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 82210 (39)

33256 (129)

RR 294 (205 to

423)

263 more per 1000 (from 186

more to 341 more)

HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_3mgkg8

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 204643 (317)

66586 (113)

RR 264 (186 to

373)

197 more per 1000 (from 153

more to 241 more)

HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_6mgkg8

1 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2986 (337)

788 (8)

RR 424 (196 to

916)

258 more per 1000 (from 143

more to 373 more)

HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Rituximab_2times1000mg

3 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 99332 (298)

34334 (102)

RR 284 (198 to

407)

197 more per 1000 (from 136

more to 259 more)

HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Tocilizumab_8mgkg4

5 randomised trials

no serious risk of

no serious inconsistency

no serious indirectness

no serious imprecision

none 6841864 (367)

1351264 (107)

RR 327 (251 to

263 more per 1000 (from 216

HIGH

IMPORTANT

Bilag 3 Evidens profil RA

bias 425) more to 311 more)

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Tofacitinib_10mgd

4 randomised trials

no serious risk of bias

serious1 no serious

indirectness no serious imprecision

none 222603 (368)

46339 (136)

RR 285 (152 to

534)

295 more per 1000 (from 139

more to 451 more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Abatacept_10mgkg4

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 26792 (33)

18537 (34)

RR 098 (038 to

253)

2 more per 1000 (from 20 fewer to

23 more)

HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Adalimumab_40mg2

7 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 791187

(67) 32839 (38)

RR 144 (095 to

22)

14 more per 1000 (from 11 fewer to

39 more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Anakinra_100mgd

2 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 1851366

(135) 59534 (11)

RR 127 (093 to

173)

32 more per 1000 (from 0 more to 65

more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Certolizumab_200 mg2

6 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 851788

(48) 28827 (34)

RR 14 (09 to 218)

19 more per 1000 (from 3 more to 34

more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Etanercept_50mg1

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 40952 (42)

54609 (89)

RR 07 (044 to

111)

22 fewer per 1000 (from 48 fewer to

4 more)

HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Golimumab_50mg4

3 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 10212

(47) 9255 (35)

RR 134 (041 to

432)

10 more per 1000 (from 35 fewer to

56 more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_3mgkg8

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 32660

(48) 17606 (28)

RR 163 (074 to

357)

24 more per 1000 (from 5 more to 44

more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_6mgkg8

1 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 986

(105) 788 (8)

RR 132 (051 to

337)

25 more per 1000 (from 61 fewer to

111 more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Rituximab_2times1000mg

3 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 10402

(25) 4361 (11)

RR 164 (038 to

708)

15 more per 1000 (from 8 fewer to

38 more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Tocilizumab_8mgkg4

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1101866 (59)

371263 (29)

RR 212 (147 to

306)

30 more per 1000 (from 16 more to

43 more)

HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Tofacitinib_10mgd

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 26303 (86)

8205 (39)

RR 209 (092 to

474)

41 more per 1000 (from 6 fewer to

89 more)

HIGH

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Abatacept_10mgkg4

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 92792

(116) 66537 (123)

RR 081 (051 to

131)

24 fewer per 1000 (from 70 fewer to

26 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Adalimumab_40mg2

7 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 1011152

(88) 54827 (65)

RR 122 (087 to

169)

12 more per 1000 (from 9 fewer to

33 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Anakinra_100mgd

2 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 961366

(7) 30534 (56)

RR 104 (069 to

155)

4 more per 1000 (from 20 fewer to

28 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Certolizumab_200 mg2

6 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1401788 (78)

47827 (57)

RR 143 (102 to

201)

27 more per 1000 (from 5 more to 49

more)

HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Etanercept_50mg1

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 66923

(72) 56580 (97)

RR 097 (055 to

171)

8 more per 1000 (from 29 fewer to

45 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Golimumab_50mg4

3 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 12212 (57)

8255 (31)

RR 184 (076 to

442)

19 more per 1000 (from 13 fewer to

51 more)

HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_3mgkg8

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 57662 (86)

59604 (98)

RR 086 (061 to

122)

11 fewer per 1000 (from 39 fewer to

18 more)

HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_6mgkg8

1 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 1486

(163) 1886

(209) RR 078 (041 to

146)

47 fewer per 1000 (from 163 fewer to

67 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Rituximab_2times1000mg

3 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 32402

(8) 23361 (64)

RR 125 (073 to

215)

25 more per 1000 (from 9 fewer to

59 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Tocilizumab_8mgkg4

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1441866 (77)

691264 (55)

RR 147 (111 to

195)

24 more per 1000 (from 7 more to 42

more)

HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Tofacitinib_10mgd

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 56624 (9)

14365 (38)

RR 193 (111 to

337)

48 more per 1000 (from 18 more to

76 more)

HIGH

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Abatacept_10mgkg4 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 391 195 - SMD 029 lower

(047 to 012 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Adalimumab_40mg2 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 183 172 - SMD 044 lower

(065 to 023 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Anakinra_100mgd (Better indicated by lower values)

0 No evidence available

none 0 - - not pooled CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Certolizumab_200 mg2 (Better indicated by lower values)

3 randomised trials

no serious risk of bias

serious1 serious

4 no serious

imprecision none 692 385 - SMD 068 lower

(108 to 029 lower)

LOW

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Etanercept_50mg1 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

very serious45

no serious imprecision

none 218 212 - SMD 036 lower (055 to 017

lower)

LOW

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Golimumab_50mg4 (Better indicated by lower values)

2 randomised trials

no serious risk of bias

no serious inconsistency

serious4 serious

6 none 170 217 - SMD 014 lower

(046 lower to 019 higher)

LOW

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_3mgkg8 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 71 64 - SMD 068 lower

(103 to 033 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_6mgkg8 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 71 64 - SMD 057 lower

(092 to 023 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Rituximab_2times1000mg (Better indicated by lower values)

0 No evidence available

none 0 - - not pooled CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Tocilizumab_8mgkg4 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 398 393 - SMD 031 lower

(045 to 017 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Tofacitinib_10mgd (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 serious

6 none 286 139 - SMD 018 lower

(038 lower to 003 higher)

LOW

CRITICAL

1 Heterogeneity

2 Upper limit of CI support potential risk of harm

3 Lower limit of CI support potential risk of no harm

4 Due to interpretation of outcome

5 Due to inclusion criteria in the TEMPO trial

6 Not statistically significant

Question Should Biologic vs Placebo be used for Rheumatoid Arthritis [DMARD failure amp naiumlve og Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic Placebo Relative

(95 CI) Absolute

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Abatacept_10mgkg4 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1391306 (106)

101923 (109)

RR 092 (07 to 121)

12 fewer per 1000 (from 39 fewer to 16

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Adalimumab_40mg2 16 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2732707

(101) 1982248

(88) RR 11 (091

to 131) 9 more per 1000

(from 6 fewer to 24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Anakinra_100mgd 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 961366 (7)

30534 (56)

RR 104 (069 to

155)

4 more per 1000 (from 20 fewer to 28

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Certolizumab_200 mg2 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1612015 (8)

531050 (5)

RR 163 (113 to

233)

34 more per 1000 (from 13 more to 55

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Etanercept_50mg1 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1041297 (8)

91898 (101)

RR 097 (071 to

133)

12 more per 1000 (from 12 fewer to 37

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Golimumab_50mg4 6 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 42623 (67)

47674 (7)

RR 093 (063 to 14)

0 fewer per 1000 (from 21 fewer to 20

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Infliximab_3mgkg8 7 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 1101049

(105) 91909 (10)

RR 102 (078 to

133)

0 fewer per 1000 (from 27 fewer to 26

more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Infliximab_6mgkg8 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 65463 (14)

50377 (133)

RR 104 (068 to

161)

9 more per 1000 (from 49 fewer to 68

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Rituximab_2times1000mg 5 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 67960 (7)

63819 (77)

RR 09 (061 to 133)

3 fewer per 1000 (from 33 fewer to 28

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Tocilizumab_8mgkg4 7 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 1572096

(75) 891477

(6) RR 126 (091 to

173)

16 more per 1000 (from 5 more to 36

more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Tofacitinib_10mgd 8 randomised

trials no serious risk of bias

serious2 no serious

indirectness serious

1 none 601110

(54) 29743 (39)

RR 1 (04 to 247)

6 more per 1000 (from 25 fewer to 37

more)

oplusoplusΟΟ LOW

CRITICAL

1 Upper limit of CI suggest potential harm

2 I-sq = 65 p-value = 0006

Question Should Biologic+DMARD vs Biologic+DMARD be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD Biologic+DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 71156 (455)

60165 (364)

RR 125 (096 to 163)

92 more per 1000 (from 16 fewer to 199

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 147318 (462)

151328 (46)

RR 1 (085 to 119)

2 more per 1000 (from 75

fewer to 79 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Infliximab_3mgkg8 vs Etanercept 1 randomised

trials serious

1 no serious

inconsistency no serious indirectness

no serious imprecision

none 314 (214)

814 (571)

RR 038 (012 to 113)

357 fewer per 1000 (from 694

fewer to 20 fewer)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 72196

(367) 67199 (337)

RR 109 (083 to 143)

31 more per 1000 (from 34 fewer to 125

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1886 (209)

2986 (337)

RR 062 (037 to 103)

128 fewer per 1000 (from 260

fewer to 4 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 5156 (32)

12165 (73)

RR 044 (016 to 122)

41 fewer per 1000 (from 89

fewer to 8 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11318 (35)

20328 (61)

RR 057 (028 to 116)

26 fewer per 1000 (from 59

fewer to 6 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept 0 No evidence

available none IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised no no serious no serious serious

3 none 25204 23204 RR 109 10 more per oplusoplusoplusΟ IMPORTANT

trials serious risk of bias

inconsistency indirectness (123) (113) (064 to 185)

1000 (from 53 fewer to 72

more)

MODERATE

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 586

(58) 986

(105) RR 056 (019 to 159)

47 fewer per 1000 (from 128

fewer to 35 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 15156 (96)

30165 (182)

RR 053 (03 to 094)

86 fewer per 1000 (from 161

fewer to 11 fewer)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious5 none 32318

(101) 30328 (91)

RR 11 (069 to 177)

9 more per 1000 (from 36

fewer to 55 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept 0 No evidence

available none - - not pooled not pooled CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 32204 (157)

18204 (88)

RR 178 (103 to 306)

69 more per 1000 (from 5 more to 132

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 1088

(114) 1486

(163) RR 07 (033 to 149)

49 fewer per 1000 (from 152

fewer to 5 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab (Better indicated by lower values) 1 randomised

trials no serious

inconsistency serious

6 no serious

imprecision none 290 289 - SMD 005

higher (012 lower to 021

higher)

CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 (Better indicated by lower values) 1 randomised no no serious serious

6 no serious none 71 71 - SMD 004 oplusoplusoplusΟ CRITICAL

trials serious risk of bias

inconsistency imprecision lower (037 lower to 029

higher)

MODERATE

1 Open-label study

2 Upper limit of CI support higher effect for Tofacitinib

3 Lower CI limit support lower risk for tofacitinib upper CI limit support lower risk for adalimumab

4 Upper limit of CI support higher risk for low dose infliximab

5 Lower CI limit support lower risk for abatacept upper CI limit support lower risk for adalimumab

6 Due to interpretation of outcome

Question Bio mono vs placebo [DMARD failure] for Rheumatoid Arthritis

Quality assessment No of patients Effect

Quality Importance No of

studies Design Risk of bias Inconsistency Indirectness Imprecision Other

considerations Bio

mono placebo [DMARD failure]

Relative (95 CI) Absolute

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 532

(156) 232

(63) RR 25 (052

to 1196) 94 more per 1000 (from 57 fewer to

250 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 99439 (226)

21326 (64)

RR 324 (171 to 612)

166 more per 1000 (from 100 more to

231 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

serious2 no serious

indirectness no serious imprecision

none 79227 (348)

11223 (49)

RR 705 (386 to 1286)

295 more per 1000 (from 83 more to

506 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 3178 (397)

480 (5)

RR 795 (294 to 2147)

347 more per 1000 (from 229 more to

466 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 29101 (287)

6105 (57)

RR 502 (218 to 1159)

230 more per 1000 (from 131 more to

329 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2255 (40)

153 (19)

RR 212 (296 to 15174)

381 more per 1000 (from 247 more to

516 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 113353 (32)

25246 (102)

RR 305 (204 to 455)

217 more per 1000 (from 154 more to

281 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 032 (0)

032 (0)

Not estimable

0 fewer per 1000 (from 59 fewer to

59 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 26439 (59)

7326 (21)

RR 3 (131 to 688)

34 more per 1000 (from 10 more to 57

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised no serious no serious no serious no serious none 13227 4223 RR 315 38 more per 1000 oplusoplusoplusoplus IMPORTANT

trials risk of bias inconsistency indirectness imprecision (57) (18) (104 to 956) (from 3 more to 72 more)

HIGH

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 278

(26) 380

(38) RR 068

(012 to 398) 12 fewer per 1000 (from 66 fewer to

43 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 2101

(2) 3105 (29)

RR 069 (012 to 406)

9 fewer per 1000 (from 51 fewer to

33 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 453

(75) RR 048

(009 to 252) 39 fewer per 1000 (from 126 fewer to

48 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 4353 (11)

9246 (37)

RR 033 (01 to 108)

22 fewer per 1000 (from 49 fewer to 5

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 54439

(123) 33326 (101)

RR 111 (069 to 179)

3 more per 1000 (from 43 fewer to

50 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 21227 (93)

6223 (27)

RR 339 (139 to 827)

63 more per 1000 (from 2 more to 105

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 1101

(099) 2105 (19)

RR 052 (005 to 564)

9 fewer per 1000 (from 42 fewer to

23 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 253

(38) RR 096

(014 to 659) 1 fewer per 1000 (from 73 fewer to

70 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2353 (057)

9246 (37)

RR 022 (005 to 099)

26 fewer per 1000 (from 55 fewer to 3

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Lower limit of CI suggest potential no effect

2 I-sq = 90 p-value = 0001

3 Upper limit of CI suggest potential harm

4 Lower limit of CI suggest potential no harm

Question Should Bio mono vs Bio mono be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations

Bio mono

Bio mono

Relative (95 CI) Absolute

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 77163 (472)

45162 (278)

RR 17 (126 to 229)

195 more per 1000 (from 91 more to 298

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1849 (367)

1053 (189)

RR 195 (1 to 38)

179 more per 1000 (from 8 more to 350

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 9162 (56)

10162 (62)

RR 09 (038 to 216)

6 fewer per 1000 (from 57 fewer to 45

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 049

(0) 253

(38) RR 022 (001 to 439)

38 fewer per 1000 (from 100 fewer to 25

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 19162 (117)

16162 (99)

RR 119 (063 to 223)

19 more per 1000 (from 50 fewer to 86

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 049 (0)

153 (19)

RR 036 (002 to 863)

19 fewer per 1000 (from 70 fewer to 33

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Upper limit of CI suggest potential harm for tofacitinib

Question Should Biologic+DMARD vs DMARD be used for Rheumatoid Arthritis [Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 52256 (203)

5133 (38)

RR 54 (221 to

132)

166 more per 1000 (from 107 more to

225 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 28153 (183)

8155 (52)

RR 355 (167 to

753)

131 more per 1000 (from 61 more to

202 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 80298 (268)

10201 (5)

RR 54 (287 to 1016)

219 more per 1000 (from 160 more to

277 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 49170 (288)

6158 (38)

RR 759 (334 to 1723)

250 more per 1000 (from 176 more to

325 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 35132 (265)

11131 (84)

RR 316 (168 to

595)

181 more per 1000 (from 92 more to

270 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 9258

(35) 5133 (38)

RR 093 (032 to

271)

3 fewer per 1000 (from 42 fewer to

37 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 5152

(33) 11155 (71)

RR 046 (016 to 13)

38 fewer per 1000 (from 87 fewer to

11 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8308

(26) 2209

(096) RR 271 (058 to 1265)

16 more per 1000 (from 6 fewer to 39

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 10175

(57) 8160 (5)

RR 114 (046 to

282)

7 more per 1000 (from 41 fewer to

55 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8133

(6) 7132 (53)

RR 113 (042 to

7 more per 1000 (from 48 fewer to

oplusoplusoplusΟ MODERATE

IMPORTANT

304) 63 more)

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 27258

(105) 15133 (113)

RR 093 (051 to

168)

8 fewer per 1000 (from 74 fewer to

57 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 11152

(72) 15155 (97)

RR 075 (035 to

158)

24 fewer per 1000 (from 87 fewer to

38 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 23308

(75) 21209 (10)

RR 074 (042 to

131)

26 fewer per 1000 (from 76 fewer to

24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11175 (63)

18160 (113)

RR 056 (027 to

115)

50 fewer per 1000 (from 110 fewer to

11 more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2133

(15) 6132 (45)

RR 033 (007 to

161)

30 fewer per 1000 (from 72 fewer to

11 more)

oplusoplusoplusΟ MODERATE

CRITICAL

1 Upper limit of CI suggest potential harm

2 Lower limit of CI suggest no harm

Question Should Biologic+DMARD vs DMARD be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect

Quality Importance No of

studies Design

Risk of bias

Inconsistency Indirectness Imprecision Other

considerations Biologic+DMARD DMARD

Relative (95 CI)

Absolute

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Abatacept_10mgkg4

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 344756 (455)

89509 (175)

RR 254 (18 to 356)

276 more per 1000 (from 200

more to 352 more)

HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Adalimumab_40mg2

7 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 4201182 (355)

95837 (114)

RR 304 (236 to

391)

256 more per 1000 (from 176

more to 333 more)

HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Anakinra_100mgd

1 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 43250 (172)

20251 (8)

RR 216 (131 to

356)

92 more per 1000 (from 35 more to

150 more)

HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Certolizumab_200 mg2

6 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 5421791 (303)

67831 (81)

RR 369 (264 to

516)

228 more per 1000 (from 153

more to 303 more)

HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Etanercept_50mg1

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 267686 (389)

105340 (309)

RR 348 (14 to 864)

300 more per 1000 (from 152

more to 449 more)

HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Golimumab_50mg4

3 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 82210 (39)

33256 (129)

RR 294 (205 to

423)

263 more per 1000 (from 186

more to 341 more)

HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_3mgkg8

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 204643 (317)

66586 (113)

RR 264 (186 to

373)

197 more per 1000 (from 153

more to 241 more)

HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_6mgkg8

1 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2986 (337)

788 (8)

RR 424 (196 to

916)

258 more per 1000 (from 143

more to 373 more)

HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Rituximab_2times1000mg

3 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 99332 (298)

34334 (102)

RR 284 (198 to

407)

197 more per 1000 (from 136

more to 259 more)

HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Tocilizumab_8mgkg4

5 randomised trials

no serious risk of

no serious inconsistency

no serious indirectness

no serious imprecision

none 6841864 (367)

1351264 (107)

RR 327 (251 to

263 more per 1000 (from 216

HIGH

IMPORTANT

Bilag 3 Evidens profil RA

bias 425) more to 311 more)

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Tofacitinib_10mgd

4 randomised trials

no serious risk of bias

serious1 no serious

indirectness no serious imprecision

none 222603 (368)

46339 (136)

RR 285 (152 to

534)

295 more per 1000 (from 139

more to 451 more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Abatacept_10mgkg4

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 26792 (33)

18537 (34)

RR 098 (038 to

253)

2 more per 1000 (from 20 fewer to

23 more)

HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Adalimumab_40mg2

7 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 791187

(67) 32839 (38)

RR 144 (095 to

22)

14 more per 1000 (from 11 fewer to

39 more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Anakinra_100mgd

2 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 1851366

(135) 59534 (11)

RR 127 (093 to

173)

32 more per 1000 (from 0 more to 65

more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Certolizumab_200 mg2

6 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 851788

(48) 28827 (34)

RR 14 (09 to 218)

19 more per 1000 (from 3 more to 34

more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Etanercept_50mg1

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 40952 (42)

54609 (89)

RR 07 (044 to

111)

22 fewer per 1000 (from 48 fewer to

4 more)

HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Golimumab_50mg4

3 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 10212

(47) 9255 (35)

RR 134 (041 to

432)

10 more per 1000 (from 35 fewer to

56 more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_3mgkg8

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 32660

(48) 17606 (28)

RR 163 (074 to

357)

24 more per 1000 (from 5 more to 44

more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_6mgkg8

1 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 986

(105) 788 (8)

RR 132 (051 to

337)

25 more per 1000 (from 61 fewer to

111 more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Rituximab_2times1000mg

3 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 10402

(25) 4361 (11)

RR 164 (038 to

708)

15 more per 1000 (from 8 fewer to

38 more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Tocilizumab_8mgkg4

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1101866 (59)

371263 (29)

RR 212 (147 to

306)

30 more per 1000 (from 16 more to

43 more)

HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Tofacitinib_10mgd

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 26303 (86)

8205 (39)

RR 209 (092 to

474)

41 more per 1000 (from 6 fewer to

89 more)

HIGH

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Abatacept_10mgkg4

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 92792

(116) 66537 (123)

RR 081 (051 to

131)

24 fewer per 1000 (from 70 fewer to

26 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Adalimumab_40mg2

7 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 1011152

(88) 54827 (65)

RR 122 (087 to

169)

12 more per 1000 (from 9 fewer to

33 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Anakinra_100mgd

2 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 961366

(7) 30534 (56)

RR 104 (069 to

155)

4 more per 1000 (from 20 fewer to

28 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Certolizumab_200 mg2

6 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1401788 (78)

47827 (57)

RR 143 (102 to

201)

27 more per 1000 (from 5 more to 49

more)

HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Etanercept_50mg1

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 66923

(72) 56580 (97)

RR 097 (055 to

171)

8 more per 1000 (from 29 fewer to

45 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Golimumab_50mg4

3 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 12212 (57)

8255 (31)

RR 184 (076 to

442)

19 more per 1000 (from 13 fewer to

51 more)

HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_3mgkg8

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 57662 (86)

59604 (98)

RR 086 (061 to

122)

11 fewer per 1000 (from 39 fewer to

18 more)

HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_6mgkg8

1 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 1486

(163) 1886

(209) RR 078 (041 to

146)

47 fewer per 1000 (from 163 fewer to

67 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Rituximab_2times1000mg

3 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 32402

(8) 23361 (64)

RR 125 (073 to

215)

25 more per 1000 (from 9 fewer to

59 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Tocilizumab_8mgkg4

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1441866 (77)

691264 (55)

RR 147 (111 to

195)

24 more per 1000 (from 7 more to 42

more)

HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Tofacitinib_10mgd

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 56624 (9)

14365 (38)

RR 193 (111 to

337)

48 more per 1000 (from 18 more to

76 more)

HIGH

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Abatacept_10mgkg4 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 391 195 - SMD 029 lower

(047 to 012 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Adalimumab_40mg2 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 183 172 - SMD 044 lower

(065 to 023 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Anakinra_100mgd (Better indicated by lower values)

0 No evidence available

none 0 - - not pooled CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Certolizumab_200 mg2 (Better indicated by lower values)

3 randomised trials

no serious risk of bias

serious1 serious

4 no serious

imprecision none 692 385 - SMD 068 lower

(108 to 029 lower)

LOW

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Etanercept_50mg1 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

very serious45

no serious imprecision

none 218 212 - SMD 036 lower (055 to 017

lower)

LOW

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Golimumab_50mg4 (Better indicated by lower values)

2 randomised trials

no serious risk of bias

no serious inconsistency

serious4 serious

6 none 170 217 - SMD 014 lower

(046 lower to 019 higher)

LOW

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_3mgkg8 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 71 64 - SMD 068 lower

(103 to 033 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_6mgkg8 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 71 64 - SMD 057 lower

(092 to 023 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Rituximab_2times1000mg (Better indicated by lower values)

0 No evidence available

none 0 - - not pooled CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Tocilizumab_8mgkg4 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 398 393 - SMD 031 lower

(045 to 017 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Tofacitinib_10mgd (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 serious

6 none 286 139 - SMD 018 lower

(038 lower to 003 higher)

LOW

CRITICAL

1 Heterogeneity

2 Upper limit of CI support potential risk of harm

3 Lower limit of CI support potential risk of no harm

4 Due to interpretation of outcome

5 Due to inclusion criteria in the TEMPO trial

6 Not statistically significant

Question Should Biologic vs Placebo be used for Rheumatoid Arthritis [DMARD failure amp naiumlve og Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic Placebo Relative

(95 CI) Absolute

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Abatacept_10mgkg4 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1391306 (106)

101923 (109)

RR 092 (07 to 121)

12 fewer per 1000 (from 39 fewer to 16

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Adalimumab_40mg2 16 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2732707

(101) 1982248

(88) RR 11 (091

to 131) 9 more per 1000

(from 6 fewer to 24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Anakinra_100mgd 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 961366 (7)

30534 (56)

RR 104 (069 to

155)

4 more per 1000 (from 20 fewer to 28

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Certolizumab_200 mg2 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1612015 (8)

531050 (5)

RR 163 (113 to

233)

34 more per 1000 (from 13 more to 55

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Etanercept_50mg1 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1041297 (8)

91898 (101)

RR 097 (071 to

133)

12 more per 1000 (from 12 fewer to 37

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Golimumab_50mg4 6 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 42623 (67)

47674 (7)

RR 093 (063 to 14)

0 fewer per 1000 (from 21 fewer to 20

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Infliximab_3mgkg8 7 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 1101049

(105) 91909 (10)

RR 102 (078 to

133)

0 fewer per 1000 (from 27 fewer to 26

more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Infliximab_6mgkg8 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 65463 (14)

50377 (133)

RR 104 (068 to

161)

9 more per 1000 (from 49 fewer to 68

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Rituximab_2times1000mg 5 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 67960 (7)

63819 (77)

RR 09 (061 to 133)

3 fewer per 1000 (from 33 fewer to 28

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Tocilizumab_8mgkg4 7 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 1572096

(75) 891477

(6) RR 126 (091 to

173)

16 more per 1000 (from 5 more to 36

more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Tofacitinib_10mgd 8 randomised

trials no serious risk of bias

serious2 no serious

indirectness serious

1 none 601110

(54) 29743 (39)

RR 1 (04 to 247)

6 more per 1000 (from 25 fewer to 37

more)

oplusoplusΟΟ LOW

CRITICAL

1 Upper limit of CI suggest potential harm

2 I-sq = 65 p-value = 0006

Question Should Biologic+DMARD vs Biologic+DMARD be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD Biologic+DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 71156 (455)

60165 (364)

RR 125 (096 to 163)

92 more per 1000 (from 16 fewer to 199

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 147318 (462)

151328 (46)

RR 1 (085 to 119)

2 more per 1000 (from 75

fewer to 79 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Infliximab_3mgkg8 vs Etanercept 1 randomised

trials serious

1 no serious

inconsistency no serious indirectness

no serious imprecision

none 314 (214)

814 (571)

RR 038 (012 to 113)

357 fewer per 1000 (from 694

fewer to 20 fewer)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 72196

(367) 67199 (337)

RR 109 (083 to 143)

31 more per 1000 (from 34 fewer to 125

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1886 (209)

2986 (337)

RR 062 (037 to 103)

128 fewer per 1000 (from 260

fewer to 4 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 5156 (32)

12165 (73)

RR 044 (016 to 122)

41 fewer per 1000 (from 89

fewer to 8 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11318 (35)

20328 (61)

RR 057 (028 to 116)

26 fewer per 1000 (from 59

fewer to 6 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept 0 No evidence

available none IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised no no serious no serious serious

3 none 25204 23204 RR 109 10 more per oplusoplusoplusΟ IMPORTANT

trials serious risk of bias

inconsistency indirectness (123) (113) (064 to 185)

1000 (from 53 fewer to 72

more)

MODERATE

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 586

(58) 986

(105) RR 056 (019 to 159)

47 fewer per 1000 (from 128

fewer to 35 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 15156 (96)

30165 (182)

RR 053 (03 to 094)

86 fewer per 1000 (from 161

fewer to 11 fewer)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious5 none 32318

(101) 30328 (91)

RR 11 (069 to 177)

9 more per 1000 (from 36

fewer to 55 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept 0 No evidence

available none - - not pooled not pooled CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 32204 (157)

18204 (88)

RR 178 (103 to 306)

69 more per 1000 (from 5 more to 132

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 1088

(114) 1486

(163) RR 07 (033 to 149)

49 fewer per 1000 (from 152

fewer to 5 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab (Better indicated by lower values) 1 randomised

trials no serious

inconsistency serious

6 no serious

imprecision none 290 289 - SMD 005

higher (012 lower to 021

higher)

CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 (Better indicated by lower values) 1 randomised no no serious serious

6 no serious none 71 71 - SMD 004 oplusoplusoplusΟ CRITICAL

trials serious risk of bias

inconsistency imprecision lower (037 lower to 029

higher)

MODERATE

1 Open-label study

2 Upper limit of CI support higher effect for Tofacitinib

3 Lower CI limit support lower risk for tofacitinib upper CI limit support lower risk for adalimumab

4 Upper limit of CI support higher risk for low dose infliximab

5 Lower CI limit support lower risk for abatacept upper CI limit support lower risk for adalimumab

6 Due to interpretation of outcome

Question Bio mono vs placebo [DMARD failure] for Rheumatoid Arthritis

Quality assessment No of patients Effect

Quality Importance No of

studies Design Risk of bias Inconsistency Indirectness Imprecision Other

considerations Bio

mono placebo [DMARD failure]

Relative (95 CI) Absolute

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 532

(156) 232

(63) RR 25 (052

to 1196) 94 more per 1000 (from 57 fewer to

250 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 99439 (226)

21326 (64)

RR 324 (171 to 612)

166 more per 1000 (from 100 more to

231 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

serious2 no serious

indirectness no serious imprecision

none 79227 (348)

11223 (49)

RR 705 (386 to 1286)

295 more per 1000 (from 83 more to

506 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 3178 (397)

480 (5)

RR 795 (294 to 2147)

347 more per 1000 (from 229 more to

466 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 29101 (287)

6105 (57)

RR 502 (218 to 1159)

230 more per 1000 (from 131 more to

329 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2255 (40)

153 (19)

RR 212 (296 to 15174)

381 more per 1000 (from 247 more to

516 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 113353 (32)

25246 (102)

RR 305 (204 to 455)

217 more per 1000 (from 154 more to

281 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 032 (0)

032 (0)

Not estimable

0 fewer per 1000 (from 59 fewer to

59 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 26439 (59)

7326 (21)

RR 3 (131 to 688)

34 more per 1000 (from 10 more to 57

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised no serious no serious no serious no serious none 13227 4223 RR 315 38 more per 1000 oplusoplusoplusoplus IMPORTANT

trials risk of bias inconsistency indirectness imprecision (57) (18) (104 to 956) (from 3 more to 72 more)

HIGH

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 278

(26) 380

(38) RR 068

(012 to 398) 12 fewer per 1000 (from 66 fewer to

43 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 2101

(2) 3105 (29)

RR 069 (012 to 406)

9 fewer per 1000 (from 51 fewer to

33 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 453

(75) RR 048

(009 to 252) 39 fewer per 1000 (from 126 fewer to

48 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 4353 (11)

9246 (37)

RR 033 (01 to 108)

22 fewer per 1000 (from 49 fewer to 5

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 54439

(123) 33326 (101)

RR 111 (069 to 179)

3 more per 1000 (from 43 fewer to

50 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 21227 (93)

6223 (27)

RR 339 (139 to 827)

63 more per 1000 (from 2 more to 105

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 1101

(099) 2105 (19)

RR 052 (005 to 564)

9 fewer per 1000 (from 42 fewer to

23 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 253

(38) RR 096

(014 to 659) 1 fewer per 1000 (from 73 fewer to

70 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2353 (057)

9246 (37)

RR 022 (005 to 099)

26 fewer per 1000 (from 55 fewer to 3

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Lower limit of CI suggest potential no effect

2 I-sq = 90 p-value = 0001

3 Upper limit of CI suggest potential harm

4 Lower limit of CI suggest potential no harm

Question Should Bio mono vs Bio mono be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations

Bio mono

Bio mono

Relative (95 CI) Absolute

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 77163 (472)

45162 (278)

RR 17 (126 to 229)

195 more per 1000 (from 91 more to 298

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1849 (367)

1053 (189)

RR 195 (1 to 38)

179 more per 1000 (from 8 more to 350

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 9162 (56)

10162 (62)

RR 09 (038 to 216)

6 fewer per 1000 (from 57 fewer to 45

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 049

(0) 253

(38) RR 022 (001 to 439)

38 fewer per 1000 (from 100 fewer to 25

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 19162 (117)

16162 (99)

RR 119 (063 to 223)

19 more per 1000 (from 50 fewer to 86

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 049 (0)

153 (19)

RR 036 (002 to 863)

19 fewer per 1000 (from 70 fewer to 33

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Upper limit of CI suggest potential harm for tofacitinib

Question Should Biologic+DMARD vs DMARD be used for Rheumatoid Arthritis [Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 52256 (203)

5133 (38)

RR 54 (221 to

132)

166 more per 1000 (from 107 more to

225 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 28153 (183)

8155 (52)

RR 355 (167 to

753)

131 more per 1000 (from 61 more to

202 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 80298 (268)

10201 (5)

RR 54 (287 to 1016)

219 more per 1000 (from 160 more to

277 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 49170 (288)

6158 (38)

RR 759 (334 to 1723)

250 more per 1000 (from 176 more to

325 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 35132 (265)

11131 (84)

RR 316 (168 to

595)

181 more per 1000 (from 92 more to

270 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 9258

(35) 5133 (38)

RR 093 (032 to

271)

3 fewer per 1000 (from 42 fewer to

37 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 5152

(33) 11155 (71)

RR 046 (016 to 13)

38 fewer per 1000 (from 87 fewer to

11 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8308

(26) 2209

(096) RR 271 (058 to 1265)

16 more per 1000 (from 6 fewer to 39

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 10175

(57) 8160 (5)

RR 114 (046 to

282)

7 more per 1000 (from 41 fewer to

55 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8133

(6) 7132 (53)

RR 113 (042 to

7 more per 1000 (from 48 fewer to

oplusoplusoplusΟ MODERATE

IMPORTANT

304) 63 more)

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 27258

(105) 15133 (113)

RR 093 (051 to

168)

8 fewer per 1000 (from 74 fewer to

57 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 11152

(72) 15155 (97)

RR 075 (035 to

158)

24 fewer per 1000 (from 87 fewer to

38 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 23308

(75) 21209 (10)

RR 074 (042 to

131)

26 fewer per 1000 (from 76 fewer to

24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11175 (63)

18160 (113)

RR 056 (027 to

115)

50 fewer per 1000 (from 110 fewer to

11 more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2133

(15) 6132 (45)

RR 033 (007 to

161)

30 fewer per 1000 (from 72 fewer to

11 more)

oplusoplusoplusΟ MODERATE

CRITICAL

1 Upper limit of CI suggest potential harm

2 Lower limit of CI suggest no harm

bias 425) more to 311 more)

ACR50 respons af Biologisk+DMARD vs DMARD [DMARD failure] - Tofacitinib_10mgd

4 randomised trials

no serious risk of bias

serious1 no serious

indirectness no serious imprecision

none 222603 (368)

46339 (136)

RR 285 (152 to

534)

295 more per 1000 (from 139

more to 451 more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Abatacept_10mgkg4

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 26792 (33)

18537 (34)

RR 098 (038 to

253)

2 more per 1000 (from 20 fewer to

23 more)

HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Adalimumab_40mg2

7 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 791187

(67) 32839 (38)

RR 144 (095 to

22)

14 more per 1000 (from 11 fewer to

39 more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Anakinra_100mgd

2 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 1851366

(135) 59534 (11)

RR 127 (093 to

173)

32 more per 1000 (from 0 more to 65

more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Certolizumab_200 mg2

6 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 851788

(48) 28827 (34)

RR 14 (09 to 218)

19 more per 1000 (from 3 more to 34

more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Etanercept_50mg1

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 40952 (42)

54609 (89)

RR 07 (044 to

111)

22 fewer per 1000 (from 48 fewer to

4 more)

HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Golimumab_50mg4

3 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 10212

(47) 9255 (35)

RR 134 (041 to

432)

10 more per 1000 (from 35 fewer to

56 more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_3mgkg8

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 32660

(48) 17606 (28)

RR 163 (074 to

357)

24 more per 1000 (from 5 more to 44

more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_6mgkg8

1 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 986

(105) 788 (8)

RR 132 (051 to

337)

25 more per 1000 (from 61 fewer to

111 more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Rituximab_2times1000mg

3 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 10402

(25) 4361 (11)

RR 164 (038 to

708)

15 more per 1000 (from 8 fewer to

38 more)

MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Tocilizumab_8mgkg4

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1101866 (59)

371263 (29)

RR 212 (147 to

306)

30 more per 1000 (from 16 more to

43 more)

HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [DMARD failure] - Tofacitinib_10mgd

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 26303 (86)

8205 (39)

RR 209 (092 to

474)

41 more per 1000 (from 6 fewer to

89 more)

HIGH

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Abatacept_10mgkg4

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 92792

(116) 66537 (123)

RR 081 (051 to

131)

24 fewer per 1000 (from 70 fewer to

26 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Adalimumab_40mg2

7 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 1011152

(88) 54827 (65)

RR 122 (087 to

169)

12 more per 1000 (from 9 fewer to

33 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Anakinra_100mgd

2 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 961366

(7) 30534 (56)

RR 104 (069 to

155)

4 more per 1000 (from 20 fewer to

28 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Certolizumab_200 mg2

6 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1401788 (78)

47827 (57)

RR 143 (102 to

201)

27 more per 1000 (from 5 more to 49

more)

HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Etanercept_50mg1

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 66923

(72) 56580 (97)

RR 097 (055 to

171)

8 more per 1000 (from 29 fewer to

45 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Golimumab_50mg4

3 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 12212 (57)

8255 (31)

RR 184 (076 to

442)

19 more per 1000 (from 13 fewer to

51 more)

HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_3mgkg8

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 57662 (86)

59604 (98)

RR 086 (061 to

122)

11 fewer per 1000 (from 39 fewer to

18 more)

HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_6mgkg8

1 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 1486

(163) 1886

(209) RR 078 (041 to

146)

47 fewer per 1000 (from 163 fewer to

67 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Rituximab_2times1000mg

3 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 32402

(8) 23361 (64)

RR 125 (073 to

215)

25 more per 1000 (from 9 fewer to

59 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Tocilizumab_8mgkg4

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1441866 (77)

691264 (55)

RR 147 (111 to

195)

24 more per 1000 (from 7 more to 42

more)

HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Tofacitinib_10mgd

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 56624 (9)

14365 (38)

RR 193 (111 to

337)

48 more per 1000 (from 18 more to

76 more)

HIGH

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Abatacept_10mgkg4 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 391 195 - SMD 029 lower

(047 to 012 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Adalimumab_40mg2 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 183 172 - SMD 044 lower

(065 to 023 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Anakinra_100mgd (Better indicated by lower values)

0 No evidence available

none 0 - - not pooled CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Certolizumab_200 mg2 (Better indicated by lower values)

3 randomised trials

no serious risk of bias

serious1 serious

4 no serious

imprecision none 692 385 - SMD 068 lower

(108 to 029 lower)

LOW

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Etanercept_50mg1 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

very serious45

no serious imprecision

none 218 212 - SMD 036 lower (055 to 017

lower)

LOW

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Golimumab_50mg4 (Better indicated by lower values)

2 randomised trials

no serious risk of bias

no serious inconsistency

serious4 serious

6 none 170 217 - SMD 014 lower

(046 lower to 019 higher)

LOW

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_3mgkg8 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 71 64 - SMD 068 lower

(103 to 033 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_6mgkg8 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 71 64 - SMD 057 lower

(092 to 023 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Rituximab_2times1000mg (Better indicated by lower values)

0 No evidence available

none 0 - - not pooled CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Tocilizumab_8mgkg4 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 398 393 - SMD 031 lower

(045 to 017 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Tofacitinib_10mgd (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 serious

6 none 286 139 - SMD 018 lower

(038 lower to 003 higher)

LOW

CRITICAL

1 Heterogeneity

2 Upper limit of CI support potential risk of harm

3 Lower limit of CI support potential risk of no harm

4 Due to interpretation of outcome

5 Due to inclusion criteria in the TEMPO trial

6 Not statistically significant

Question Should Biologic vs Placebo be used for Rheumatoid Arthritis [DMARD failure amp naiumlve og Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic Placebo Relative

(95 CI) Absolute

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Abatacept_10mgkg4 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1391306 (106)

101923 (109)

RR 092 (07 to 121)

12 fewer per 1000 (from 39 fewer to 16

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Adalimumab_40mg2 16 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2732707

(101) 1982248

(88) RR 11 (091

to 131) 9 more per 1000

(from 6 fewer to 24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Anakinra_100mgd 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 961366 (7)

30534 (56)

RR 104 (069 to

155)

4 more per 1000 (from 20 fewer to 28

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Certolizumab_200 mg2 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1612015 (8)

531050 (5)

RR 163 (113 to

233)

34 more per 1000 (from 13 more to 55

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Etanercept_50mg1 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1041297 (8)

91898 (101)

RR 097 (071 to

133)

12 more per 1000 (from 12 fewer to 37

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Golimumab_50mg4 6 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 42623 (67)

47674 (7)

RR 093 (063 to 14)

0 fewer per 1000 (from 21 fewer to 20

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Infliximab_3mgkg8 7 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 1101049

(105) 91909 (10)

RR 102 (078 to

133)

0 fewer per 1000 (from 27 fewer to 26

more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Infliximab_6mgkg8 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 65463 (14)

50377 (133)

RR 104 (068 to

161)

9 more per 1000 (from 49 fewer to 68

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Rituximab_2times1000mg 5 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 67960 (7)

63819 (77)

RR 09 (061 to 133)

3 fewer per 1000 (from 33 fewer to 28

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Tocilizumab_8mgkg4 7 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 1572096

(75) 891477

(6) RR 126 (091 to

173)

16 more per 1000 (from 5 more to 36

more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Tofacitinib_10mgd 8 randomised

trials no serious risk of bias

serious2 no serious

indirectness serious

1 none 601110

(54) 29743 (39)

RR 1 (04 to 247)

6 more per 1000 (from 25 fewer to 37

more)

oplusoplusΟΟ LOW

CRITICAL

1 Upper limit of CI suggest potential harm

2 I-sq = 65 p-value = 0006

Question Should Biologic+DMARD vs Biologic+DMARD be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD Biologic+DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 71156 (455)

60165 (364)

RR 125 (096 to 163)

92 more per 1000 (from 16 fewer to 199

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 147318 (462)

151328 (46)

RR 1 (085 to 119)

2 more per 1000 (from 75

fewer to 79 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Infliximab_3mgkg8 vs Etanercept 1 randomised

trials serious

1 no serious

inconsistency no serious indirectness

no serious imprecision

none 314 (214)

814 (571)

RR 038 (012 to 113)

357 fewer per 1000 (from 694

fewer to 20 fewer)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 72196

(367) 67199 (337)

RR 109 (083 to 143)

31 more per 1000 (from 34 fewer to 125

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1886 (209)

2986 (337)

RR 062 (037 to 103)

128 fewer per 1000 (from 260

fewer to 4 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 5156 (32)

12165 (73)

RR 044 (016 to 122)

41 fewer per 1000 (from 89

fewer to 8 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11318 (35)

20328 (61)

RR 057 (028 to 116)

26 fewer per 1000 (from 59

fewer to 6 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept 0 No evidence

available none IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised no no serious no serious serious

3 none 25204 23204 RR 109 10 more per oplusoplusoplusΟ IMPORTANT

trials serious risk of bias

inconsistency indirectness (123) (113) (064 to 185)

1000 (from 53 fewer to 72

more)

MODERATE

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 586

(58) 986

(105) RR 056 (019 to 159)

47 fewer per 1000 (from 128

fewer to 35 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 15156 (96)

30165 (182)

RR 053 (03 to 094)

86 fewer per 1000 (from 161

fewer to 11 fewer)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious5 none 32318

(101) 30328 (91)

RR 11 (069 to 177)

9 more per 1000 (from 36

fewer to 55 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept 0 No evidence

available none - - not pooled not pooled CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 32204 (157)

18204 (88)

RR 178 (103 to 306)

69 more per 1000 (from 5 more to 132

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 1088

(114) 1486

(163) RR 07 (033 to 149)

49 fewer per 1000 (from 152

fewer to 5 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab (Better indicated by lower values) 1 randomised

trials no serious

inconsistency serious

6 no serious

imprecision none 290 289 - SMD 005

higher (012 lower to 021

higher)

CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 (Better indicated by lower values) 1 randomised no no serious serious

6 no serious none 71 71 - SMD 004 oplusoplusoplusΟ CRITICAL

trials serious risk of bias

inconsistency imprecision lower (037 lower to 029

higher)

MODERATE

1 Open-label study

2 Upper limit of CI support higher effect for Tofacitinib

3 Lower CI limit support lower risk for tofacitinib upper CI limit support lower risk for adalimumab

4 Upper limit of CI support higher risk for low dose infliximab

5 Lower CI limit support lower risk for abatacept upper CI limit support lower risk for adalimumab

6 Due to interpretation of outcome

Question Bio mono vs placebo [DMARD failure] for Rheumatoid Arthritis

Quality assessment No of patients Effect

Quality Importance No of

studies Design Risk of bias Inconsistency Indirectness Imprecision Other

considerations Bio

mono placebo [DMARD failure]

Relative (95 CI) Absolute

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 532

(156) 232

(63) RR 25 (052

to 1196) 94 more per 1000 (from 57 fewer to

250 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 99439 (226)

21326 (64)

RR 324 (171 to 612)

166 more per 1000 (from 100 more to

231 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

serious2 no serious

indirectness no serious imprecision

none 79227 (348)

11223 (49)

RR 705 (386 to 1286)

295 more per 1000 (from 83 more to

506 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 3178 (397)

480 (5)

RR 795 (294 to 2147)

347 more per 1000 (from 229 more to

466 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 29101 (287)

6105 (57)

RR 502 (218 to 1159)

230 more per 1000 (from 131 more to

329 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2255 (40)

153 (19)

RR 212 (296 to 15174)

381 more per 1000 (from 247 more to

516 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 113353 (32)

25246 (102)

RR 305 (204 to 455)

217 more per 1000 (from 154 more to

281 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 032 (0)

032 (0)

Not estimable

0 fewer per 1000 (from 59 fewer to

59 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 26439 (59)

7326 (21)

RR 3 (131 to 688)

34 more per 1000 (from 10 more to 57

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised no serious no serious no serious no serious none 13227 4223 RR 315 38 more per 1000 oplusoplusoplusoplus IMPORTANT

trials risk of bias inconsistency indirectness imprecision (57) (18) (104 to 956) (from 3 more to 72 more)

HIGH

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 278

(26) 380

(38) RR 068

(012 to 398) 12 fewer per 1000 (from 66 fewer to

43 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 2101

(2) 3105 (29)

RR 069 (012 to 406)

9 fewer per 1000 (from 51 fewer to

33 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 453

(75) RR 048

(009 to 252) 39 fewer per 1000 (from 126 fewer to

48 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 4353 (11)

9246 (37)

RR 033 (01 to 108)

22 fewer per 1000 (from 49 fewer to 5

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 54439

(123) 33326 (101)

RR 111 (069 to 179)

3 more per 1000 (from 43 fewer to

50 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 21227 (93)

6223 (27)

RR 339 (139 to 827)

63 more per 1000 (from 2 more to 105

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 1101

(099) 2105 (19)

RR 052 (005 to 564)

9 fewer per 1000 (from 42 fewer to

23 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 253

(38) RR 096

(014 to 659) 1 fewer per 1000 (from 73 fewer to

70 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2353 (057)

9246 (37)

RR 022 (005 to 099)

26 fewer per 1000 (from 55 fewer to 3

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Lower limit of CI suggest potential no effect

2 I-sq = 90 p-value = 0001

3 Upper limit of CI suggest potential harm

4 Lower limit of CI suggest potential no harm

Question Should Bio mono vs Bio mono be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations

Bio mono

Bio mono

Relative (95 CI) Absolute

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 77163 (472)

45162 (278)

RR 17 (126 to 229)

195 more per 1000 (from 91 more to 298

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1849 (367)

1053 (189)

RR 195 (1 to 38)

179 more per 1000 (from 8 more to 350

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 9162 (56)

10162 (62)

RR 09 (038 to 216)

6 fewer per 1000 (from 57 fewer to 45

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 049

(0) 253

(38) RR 022 (001 to 439)

38 fewer per 1000 (from 100 fewer to 25

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 19162 (117)

16162 (99)

RR 119 (063 to 223)

19 more per 1000 (from 50 fewer to 86

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 049 (0)

153 (19)

RR 036 (002 to 863)

19 fewer per 1000 (from 70 fewer to 33

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Upper limit of CI suggest potential harm for tofacitinib

Question Should Biologic+DMARD vs DMARD be used for Rheumatoid Arthritis [Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 52256 (203)

5133 (38)

RR 54 (221 to

132)

166 more per 1000 (from 107 more to

225 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 28153 (183)

8155 (52)

RR 355 (167 to

753)

131 more per 1000 (from 61 more to

202 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 80298 (268)

10201 (5)

RR 54 (287 to 1016)

219 more per 1000 (from 160 more to

277 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 49170 (288)

6158 (38)

RR 759 (334 to 1723)

250 more per 1000 (from 176 more to

325 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 35132 (265)

11131 (84)

RR 316 (168 to

595)

181 more per 1000 (from 92 more to

270 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 9258

(35) 5133 (38)

RR 093 (032 to

271)

3 fewer per 1000 (from 42 fewer to

37 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 5152

(33) 11155 (71)

RR 046 (016 to 13)

38 fewer per 1000 (from 87 fewer to

11 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8308

(26) 2209

(096) RR 271 (058 to 1265)

16 more per 1000 (from 6 fewer to 39

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 10175

(57) 8160 (5)

RR 114 (046 to

282)

7 more per 1000 (from 41 fewer to

55 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8133

(6) 7132 (53)

RR 113 (042 to

7 more per 1000 (from 48 fewer to

oplusoplusoplusΟ MODERATE

IMPORTANT

304) 63 more)

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 27258

(105) 15133 (113)

RR 093 (051 to

168)

8 fewer per 1000 (from 74 fewer to

57 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 11152

(72) 15155 (97)

RR 075 (035 to

158)

24 fewer per 1000 (from 87 fewer to

38 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 23308

(75) 21209 (10)

RR 074 (042 to

131)

26 fewer per 1000 (from 76 fewer to

24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11175 (63)

18160 (113)

RR 056 (027 to

115)

50 fewer per 1000 (from 110 fewer to

11 more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2133

(15) 6132 (45)

RR 033 (007 to

161)

30 fewer per 1000 (from 72 fewer to

11 more)

oplusoplusoplusΟ MODERATE

CRITICAL

1 Upper limit of CI suggest potential harm

2 Lower limit of CI suggest no harm

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 26303 (86)

8205 (39)

RR 209 (092 to

474)

41 more per 1000 (from 6 fewer to

89 more)

HIGH

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Abatacept_10mgkg4

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 92792

(116) 66537 (123)

RR 081 (051 to

131)

24 fewer per 1000 (from 70 fewer to

26 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Adalimumab_40mg2

7 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 1011152

(88) 54827 (65)

RR 122 (087 to

169)

12 more per 1000 (from 9 fewer to

33 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Anakinra_100mgd

2 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 961366

(7) 30534 (56)

RR 104 (069 to

155)

4 more per 1000 (from 20 fewer to

28 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Certolizumab_200 mg2

6 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1401788 (78)

47827 (57)

RR 143 (102 to

201)

27 more per 1000 (from 5 more to 49

more)

HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Etanercept_50mg1

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 66923

(72) 56580 (97)

RR 097 (055 to

171)

8 more per 1000 (from 29 fewer to

45 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Golimumab_50mg4

3 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 12212 (57)

8255 (31)

RR 184 (076 to

442)

19 more per 1000 (from 13 fewer to

51 more)

HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_3mgkg8

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 57662 (86)

59604 (98)

RR 086 (061 to

122)

11 fewer per 1000 (from 39 fewer to

18 more)

HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_6mgkg8

1 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 1486

(163) 1886

(209) RR 078 (041 to

146)

47 fewer per 1000 (from 163 fewer to

67 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Rituximab_2times1000mg

3 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 32402

(8) 23361 (64)

RR 125 (073 to

215)

25 more per 1000 (from 9 fewer to

59 more)

MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Tocilizumab_8mgkg4

5 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1441866 (77)

691264 (55)

RR 147 (111 to

195)

24 more per 1000 (from 7 more to 42

more)

HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure] - Tofacitinib_10mgd

4 randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 56624 (9)

14365 (38)

RR 193 (111 to

337)

48 more per 1000 (from 18 more to

76 more)

HIGH

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Abatacept_10mgkg4 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 391 195 - SMD 029 lower

(047 to 012 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Adalimumab_40mg2 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 183 172 - SMD 044 lower

(065 to 023 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Anakinra_100mgd (Better indicated by lower values)

0 No evidence available

none 0 - - not pooled CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Certolizumab_200 mg2 (Better indicated by lower values)

3 randomised trials

no serious risk of bias

serious1 serious

4 no serious

imprecision none 692 385 - SMD 068 lower

(108 to 029 lower)

LOW

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Etanercept_50mg1 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

very serious45

no serious imprecision

none 218 212 - SMD 036 lower (055 to 017

lower)

LOW

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Golimumab_50mg4 (Better indicated by lower values)

2 randomised trials

no serious risk of bias

no serious inconsistency

serious4 serious

6 none 170 217 - SMD 014 lower

(046 lower to 019 higher)

LOW

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_3mgkg8 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 71 64 - SMD 068 lower

(103 to 033 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_6mgkg8 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 71 64 - SMD 057 lower

(092 to 023 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Rituximab_2times1000mg (Better indicated by lower values)

0 No evidence available

none 0 - - not pooled CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Tocilizumab_8mgkg4 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 398 393 - SMD 031 lower

(045 to 017 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Tofacitinib_10mgd (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 serious

6 none 286 139 - SMD 018 lower

(038 lower to 003 higher)

LOW

CRITICAL

1 Heterogeneity

2 Upper limit of CI support potential risk of harm

3 Lower limit of CI support potential risk of no harm

4 Due to interpretation of outcome

5 Due to inclusion criteria in the TEMPO trial

6 Not statistically significant

Question Should Biologic vs Placebo be used for Rheumatoid Arthritis [DMARD failure amp naiumlve og Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic Placebo Relative

(95 CI) Absolute

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Abatacept_10mgkg4 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1391306 (106)

101923 (109)

RR 092 (07 to 121)

12 fewer per 1000 (from 39 fewer to 16

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Adalimumab_40mg2 16 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2732707

(101) 1982248

(88) RR 11 (091

to 131) 9 more per 1000

(from 6 fewer to 24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Anakinra_100mgd 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 961366 (7)

30534 (56)

RR 104 (069 to

155)

4 more per 1000 (from 20 fewer to 28

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Certolizumab_200 mg2 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1612015 (8)

531050 (5)

RR 163 (113 to

233)

34 more per 1000 (from 13 more to 55

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Etanercept_50mg1 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1041297 (8)

91898 (101)

RR 097 (071 to

133)

12 more per 1000 (from 12 fewer to 37

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Golimumab_50mg4 6 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 42623 (67)

47674 (7)

RR 093 (063 to 14)

0 fewer per 1000 (from 21 fewer to 20

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Infliximab_3mgkg8 7 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 1101049

(105) 91909 (10)

RR 102 (078 to

133)

0 fewer per 1000 (from 27 fewer to 26

more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Infliximab_6mgkg8 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 65463 (14)

50377 (133)

RR 104 (068 to

161)

9 more per 1000 (from 49 fewer to 68

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Rituximab_2times1000mg 5 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 67960 (7)

63819 (77)

RR 09 (061 to 133)

3 fewer per 1000 (from 33 fewer to 28

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Tocilizumab_8mgkg4 7 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 1572096

(75) 891477

(6) RR 126 (091 to

173)

16 more per 1000 (from 5 more to 36

more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Tofacitinib_10mgd 8 randomised

trials no serious risk of bias

serious2 no serious

indirectness serious

1 none 601110

(54) 29743 (39)

RR 1 (04 to 247)

6 more per 1000 (from 25 fewer to 37

more)

oplusoplusΟΟ LOW

CRITICAL

1 Upper limit of CI suggest potential harm

2 I-sq = 65 p-value = 0006

Question Should Biologic+DMARD vs Biologic+DMARD be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD Biologic+DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 71156 (455)

60165 (364)

RR 125 (096 to 163)

92 more per 1000 (from 16 fewer to 199

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 147318 (462)

151328 (46)

RR 1 (085 to 119)

2 more per 1000 (from 75

fewer to 79 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Infliximab_3mgkg8 vs Etanercept 1 randomised

trials serious

1 no serious

inconsistency no serious indirectness

no serious imprecision

none 314 (214)

814 (571)

RR 038 (012 to 113)

357 fewer per 1000 (from 694

fewer to 20 fewer)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 72196

(367) 67199 (337)

RR 109 (083 to 143)

31 more per 1000 (from 34 fewer to 125

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1886 (209)

2986 (337)

RR 062 (037 to 103)

128 fewer per 1000 (from 260

fewer to 4 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 5156 (32)

12165 (73)

RR 044 (016 to 122)

41 fewer per 1000 (from 89

fewer to 8 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11318 (35)

20328 (61)

RR 057 (028 to 116)

26 fewer per 1000 (from 59

fewer to 6 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept 0 No evidence

available none IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised no no serious no serious serious

3 none 25204 23204 RR 109 10 more per oplusoplusoplusΟ IMPORTANT

trials serious risk of bias

inconsistency indirectness (123) (113) (064 to 185)

1000 (from 53 fewer to 72

more)

MODERATE

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 586

(58) 986

(105) RR 056 (019 to 159)

47 fewer per 1000 (from 128

fewer to 35 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 15156 (96)

30165 (182)

RR 053 (03 to 094)

86 fewer per 1000 (from 161

fewer to 11 fewer)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious5 none 32318

(101) 30328 (91)

RR 11 (069 to 177)

9 more per 1000 (from 36

fewer to 55 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept 0 No evidence

available none - - not pooled not pooled CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 32204 (157)

18204 (88)

RR 178 (103 to 306)

69 more per 1000 (from 5 more to 132

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 1088

(114) 1486

(163) RR 07 (033 to 149)

49 fewer per 1000 (from 152

fewer to 5 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab (Better indicated by lower values) 1 randomised

trials no serious

inconsistency serious

6 no serious

imprecision none 290 289 - SMD 005

higher (012 lower to 021

higher)

CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 (Better indicated by lower values) 1 randomised no no serious serious

6 no serious none 71 71 - SMD 004 oplusoplusoplusΟ CRITICAL

trials serious risk of bias

inconsistency imprecision lower (037 lower to 029

higher)

MODERATE

1 Open-label study

2 Upper limit of CI support higher effect for Tofacitinib

3 Lower CI limit support lower risk for tofacitinib upper CI limit support lower risk for adalimumab

4 Upper limit of CI support higher risk for low dose infliximab

5 Lower CI limit support lower risk for abatacept upper CI limit support lower risk for adalimumab

6 Due to interpretation of outcome

Question Bio mono vs placebo [DMARD failure] for Rheumatoid Arthritis

Quality assessment No of patients Effect

Quality Importance No of

studies Design Risk of bias Inconsistency Indirectness Imprecision Other

considerations Bio

mono placebo [DMARD failure]

Relative (95 CI) Absolute

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 532

(156) 232

(63) RR 25 (052

to 1196) 94 more per 1000 (from 57 fewer to

250 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 99439 (226)

21326 (64)

RR 324 (171 to 612)

166 more per 1000 (from 100 more to

231 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

serious2 no serious

indirectness no serious imprecision

none 79227 (348)

11223 (49)

RR 705 (386 to 1286)

295 more per 1000 (from 83 more to

506 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 3178 (397)

480 (5)

RR 795 (294 to 2147)

347 more per 1000 (from 229 more to

466 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 29101 (287)

6105 (57)

RR 502 (218 to 1159)

230 more per 1000 (from 131 more to

329 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2255 (40)

153 (19)

RR 212 (296 to 15174)

381 more per 1000 (from 247 more to

516 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 113353 (32)

25246 (102)

RR 305 (204 to 455)

217 more per 1000 (from 154 more to

281 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 032 (0)

032 (0)

Not estimable

0 fewer per 1000 (from 59 fewer to

59 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 26439 (59)

7326 (21)

RR 3 (131 to 688)

34 more per 1000 (from 10 more to 57

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised no serious no serious no serious no serious none 13227 4223 RR 315 38 more per 1000 oplusoplusoplusoplus IMPORTANT

trials risk of bias inconsistency indirectness imprecision (57) (18) (104 to 956) (from 3 more to 72 more)

HIGH

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 278

(26) 380

(38) RR 068

(012 to 398) 12 fewer per 1000 (from 66 fewer to

43 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 2101

(2) 3105 (29)

RR 069 (012 to 406)

9 fewer per 1000 (from 51 fewer to

33 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 453

(75) RR 048

(009 to 252) 39 fewer per 1000 (from 126 fewer to

48 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 4353 (11)

9246 (37)

RR 033 (01 to 108)

22 fewer per 1000 (from 49 fewer to 5

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 54439

(123) 33326 (101)

RR 111 (069 to 179)

3 more per 1000 (from 43 fewer to

50 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 21227 (93)

6223 (27)

RR 339 (139 to 827)

63 more per 1000 (from 2 more to 105

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 1101

(099) 2105 (19)

RR 052 (005 to 564)

9 fewer per 1000 (from 42 fewer to

23 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 253

(38) RR 096

(014 to 659) 1 fewer per 1000 (from 73 fewer to

70 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2353 (057)

9246 (37)

RR 022 (005 to 099)

26 fewer per 1000 (from 55 fewer to 3

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Lower limit of CI suggest potential no effect

2 I-sq = 90 p-value = 0001

3 Upper limit of CI suggest potential harm

4 Lower limit of CI suggest potential no harm

Question Should Bio mono vs Bio mono be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations

Bio mono

Bio mono

Relative (95 CI) Absolute

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 77163 (472)

45162 (278)

RR 17 (126 to 229)

195 more per 1000 (from 91 more to 298

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1849 (367)

1053 (189)

RR 195 (1 to 38)

179 more per 1000 (from 8 more to 350

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 9162 (56)

10162 (62)

RR 09 (038 to 216)

6 fewer per 1000 (from 57 fewer to 45

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 049

(0) 253

(38) RR 022 (001 to 439)

38 fewer per 1000 (from 100 fewer to 25

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 19162 (117)

16162 (99)

RR 119 (063 to 223)

19 more per 1000 (from 50 fewer to 86

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 049 (0)

153 (19)

RR 036 (002 to 863)

19 fewer per 1000 (from 70 fewer to 33

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Upper limit of CI suggest potential harm for tofacitinib

Question Should Biologic+DMARD vs DMARD be used for Rheumatoid Arthritis [Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 52256 (203)

5133 (38)

RR 54 (221 to

132)

166 more per 1000 (from 107 more to

225 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 28153 (183)

8155 (52)

RR 355 (167 to

753)

131 more per 1000 (from 61 more to

202 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 80298 (268)

10201 (5)

RR 54 (287 to 1016)

219 more per 1000 (from 160 more to

277 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 49170 (288)

6158 (38)

RR 759 (334 to 1723)

250 more per 1000 (from 176 more to

325 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 35132 (265)

11131 (84)

RR 316 (168 to

595)

181 more per 1000 (from 92 more to

270 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 9258

(35) 5133 (38)

RR 093 (032 to

271)

3 fewer per 1000 (from 42 fewer to

37 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 5152

(33) 11155 (71)

RR 046 (016 to 13)

38 fewer per 1000 (from 87 fewer to

11 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8308

(26) 2209

(096) RR 271 (058 to 1265)

16 more per 1000 (from 6 fewer to 39

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 10175

(57) 8160 (5)

RR 114 (046 to

282)

7 more per 1000 (from 41 fewer to

55 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8133

(6) 7132 (53)

RR 113 (042 to

7 more per 1000 (from 48 fewer to

oplusoplusoplusΟ MODERATE

IMPORTANT

304) 63 more)

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 27258

(105) 15133 (113)

RR 093 (051 to

168)

8 fewer per 1000 (from 74 fewer to

57 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 11152

(72) 15155 (97)

RR 075 (035 to

158)

24 fewer per 1000 (from 87 fewer to

38 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 23308

(75) 21209 (10)

RR 074 (042 to

131)

26 fewer per 1000 (from 76 fewer to

24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11175 (63)

18160 (113)

RR 056 (027 to

115)

50 fewer per 1000 (from 110 fewer to

11 more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2133

(15) 6132 (45)

RR 033 (007 to

161)

30 fewer per 1000 (from 72 fewer to

11 more)

oplusoplusoplusΟ MODERATE

CRITICAL

1 Upper limit of CI suggest potential harm

2 Lower limit of CI suggest no harm

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Abatacept_10mgkg4 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 391 195 - SMD 029 lower

(047 to 012 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Adalimumab_40mg2 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 183 172 - SMD 044 lower

(065 to 023 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Anakinra_100mgd (Better indicated by lower values)

0 No evidence available

none 0 - - not pooled CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Certolizumab_200 mg2 (Better indicated by lower values)

3 randomised trials

no serious risk of bias

serious1 serious

4 no serious

imprecision none 692 385 - SMD 068 lower

(108 to 029 lower)

LOW

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Etanercept_50mg1 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

very serious45

no serious imprecision

none 218 212 - SMD 036 lower (055 to 017

lower)

LOW

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Golimumab_50mg4 (Better indicated by lower values)

2 randomised trials

no serious risk of bias

no serious inconsistency

serious4 serious

6 none 170 217 - SMD 014 lower

(046 lower to 019 higher)

LOW

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_3mgkg8 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 71 64 - SMD 068 lower

(103 to 033 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Infliximab_6mgkg8 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 71 64 - SMD 057 lower

(092 to 023 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Rituximab_2times1000mg (Better indicated by lower values)

0 No evidence available

none 0 - - not pooled CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Tocilizumab_8mgkg4 (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 no serious

imprecision none 398 393 - SMD 031 lower

(045 to 017 lower)

MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs DMARD [DMARD failure] - Tofacitinib_10mgd (Better indicated by lower values)

1 randomised trials

no serious risk of bias

no serious inconsistency

serious4 serious

6 none 286 139 - SMD 018 lower

(038 lower to 003 higher)

LOW

CRITICAL

1 Heterogeneity

2 Upper limit of CI support potential risk of harm

3 Lower limit of CI support potential risk of no harm

4 Due to interpretation of outcome

5 Due to inclusion criteria in the TEMPO trial

6 Not statistically significant

Question Should Biologic vs Placebo be used for Rheumatoid Arthritis [DMARD failure amp naiumlve og Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic Placebo Relative

(95 CI) Absolute

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Abatacept_10mgkg4 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1391306 (106)

101923 (109)

RR 092 (07 to 121)

12 fewer per 1000 (from 39 fewer to 16

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Adalimumab_40mg2 16 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2732707

(101) 1982248

(88) RR 11 (091

to 131) 9 more per 1000

(from 6 fewer to 24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Anakinra_100mgd 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 961366 (7)

30534 (56)

RR 104 (069 to

155)

4 more per 1000 (from 20 fewer to 28

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Certolizumab_200 mg2 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1612015 (8)

531050 (5)

RR 163 (113 to

233)

34 more per 1000 (from 13 more to 55

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Etanercept_50mg1 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1041297 (8)

91898 (101)

RR 097 (071 to

133)

12 more per 1000 (from 12 fewer to 37

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Golimumab_50mg4 6 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 42623 (67)

47674 (7)

RR 093 (063 to 14)

0 fewer per 1000 (from 21 fewer to 20

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Infliximab_3mgkg8 7 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 1101049

(105) 91909 (10)

RR 102 (078 to

133)

0 fewer per 1000 (from 27 fewer to 26

more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Infliximab_6mgkg8 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 65463 (14)

50377 (133)

RR 104 (068 to

161)

9 more per 1000 (from 49 fewer to 68

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Rituximab_2times1000mg 5 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 67960 (7)

63819 (77)

RR 09 (061 to 133)

3 fewer per 1000 (from 33 fewer to 28

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Tocilizumab_8mgkg4 7 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 1572096

(75) 891477

(6) RR 126 (091 to

173)

16 more per 1000 (from 5 more to 36

more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Tofacitinib_10mgd 8 randomised

trials no serious risk of bias

serious2 no serious

indirectness serious

1 none 601110

(54) 29743 (39)

RR 1 (04 to 247)

6 more per 1000 (from 25 fewer to 37

more)

oplusoplusΟΟ LOW

CRITICAL

1 Upper limit of CI suggest potential harm

2 I-sq = 65 p-value = 0006

Question Should Biologic+DMARD vs Biologic+DMARD be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD Biologic+DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 71156 (455)

60165 (364)

RR 125 (096 to 163)

92 more per 1000 (from 16 fewer to 199

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 147318 (462)

151328 (46)

RR 1 (085 to 119)

2 more per 1000 (from 75

fewer to 79 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Infliximab_3mgkg8 vs Etanercept 1 randomised

trials serious

1 no serious

inconsistency no serious indirectness

no serious imprecision

none 314 (214)

814 (571)

RR 038 (012 to 113)

357 fewer per 1000 (from 694

fewer to 20 fewer)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 72196

(367) 67199 (337)

RR 109 (083 to 143)

31 more per 1000 (from 34 fewer to 125

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1886 (209)

2986 (337)

RR 062 (037 to 103)

128 fewer per 1000 (from 260

fewer to 4 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 5156 (32)

12165 (73)

RR 044 (016 to 122)

41 fewer per 1000 (from 89

fewer to 8 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11318 (35)

20328 (61)

RR 057 (028 to 116)

26 fewer per 1000 (from 59

fewer to 6 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept 0 No evidence

available none IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised no no serious no serious serious

3 none 25204 23204 RR 109 10 more per oplusoplusoplusΟ IMPORTANT

trials serious risk of bias

inconsistency indirectness (123) (113) (064 to 185)

1000 (from 53 fewer to 72

more)

MODERATE

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 586

(58) 986

(105) RR 056 (019 to 159)

47 fewer per 1000 (from 128

fewer to 35 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 15156 (96)

30165 (182)

RR 053 (03 to 094)

86 fewer per 1000 (from 161

fewer to 11 fewer)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious5 none 32318

(101) 30328 (91)

RR 11 (069 to 177)

9 more per 1000 (from 36

fewer to 55 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept 0 No evidence

available none - - not pooled not pooled CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 32204 (157)

18204 (88)

RR 178 (103 to 306)

69 more per 1000 (from 5 more to 132

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 1088

(114) 1486

(163) RR 07 (033 to 149)

49 fewer per 1000 (from 152

fewer to 5 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab (Better indicated by lower values) 1 randomised

trials no serious

inconsistency serious

6 no serious

imprecision none 290 289 - SMD 005

higher (012 lower to 021

higher)

CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 (Better indicated by lower values) 1 randomised no no serious serious

6 no serious none 71 71 - SMD 004 oplusoplusoplusΟ CRITICAL

trials serious risk of bias

inconsistency imprecision lower (037 lower to 029

higher)

MODERATE

1 Open-label study

2 Upper limit of CI support higher effect for Tofacitinib

3 Lower CI limit support lower risk for tofacitinib upper CI limit support lower risk for adalimumab

4 Upper limit of CI support higher risk for low dose infliximab

5 Lower CI limit support lower risk for abatacept upper CI limit support lower risk for adalimumab

6 Due to interpretation of outcome

Question Bio mono vs placebo [DMARD failure] for Rheumatoid Arthritis

Quality assessment No of patients Effect

Quality Importance No of

studies Design Risk of bias Inconsistency Indirectness Imprecision Other

considerations Bio

mono placebo [DMARD failure]

Relative (95 CI) Absolute

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 532

(156) 232

(63) RR 25 (052

to 1196) 94 more per 1000 (from 57 fewer to

250 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 99439 (226)

21326 (64)

RR 324 (171 to 612)

166 more per 1000 (from 100 more to

231 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

serious2 no serious

indirectness no serious imprecision

none 79227 (348)

11223 (49)

RR 705 (386 to 1286)

295 more per 1000 (from 83 more to

506 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 3178 (397)

480 (5)

RR 795 (294 to 2147)

347 more per 1000 (from 229 more to

466 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 29101 (287)

6105 (57)

RR 502 (218 to 1159)

230 more per 1000 (from 131 more to

329 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2255 (40)

153 (19)

RR 212 (296 to 15174)

381 more per 1000 (from 247 more to

516 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 113353 (32)

25246 (102)

RR 305 (204 to 455)

217 more per 1000 (from 154 more to

281 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 032 (0)

032 (0)

Not estimable

0 fewer per 1000 (from 59 fewer to

59 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 26439 (59)

7326 (21)

RR 3 (131 to 688)

34 more per 1000 (from 10 more to 57

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised no serious no serious no serious no serious none 13227 4223 RR 315 38 more per 1000 oplusoplusoplusoplus IMPORTANT

trials risk of bias inconsistency indirectness imprecision (57) (18) (104 to 956) (from 3 more to 72 more)

HIGH

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 278

(26) 380

(38) RR 068

(012 to 398) 12 fewer per 1000 (from 66 fewer to

43 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 2101

(2) 3105 (29)

RR 069 (012 to 406)

9 fewer per 1000 (from 51 fewer to

33 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 453

(75) RR 048

(009 to 252) 39 fewer per 1000 (from 126 fewer to

48 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 4353 (11)

9246 (37)

RR 033 (01 to 108)

22 fewer per 1000 (from 49 fewer to 5

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 54439

(123) 33326 (101)

RR 111 (069 to 179)

3 more per 1000 (from 43 fewer to

50 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 21227 (93)

6223 (27)

RR 339 (139 to 827)

63 more per 1000 (from 2 more to 105

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 1101

(099) 2105 (19)

RR 052 (005 to 564)

9 fewer per 1000 (from 42 fewer to

23 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 253

(38) RR 096

(014 to 659) 1 fewer per 1000 (from 73 fewer to

70 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2353 (057)

9246 (37)

RR 022 (005 to 099)

26 fewer per 1000 (from 55 fewer to 3

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Lower limit of CI suggest potential no effect

2 I-sq = 90 p-value = 0001

3 Upper limit of CI suggest potential harm

4 Lower limit of CI suggest potential no harm

Question Should Bio mono vs Bio mono be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations

Bio mono

Bio mono

Relative (95 CI) Absolute

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 77163 (472)

45162 (278)

RR 17 (126 to 229)

195 more per 1000 (from 91 more to 298

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1849 (367)

1053 (189)

RR 195 (1 to 38)

179 more per 1000 (from 8 more to 350

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 9162 (56)

10162 (62)

RR 09 (038 to 216)

6 fewer per 1000 (from 57 fewer to 45

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 049

(0) 253

(38) RR 022 (001 to 439)

38 fewer per 1000 (from 100 fewer to 25

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 19162 (117)

16162 (99)

RR 119 (063 to 223)

19 more per 1000 (from 50 fewer to 86

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 049 (0)

153 (19)

RR 036 (002 to 863)

19 fewer per 1000 (from 70 fewer to 33

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Upper limit of CI suggest potential harm for tofacitinib

Question Should Biologic+DMARD vs DMARD be used for Rheumatoid Arthritis [Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 52256 (203)

5133 (38)

RR 54 (221 to

132)

166 more per 1000 (from 107 more to

225 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 28153 (183)

8155 (52)

RR 355 (167 to

753)

131 more per 1000 (from 61 more to

202 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 80298 (268)

10201 (5)

RR 54 (287 to 1016)

219 more per 1000 (from 160 more to

277 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 49170 (288)

6158 (38)

RR 759 (334 to 1723)

250 more per 1000 (from 176 more to

325 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 35132 (265)

11131 (84)

RR 316 (168 to

595)

181 more per 1000 (from 92 more to

270 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 9258

(35) 5133 (38)

RR 093 (032 to

271)

3 fewer per 1000 (from 42 fewer to

37 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 5152

(33) 11155 (71)

RR 046 (016 to 13)

38 fewer per 1000 (from 87 fewer to

11 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8308

(26) 2209

(096) RR 271 (058 to 1265)

16 more per 1000 (from 6 fewer to 39

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 10175

(57) 8160 (5)

RR 114 (046 to

282)

7 more per 1000 (from 41 fewer to

55 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8133

(6) 7132 (53)

RR 113 (042 to

7 more per 1000 (from 48 fewer to

oplusoplusoplusΟ MODERATE

IMPORTANT

304) 63 more)

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 27258

(105) 15133 (113)

RR 093 (051 to

168)

8 fewer per 1000 (from 74 fewer to

57 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 11152

(72) 15155 (97)

RR 075 (035 to

158)

24 fewer per 1000 (from 87 fewer to

38 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 23308

(75) 21209 (10)

RR 074 (042 to

131)

26 fewer per 1000 (from 76 fewer to

24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11175 (63)

18160 (113)

RR 056 (027 to

115)

50 fewer per 1000 (from 110 fewer to

11 more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2133

(15) 6132 (45)

RR 033 (007 to

161)

30 fewer per 1000 (from 72 fewer to

11 more)

oplusoplusoplusΟ MODERATE

CRITICAL

1 Upper limit of CI suggest potential harm

2 Lower limit of CI suggest no harm

5 Due to inclusion criteria in the TEMPO trial

6 Not statistically significant

Question Should Biologic vs Placebo be used for Rheumatoid Arthritis [DMARD failure amp naiumlve og Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic Placebo Relative

(95 CI) Absolute

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Abatacept_10mgkg4 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1391306 (106)

101923 (109)

RR 092 (07 to 121)

12 fewer per 1000 (from 39 fewer to 16

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Adalimumab_40mg2 16 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2732707

(101) 1982248

(88) RR 11 (091

to 131) 9 more per 1000

(from 6 fewer to 24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Anakinra_100mgd 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 961366 (7)

30534 (56)

RR 104 (069 to

155)

4 more per 1000 (from 20 fewer to 28

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Certolizumab_200 mg2 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1612015 (8)

531050 (5)

RR 163 (113 to

233)

34 more per 1000 (from 13 more to 55

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Etanercept_50mg1 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1041297 (8)

91898 (101)

RR 097 (071 to

133)

12 more per 1000 (from 12 fewer to 37

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Golimumab_50mg4 6 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 42623 (67)

47674 (7)

RR 093 (063 to 14)

0 fewer per 1000 (from 21 fewer to 20

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Infliximab_3mgkg8 7 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 1101049

(105) 91909 (10)

RR 102 (078 to

133)

0 fewer per 1000 (from 27 fewer to 26

more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Infliximab_6mgkg8 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 65463 (14)

50377 (133)

RR 104 (068 to

161)

9 more per 1000 (from 49 fewer to 68

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Rituximab_2times1000mg 5 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 67960 (7)

63819 (77)

RR 09 (061 to 133)

3 fewer per 1000 (from 33 fewer to 28

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Tocilizumab_8mgkg4 7 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 1572096

(75) 891477

(6) RR 126 (091 to

173)

16 more per 1000 (from 5 more to 36

more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Tofacitinib_10mgd 8 randomised

trials no serious risk of bias

serious2 no serious

indirectness serious

1 none 601110

(54) 29743 (39)

RR 1 (04 to 247)

6 more per 1000 (from 25 fewer to 37

more)

oplusoplusΟΟ LOW

CRITICAL

1 Upper limit of CI suggest potential harm

2 I-sq = 65 p-value = 0006

Question Should Biologic+DMARD vs Biologic+DMARD be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD Biologic+DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 71156 (455)

60165 (364)

RR 125 (096 to 163)

92 more per 1000 (from 16 fewer to 199

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 147318 (462)

151328 (46)

RR 1 (085 to 119)

2 more per 1000 (from 75

fewer to 79 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Infliximab_3mgkg8 vs Etanercept 1 randomised

trials serious

1 no serious

inconsistency no serious indirectness

no serious imprecision

none 314 (214)

814 (571)

RR 038 (012 to 113)

357 fewer per 1000 (from 694

fewer to 20 fewer)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 72196

(367) 67199 (337)

RR 109 (083 to 143)

31 more per 1000 (from 34 fewer to 125

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1886 (209)

2986 (337)

RR 062 (037 to 103)

128 fewer per 1000 (from 260

fewer to 4 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 5156 (32)

12165 (73)

RR 044 (016 to 122)

41 fewer per 1000 (from 89

fewer to 8 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11318 (35)

20328 (61)

RR 057 (028 to 116)

26 fewer per 1000 (from 59

fewer to 6 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept 0 No evidence

available none IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised no no serious no serious serious

3 none 25204 23204 RR 109 10 more per oplusoplusoplusΟ IMPORTANT

trials serious risk of bias

inconsistency indirectness (123) (113) (064 to 185)

1000 (from 53 fewer to 72

more)

MODERATE

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 586

(58) 986

(105) RR 056 (019 to 159)

47 fewer per 1000 (from 128

fewer to 35 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 15156 (96)

30165 (182)

RR 053 (03 to 094)

86 fewer per 1000 (from 161

fewer to 11 fewer)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious5 none 32318

(101) 30328 (91)

RR 11 (069 to 177)

9 more per 1000 (from 36

fewer to 55 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept 0 No evidence

available none - - not pooled not pooled CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 32204 (157)

18204 (88)

RR 178 (103 to 306)

69 more per 1000 (from 5 more to 132

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 1088

(114) 1486

(163) RR 07 (033 to 149)

49 fewer per 1000 (from 152

fewer to 5 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab (Better indicated by lower values) 1 randomised

trials no serious

inconsistency serious

6 no serious

imprecision none 290 289 - SMD 005

higher (012 lower to 021

higher)

CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 (Better indicated by lower values) 1 randomised no no serious serious

6 no serious none 71 71 - SMD 004 oplusoplusoplusΟ CRITICAL

trials serious risk of bias

inconsistency imprecision lower (037 lower to 029

higher)

MODERATE

1 Open-label study

2 Upper limit of CI support higher effect for Tofacitinib

3 Lower CI limit support lower risk for tofacitinib upper CI limit support lower risk for adalimumab

4 Upper limit of CI support higher risk for low dose infliximab

5 Lower CI limit support lower risk for abatacept upper CI limit support lower risk for adalimumab

6 Due to interpretation of outcome

Question Bio mono vs placebo [DMARD failure] for Rheumatoid Arthritis

Quality assessment No of patients Effect

Quality Importance No of

studies Design Risk of bias Inconsistency Indirectness Imprecision Other

considerations Bio

mono placebo [DMARD failure]

Relative (95 CI) Absolute

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 532

(156) 232

(63) RR 25 (052

to 1196) 94 more per 1000 (from 57 fewer to

250 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 99439 (226)

21326 (64)

RR 324 (171 to 612)

166 more per 1000 (from 100 more to

231 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

serious2 no serious

indirectness no serious imprecision

none 79227 (348)

11223 (49)

RR 705 (386 to 1286)

295 more per 1000 (from 83 more to

506 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 3178 (397)

480 (5)

RR 795 (294 to 2147)

347 more per 1000 (from 229 more to

466 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 29101 (287)

6105 (57)

RR 502 (218 to 1159)

230 more per 1000 (from 131 more to

329 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2255 (40)

153 (19)

RR 212 (296 to 15174)

381 more per 1000 (from 247 more to

516 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 113353 (32)

25246 (102)

RR 305 (204 to 455)

217 more per 1000 (from 154 more to

281 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 032 (0)

032 (0)

Not estimable

0 fewer per 1000 (from 59 fewer to

59 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 26439 (59)

7326 (21)

RR 3 (131 to 688)

34 more per 1000 (from 10 more to 57

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised no serious no serious no serious no serious none 13227 4223 RR 315 38 more per 1000 oplusoplusoplusoplus IMPORTANT

trials risk of bias inconsistency indirectness imprecision (57) (18) (104 to 956) (from 3 more to 72 more)

HIGH

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 278

(26) 380

(38) RR 068

(012 to 398) 12 fewer per 1000 (from 66 fewer to

43 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 2101

(2) 3105 (29)

RR 069 (012 to 406)

9 fewer per 1000 (from 51 fewer to

33 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 453

(75) RR 048

(009 to 252) 39 fewer per 1000 (from 126 fewer to

48 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 4353 (11)

9246 (37)

RR 033 (01 to 108)

22 fewer per 1000 (from 49 fewer to 5

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 54439

(123) 33326 (101)

RR 111 (069 to 179)

3 more per 1000 (from 43 fewer to

50 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 21227 (93)

6223 (27)

RR 339 (139 to 827)

63 more per 1000 (from 2 more to 105

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 1101

(099) 2105 (19)

RR 052 (005 to 564)

9 fewer per 1000 (from 42 fewer to

23 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 253

(38) RR 096

(014 to 659) 1 fewer per 1000 (from 73 fewer to

70 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2353 (057)

9246 (37)

RR 022 (005 to 099)

26 fewer per 1000 (from 55 fewer to 3

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Lower limit of CI suggest potential no effect

2 I-sq = 90 p-value = 0001

3 Upper limit of CI suggest potential harm

4 Lower limit of CI suggest potential no harm

Question Should Bio mono vs Bio mono be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations

Bio mono

Bio mono

Relative (95 CI) Absolute

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 77163 (472)

45162 (278)

RR 17 (126 to 229)

195 more per 1000 (from 91 more to 298

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1849 (367)

1053 (189)

RR 195 (1 to 38)

179 more per 1000 (from 8 more to 350

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 9162 (56)

10162 (62)

RR 09 (038 to 216)

6 fewer per 1000 (from 57 fewer to 45

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 049

(0) 253

(38) RR 022 (001 to 439)

38 fewer per 1000 (from 100 fewer to 25

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 19162 (117)

16162 (99)

RR 119 (063 to 223)

19 more per 1000 (from 50 fewer to 86

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 049 (0)

153 (19)

RR 036 (002 to 863)

19 fewer per 1000 (from 70 fewer to 33

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Upper limit of CI suggest potential harm for tofacitinib

Question Should Biologic+DMARD vs DMARD be used for Rheumatoid Arthritis [Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 52256 (203)

5133 (38)

RR 54 (221 to

132)

166 more per 1000 (from 107 more to

225 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 28153 (183)

8155 (52)

RR 355 (167 to

753)

131 more per 1000 (from 61 more to

202 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 80298 (268)

10201 (5)

RR 54 (287 to 1016)

219 more per 1000 (from 160 more to

277 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 49170 (288)

6158 (38)

RR 759 (334 to 1723)

250 more per 1000 (from 176 more to

325 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 35132 (265)

11131 (84)

RR 316 (168 to

595)

181 more per 1000 (from 92 more to

270 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 9258

(35) 5133 (38)

RR 093 (032 to

271)

3 fewer per 1000 (from 42 fewer to

37 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 5152

(33) 11155 (71)

RR 046 (016 to 13)

38 fewer per 1000 (from 87 fewer to

11 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8308

(26) 2209

(096) RR 271 (058 to 1265)

16 more per 1000 (from 6 fewer to 39

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 10175

(57) 8160 (5)

RR 114 (046 to

282)

7 more per 1000 (from 41 fewer to

55 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8133

(6) 7132 (53)

RR 113 (042 to

7 more per 1000 (from 48 fewer to

oplusoplusoplusΟ MODERATE

IMPORTANT

304) 63 more)

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 27258

(105) 15133 (113)

RR 093 (051 to

168)

8 fewer per 1000 (from 74 fewer to

57 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 11152

(72) 15155 (97)

RR 075 (035 to

158)

24 fewer per 1000 (from 87 fewer to

38 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 23308

(75) 21209 (10)

RR 074 (042 to

131)

26 fewer per 1000 (from 76 fewer to

24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11175 (63)

18160 (113)

RR 056 (027 to

115)

50 fewer per 1000 (from 110 fewer to

11 more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2133

(15) 6132 (45)

RR 033 (007 to

161)

30 fewer per 1000 (from 72 fewer to

11 more)

oplusoplusoplusΟ MODERATE

CRITICAL

1 Upper limit of CI suggest potential harm

2 Lower limit of CI suggest no harm

Question Should Biologic vs Placebo be used for Rheumatoid Arthritis [DMARD failure amp naiumlve og Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic Placebo Relative

(95 CI) Absolute

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Abatacept_10mgkg4 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1391306 (106)

101923 (109)

RR 092 (07 to 121)

12 fewer per 1000 (from 39 fewer to 16

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Adalimumab_40mg2 16 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2732707

(101) 1982248

(88) RR 11 (091

to 131) 9 more per 1000

(from 6 fewer to 24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Anakinra_100mgd 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 961366 (7)

30534 (56)

RR 104 (069 to

155)

4 more per 1000 (from 20 fewer to 28

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Certolizumab_200 mg2 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1612015 (8)

531050 (5)

RR 163 (113 to

233)

34 more per 1000 (from 13 more to 55

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Etanercept_50mg1 8 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1041297 (8)

91898 (101)

RR 097 (071 to

133)

12 more per 1000 (from 12 fewer to 37

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Golimumab_50mg4 6 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 42623 (67)

47674 (7)

RR 093 (063 to 14)

0 fewer per 1000 (from 21 fewer to 20

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Infliximab_3mgkg8 7 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 1101049

(105) 91909 (10)

RR 102 (078 to

133)

0 fewer per 1000 (from 27 fewer to 26

more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Infliximab_6mgkg8 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 65463 (14)

50377 (133)

RR 104 (068 to

161)

9 more per 1000 (from 49 fewer to 68

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Rituximab_2times1000mg 5 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 67960 (7)

63819 (77)

RR 09 (061 to 133)

3 fewer per 1000 (from 33 fewer to 28

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Tocilizumab_8mgkg4 7 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 1572096

(75) 891477

(6) RR 126 (091 to

173)

16 more per 1000 (from 5 more to 36

more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Tofacitinib_10mgd 8 randomised

trials no serious risk of bias

serious2 no serious

indirectness serious

1 none 601110

(54) 29743 (39)

RR 1 (04 to 247)

6 more per 1000 (from 25 fewer to 37

more)

oplusoplusΟΟ LOW

CRITICAL

1 Upper limit of CI suggest potential harm

2 I-sq = 65 p-value = 0006

Question Should Biologic+DMARD vs Biologic+DMARD be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD Biologic+DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 71156 (455)

60165 (364)

RR 125 (096 to 163)

92 more per 1000 (from 16 fewer to 199

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 147318 (462)

151328 (46)

RR 1 (085 to 119)

2 more per 1000 (from 75

fewer to 79 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Infliximab_3mgkg8 vs Etanercept 1 randomised

trials serious

1 no serious

inconsistency no serious indirectness

no serious imprecision

none 314 (214)

814 (571)

RR 038 (012 to 113)

357 fewer per 1000 (from 694

fewer to 20 fewer)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 72196

(367) 67199 (337)

RR 109 (083 to 143)

31 more per 1000 (from 34 fewer to 125

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1886 (209)

2986 (337)

RR 062 (037 to 103)

128 fewer per 1000 (from 260

fewer to 4 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 5156 (32)

12165 (73)

RR 044 (016 to 122)

41 fewer per 1000 (from 89

fewer to 8 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11318 (35)

20328 (61)

RR 057 (028 to 116)

26 fewer per 1000 (from 59

fewer to 6 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept 0 No evidence

available none IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised no no serious no serious serious

3 none 25204 23204 RR 109 10 more per oplusoplusoplusΟ IMPORTANT

trials serious risk of bias

inconsistency indirectness (123) (113) (064 to 185)

1000 (from 53 fewer to 72

more)

MODERATE

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 586

(58) 986

(105) RR 056 (019 to 159)

47 fewer per 1000 (from 128

fewer to 35 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 15156 (96)

30165 (182)

RR 053 (03 to 094)

86 fewer per 1000 (from 161

fewer to 11 fewer)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious5 none 32318

(101) 30328 (91)

RR 11 (069 to 177)

9 more per 1000 (from 36

fewer to 55 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept 0 No evidence

available none - - not pooled not pooled CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 32204 (157)

18204 (88)

RR 178 (103 to 306)

69 more per 1000 (from 5 more to 132

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 1088

(114) 1486

(163) RR 07 (033 to 149)

49 fewer per 1000 (from 152

fewer to 5 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab (Better indicated by lower values) 1 randomised

trials no serious

inconsistency serious

6 no serious

imprecision none 290 289 - SMD 005

higher (012 lower to 021

higher)

CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 (Better indicated by lower values) 1 randomised no no serious serious

6 no serious none 71 71 - SMD 004 oplusoplusoplusΟ CRITICAL

trials serious risk of bias

inconsistency imprecision lower (037 lower to 029

higher)

MODERATE

1 Open-label study

2 Upper limit of CI support higher effect for Tofacitinib

3 Lower CI limit support lower risk for tofacitinib upper CI limit support lower risk for adalimumab

4 Upper limit of CI support higher risk for low dose infliximab

5 Lower CI limit support lower risk for abatacept upper CI limit support lower risk for adalimumab

6 Due to interpretation of outcome

Question Bio mono vs placebo [DMARD failure] for Rheumatoid Arthritis

Quality assessment No of patients Effect

Quality Importance No of

studies Design Risk of bias Inconsistency Indirectness Imprecision Other

considerations Bio

mono placebo [DMARD failure]

Relative (95 CI) Absolute

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 532

(156) 232

(63) RR 25 (052

to 1196) 94 more per 1000 (from 57 fewer to

250 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 99439 (226)

21326 (64)

RR 324 (171 to 612)

166 more per 1000 (from 100 more to

231 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

serious2 no serious

indirectness no serious imprecision

none 79227 (348)

11223 (49)

RR 705 (386 to 1286)

295 more per 1000 (from 83 more to

506 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 3178 (397)

480 (5)

RR 795 (294 to 2147)

347 more per 1000 (from 229 more to

466 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 29101 (287)

6105 (57)

RR 502 (218 to 1159)

230 more per 1000 (from 131 more to

329 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2255 (40)

153 (19)

RR 212 (296 to 15174)

381 more per 1000 (from 247 more to

516 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 113353 (32)

25246 (102)

RR 305 (204 to 455)

217 more per 1000 (from 154 more to

281 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 032 (0)

032 (0)

Not estimable

0 fewer per 1000 (from 59 fewer to

59 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 26439 (59)

7326 (21)

RR 3 (131 to 688)

34 more per 1000 (from 10 more to 57

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised no serious no serious no serious no serious none 13227 4223 RR 315 38 more per 1000 oplusoplusoplusoplus IMPORTANT

trials risk of bias inconsistency indirectness imprecision (57) (18) (104 to 956) (from 3 more to 72 more)

HIGH

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 278

(26) 380

(38) RR 068

(012 to 398) 12 fewer per 1000 (from 66 fewer to

43 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 2101

(2) 3105 (29)

RR 069 (012 to 406)

9 fewer per 1000 (from 51 fewer to

33 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 453

(75) RR 048

(009 to 252) 39 fewer per 1000 (from 126 fewer to

48 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 4353 (11)

9246 (37)

RR 033 (01 to 108)

22 fewer per 1000 (from 49 fewer to 5

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 54439

(123) 33326 (101)

RR 111 (069 to 179)

3 more per 1000 (from 43 fewer to

50 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 21227 (93)

6223 (27)

RR 339 (139 to 827)

63 more per 1000 (from 2 more to 105

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 1101

(099) 2105 (19)

RR 052 (005 to 564)

9 fewer per 1000 (from 42 fewer to

23 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 253

(38) RR 096

(014 to 659) 1 fewer per 1000 (from 73 fewer to

70 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2353 (057)

9246 (37)

RR 022 (005 to 099)

26 fewer per 1000 (from 55 fewer to 3

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Lower limit of CI suggest potential no effect

2 I-sq = 90 p-value = 0001

3 Upper limit of CI suggest potential harm

4 Lower limit of CI suggest potential no harm

Question Should Bio mono vs Bio mono be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations

Bio mono

Bio mono

Relative (95 CI) Absolute

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 77163 (472)

45162 (278)

RR 17 (126 to 229)

195 more per 1000 (from 91 more to 298

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1849 (367)

1053 (189)

RR 195 (1 to 38)

179 more per 1000 (from 8 more to 350

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 9162 (56)

10162 (62)

RR 09 (038 to 216)

6 fewer per 1000 (from 57 fewer to 45

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 049

(0) 253

(38) RR 022 (001 to 439)

38 fewer per 1000 (from 100 fewer to 25

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 19162 (117)

16162 (99)

RR 119 (063 to 223)

19 more per 1000 (from 50 fewer to 86

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 049 (0)

153 (19)

RR 036 (002 to 863)

19 fewer per 1000 (from 70 fewer to 33

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Upper limit of CI suggest potential harm for tofacitinib

Question Should Biologic+DMARD vs DMARD be used for Rheumatoid Arthritis [Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 52256 (203)

5133 (38)

RR 54 (221 to

132)

166 more per 1000 (from 107 more to

225 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 28153 (183)

8155 (52)

RR 355 (167 to

753)

131 more per 1000 (from 61 more to

202 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 80298 (268)

10201 (5)

RR 54 (287 to 1016)

219 more per 1000 (from 160 more to

277 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 49170 (288)

6158 (38)

RR 759 (334 to 1723)

250 more per 1000 (from 176 more to

325 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 35132 (265)

11131 (84)

RR 316 (168 to

595)

181 more per 1000 (from 92 more to

270 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 9258

(35) 5133 (38)

RR 093 (032 to

271)

3 fewer per 1000 (from 42 fewer to

37 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 5152

(33) 11155 (71)

RR 046 (016 to 13)

38 fewer per 1000 (from 87 fewer to

11 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8308

(26) 2209

(096) RR 271 (058 to 1265)

16 more per 1000 (from 6 fewer to 39

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 10175

(57) 8160 (5)

RR 114 (046 to

282)

7 more per 1000 (from 41 fewer to

55 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8133

(6) 7132 (53)

RR 113 (042 to

7 more per 1000 (from 48 fewer to

oplusoplusoplusΟ MODERATE

IMPORTANT

304) 63 more)

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 27258

(105) 15133 (113)

RR 093 (051 to

168)

8 fewer per 1000 (from 74 fewer to

57 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 11152

(72) 15155 (97)

RR 075 (035 to

158)

24 fewer per 1000 (from 87 fewer to

38 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 23308

(75) 21209 (10)

RR 074 (042 to

131)

26 fewer per 1000 (from 76 fewer to

24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11175 (63)

18160 (113)

RR 056 (027 to

115)

50 fewer per 1000 (from 110 fewer to

11 more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2133

(15) 6132 (45)

RR 033 (007 to

161)

30 fewer per 1000 (from 72 fewer to

11 more)

oplusoplusoplusΟ MODERATE

CRITICAL

1 Upper limit of CI suggest potential harm

2 Lower limit of CI suggest no harm

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [DMARD failure amp naiumlve] - Tofacitinib_10mgd 8 randomised

trials no serious risk of bias

serious2 no serious

indirectness serious

1 none 601110

(54) 29743 (39)

RR 1 (04 to 247)

6 more per 1000 (from 25 fewer to 37

more)

oplusoplusΟΟ LOW

CRITICAL

1 Upper limit of CI suggest potential harm

2 I-sq = 65 p-value = 0006

Question Should Biologic+DMARD vs Biologic+DMARD be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD Biologic+DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 71156 (455)

60165 (364)

RR 125 (096 to 163)

92 more per 1000 (from 16 fewer to 199

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 147318 (462)

151328 (46)

RR 1 (085 to 119)

2 more per 1000 (from 75

fewer to 79 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Infliximab_3mgkg8 vs Etanercept 1 randomised

trials serious

1 no serious

inconsistency no serious indirectness

no serious imprecision

none 314 (214)

814 (571)

RR 038 (012 to 113)

357 fewer per 1000 (from 694

fewer to 20 fewer)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 72196

(367) 67199 (337)

RR 109 (083 to 143)

31 more per 1000 (from 34 fewer to 125

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1886 (209)

2986 (337)

RR 062 (037 to 103)

128 fewer per 1000 (from 260

fewer to 4 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 5156 (32)

12165 (73)

RR 044 (016 to 122)

41 fewer per 1000 (from 89

fewer to 8 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11318 (35)

20328 (61)

RR 057 (028 to 116)

26 fewer per 1000 (from 59

fewer to 6 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept 0 No evidence

available none IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised no no serious no serious serious

3 none 25204 23204 RR 109 10 more per oplusoplusoplusΟ IMPORTANT

trials serious risk of bias

inconsistency indirectness (123) (113) (064 to 185)

1000 (from 53 fewer to 72

more)

MODERATE

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 586

(58) 986

(105) RR 056 (019 to 159)

47 fewer per 1000 (from 128

fewer to 35 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 15156 (96)

30165 (182)

RR 053 (03 to 094)

86 fewer per 1000 (from 161

fewer to 11 fewer)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious5 none 32318

(101) 30328 (91)

RR 11 (069 to 177)

9 more per 1000 (from 36

fewer to 55 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept 0 No evidence

available none - - not pooled not pooled CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 32204 (157)

18204 (88)

RR 178 (103 to 306)

69 more per 1000 (from 5 more to 132

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 1088

(114) 1486

(163) RR 07 (033 to 149)

49 fewer per 1000 (from 152

fewer to 5 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab (Better indicated by lower values) 1 randomised

trials no serious

inconsistency serious

6 no serious

imprecision none 290 289 - SMD 005

higher (012 lower to 021

higher)

CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 (Better indicated by lower values) 1 randomised no no serious serious

6 no serious none 71 71 - SMD 004 oplusoplusoplusΟ CRITICAL

trials serious risk of bias

inconsistency imprecision lower (037 lower to 029

higher)

MODERATE

1 Open-label study

2 Upper limit of CI support higher effect for Tofacitinib

3 Lower CI limit support lower risk for tofacitinib upper CI limit support lower risk for adalimumab

4 Upper limit of CI support higher risk for low dose infliximab

5 Lower CI limit support lower risk for abatacept upper CI limit support lower risk for adalimumab

6 Due to interpretation of outcome

Question Bio mono vs placebo [DMARD failure] for Rheumatoid Arthritis

Quality assessment No of patients Effect

Quality Importance No of

studies Design Risk of bias Inconsistency Indirectness Imprecision Other

considerations Bio

mono placebo [DMARD failure]

Relative (95 CI) Absolute

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 532

(156) 232

(63) RR 25 (052

to 1196) 94 more per 1000 (from 57 fewer to

250 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 99439 (226)

21326 (64)

RR 324 (171 to 612)

166 more per 1000 (from 100 more to

231 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

serious2 no serious

indirectness no serious imprecision

none 79227 (348)

11223 (49)

RR 705 (386 to 1286)

295 more per 1000 (from 83 more to

506 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 3178 (397)

480 (5)

RR 795 (294 to 2147)

347 more per 1000 (from 229 more to

466 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 29101 (287)

6105 (57)

RR 502 (218 to 1159)

230 more per 1000 (from 131 more to

329 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2255 (40)

153 (19)

RR 212 (296 to 15174)

381 more per 1000 (from 247 more to

516 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 113353 (32)

25246 (102)

RR 305 (204 to 455)

217 more per 1000 (from 154 more to

281 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 032 (0)

032 (0)

Not estimable

0 fewer per 1000 (from 59 fewer to

59 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 26439 (59)

7326 (21)

RR 3 (131 to 688)

34 more per 1000 (from 10 more to 57

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised no serious no serious no serious no serious none 13227 4223 RR 315 38 more per 1000 oplusoplusoplusoplus IMPORTANT

trials risk of bias inconsistency indirectness imprecision (57) (18) (104 to 956) (from 3 more to 72 more)

HIGH

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 278

(26) 380

(38) RR 068

(012 to 398) 12 fewer per 1000 (from 66 fewer to

43 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 2101

(2) 3105 (29)

RR 069 (012 to 406)

9 fewer per 1000 (from 51 fewer to

33 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 453

(75) RR 048

(009 to 252) 39 fewer per 1000 (from 126 fewer to

48 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 4353 (11)

9246 (37)

RR 033 (01 to 108)

22 fewer per 1000 (from 49 fewer to 5

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 54439

(123) 33326 (101)

RR 111 (069 to 179)

3 more per 1000 (from 43 fewer to

50 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 21227 (93)

6223 (27)

RR 339 (139 to 827)

63 more per 1000 (from 2 more to 105

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 1101

(099) 2105 (19)

RR 052 (005 to 564)

9 fewer per 1000 (from 42 fewer to

23 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 253

(38) RR 096

(014 to 659) 1 fewer per 1000 (from 73 fewer to

70 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2353 (057)

9246 (37)

RR 022 (005 to 099)

26 fewer per 1000 (from 55 fewer to 3

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Lower limit of CI suggest potential no effect

2 I-sq = 90 p-value = 0001

3 Upper limit of CI suggest potential harm

4 Lower limit of CI suggest potential no harm

Question Should Bio mono vs Bio mono be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations

Bio mono

Bio mono

Relative (95 CI) Absolute

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 77163 (472)

45162 (278)

RR 17 (126 to 229)

195 more per 1000 (from 91 more to 298

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1849 (367)

1053 (189)

RR 195 (1 to 38)

179 more per 1000 (from 8 more to 350

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 9162 (56)

10162 (62)

RR 09 (038 to 216)

6 fewer per 1000 (from 57 fewer to 45

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 049

(0) 253

(38) RR 022 (001 to 439)

38 fewer per 1000 (from 100 fewer to 25

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 19162 (117)

16162 (99)

RR 119 (063 to 223)

19 more per 1000 (from 50 fewer to 86

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 049 (0)

153 (19)

RR 036 (002 to 863)

19 fewer per 1000 (from 70 fewer to 33

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Upper limit of CI suggest potential harm for tofacitinib

Question Should Biologic+DMARD vs DMARD be used for Rheumatoid Arthritis [Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 52256 (203)

5133 (38)

RR 54 (221 to

132)

166 more per 1000 (from 107 more to

225 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 28153 (183)

8155 (52)

RR 355 (167 to

753)

131 more per 1000 (from 61 more to

202 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 80298 (268)

10201 (5)

RR 54 (287 to 1016)

219 more per 1000 (from 160 more to

277 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 49170 (288)

6158 (38)

RR 759 (334 to 1723)

250 more per 1000 (from 176 more to

325 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 35132 (265)

11131 (84)

RR 316 (168 to

595)

181 more per 1000 (from 92 more to

270 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 9258

(35) 5133 (38)

RR 093 (032 to

271)

3 fewer per 1000 (from 42 fewer to

37 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 5152

(33) 11155 (71)

RR 046 (016 to 13)

38 fewer per 1000 (from 87 fewer to

11 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8308

(26) 2209

(096) RR 271 (058 to 1265)

16 more per 1000 (from 6 fewer to 39

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 10175

(57) 8160 (5)

RR 114 (046 to

282)

7 more per 1000 (from 41 fewer to

55 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8133

(6) 7132 (53)

RR 113 (042 to

7 more per 1000 (from 48 fewer to

oplusoplusoplusΟ MODERATE

IMPORTANT

304) 63 more)

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 27258

(105) 15133 (113)

RR 093 (051 to

168)

8 fewer per 1000 (from 74 fewer to

57 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 11152

(72) 15155 (97)

RR 075 (035 to

158)

24 fewer per 1000 (from 87 fewer to

38 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 23308

(75) 21209 (10)

RR 074 (042 to

131)

26 fewer per 1000 (from 76 fewer to

24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11175 (63)

18160 (113)

RR 056 (027 to

115)

50 fewer per 1000 (from 110 fewer to

11 more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2133

(15) 6132 (45)

RR 033 (007 to

161)

30 fewer per 1000 (from 72 fewer to

11 more)

oplusoplusoplusΟ MODERATE

CRITICAL

1 Upper limit of CI suggest potential harm

2 Lower limit of CI suggest no harm

Question Should Biologic+DMARD vs Biologic+DMARD be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD Biologic+DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 71156 (455)

60165 (364)

RR 125 (096 to 163)

92 more per 1000 (from 16 fewer to 199

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 147318 (462)

151328 (46)

RR 1 (085 to 119)

2 more per 1000 (from 75

fewer to 79 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Infliximab_3mgkg8 vs Etanercept 1 randomised

trials serious

1 no serious

inconsistency no serious indirectness

no serious imprecision

none 314 (214)

814 (571)

RR 038 (012 to 113)

357 fewer per 1000 (from 694

fewer to 20 fewer)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 72196

(367) 67199 (337)

RR 109 (083 to 143)

31 more per 1000 (from 34 fewer to 125

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk+DMARD vs Biologic+DMARD [Biologic failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1886 (209)

2986 (337)

RR 062 (037 to 103)

128 fewer per 1000 (from 260

fewer to 4 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 5156 (32)

12165 (73)

RR 044 (016 to 122)

41 fewer per 1000 (from 89

fewer to 8 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11318 (35)

20328 (61)

RR 057 (028 to 116)

26 fewer per 1000 (from 59

fewer to 6 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept 0 No evidence

available none IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised no no serious no serious serious

3 none 25204 23204 RR 109 10 more per oplusoplusoplusΟ IMPORTANT

trials serious risk of bias

inconsistency indirectness (123) (113) (064 to 185)

1000 (from 53 fewer to 72

more)

MODERATE

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 586

(58) 986

(105) RR 056 (019 to 159)

47 fewer per 1000 (from 128

fewer to 35 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 15156 (96)

30165 (182)

RR 053 (03 to 094)

86 fewer per 1000 (from 161

fewer to 11 fewer)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious5 none 32318

(101) 30328 (91)

RR 11 (069 to 177)

9 more per 1000 (from 36

fewer to 55 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept 0 No evidence

available none - - not pooled not pooled CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 32204 (157)

18204 (88)

RR 178 (103 to 306)

69 more per 1000 (from 5 more to 132

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 1088

(114) 1486

(163) RR 07 (033 to 149)

49 fewer per 1000 (from 152

fewer to 5 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab (Better indicated by lower values) 1 randomised

trials no serious

inconsistency serious

6 no serious

imprecision none 290 289 - SMD 005

higher (012 lower to 021

higher)

CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 (Better indicated by lower values) 1 randomised no no serious serious

6 no serious none 71 71 - SMD 004 oplusoplusoplusΟ CRITICAL

trials serious risk of bias

inconsistency imprecision lower (037 lower to 029

higher)

MODERATE

1 Open-label study

2 Upper limit of CI support higher effect for Tofacitinib

3 Lower CI limit support lower risk for tofacitinib upper CI limit support lower risk for adalimumab

4 Upper limit of CI support higher risk for low dose infliximab

5 Lower CI limit support lower risk for abatacept upper CI limit support lower risk for adalimumab

6 Due to interpretation of outcome

Question Bio mono vs placebo [DMARD failure] for Rheumatoid Arthritis

Quality assessment No of patients Effect

Quality Importance No of

studies Design Risk of bias Inconsistency Indirectness Imprecision Other

considerations Bio

mono placebo [DMARD failure]

Relative (95 CI) Absolute

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 532

(156) 232

(63) RR 25 (052

to 1196) 94 more per 1000 (from 57 fewer to

250 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 99439 (226)

21326 (64)

RR 324 (171 to 612)

166 more per 1000 (from 100 more to

231 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

serious2 no serious

indirectness no serious imprecision

none 79227 (348)

11223 (49)

RR 705 (386 to 1286)

295 more per 1000 (from 83 more to

506 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 3178 (397)

480 (5)

RR 795 (294 to 2147)

347 more per 1000 (from 229 more to

466 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 29101 (287)

6105 (57)

RR 502 (218 to 1159)

230 more per 1000 (from 131 more to

329 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2255 (40)

153 (19)

RR 212 (296 to 15174)

381 more per 1000 (from 247 more to

516 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 113353 (32)

25246 (102)

RR 305 (204 to 455)

217 more per 1000 (from 154 more to

281 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 032 (0)

032 (0)

Not estimable

0 fewer per 1000 (from 59 fewer to

59 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 26439 (59)

7326 (21)

RR 3 (131 to 688)

34 more per 1000 (from 10 more to 57

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised no serious no serious no serious no serious none 13227 4223 RR 315 38 more per 1000 oplusoplusoplusoplus IMPORTANT

trials risk of bias inconsistency indirectness imprecision (57) (18) (104 to 956) (from 3 more to 72 more)

HIGH

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 278

(26) 380

(38) RR 068

(012 to 398) 12 fewer per 1000 (from 66 fewer to

43 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 2101

(2) 3105 (29)

RR 069 (012 to 406)

9 fewer per 1000 (from 51 fewer to

33 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 453

(75) RR 048

(009 to 252) 39 fewer per 1000 (from 126 fewer to

48 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 4353 (11)

9246 (37)

RR 033 (01 to 108)

22 fewer per 1000 (from 49 fewer to 5

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 54439

(123) 33326 (101)

RR 111 (069 to 179)

3 more per 1000 (from 43 fewer to

50 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 21227 (93)

6223 (27)

RR 339 (139 to 827)

63 more per 1000 (from 2 more to 105

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 1101

(099) 2105 (19)

RR 052 (005 to 564)

9 fewer per 1000 (from 42 fewer to

23 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 253

(38) RR 096

(014 to 659) 1 fewer per 1000 (from 73 fewer to

70 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2353 (057)

9246 (37)

RR 022 (005 to 099)

26 fewer per 1000 (from 55 fewer to 3

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Lower limit of CI suggest potential no effect

2 I-sq = 90 p-value = 0001

3 Upper limit of CI suggest potential harm

4 Lower limit of CI suggest potential no harm

Question Should Bio mono vs Bio mono be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations

Bio mono

Bio mono

Relative (95 CI) Absolute

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 77163 (472)

45162 (278)

RR 17 (126 to 229)

195 more per 1000 (from 91 more to 298

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1849 (367)

1053 (189)

RR 195 (1 to 38)

179 more per 1000 (from 8 more to 350

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 9162 (56)

10162 (62)

RR 09 (038 to 216)

6 fewer per 1000 (from 57 fewer to 45

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 049

(0) 253

(38) RR 022 (001 to 439)

38 fewer per 1000 (from 100 fewer to 25

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 19162 (117)

16162 (99)

RR 119 (063 to 223)

19 more per 1000 (from 50 fewer to 86

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 049 (0)

153 (19)

RR 036 (002 to 863)

19 fewer per 1000 (from 70 fewer to 33

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Upper limit of CI suggest potential harm for tofacitinib

Question Should Biologic+DMARD vs DMARD be used for Rheumatoid Arthritis [Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 52256 (203)

5133 (38)

RR 54 (221 to

132)

166 more per 1000 (from 107 more to

225 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 28153 (183)

8155 (52)

RR 355 (167 to

753)

131 more per 1000 (from 61 more to

202 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 80298 (268)

10201 (5)

RR 54 (287 to 1016)

219 more per 1000 (from 160 more to

277 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 49170 (288)

6158 (38)

RR 759 (334 to 1723)

250 more per 1000 (from 176 more to

325 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 35132 (265)

11131 (84)

RR 316 (168 to

595)

181 more per 1000 (from 92 more to

270 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 9258

(35) 5133 (38)

RR 093 (032 to

271)

3 fewer per 1000 (from 42 fewer to

37 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 5152

(33) 11155 (71)

RR 046 (016 to 13)

38 fewer per 1000 (from 87 fewer to

11 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8308

(26) 2209

(096) RR 271 (058 to 1265)

16 more per 1000 (from 6 fewer to 39

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 10175

(57) 8160 (5)

RR 114 (046 to

282)

7 more per 1000 (from 41 fewer to

55 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8133

(6) 7132 (53)

RR 113 (042 to

7 more per 1000 (from 48 fewer to

oplusoplusoplusΟ MODERATE

IMPORTANT

304) 63 more)

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 27258

(105) 15133 (113)

RR 093 (051 to

168)

8 fewer per 1000 (from 74 fewer to

57 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 11152

(72) 15155 (97)

RR 075 (035 to

158)

24 fewer per 1000 (from 87 fewer to

38 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 23308

(75) 21209 (10)

RR 074 (042 to

131)

26 fewer per 1000 (from 76 fewer to

24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11175 (63)

18160 (113)

RR 056 (027 to

115)

50 fewer per 1000 (from 110 fewer to

11 more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2133

(15) 6132 (45)

RR 033 (007 to

161)

30 fewer per 1000 (from 72 fewer to

11 more)

oplusoplusoplusΟ MODERATE

CRITICAL

1 Upper limit of CI suggest potential harm

2 Lower limit of CI suggest no harm

trials serious risk of bias

inconsistency indirectness (123) (113) (064 to 185)

1000 (from 53 fewer to 72

more)

MODERATE

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 586

(58) 986

(105) RR 056 (019 to 159)

47 fewer per 1000 (from 128

fewer to 35 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 15156 (96)

30165 (182)

RR 053 (03 to 094)

86 fewer per 1000 (from 161

fewer to 11 fewer)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious5 none 32318

(101) 30328 (91)

RR 11 (069 to 177)

9 more per 1000 (from 36

fewer to 55 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept 0 No evidence

available none - - not pooled not pooled CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 32204 (157)

18204 (88)

RR 178 (103 to 306)

69 more per 1000 (from 5 more to 132

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs Biologisk+DMARD [DMARD failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 1088

(114) 1486

(163) RR 07 (033 to 149)

49 fewer per 1000 (from 152

fewer to 5 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Abatacept_10mgkg4 vs Infliximab (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Abatacept(sc)_125mg1 vs Adalimumab (Better indicated by lower values) 1 randomised

trials no serious

inconsistency serious

6 no serious

imprecision none 290 289 - SMD 005

higher (012 lower to 021

higher)

CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Infliximab_3mgkg8 vs Etanercept (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Tofacitinib_10mgd vs Adalimumab (Better indicated by lower values) 0 No evidence

available none CRITICAL

Total Sharp Score af Biologisk+DMARD vs Biologic+DMARD [DMARD failure] - Infliximab_3mgkg8 vs 3 vs Infliximab 6mgkg8 (Better indicated by lower values) 1 randomised no no serious serious

6 no serious none 71 71 - SMD 004 oplusoplusoplusΟ CRITICAL

trials serious risk of bias

inconsistency imprecision lower (037 lower to 029

higher)

MODERATE

1 Open-label study

2 Upper limit of CI support higher effect for Tofacitinib

3 Lower CI limit support lower risk for tofacitinib upper CI limit support lower risk for adalimumab

4 Upper limit of CI support higher risk for low dose infliximab

5 Lower CI limit support lower risk for abatacept upper CI limit support lower risk for adalimumab

6 Due to interpretation of outcome

Question Bio mono vs placebo [DMARD failure] for Rheumatoid Arthritis

Quality assessment No of patients Effect

Quality Importance No of

studies Design Risk of bias Inconsistency Indirectness Imprecision Other

considerations Bio

mono placebo [DMARD failure]

Relative (95 CI) Absolute

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 532

(156) 232

(63) RR 25 (052

to 1196) 94 more per 1000 (from 57 fewer to

250 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 99439 (226)

21326 (64)

RR 324 (171 to 612)

166 more per 1000 (from 100 more to

231 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

serious2 no serious

indirectness no serious imprecision

none 79227 (348)

11223 (49)

RR 705 (386 to 1286)

295 more per 1000 (from 83 more to

506 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 3178 (397)

480 (5)

RR 795 (294 to 2147)

347 more per 1000 (from 229 more to

466 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 29101 (287)

6105 (57)

RR 502 (218 to 1159)

230 more per 1000 (from 131 more to

329 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2255 (40)

153 (19)

RR 212 (296 to 15174)

381 more per 1000 (from 247 more to

516 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 113353 (32)

25246 (102)

RR 305 (204 to 455)

217 more per 1000 (from 154 more to

281 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 032 (0)

032 (0)

Not estimable

0 fewer per 1000 (from 59 fewer to

59 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 26439 (59)

7326 (21)

RR 3 (131 to 688)

34 more per 1000 (from 10 more to 57

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised no serious no serious no serious no serious none 13227 4223 RR 315 38 more per 1000 oplusoplusoplusoplus IMPORTANT

trials risk of bias inconsistency indirectness imprecision (57) (18) (104 to 956) (from 3 more to 72 more)

HIGH

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 278

(26) 380

(38) RR 068

(012 to 398) 12 fewer per 1000 (from 66 fewer to

43 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 2101

(2) 3105 (29)

RR 069 (012 to 406)

9 fewer per 1000 (from 51 fewer to

33 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 453

(75) RR 048

(009 to 252) 39 fewer per 1000 (from 126 fewer to

48 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 4353 (11)

9246 (37)

RR 033 (01 to 108)

22 fewer per 1000 (from 49 fewer to 5

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 54439

(123) 33326 (101)

RR 111 (069 to 179)

3 more per 1000 (from 43 fewer to

50 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 21227 (93)

6223 (27)

RR 339 (139 to 827)

63 more per 1000 (from 2 more to 105

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 1101

(099) 2105 (19)

RR 052 (005 to 564)

9 fewer per 1000 (from 42 fewer to

23 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 253

(38) RR 096

(014 to 659) 1 fewer per 1000 (from 73 fewer to

70 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2353 (057)

9246 (37)

RR 022 (005 to 099)

26 fewer per 1000 (from 55 fewer to 3

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Lower limit of CI suggest potential no effect

2 I-sq = 90 p-value = 0001

3 Upper limit of CI suggest potential harm

4 Lower limit of CI suggest potential no harm

Question Should Bio mono vs Bio mono be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations

Bio mono

Bio mono

Relative (95 CI) Absolute

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 77163 (472)

45162 (278)

RR 17 (126 to 229)

195 more per 1000 (from 91 more to 298

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1849 (367)

1053 (189)

RR 195 (1 to 38)

179 more per 1000 (from 8 more to 350

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 9162 (56)

10162 (62)

RR 09 (038 to 216)

6 fewer per 1000 (from 57 fewer to 45

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 049

(0) 253

(38) RR 022 (001 to 439)

38 fewer per 1000 (from 100 fewer to 25

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 19162 (117)

16162 (99)

RR 119 (063 to 223)

19 more per 1000 (from 50 fewer to 86

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 049 (0)

153 (19)

RR 036 (002 to 863)

19 fewer per 1000 (from 70 fewer to 33

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Upper limit of CI suggest potential harm for tofacitinib

Question Should Biologic+DMARD vs DMARD be used for Rheumatoid Arthritis [Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 52256 (203)

5133 (38)

RR 54 (221 to

132)

166 more per 1000 (from 107 more to

225 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 28153 (183)

8155 (52)

RR 355 (167 to

753)

131 more per 1000 (from 61 more to

202 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 80298 (268)

10201 (5)

RR 54 (287 to 1016)

219 more per 1000 (from 160 more to

277 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 49170 (288)

6158 (38)

RR 759 (334 to 1723)

250 more per 1000 (from 176 more to

325 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 35132 (265)

11131 (84)

RR 316 (168 to

595)

181 more per 1000 (from 92 more to

270 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 9258

(35) 5133 (38)

RR 093 (032 to

271)

3 fewer per 1000 (from 42 fewer to

37 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 5152

(33) 11155 (71)

RR 046 (016 to 13)

38 fewer per 1000 (from 87 fewer to

11 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8308

(26) 2209

(096) RR 271 (058 to 1265)

16 more per 1000 (from 6 fewer to 39

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 10175

(57) 8160 (5)

RR 114 (046 to

282)

7 more per 1000 (from 41 fewer to

55 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8133

(6) 7132 (53)

RR 113 (042 to

7 more per 1000 (from 48 fewer to

oplusoplusoplusΟ MODERATE

IMPORTANT

304) 63 more)

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 27258

(105) 15133 (113)

RR 093 (051 to

168)

8 fewer per 1000 (from 74 fewer to

57 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 11152

(72) 15155 (97)

RR 075 (035 to

158)

24 fewer per 1000 (from 87 fewer to

38 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 23308

(75) 21209 (10)

RR 074 (042 to

131)

26 fewer per 1000 (from 76 fewer to

24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11175 (63)

18160 (113)

RR 056 (027 to

115)

50 fewer per 1000 (from 110 fewer to

11 more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2133

(15) 6132 (45)

RR 033 (007 to

161)

30 fewer per 1000 (from 72 fewer to

11 more)

oplusoplusoplusΟ MODERATE

CRITICAL

1 Upper limit of CI suggest potential harm

2 Lower limit of CI suggest no harm

trials serious risk of bias

inconsistency imprecision lower (037 lower to 029

higher)

MODERATE

1 Open-label study

2 Upper limit of CI support higher effect for Tofacitinib

3 Lower CI limit support lower risk for tofacitinib upper CI limit support lower risk for adalimumab

4 Upper limit of CI support higher risk for low dose infliximab

5 Lower CI limit support lower risk for abatacept upper CI limit support lower risk for adalimumab

6 Due to interpretation of outcome

Question Bio mono vs placebo [DMARD failure] for Rheumatoid Arthritis

Quality assessment No of patients Effect

Quality Importance No of

studies Design Risk of bias Inconsistency Indirectness Imprecision Other

considerations Bio

mono placebo [DMARD failure]

Relative (95 CI) Absolute

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 532

(156) 232

(63) RR 25 (052

to 1196) 94 more per 1000 (from 57 fewer to

250 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 99439 (226)

21326 (64)

RR 324 (171 to 612)

166 more per 1000 (from 100 more to

231 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

serious2 no serious

indirectness no serious imprecision

none 79227 (348)

11223 (49)

RR 705 (386 to 1286)

295 more per 1000 (from 83 more to

506 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 3178 (397)

480 (5)

RR 795 (294 to 2147)

347 more per 1000 (from 229 more to

466 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 29101 (287)

6105 (57)

RR 502 (218 to 1159)

230 more per 1000 (from 131 more to

329 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2255 (40)

153 (19)

RR 212 (296 to 15174)

381 more per 1000 (from 247 more to

516 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 113353 (32)

25246 (102)

RR 305 (204 to 455)

217 more per 1000 (from 154 more to

281 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 032 (0)

032 (0)

Not estimable

0 fewer per 1000 (from 59 fewer to

59 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 26439 (59)

7326 (21)

RR 3 (131 to 688)

34 more per 1000 (from 10 more to 57

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised no serious no serious no serious no serious none 13227 4223 RR 315 38 more per 1000 oplusoplusoplusoplus IMPORTANT

trials risk of bias inconsistency indirectness imprecision (57) (18) (104 to 956) (from 3 more to 72 more)

HIGH

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 278

(26) 380

(38) RR 068

(012 to 398) 12 fewer per 1000 (from 66 fewer to

43 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 2101

(2) 3105 (29)

RR 069 (012 to 406)

9 fewer per 1000 (from 51 fewer to

33 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 453

(75) RR 048

(009 to 252) 39 fewer per 1000 (from 126 fewer to

48 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 4353 (11)

9246 (37)

RR 033 (01 to 108)

22 fewer per 1000 (from 49 fewer to 5

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 54439

(123) 33326 (101)

RR 111 (069 to 179)

3 more per 1000 (from 43 fewer to

50 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 21227 (93)

6223 (27)

RR 339 (139 to 827)

63 more per 1000 (from 2 more to 105

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 1101

(099) 2105 (19)

RR 052 (005 to 564)

9 fewer per 1000 (from 42 fewer to

23 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 253

(38) RR 096

(014 to 659) 1 fewer per 1000 (from 73 fewer to

70 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2353 (057)

9246 (37)

RR 022 (005 to 099)

26 fewer per 1000 (from 55 fewer to 3

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Lower limit of CI suggest potential no effect

2 I-sq = 90 p-value = 0001

3 Upper limit of CI suggest potential harm

4 Lower limit of CI suggest potential no harm

Question Should Bio mono vs Bio mono be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations

Bio mono

Bio mono

Relative (95 CI) Absolute

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 77163 (472)

45162 (278)

RR 17 (126 to 229)

195 more per 1000 (from 91 more to 298

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1849 (367)

1053 (189)

RR 195 (1 to 38)

179 more per 1000 (from 8 more to 350

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 9162 (56)

10162 (62)

RR 09 (038 to 216)

6 fewer per 1000 (from 57 fewer to 45

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 049

(0) 253

(38) RR 022 (001 to 439)

38 fewer per 1000 (from 100 fewer to 25

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 19162 (117)

16162 (99)

RR 119 (063 to 223)

19 more per 1000 (from 50 fewer to 86

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 049 (0)

153 (19)

RR 036 (002 to 863)

19 fewer per 1000 (from 70 fewer to 33

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Upper limit of CI suggest potential harm for tofacitinib

Question Should Biologic+DMARD vs DMARD be used for Rheumatoid Arthritis [Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 52256 (203)

5133 (38)

RR 54 (221 to

132)

166 more per 1000 (from 107 more to

225 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 28153 (183)

8155 (52)

RR 355 (167 to

753)

131 more per 1000 (from 61 more to

202 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 80298 (268)

10201 (5)

RR 54 (287 to 1016)

219 more per 1000 (from 160 more to

277 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 49170 (288)

6158 (38)

RR 759 (334 to 1723)

250 more per 1000 (from 176 more to

325 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 35132 (265)

11131 (84)

RR 316 (168 to

595)

181 more per 1000 (from 92 more to

270 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 9258

(35) 5133 (38)

RR 093 (032 to

271)

3 fewer per 1000 (from 42 fewer to

37 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 5152

(33) 11155 (71)

RR 046 (016 to 13)

38 fewer per 1000 (from 87 fewer to

11 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8308

(26) 2209

(096) RR 271 (058 to 1265)

16 more per 1000 (from 6 fewer to 39

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 10175

(57) 8160 (5)

RR 114 (046 to

282)

7 more per 1000 (from 41 fewer to

55 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8133

(6) 7132 (53)

RR 113 (042 to

7 more per 1000 (from 48 fewer to

oplusoplusoplusΟ MODERATE

IMPORTANT

304) 63 more)

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 27258

(105) 15133 (113)

RR 093 (051 to

168)

8 fewer per 1000 (from 74 fewer to

57 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 11152

(72) 15155 (97)

RR 075 (035 to

158)

24 fewer per 1000 (from 87 fewer to

38 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 23308

(75) 21209 (10)

RR 074 (042 to

131)

26 fewer per 1000 (from 76 fewer to

24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11175 (63)

18160 (113)

RR 056 (027 to

115)

50 fewer per 1000 (from 110 fewer to

11 more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2133

(15) 6132 (45)

RR 033 (007 to

161)

30 fewer per 1000 (from 72 fewer to

11 more)

oplusoplusoplusΟ MODERATE

CRITICAL

1 Upper limit of CI suggest potential harm

2 Lower limit of CI suggest no harm

Question Bio mono vs placebo [DMARD failure] for Rheumatoid Arthritis

Quality assessment No of patients Effect

Quality Importance No of

studies Design Risk of bias Inconsistency Indirectness Imprecision Other

considerations Bio

mono placebo [DMARD failure]

Relative (95 CI) Absolute

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 532

(156) 232

(63) RR 25 (052

to 1196) 94 more per 1000 (from 57 fewer to

250 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 99439 (226)

21326 (64)

RR 324 (171 to 612)

166 more per 1000 (from 100 more to

231 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

serious2 no serious

indirectness no serious imprecision

none 79227 (348)

11223 (49)

RR 705 (386 to 1286)

295 more per 1000 (from 83 more to

506 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 3178 (397)

480 (5)

RR 795 (294 to 2147)

347 more per 1000 (from 229 more to

466 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 29101 (287)

6105 (57)

RR 502 (218 to 1159)

230 more per 1000 (from 131 more to

329 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2255 (40)

153 (19)

RR 212 (296 to 15174)

381 more per 1000 (from 247 more to

516 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 113353 (32)

25246 (102)

RR 305 (204 to 455)

217 more per 1000 (from 154 more to

281 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 032 (0)

032 (0)

Not estimable

0 fewer per 1000 (from 59 fewer to

59 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 26439 (59)

7326 (21)

RR 3 (131 to 688)

34 more per 1000 (from 10 more to 57

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised no serious no serious no serious no serious none 13227 4223 RR 315 38 more per 1000 oplusoplusoplusoplus IMPORTANT

trials risk of bias inconsistency indirectness imprecision (57) (18) (104 to 956) (from 3 more to 72 more)

HIGH

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 278

(26) 380

(38) RR 068

(012 to 398) 12 fewer per 1000 (from 66 fewer to

43 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 2101

(2) 3105 (29)

RR 069 (012 to 406)

9 fewer per 1000 (from 51 fewer to

33 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 453

(75) RR 048

(009 to 252) 39 fewer per 1000 (from 126 fewer to

48 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 4353 (11)

9246 (37)

RR 033 (01 to 108)

22 fewer per 1000 (from 49 fewer to 5

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 54439

(123) 33326 (101)

RR 111 (069 to 179)

3 more per 1000 (from 43 fewer to

50 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 21227 (93)

6223 (27)

RR 339 (139 to 827)

63 more per 1000 (from 2 more to 105

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 1101

(099) 2105 (19)

RR 052 (005 to 564)

9 fewer per 1000 (from 42 fewer to

23 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 253

(38) RR 096

(014 to 659) 1 fewer per 1000 (from 73 fewer to

70 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2353 (057)

9246 (37)

RR 022 (005 to 099)

26 fewer per 1000 (from 55 fewer to 3

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Lower limit of CI suggest potential no effect

2 I-sq = 90 p-value = 0001

3 Upper limit of CI suggest potential harm

4 Lower limit of CI suggest potential no harm

Question Should Bio mono vs Bio mono be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations

Bio mono

Bio mono

Relative (95 CI) Absolute

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 77163 (472)

45162 (278)

RR 17 (126 to 229)

195 more per 1000 (from 91 more to 298

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1849 (367)

1053 (189)

RR 195 (1 to 38)

179 more per 1000 (from 8 more to 350

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 9162 (56)

10162 (62)

RR 09 (038 to 216)

6 fewer per 1000 (from 57 fewer to 45

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 049

(0) 253

(38) RR 022 (001 to 439)

38 fewer per 1000 (from 100 fewer to 25

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 19162 (117)

16162 (99)

RR 119 (063 to 223)

19 more per 1000 (from 50 fewer to 86

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 049 (0)

153 (19)

RR 036 (002 to 863)

19 fewer per 1000 (from 70 fewer to 33

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Upper limit of CI suggest potential harm for tofacitinib

Question Should Biologic+DMARD vs DMARD be used for Rheumatoid Arthritis [Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 52256 (203)

5133 (38)

RR 54 (221 to

132)

166 more per 1000 (from 107 more to

225 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 28153 (183)

8155 (52)

RR 355 (167 to

753)

131 more per 1000 (from 61 more to

202 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 80298 (268)

10201 (5)

RR 54 (287 to 1016)

219 more per 1000 (from 160 more to

277 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 49170 (288)

6158 (38)

RR 759 (334 to 1723)

250 more per 1000 (from 176 more to

325 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 35132 (265)

11131 (84)

RR 316 (168 to

595)

181 more per 1000 (from 92 more to

270 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 9258

(35) 5133 (38)

RR 093 (032 to

271)

3 fewer per 1000 (from 42 fewer to

37 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 5152

(33) 11155 (71)

RR 046 (016 to 13)

38 fewer per 1000 (from 87 fewer to

11 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8308

(26) 2209

(096) RR 271 (058 to 1265)

16 more per 1000 (from 6 fewer to 39

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 10175

(57) 8160 (5)

RR 114 (046 to

282)

7 more per 1000 (from 41 fewer to

55 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8133

(6) 7132 (53)

RR 113 (042 to

7 more per 1000 (from 48 fewer to

oplusoplusoplusΟ MODERATE

IMPORTANT

304) 63 more)

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 27258

(105) 15133 (113)

RR 093 (051 to

168)

8 fewer per 1000 (from 74 fewer to

57 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 11152

(72) 15155 (97)

RR 075 (035 to

158)

24 fewer per 1000 (from 87 fewer to

38 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 23308

(75) 21209 (10)

RR 074 (042 to

131)

26 fewer per 1000 (from 76 fewer to

24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11175 (63)

18160 (113)

RR 056 (027 to

115)

50 fewer per 1000 (from 110 fewer to

11 more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2133

(15) 6132 (45)

RR 033 (007 to

161)

30 fewer per 1000 (from 72 fewer to

11 more)

oplusoplusoplusΟ MODERATE

CRITICAL

1 Upper limit of CI suggest potential harm

2 Lower limit of CI suggest no harm

trials risk of bias inconsistency indirectness imprecision (57) (18) (104 to 956) (from 3 more to 72 more)

HIGH

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 278

(26) 380

(38) RR 068

(012 to 398) 12 fewer per 1000 (from 66 fewer to

43 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 2101

(2) 3105 (29)

RR 069 (012 to 406)

9 fewer per 1000 (from 51 fewer to

33 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 453

(75) RR 048

(009 to 252) 39 fewer per 1000 (from 126 fewer to

48 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 4353 (11)

9246 (37)

RR 033 (01 to 108)

22 fewer per 1000 (from 49 fewer to 5

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Abatacept_10mgkg4 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Adalimumab_40mg2 4 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious4 none 54439

(123) 33326 (101)

RR 111 (069 to 179)

3 more per 1000 (from 43 fewer to

50 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Certolizumab_200 mg2 2 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 21227 (93)

6223 (27)

RR 339 (139 to 827)

63 more per 1000 (from 2 more to 105

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Etanercept_50mg1 0 No evidence

available none CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 1101

(099) 2105 (19)

RR 052 (005 to 564)

9 fewer per 1000 (from 42 fewer to

23 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious3 none 255

(36) 253

(38) RR 096

(014 to 659) 1 fewer per 1000 (from 73 fewer to

70 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk vs Placebo [Mono DMARD failure] - Tofacitinib_10mgd 3 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 2353 (057)

9246 (37)

RR 022 (005 to 099)

26 fewer per 1000 (from 55 fewer to 3

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Lower limit of CI suggest potential no effect

2 I-sq = 90 p-value = 0001

3 Upper limit of CI suggest potential harm

4 Lower limit of CI suggest potential no harm

Question Should Bio mono vs Bio mono be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations

Bio mono

Bio mono

Relative (95 CI) Absolute

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 77163 (472)

45162 (278)

RR 17 (126 to 229)

195 more per 1000 (from 91 more to 298

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1849 (367)

1053 (189)

RR 195 (1 to 38)

179 more per 1000 (from 8 more to 350

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 9162 (56)

10162 (62)

RR 09 (038 to 216)

6 fewer per 1000 (from 57 fewer to 45

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 049

(0) 253

(38) RR 022 (001 to 439)

38 fewer per 1000 (from 100 fewer to 25

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 19162 (117)

16162 (99)

RR 119 (063 to 223)

19 more per 1000 (from 50 fewer to 86

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 049 (0)

153 (19)

RR 036 (002 to 863)

19 fewer per 1000 (from 70 fewer to 33

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Upper limit of CI suggest potential harm for tofacitinib

Question Should Biologic+DMARD vs DMARD be used for Rheumatoid Arthritis [Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 52256 (203)

5133 (38)

RR 54 (221 to

132)

166 more per 1000 (from 107 more to

225 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 28153 (183)

8155 (52)

RR 355 (167 to

753)

131 more per 1000 (from 61 more to

202 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 80298 (268)

10201 (5)

RR 54 (287 to 1016)

219 more per 1000 (from 160 more to

277 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 49170 (288)

6158 (38)

RR 759 (334 to 1723)

250 more per 1000 (from 176 more to

325 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 35132 (265)

11131 (84)

RR 316 (168 to

595)

181 more per 1000 (from 92 more to

270 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 9258

(35) 5133 (38)

RR 093 (032 to

271)

3 fewer per 1000 (from 42 fewer to

37 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 5152

(33) 11155 (71)

RR 046 (016 to 13)

38 fewer per 1000 (from 87 fewer to

11 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8308

(26) 2209

(096) RR 271 (058 to 1265)

16 more per 1000 (from 6 fewer to 39

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 10175

(57) 8160 (5)

RR 114 (046 to

282)

7 more per 1000 (from 41 fewer to

55 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8133

(6) 7132 (53)

RR 113 (042 to

7 more per 1000 (from 48 fewer to

oplusoplusoplusΟ MODERATE

IMPORTANT

304) 63 more)

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 27258

(105) 15133 (113)

RR 093 (051 to

168)

8 fewer per 1000 (from 74 fewer to

57 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 11152

(72) 15155 (97)

RR 075 (035 to

158)

24 fewer per 1000 (from 87 fewer to

38 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 23308

(75) 21209 (10)

RR 074 (042 to

131)

26 fewer per 1000 (from 76 fewer to

24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11175 (63)

18160 (113)

RR 056 (027 to

115)

50 fewer per 1000 (from 110 fewer to

11 more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2133

(15) 6132 (45)

RR 033 (007 to

161)

30 fewer per 1000 (from 72 fewer to

11 more)

oplusoplusoplusΟ MODERATE

CRITICAL

1 Upper limit of CI suggest potential harm

2 Lower limit of CI suggest no harm

3 Upper limit of CI suggest potential harm

4 Lower limit of CI suggest potential no harm

Question Should Bio mono vs Bio mono be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations

Bio mono

Bio mono

Relative (95 CI) Absolute

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 77163 (472)

45162 (278)

RR 17 (126 to 229)

195 more per 1000 (from 91 more to 298

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1849 (367)

1053 (189)

RR 195 (1 to 38)

179 more per 1000 (from 8 more to 350

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 9162 (56)

10162 (62)

RR 09 (038 to 216)

6 fewer per 1000 (from 57 fewer to 45

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 049

(0) 253

(38) RR 022 (001 to 439)

38 fewer per 1000 (from 100 fewer to 25

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 19162 (117)

16162 (99)

RR 119 (063 to 223)

19 more per 1000 (from 50 fewer to 86

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 049 (0)

153 (19)

RR 036 (002 to 863)

19 fewer per 1000 (from 70 fewer to 33

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Upper limit of CI suggest potential harm for tofacitinib

Question Should Biologic+DMARD vs DMARD be used for Rheumatoid Arthritis [Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 52256 (203)

5133 (38)

RR 54 (221 to

132)

166 more per 1000 (from 107 more to

225 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 28153 (183)

8155 (52)

RR 355 (167 to

753)

131 more per 1000 (from 61 more to

202 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 80298 (268)

10201 (5)

RR 54 (287 to 1016)

219 more per 1000 (from 160 more to

277 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 49170 (288)

6158 (38)

RR 759 (334 to 1723)

250 more per 1000 (from 176 more to

325 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 35132 (265)

11131 (84)

RR 316 (168 to

595)

181 more per 1000 (from 92 more to

270 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 9258

(35) 5133 (38)

RR 093 (032 to

271)

3 fewer per 1000 (from 42 fewer to

37 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 5152

(33) 11155 (71)

RR 046 (016 to 13)

38 fewer per 1000 (from 87 fewer to

11 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8308

(26) 2209

(096) RR 271 (058 to 1265)

16 more per 1000 (from 6 fewer to 39

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 10175

(57) 8160 (5)

RR 114 (046 to

282)

7 more per 1000 (from 41 fewer to

55 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8133

(6) 7132 (53)

RR 113 (042 to

7 more per 1000 (from 48 fewer to

oplusoplusoplusΟ MODERATE

IMPORTANT

304) 63 more)

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 27258

(105) 15133 (113)

RR 093 (051 to

168)

8 fewer per 1000 (from 74 fewer to

57 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 11152

(72) 15155 (97)

RR 075 (035 to

158)

24 fewer per 1000 (from 87 fewer to

38 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 23308

(75) 21209 (10)

RR 074 (042 to

131)

26 fewer per 1000 (from 76 fewer to

24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11175 (63)

18160 (113)

RR 056 (027 to

115)

50 fewer per 1000 (from 110 fewer to

11 more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2133

(15) 6132 (45)

RR 033 (007 to

161)

30 fewer per 1000 (from 72 fewer to

11 more)

oplusoplusoplusΟ MODERATE

CRITICAL

1 Upper limit of CI suggest potential harm

2 Lower limit of CI suggest no harm

Question Should Bio mono vs Bio mono be used for Rheumatoid Arthritis [DMARD failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations

Bio mono

Bio mono

Relative (95 CI) Absolute

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 77163 (472)

45162 (278)

RR 17 (126 to 229)

195 more per 1000 (from 91 more to 298

more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 response af Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1849 (367)

1053 (189)

RR 195 (1 to 38)

179 more per 1000 (from 8 more to 350

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 9162 (56)

10162 (62)

RR 09 (038 to 216)

6 fewer per 1000 (from 57 fewer to 45

more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 049

(0) 253

(38) RR 022 (001 to 439)

38 fewer per 1000 (from 100 fewer to 25

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tocilizumab_8mgkg4 vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 19162 (117)

16162 (99)

RR 119 (063 to 223)

19 more per 1000 (from 50 fewer to 86

more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger Bio mono vs Bio mono [DMARD failure] - Tofacitinib_10mgd vs Adalimumab 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 049 (0)

153 (19)

RR 036 (002 to 863)

19 fewer per 1000 (from 70 fewer to 33

more)

oplusoplusoplusoplus HIGH

CRITICAL

1 Upper limit of CI suggest potential harm for tofacitinib

Question Should Biologic+DMARD vs DMARD be used for Rheumatoid Arthritis [Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 52256 (203)

5133 (38)

RR 54 (221 to

132)

166 more per 1000 (from 107 more to

225 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 28153 (183)

8155 (52)

RR 355 (167 to

753)

131 more per 1000 (from 61 more to

202 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 80298 (268)

10201 (5)

RR 54 (287 to 1016)

219 more per 1000 (from 160 more to

277 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 49170 (288)

6158 (38)

RR 759 (334 to 1723)

250 more per 1000 (from 176 more to

325 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 35132 (265)

11131 (84)

RR 316 (168 to

595)

181 more per 1000 (from 92 more to

270 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 9258

(35) 5133 (38)

RR 093 (032 to

271)

3 fewer per 1000 (from 42 fewer to

37 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 5152

(33) 11155 (71)

RR 046 (016 to 13)

38 fewer per 1000 (from 87 fewer to

11 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8308

(26) 2209

(096) RR 271 (058 to 1265)

16 more per 1000 (from 6 fewer to 39

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 10175

(57) 8160 (5)

RR 114 (046 to

282)

7 more per 1000 (from 41 fewer to

55 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8133

(6) 7132 (53)

RR 113 (042 to

7 more per 1000 (from 48 fewer to

oplusoplusoplusΟ MODERATE

IMPORTANT

304) 63 more)

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 27258

(105) 15133 (113)

RR 093 (051 to

168)

8 fewer per 1000 (from 74 fewer to

57 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 11152

(72) 15155 (97)

RR 075 (035 to

158)

24 fewer per 1000 (from 87 fewer to

38 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 23308

(75) 21209 (10)

RR 074 (042 to

131)

26 fewer per 1000 (from 76 fewer to

24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11175 (63)

18160 (113)

RR 056 (027 to

115)

50 fewer per 1000 (from 110 fewer to

11 more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2133

(15) 6132 (45)

RR 033 (007 to

161)

30 fewer per 1000 (from 72 fewer to

11 more)

oplusoplusoplusΟ MODERATE

CRITICAL

1 Upper limit of CI suggest potential harm

2 Lower limit of CI suggest no harm

Question Should Biologic+DMARD vs DMARD be used for Rheumatoid Arthritis [Biologic failure]

Quality assessment No of patients Effect Quality Importance

No of studies Design Risk of

bias Inconsistency Indirectness Imprecision Other considerations Biologic+DMARD DMARD Relative

(95 CI) Absolute

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 52256 (203)

5133 (38)

RR 54 (221 to

132)

166 more per 1000 (from 107 more to

225 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 28153 (183)

8155 (52)

RR 355 (167 to

753)

131 more per 1000 (from 61 more to

202 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 80298 (268)

10201 (5)

RR 54 (287 to 1016)

219 more per 1000 (from 160 more to

277 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 49170 (288)

6158 (38)

RR 759 (334 to 1723)

250 more per 1000 (from 176 more to

325 more)

oplusoplusoplusoplus HIGH

IMPORTANT

ACR50 respons af Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 35132 (265)

11131 (84)

RR 316 (168 to

595)

181 more per 1000 (from 92 more to

270 more)

oplusoplusoplusoplus HIGH

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 9258

(35) 5133 (38)

RR 093 (032 to

271)

3 fewer per 1000 (from 42 fewer to

37 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 5152

(33) 11155 (71)

RR 046 (016 to 13)

38 fewer per 1000 (from 87 fewer to

11 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8308

(26) 2209

(096) RR 271 (058 to 1265)

16 more per 1000 (from 6 fewer to 39

more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 10175

(57) 8160 (5)

RR 114 (046 to

282)

7 more per 1000 (from 41 fewer to

55 more)

oplusoplusoplusΟ MODERATE

IMPORTANT

Frafald (drop-out) pga bivirkninger Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 8133

(6) 7132 (53)

RR 113 (042 to

7 more per 1000 (from 48 fewer to

oplusoplusoplusΟ MODERATE

IMPORTANT

304) 63 more)

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 27258

(105) 15133 (113)

RR 093 (051 to

168)

8 fewer per 1000 (from 74 fewer to

57 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 11152

(72) 15155 (97)

RR 075 (035 to

158)

24 fewer per 1000 (from 87 fewer to

38 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 23308

(75) 21209 (10)

RR 074 (042 to

131)

26 fewer per 1000 (from 76 fewer to

24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11175 (63)

18160 (113)

RR 056 (027 to

115)

50 fewer per 1000 (from 110 fewer to

11 more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2133

(15) 6132 (45)

RR 033 (007 to

161)

30 fewer per 1000 (from 72 fewer to

11 more)

oplusoplusoplusΟ MODERATE

CRITICAL

1 Upper limit of CI suggest potential harm

2 Lower limit of CI suggest no harm

304) 63 more)

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Abatacept_10mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 27258

(105) 15133 (113)

RR 093 (051 to

168)

8 fewer per 1000 (from 74 fewer to

57 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Golimumab_50mg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 11152

(72) 15155 (97)

RR 075 (035 to

158)

24 fewer per 1000 (from 87 fewer to

38 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Rituximab_2times1000mg 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 23308

(75) 21209 (10)

RR 074 (042 to

131)

26 fewer per 1000 (from 76 fewer to

24 more)

oplusoplusoplusΟ MODERATE

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tocilizumab_8mgkg4 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 11175 (63)

18160 (113)

RR 056 (027 to

115)

50 fewer per 1000 (from 110 fewer to

11 more)

oplusoplusoplusoplus HIGH

CRITICAL

Alvorlige bivirkninger (SAEs) Biologisk+DMARD vs DMARD [Biologic failure] - Tofacitinib_10mgd 1 randomised

trials no serious risk of bias

no serious inconsistency

no serious indirectness

serious1 none 2133

(15) 6132 (45)

RR 033 (007 to

161)

30 fewer per 1000 (from 72 fewer to

11 more)

oplusoplusoplusΟ MODERATE

CRITICAL

1 Upper limit of CI suggest potential harm

2 Lower limit of CI suggest no harm