systemisk lupus erythematosus og andre bindevÆvslidelser · systemisk lupus erythematosus og....

Kristian Stengaard-Pedersen

Reumatologisk afdeling U, Århus Universitetshospital

SYSTEMISK LUPUS ERYTHEMATOSUS OGANDRE BINDEVÆVSLIDELSER

BINDEVÆVSSYGDOMME

BINDEVÆVSSYGDOMME, ANDREPolymyositis, dermatornyositisProgressiv systemisk sklerodermiSjogren's syndromAntifosfolipidsyndrom

VASKULITWegners granulomatoseArteritis temporalisPolymyalgia rheumatica etc.

SYSTEMISK LUPUS ERYTHEMATOSUS (SLE, LED)

BINDEVÆVSSYGDOMME• Fællestræk

Flere organsystemer indvolveretVasculitis er hyppigFasereaktanter ofte forhøjetImmunologiske fund ofte karakteristiske

• ForskelleHvilke organer der rammesKøn og aldersfordelingDe immunologiske fundDen inflammatoriske reaktionsfase(inflammation – fibrose)

EPIDEMIOLOGi

SLE

• 20 – 40 SLE pt. / 100000 i befolkningen

• > 90% er kvinder

• topincidens 20 - 40 år

Prevalence 0.4/1000 inhabitants

Debut 20/40 years

Female:male ratio 9:1

ÅRSAGER TIL SLE KRONISK FORSTYRRELSE I IMMUNFORSVARET

AUTOIMMUNITY

T-CELL TOLERANCE

AUTOIMMUNE DISEASE HOW T-CELL TOLERANCE BREAKS DOWN

Defekt apoptose øget B-lymfocytfunktion

Immunkompleksafhængig inflammation antistofafhængig måldestruktion

strukturel og funktionel cellebeskadigelse

sygdomsmanifestationer

PATOGENESE VED SLEGener, hormoner,

infektioner

hyperimmunoglobulinæmi og

autoantistoffer

IMMUNE COMPLEX ACTIVATION OF INFLAMMATION

AUTOIMMUNE DISEASES DEFINITIONS

AutoimmunityImmunoglobulin antibodies and /or T-lymphocyte receptors against self-antigens

Autoimmune diseasesTissue damage caused by autoimmunity

CLINICAL FEATURES ON PRESENTATION IN SLE

Arthritis or arthralgia 55%

Skin involvement 20%

Nephritis 5%

Fever 5%

Other 15%

ORGANINVOLVEMENT IN SLE

Joints 90%Skin- rashes- discoid lesions- alopecia

70%30%40%

Pleuropericardium 60%Kidney 50%Raynaud’s 20%Mucous membranes 15%

CNS (psychosis/convulsions) 15%

HUDSYGDOM VED SLE

• Photosensitivity • Vascular lesion• Acute, erythematous,

edematous Periungual erythema

Subacute Livedo reticularisAnnular/polycyclic TeleangiectasiaPsoriasiform Raynaud's phenomenonDiscoid VasculitisLupus profundus/panniculitis Urtecaria purpuraNeonatal LE Atrophie blance

• Alopecia Chilblain lupus

Bullous lesions Steroid-induced ecchymoses

Mucous membranes

MUCOCUTANEOUS LESIONS

Systemic lupus erythematosusPhotosensitivity, butterfly rash

Skin biopsy: immunoglobuline and complement deposition

Systemic lupus erythematosus: skalp alopecia

Systemic erythematosus: bullous lesions, palate

RAYNAUD’S FÆNOMENvarme kulde

Normal

Raynaud’s fænomen

Endarteritis

RAYNAUD’S FÆNOMEN

Raynaud's phenomenon

Systemic lupus erythematosus, livedo reticularis

HUDUNDERSØGELSER

• Anamnese og objektiv undersøgelse

• Stansebiopsi

- Histologisk

- Immunfluorescens

Systemic lupus erythematosus: vasculitis

Systemic lupus erythematosus: vasculitis

Systemic lupus erythematosus: vasculitis, digital gangrene

Systemic lupus erythematosus: vasculitis

Systemic lupus erythematosus: vasculitis

Systemic lupus erythematosus: vasculitis

Vasculitis of vasa vasorum• Sensory neuropathy• Mononeuritis muliplex

Systemic lupus erythematosus

Vasculitis ved SLE

• Huden afficeres hyppigst

• Cor, lunger, CNS / perifere nerver mv.

afficeres også og hyppigt livstruende

KNOGLER OG LED

MUSKLER OG SENER

LED, SENER OG MUSKLER

• Artralgier

• Polyartrit, specielt hænder og knæled

• Osteonekrose

• Tendosynovit

• Myalgier / myosit

SLE RA

Arthralgia Common Common• Arthritis Common Deforming

Symmetry Yes Yes

• Joints involved PIP>MCP >wrist>knee MCP>wrist >knee

• Synovial hypertrophy Rare CommonSynovial membrane abnormality Minimal Proliferative

• Synovial fluid Transudate Exudate• Subcutaneous nodules Rare 35%• Erosions Very Rare Common

Morning stiffness Minutes HoursMyalgia Common CommonMyositis Rare UncommonOsteoporosis Variable CommonAvascular necrosis 5-50% UncommonDeforming arthritis Uncommon CommonSwan neck 10% CommonUlnar deviation 5% Common

MUSKULOSKELETAL MANIFESTATIONS IN SLE

Systemic lupus erythematosus: arthritis

Systemic lupus erythematosus: Charcot's artropathy

Systemic lupus erythematosus: knee pain / avascular necrosis

Systemic lupus erythematosus: shoulder pain / avascular necrosis

Systemic lupus erythematosus: hip pain / avascular necrosis, scintigraphy

BEVÆGEAPPARATSUNDERSØGELSER• Anamnese, objektiv undersøgelse

• Blodanalyser: fasereaktanter, leukocytter etc.

• Ledvæskeundersøgelse

• Billeddiagnostiske undersøgelser

- Konventionel røntgen

- Ultralydscanning

- MR-scanning

- Scintigrafi

SYGDOM I INDVENDIGE ORGANER VED SLE

LUNGER OG HJERTE• Pleuritis

• Lungefibrose

• Pulmonal hypertension

• Pericarditis

• Mitralklapsygdom / vegetationer

• Myokardieinfarkt

• Hjerteinsufficiens

Systemic lupus erythematosus: pleuritis and pericarditis

Systemic lupus erythematosus: pulmonary vasculitis

Systemic lupus erythematous: vasculitis

Histology Immunofluorescens

LUNGEUNDERSØGELSER

• Anamnese, objektiv undersøgelse

• Lungefunktionsundersøgelse

• Konventional røntgen

• HR-CT-scanning

• BAL, transbronkial biopsi

• Torakoskopisk biopsi

Systemic lupus erythematosus: premature atherosclerosisAngina, myocardial infarction, heart failure

Systemic lupus erythematosus: Libman - Sacks endocarditis

HJERTEUNDERSØGELSER

• Anamnese, objektiv undersøgelse

• Ekg, røntgen af thorax

• Ekkokardiografi

NYRESYGDOM VED SLE

SYSTEMIC LUPUS ERYTHEMATOSUS: RENAL HISTOLOGY• Normal light microscopy, but immunoglobulin

or complement protein deposits present

• Mesangial lupus nephritis

• Mild focal glomerulonephritis

• Diffuse proliferative glomerulonephritis

• Membranous glomerulonephritis

• Interstitial and tubular nephritis

Systemic lupus erythematosus: mesangial glomerulonephritis

Systemic lupus erythematosus: focal glomerulonephritis

Systemic lupus erythematosus: focal glomerulonephritis

Systemic lupus erythematosus: immunoglobulin and complement deposition

Systemic lupus erythematosus: electron micrograph of glomerulonephritis

NYREUNDERSØGELSER

• Anamnese, objektiv undersøgelse

• S-kreatinin, kreatinin clearance

• Døgnurin-protein, U-sediment

• Blodtryksmåling

• Nyrebiopsi

SLE SYGDOM I HJERNE, RYGMARV OG PERIFERE NERVER

CNS LUPUS• Central nervous system

EpilepsyHemiparesisCranial nerve lesionsBrain stem/cord lesionsAseptic meningitisTransverse myelitis

• Peripheral nervous systemPeripheral neuropathiesMyasthenia gravisMononeuritis multiplex

• PsychiatricDisorders of mental function

- organic- non-organic

Systemic lupus erythematosus: MRI of the brain White matter lesions: microinfarcts or vasculitis

Systemic lupus erythematosus: MRI of the brain

T1-weigthed, cerebral vasculitis T2-weigthed, cerebral vasculitis

NERVESYSTEMSUNDERSØGELSER

• Anamnese, objektiv undersøgelse

• MR-scanning

• Cerebrospinalvæskeundersøgelser

• Neurofysiologiske undersøgelser

• N. suralisbiopsi

Acute episodes Chronic morbidity

Glomerulonephritis End-stage renal disease, dialysis, transplantation

Vasculitis Atherosclerosis, venous syndromes, pulmonary emboli

Arthritis Osteonecrosis

Cerebritis Neuropsychiatric dysfunction

Pneumonitis Shrinking lung syndrome

LATE COMPLICATIONS OF SLE

FREQUENCY OF CLINICAL SYMPTOMS IN SLE AT ANY TIME

Symptoms Percentage● Fatigue 80-100

Fever >80Weight loss >60

● Arthritis, arthralgia 95● Skin >80

Butterfly rash >50Photosensitivity <58Mucous membrane lesion 27-41

Alopecia <71Raynaud's phenomenon 17-30Purpura 15Urticaria 8

FREQUENCY OF CLINICAL SYMPTOMS IN SLE AT ANY TIME

Symptoms % Symptoms %

● Renal 50 Murmurs 23

Nephrosis 18 ECG changes 34-70

● Gastrointestinal 38 ● Lymphadenopathy 50

● Pulmonary 0.9-98 ● Splenomegaly 10-20

Pleurisy 45 ● Hepatomegaly 25

Effusion 24 ● Central nervous system 25-75

Pneumonia 29 ● Functional most

● Cardiac 46 Psychosis 5-52

Pericarditis 8-48 Convulsions 15-20

BLODPRØVER VED SLE

BLODPRØVER• C-reaktivt protein (blodsænkning)

• Hæmoglobin (blodprocent)

• Antistoffer

IgG, ANA, anti-DNA

• Komplement C3 og C4

• Erytrocytter, leukocytter, trombocytter

• S-kreatinin, kreatinin clearance (nyrefunktion)

• Urin for protein og blod

FOREKOMST OG REAKTIVITET AF ANTINUKLEÆRE ANTISTOFFER VED INFLAMMATORISKE REUMATISKE SYGDOMME

Sygdom Hyppighed af ANA (%) Positivitet/titer

SLE 95 stærk/høj*

Medikamentel LE 95 stærk/høj

MCTD 95 stærk/høj

Sklerodermi 90 stærk/høj

Primær SS 80 stærk/høj

PM/DM 40 middel/middelhøj**

RA 50 middel/middelhøj

Juvenil RA 70 middel/middelhøjUgeskrift for læger; 2002:610-14, Allan Wiik*) 1.280

**) 320-640

Antigen Sygdom Sensitivitet SpecificitetKerneantigen i RA 50-75 ModeratGranulocytter og monocytter* Feltys syndrom -100 ModeratHistoner Med. SLE 90 Lavds-dna** SLE 50-60 Højn-RNP*** MCTD 100 LavSm SLE 15-30 Meget højSSA Primær Sjögren 80-100 LavSSB Primær Sjögren 70-95 LavScl-70 Sklerodermi 20-60 HøjCentromer CREST**** 60-90 Høj

* Antistoffet: GS-ANA** ds-DNA: dobbeltstrenget DNA*** n-RNP: nukleaert ribonukleoprotein**** Undergruppe af sklerodermi med kalcinose, Raynauds fænomen,

esophagusdysmotilitet, sklerodaktyli og teleangiektasier

FOREKOMST AF ANTINUKLEÆRE ANTISTOFFER

Negativ

ANA, hep-2-celler

Positiv

Anti-DNA Anti-ENA Anti-SSB

SLE

Sm Anti-RNP

SLE Sklerodermi, MTC, andre

Sjögren

ANTINUKLEÆRE CELLER

AUTOANTIBODY-DISEASE ASSOCIATIONS:SLE AND DRUG-INDUCED LUPUSAntigen SLE Drug-induced LE

Native DNA 40% No

Denatured DNA 70% 75-80%

Histones 70% >95%

SM Antigen 30% No

Nuclear RNP 30% No

Ribosomal RNP 10%

SS-A/RO 35% No

SS.B/La 15% No

CLINICAL MANIFESTATIONSSUMMARY

• Fatigue, artralgia / arthritis, rash (all)

• Lympho-, neutro-,trombocytopenia

complement low, anti-DNA high (all)

• Renal-, CNS-, Cardio-pulmonary

manifestations (feared by all)

DIAGNOSEN SLE

4 ud af 11 bestemte sygdomstræk og abnormiteter i blodprøver skal være tilstede for at diagnosen kan stillesOftest en speciallægeopgave at stille diagnosen

SLE: 1982 CLASSIFICATION CRITERIA*Malar rash

Renal disorder

Neurologic disorder

Hematologic disorder

Immunologic disorder

Antinuclear antibody

Discoid rash

Photosensitivity

Oral ulcers

Arthritis

SerositisACR *Must have four criteria simultaneously or serially

SYSTEMIC LUPUS ERYTHEMATOSUS1982 CLASSIFICATION CRITERIA DEFINITIONS(continued)

Oral or nasopharyngeal ulcers

Usually painless

Arthritis Non-erosive, inflammatory in two or more peripheral joints

Serositis Pleuritis or pericarditis

SYSTEMIC LUPUS ERYTHEMATOSUS1982 CLASSIFICATION CRITERIA DEFINITIONS(continued)

Renal disorder Persistent proteinuria or cellular casts

Neurologic disorder Seizures of psychosis

Hematologic disorder

Hemolytic anemia,Leukopenia (>4,000/mm3)Lymphopenia (>1,500/mm3),or thrombocytopenia (>100,00/mm3)

SYSTEMIC LUPUS ERYTHEMATOSUS1982 CLASSIFICATION CRITERIA DEFINITIONS(continued)

Immunologic disorderantibodies to aca or ds-DNA or SM or false positive serologic test for syphillis

Antinuclear antibody test Positive

ANTI-PHOSPHOLIPID ANTIBODY TESTS

• Lupus anticoagulant: prolonged PTT or PT not corrected by adding normal plasma

• Anti-cardiolipin antibody by ELISA

• VDRL positive, FTA-ABS negative

BEHANDLING AF SLE

Ingen livs- eller organtruende sygdom

•Simple analgetika

•NSAID

•OH-klorokinfosfat

• Lokale steroider

• SolbeskyttelsesfaktorPlus livs- eller organtruende sygdom

• Glukokortikoider

• Immunodepressiva- Azathioprin, MTX- Cyklofosfamid- Rituximab

Antifosfolipidantistoffer + trombose

- AK behandling- Rituximab

Symptomatisk behandling

• Hypertension

• Infektion

• Nyreinsufficiens

• Raynaud’s fænomen

NO LIFE OR ORGAN THREATENING DISEASE ACTIVITY

• Tabl. chloroquine phosphate 250 mg daily

• NSAID, simple analgesics

• Local steroids, chemical sun protection

TREATMENT OF SLE - LIFE-THREATENING DISEASE ACTIVITY

Indications: Vasculitis, glomerulonephritis

Treatment: Glucocorticoids, cyclophosphamide

Tabl. prednisolone 1-2 mg / kg / daily

and / or

methylprednisolone i.v. 1000 mg daily times three every fourth week

and

reduce dose after few weeks, maintenance dose tabl. prednisone 7,5 – 15 mg daily

Tabl. Cyclophosphamide 1-2 mg / kilo daily

or

cyclophosphamide i.v. 1000 mg / m2 body surface every four week for 6 –12 months

Azathioprine 1 – 2 mg / kg / daily or methotrexate 1o – 25 mg once weekly can after 6 – 12 months substitute cyclophosphamide

GRAVIDITET VED SLE

SLE OG GRAVIDITET

• SLE-aktivitet, præeklampsi

• Sen abort, tidlig fødsel / lille barn ( APS )

• Kongenit AV blok (anti-SSA / SSB )

• Kongenit SLE

SLE OG GRAVIDITET

• Us. for klinisk og biokemisk sygdomsaktivitet

Ro i >1år før graviditet

• IgM og IgG antikardiolipin ab

beta-2-GP-1 ab, lupus antikoagulans

• anti-SSA / SSB

hæmolyse, penier i blodbilledet,ændring i C3 / C4 og anti-DNA

SLE OG GRAVIDITET

ALTID

• Us. for klinisk og biokemisk sygdomsaktivitet

Ro i >1år før graviditet

• Hyppig kontrol reumatologisk / obstetrisk

Klinisk, biokemisk, UL

LUPUS-LIKE SYNDROMS: DRUGS IMPLICATED IN INDUCTION

Common Rare

Procainamide Beta-blockers

Hydralazine D-penicillamineIsoniazidQuinidinePropylthiouracilHydantoinsTrimethadioneChlorpromazine

LUPUS-LIKE SYNDROMS: DRUGS IMPLICATED IN INDUCTION (continued)

Ambiguous or single case reportsAllopurinol MethysergideChlorprothixene MethylthiouracilEstrogen/progestin PhenylbutazoneEthylphenacemide PrimidoneGold salts PropafenoneGriseofulvin ReserpineMethyldopa Streptomycin

Tetracycline

Kristian Stengaard-Pedersen

Reumatologisk afdeling U, Århus Universitetshospital

SYSTEMISK LUPUS ERYTHEMATOSUS OGANDRE BINDEVÆVSLIDELSER