igra in the face of immune modifiers - uc san diego ... · pdf file3rd global symposium on...

3rd Global Symposium on

IGRAs 2012

IGRA in the face of IGRA in the face of Immune ModifiersImmune Modifiers

Stephan D. Gadola, DM, PhD, FRCPProfessor of Immunology & Consultant RheumatologistFaculty of Medicine, University of Southampton, UK

[email protected]

before we start… !

TST LTBITST+ ≠ LTBI

IGRA+ ≠ LTBI

TST+ ≠ IGRA+

LTBI

TST+ IGRA+LTBI

LTBI

Stress,DepressionStress,Depression, ,

“Immune Modifiers”“Immune Modifiers”

Drugs (DMARDs, Drugs (DMARDs, Biologics, others)Biologics, others)

IMID: Immune mediated IMID: Immune mediated inflammatory diseasesinflammatory diseases

sleep disturbance, sleep disturbance, anxiety, PTSD, etc.anxiety, PTSD, etc.

Aromatic hydrocarbons, Aromatic hydrocarbons, smoking, heavy metals, etc.smoking, heavy metals, etc.

and many others….

Stress,DepressionStress,Depression, ,

“Immune Modifiers”“Immune Modifiers”

Drugs (DMARDs, Drugs (DMARDs, Biologics, others)Biologics, others)

IMID: Immune mediated IMID: Immune mediated inflammatory diseasesinflammatory diseases

sleep disturbance, sleep disturbance, anxiety, PTSD, etc.anxiety, PTSD, etc.

Aromatic hydrocarbons, Aromatic hydrocarbons, smoking, heavy metals, etc.smoking, heavy metals, etc.

and many others….

ContentContent

•• Special aspects Special aspects of of TB screening in TB screening in IMIDIMID

•• ReliabilityReliability ofof the TST inthe TST in this settingthis setting•• ReliabilityReliability of of the TST in the TST in this setting this setting

•• Are Are IGRAIGRAmore reliable more reliable in in immunocompromisedimmunocompromised patients ?patients ?

•• How How safesafe it is to it is to base base treatment decisions treatment decisions on on either the TST either the TST or IGRA in IMID patients awaiting TNFor IGRA in IMID patients awaiting TNFαα blocker therapy blocker therapy ??

•• How useful are IGRA and the TSTHow useful are IGRA and the TST forfor repeated testingrepeated testing duringduringHow useful are IGRA and the TST How useful are IGRA and the TST for for repeated testing repeated testing during during TNFTNFαα blocker therapy blocker therapy ??

•• Are Are currentcurrent cutcut‐‐off levels off levels for for IGRA (QFT) testing appropriate ?IGRA (QFT) testing appropriate ?

•• CostCost‐‐effectivenesseffectiveness of TST of TST and IGRA in IMID patients and IGRA in IMID patients ??

Importance of TB screening in IMID Importance of TB screening in IMID and immunosuppressed patientsand immunosuppressed patients

Pulmonary TB in Pulmonary TB in immunocompromisedimmunocompromised patientspatients

• often misdiagnosed as pneumonia misdiagnosed as pneumonia at admission

• more likely to be smearsmear‐‐positivepositive

• more likely to be TSTTST‐‐

• more likely to have respiratory symptomsrespiratory symptoms

• typically in a hyponutritionalhyponutritional state state

•• atypical atypical radiological radiological findings findings – e.g. less often cavities or calcification

•• increased mortality increased mortality raterate

Kobashi Y, et al. J Infect Chemother 2007; 13:405‐10.

Rheumatoid ArthritisRheumatoid Arthritis Ankylosing SpondylitisAnkylosing Spondylitis

TNFα in chronic inflammatory diseases

Crohn’s diseaseCrohn’s diseasePsoriasisPsoriasis

• N Engl J Med 2001;345:1098–104. Tuberculosis associated with infliximab, a tumor necrosis factor ‐neutralizing agent. Keane J, Gershon S, Wise RP, Mirabile‐Levens E, Kasznica J, Schwieterman WD, et al.

• Arthritis Rheum 2003; 48:2122–7. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenteractive‐surveillance report. Gomez‐Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD,

• N Engl J Med 2001;345:1098–104. Tuberculosis associated with infliximab, a tumor necrosis factor ‐neutralizing agent. Keane J, Gershon S, Wise RP, Mirabile‐Levens E, Kasznica J, Schwieterman WD, et al.

• Arthritis Rheum 2003; 48:2122–7. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenteractive‐surveillance report. Gomez‐Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD,

TNFTNFαα‐‐blocking therapy and ↑↑TB risk in RA patientsblocking therapy and ↑↑TB risk in RA patients

p , , , , ,on behalf of the BIOBADASER Group.

• Lancet Infect Dis 2003;3:148–55. Anti‐tumor necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, et al.

• Arthritis Rheum 2003; 48:35–45. Adalimumab, a fully human anti–tumor necrosis factor monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, et al.

• Arthritis Rheum 2004;50:372–9 Tuberculosis infection in patients with rheumatoid arthritis

p , , , , ,on behalf of the BIOBADASER Group.

• Lancet Infect Dis 2003;3:148–55. Anti‐tumor necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, et al.

• Arthritis Rheum 2003; 48:35–45. Adalimumab, a fully human anti–tumor necrosis factor monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, et al.

• Arthritis Rheum 2004;50:372–9 Tuberculosis infection in patients with rheumatoid arthritisArthritis Rheum 2004;50:372 9. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Wolfe F, Michaud K, Anderson J, Urbansky K.

• Arthritis Rheum 2005;52:1986‐92. Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden. Askling J, Fored CM, Brandt L, et al.

• Ann Rheum Dis 2006;65:889–94. Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Schiff MH, Burmester GR, Kent JD, Pangan AL, Kupper H, Fitzpatrick SB, et al.

Arthritis Rheum 2004;50:372 9. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Wolfe F, Michaud K, Anderson J, Urbansky K.

• Arthritis Rheum 2005;52:1986‐92. Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden. Askling J, Fored CM, Brandt L, et al.

• Ann Rheum Dis 2006;65:889–94. Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Schiff MH, Burmester GR, Kent JD, Pangan AL, Kupper H, Fitzpatrick SB, et al.

aand others…nd others…aand others…nd others…

Global TB BurdenGlobal TB Burden& use of & use of TNFTNFαα blockersblockers

Source: World Lung Foundation (http://www.ariatlas.org/maps?id=0006)

Country TB/105 Pat. TB/105 Pat. Ratio

AntiAnti--TNFTNFαα--Therapy increases TBTherapy increases TB--RiskRisk

+ anti-TNFα Background*

Europe (all) 150 20 7.5

USA 37 6.2 6

S i 1540 134 11 5Spain 1540 134 11.5

* Patients with Rheumatoid Arthritis

Data from FDA (08/02) & BIOBADASER/EMECAR study group

Drug Treated patients

TB cases Per 100.000(projected)

AntiAnti--TNFTNFαα--Therapy increases TBTherapy increases TB--RiskRisk

(p j )

Infliximab 924 6 640

Adalimumab prior screening

524 8 1500

Adalimumabafter screening

with the TST

1900 5 263

Projections based on data published by Winthrop K, et al. 2005

TB risk in Rheumatoid ArthritisTB risk in Rheumatoid ArthritisA systematic review of 14 Medline articlesA systematic review of 14 Medline articlesRA unexposed to TNFα blockers: TB risk ↑ 2 RA unexposed to TNFα blockers: TB risk ↑ 2 ‐‐ 10x 10x

RA exposed to TNFα blockers: TB risk ↑ 2 RA exposed to TNFα blockers: TB risk ↑ 2 ‐‐ 4x 4x pp(incidence 9.3 to 449/100,000 according to country, observation period and type of TNFα blocker)

greater risk with monoclonal antibodies greater risk with monoclonal antibodies

RRecommendations may have decreased TB risk of ecommendations may have decreased TB risk of TNFα blockerTNFα blocker threrapythrerapy

Baronnet L, et al. Joint Bone Spine. 2011;78:279‐84.

TNFα blocker TNFα blocker threrapythrerapy

Alternative explanation: Inclusion of flawed studies… ?Alternative explanation: Inclusion of flawed studies… ?

Mohan AK, et al. Clin Infect Dis 2004; Gomez‐Reino JJ, et al. Arthritis Rheum 2003; Keane, et al, NEJM 2001

NO TIME to...NO TIME to...

Diagnose Diagnose latent TB before TNFlatent TB before TNFαα--Inhibitor therapy !Inhibitor therapy !

How reliable is the TST in IMID How reliable is the TST in IMID +/+/-- immunesuppressiveimmunesuppressive therapy ?therapy ?

Felix Felix Mendel Mendel 19081908 20122012

19481948

TST = TST = Delayed type hypersensitivity (DTH)Delayed type hypersensitivity (DTH)

mechanicalmechanicaltoxic (Phenol)toxic (Phenol)

Mediator releaseMediator release•• TNFTNFαα (Mast cells)(Mast cells)Mediator releaseMediator release•• TNFTNFαα (Mast cells)(Mast cells)

ccontained in ontained in PPD ?PPD ?

•• TNFTNFαα (Mast cells)(Mast cells)•• EicosanoidsEicosanoids•• HistaminHistamin, , a.o.a.o.

•• TNFTNFαα (Mast cells)(Mast cells)•• EicosanoidsEicosanoids•• HistaminHistamin, , a.o.a.o.

MØMØMZMZ

Early immigrantsEarly immigrants(< 6h)(< 6h)

MM

L t i i tL t i i t

NKTNKTNKNK

Cytokines/EnzymesCytokines/Enzymes•• Interleukins, IFNsInterleukins, IFNs•• ProteasesProteases•• ChemokinesChemokines


Antigen ProcessingAntigen Processing& P t ti& P t tiAntigen ProcessingAntigen Processing& P t ti& P t ti

Inna

teInna

teAda

ptive

Ada

ptive

DCDC

Later immigrantsLater immigrants(12 (12 -- 48h)48h)

BB

DCDC TTTTTT

TTTT

TT

MM

MM

TT

TTTT MM

MM

& Presentation& Presentation& Presentation& Presentation

Poulter et al., 1982; Scheynius et al., 1982; Platt et al., 1983

AA

•• Hydrocortisone, cyclophosphamide, azathioprine and Hydrocortisone, cyclophosphamide, azathioprine and methotrexate methotrexate depressed DTH to intradermal depressed DTH to intradermal ovalbumin ovalbumin in rats sensiti ed to OA in Freund's complete adjuvantin rats sensiti ed to OA in Freund's complete adjuvant11

•• Hydrocortisone, cyclophosphamide, azathioprine and Hydrocortisone, cyclophosphamide, azathioprine and methotrexate methotrexate depressed DTH to intradermal depressed DTH to intradermal ovalbumin ovalbumin in rats sensiti ed to OA in Freund's complete adjuvantin rats sensiti ed to OA in Freund's complete adjuvant11

Skin DTH is compromised in immunosuppressed Skin DTH is compromised in immunosuppressed experimental animals under controlled conditionsexperimental animals under controlled conditions

in rats sensitized to OA in Freund's complete adjuvantin rats sensitized to OA in Freund's complete adjuvant11

– the degree of depression varied with the time of drug administration relative to sensitization and challenge, and the dose of drug used.

•• LowLow‐‐dose dose intermittent methotrexate intermittent methotrexate ((MTX; analogous MTX; analogous to to its use in rheumatoid arthritis) has immunosuppressiveits use in rheumatoid arthritis) has immunosuppressive

in rats sensitized to OA in Freund's complete adjuvantin rats sensitized to OA in Freund's complete adjuvant11

– the degree of depression varied with the time of drug administration relative to sensitization and challenge, and the dose of drug used.

•• LowLow‐‐dose dose intermittent methotrexate intermittent methotrexate ((MTX; analogous MTX; analogous to to its use in rheumatoid arthritis) has immunosuppressiveits use in rheumatoid arthritis) has immunosuppressive

1 Int Arch Allergy Appl Immunol. 1979;60(1):50‐9.2 J Rheumatol. 1986 Aug;13(4):710‐4.

its use in rheumatoid arthritis) has immunosuppressive its use in rheumatoid arthritis) has immunosuppressive effects on the induction of primary DTH in normal effects on the induction of primary DTH in normal micemice22. . – even if last MTX injection was 4 days before immunization– No effect was seen on established DTH

its use in rheumatoid arthritis) has immunosuppressive its use in rheumatoid arthritis) has immunosuppressive effects on the induction of primary DTH in normal effects on the induction of primary DTH in normal micemice22. . – even if last MTX injection was 4 days before immunization– No effect was seen on established DTH

TST (PPD) in 105 RA TST (PPD) in 105 RA patients under treatment with patients under treatment with DMARDs (Methotrexate, MTX) and SteroidsDMARDs (Methotrexate, MTX) and Steroids

In Argentina (TB Incidence 30In Argentina (TB Incidence 30‐‐80/100,000; all BCG vaccinated)80/100,000; all BCG vaccinated)

87 680809090100100

ss

69.5

87.6

12 410102020303040405050606070708080

% of R

A patients

% of R

A patients

12.400

PPD 0mmPPD 0mm PPD <5mmPPD <5mm PPD >5mm≥PPD >5mm≥

MTX and MTX and higher steroid dose were significantly associated with higher steroid dose were significantly associated with anergyanergy

Tamborenea MN, et al. Rheumatol Int. 2010; 30:613‐6.

Cutaneous Cutaneous anergyanergy in 20 in 20 –– 50% of RA patients !50% of RA patients !

Andrianakos AA, et al. Ann Rheum Dis. 1977 Feb;36(1):13‐20.

Kaćaki J, et al. Rheumatology. 1975;6:72‐9.‐ PHA and PPD skin DTH (Mantoux) in 30 RA greatly reduced (vs controls)

Pre‐DMA

Epstein, W. L. and Jessar, R.A., Arthritis & Rheumatism 1959; 2: 178–181Contact‐type delayed hypersensitivity in patients with rheumatoid arthritis.

Emery P, et al. Ann Rheum Dis. 1984 Jun;43(3):430‐4.‐ 104 RA patients, 67 controls‐ Anergy to 7 antigens (Multitest CMI) in 36% of RA pat., 0% of controls

, ; ( )‐ 107 RA patients, 94 controls‐ Anergy to 6 antigens (Mantoux Method) in 20% of RA patients

Helliwell M G, et al. Clin Rheumatol 1984; 3: 39– 45.‐ 50 RA patients , 50 matched controls‐ Anergy to 7 antigens (Multitest CMI) in 24% of patients

ARD

Pre‐Biolog

‐ 26 early RA patients and controls‐ Anergy to 7 antigens (Multitest CMI) in 50%, compared to 7% of controls

Paimela L, et al. Clin Exp Rheumatol 1990; 8: 433– 437.

Coaccioli S, et al. Panminerva Med 2000; 42:263‐6. ‐ 48 early untreated RA and matched controls‐ Anergy to 7 antigens (CMI) in 43.75% RA, compared to 2% of controls

aand others…nd others…aand others…nd others…

icsEarly RA

Early RA

TST is suppressed in inflammatory bowel diseaseTST is suppressed in inflammatory bowel disease

82 IBD82 IBD

PPD (TST)PPD (TST) ControlControl AgsAgs8282

PPD (TST) PPD (TST)

0%0% 100%100%

TST+TST+ TSTTST‐‐

4848

on on DMARDs DMARDs a/o steroidsa/o steroidsuntreateduntreated

2121

6969Control Control AgsAgs((MantouxMantoux))

Mow WS, et al. Clin Gastroenterol Hepatol. 2004 ;2:309‐313

Anergy:Anergy: 443%3% 883%3%p<0.002p<0.002

Suppressed TST in IMID (RA)Suppressed TST in IMID (RA)Example 1: Example 1: Ponce de León Ponce de León D, et al. D, et al. Ann Rheum Dis. Ann Rheum Dis. 20052005 ;64:1360;64:1360‐‐11PPD PPD in in 112 112 RA and 96 matched RA and 96 matched controlscontrolsTB TB endemic endemic area (TBarea (TB‐‐Incidence 130/10Incidence 130/1055), ), BCG BCG vaccination policyvaccination policy

Example 1: Example 1: Ponce de León Ponce de León D, et al. D, et al. Ann Rheum Dis. Ann Rheum Dis. 20052005 ;64:1360;64:1360‐‐11PPD PPD in in 112 112 RA and 96 matched RA and 96 matched controlscontrolsTB TB endemic endemic area (TBarea (TB‐‐Incidence 130/10Incidence 130/1055), ), BCG BCG vaccination policyvaccination policy

TST less likely to be positive in RATST less likely to be positive in RA Weaker TST reaction in RAWeaker TST reaction in RA

29 4

74

40

60

80

ST+ subjects

ST+ subjects

P < 0.01P < 0.01 11.5

4

6

8

10

12

diam

eter (m

m)

diam

eter (m

m)

P < 0.01P < 0.01

TST less likely to be positive in RATST less likely to be positive in RA Weaker TST reaction in RAWeaker TST reaction in RA

29.4

0

20

RARA ControlsControls

% TS

% TS

4.5

0

2

RARA controlscontrols

TST d

TST d

Results were not Results were not influenced by disease activity or duration of influenced by disease activity or duration of RARA

Reduced skin DTH (PPD) in Japanese Reduced skin DTH (PPD) in Japanese RA patients with previous TBRA patients with previous TB

5050

6060

previous TBprevious TB

1010

2020

3030

4040

%

ppno TBno TB

00TST >10mmTST >10mm TST > 20mmTST > 20mm TST > 30mmTST > 30mm

Maeda T, et al. J Infect Chemother. 2011 Apr 29. [Epub ahead of print].

Data suggest that in BCG vaccinated RA the TST does not Data suggest that in BCG vaccinated RA the TST does not discriminate patients with and without LTBIdiscriminate patients with and without LTBI

British Thoracic British Thoracic Society 2005Society 2005

“Th TST“Th TST i h l f l di h l f l d h ldh ld“Th TST“Th TST i h l f l di h l f l d h ldh ld“The TST “The TST is not helpful and is not helpful and should not should not

be be performed in low TB risk performed in low TB risk patientspatients

with a normal chest with a normal chest XX‐‐ray who are ray who are on on immunosuppressive therapy.”immunosuppressive therapy.”

“The TST “The TST is not helpful and is not helpful and should not should not

be be performed in low TB risk performed in low TB risk patientspatients

with a normal chest with a normal chest XX‐‐ray who are ray who are on on immunosuppressive therapy.”immunosuppressive therapy.”

Thorax 60:800–805. Thorax 2005;60:800‐5. Joint Tuberculosis Committee of the British Thoracic Society (2005) BTS recommendations for assessing risk and for managing

M. tuberculosis infection and disease in patients due to start anti‐TNF‐alpha treatment. Ormerod LP, Milburn HJ, Gillespie J, Ledingham J, Rampton D.

Are IGRA more reliable than the TST Are IGRA more reliable than the TST in IMID +/in IMID +/‐‐ Immunosuppression ?Immunosuppression ?

mechanicalmechanicaltoxic (Phenol)toxic (Phenol)

Mediator releaseMediator releaseMediator releaseMediator release

ccontained in ontained in PPD ?PPD ?

•• TNFaTNFa (Mast cells)(Mast cells)•• EicosanoidsEicosanoids•• HistaminHistamin, , a.o.a.o.

•• TNFaTNFa (Mast cells)(Mast cells)•• EicosanoidsEicosanoids•• HistaminHistamin, , a.o.a.o.

MØMØMZMZ

Early immigrantsEarly immigrants(< 6h)(< 6h)

MM

L t i i tL t i i t

NKTNKTNKNK



Antigen ProcessingAntigen ProcessingAntigen ProcessingAntigen Processing

DCDC

Later immigrantsLater immigrants(12 (12 -- 48h)48h)

BB

DCDC TTTTTT

TTTT

TT

MM

MM

TT

TTTT MM

MM

g gg g& Presentation& Presentation

g gg g& Presentation& Presentation

Poulter et al., 1982; Scheynius et al., 1982; Platt et al., 1983

Mechanisms of TST (skin DTH) Mechanisms of TST (skin DTH) vsvs IGRAIGRA

Mechanism required TST (skin DTH) IGRA

Antigen injected in vivo Yes No

A ti dd d i N YAntigen added ex vivo No Yes

Recruitment of leukocytes to injection

Neutrophils, Monocytes,T‐cells, plasmacytoid DC, myeloid DC, B‐cells (few)

No

Antigen uptake by APC Yes Yes

Antigen processing +++ + (synth.peptides)Antigen processing (synth.peptides)

Secretion of cytokinesand/or chemokines

TNFα, IFNγ and others IFNγ

DC migration to SLO* Yes No

*SLO: secondary lymphoid organs

PPDPPD CFPCFP‐‐1010

ation

ation

ssay)

ssay)

AntigenAntigen

Peripheral blood TPeripheral blood T‐‐cell responses to PPD and TBcell responses to PPD and TB‐‐specific specific antigens in IMID with or without previous TBantigens in IMID with or without previous TB

Prolife

raProlife

ra(PKH

(PKH

‐‐26 a

26 a

secretion

secretion

LISPOT)

LISPOT)

iin vitro

n vitro assays

assays

TT‐‐cell function

cell function

IFN

IFNγγss

(EL

(EL

previous TB previous TB ‐‐ + + ‐‐ + + ‐‐ + + ‐‐ + + ‐‐ + + ‐‐ + + ‐‐ + + ‐‐ + + ‐‐ + + ‐‐ ++

Hamdi H, et al. Arthritis Res Ther 2006; 8:R114

QFTQFT‐‐2G 2G vsvs TST to detect active TB in TST to detect active TB in 32 immunosuppressed patients32 immunosuppressed patients

TST+ TST T t l QFTTST+ TST T t l QFTTST+ TST‐ Total QFT

QFT+ 15 10 25

QFT‐ 0 2 2

IDR 1 4 5

TST+ TST‐ Total QFT

QFT+ 15 10 25

QFT‐ 0 2 2

IDR 1 4 5

Total TST 16 16 32active TB

Total TST 16 16 32active TB

Kobashi Y, Mouri K, Obase Y, et al. Eur Respir J 2007; 30:945‐50.

Performance of QFT Performance of QFT vsvs TST in 32 Japanese TST in 32 Japanese immunocompromisedimmunocompromised patients with active TBpatients with active TB

(BCG(BCG‐‐vaccinated population)vaccinated population)

69.469.470

80

15.615.615.715.710 710 7

20

30

40

50

60

70

B incide

nce (%

)B incide

nce (%

) QFT TST

1.11.110.710.7

0

10

positive testpositive test negative testnegative test QFT IDRQFT IDR

TBTB

Kobashi Y, Mouri K, Obase Y, et al. Eur Respir J 2007; 30:945‐50.

NA

Accuracy of IGRA Accuracy of IGRA vsvs TST to identify TST to identify LTBILTBIin IMID/immunosuppressed patients ?in IMID/immunosuppressed patients ?

??Sensitivity: Correlation with TB risk ?Sensitivity: Correlation with TB risk ?

Specificity: Correlation with BCG vaccination status ?Specificity: Correlation with BCG vaccination status ?

??

Is it safe to base treatment decisions in IMID on the TST ?Is it safe to base treatment decisions in IMID on the TST ?

Is it safe to base treatment decisions in IMID on IGRA ?Is it safe to base treatment decisions in IMID on IGRA ?

QFT indeterminate results: QFT indeterminate results: RA: 1.9%; Healthy: 0%RA: 1.9%; Healthy: 0%Prednisone (< 10mg/d): Prednisone (< 10mg/d): RA: 91%RA: 91%

TST TST vsvs QFTQFT‐‐IT in RA (n=101) IT in RA (n=101) vsvs Healthy (n=93)Healthy (n=93)high incidence high incidence TB, 80% BCGTB, 80% BCG‐‐vaccinated (Peru)vaccinated (Peru)

65.659.1

44.6

30

40

50

60

70 ControlsControls RARA

1110

15

20

eter (cm)

eter (cm)

th positive Test (%

)th positive Test (%

)

Ponce de Leon, et al. J Rheum 2008; 35: 776‐781

26.7

0

10

20

30

LTBI with TSTLTBI with TST LTBI with QFTLTBI with QFT

TST:TST:41%41%

QFT:QFT:75%75%

3.70

5

TST Diam

TST Diam

RARA HealthyHealthySubjects wit

Subjects wit

AS (n=61) RA (n=46)

TST TST vsvs QFTQFT‐‐IT in RA and AS in South Korea IT in RA and AS in South Korea high TB incidencehigh TB incidence, 99% BCG, 99% BCG‐‐vaccinatedvaccinated

RA RA (Ø 52y(Ø 52y): ): Pred. 67Pred. 67%, MTX 85%%, MTX 85%ASAS ((ØØ 31y31y)) Pred 10Pred 10% MTX 5%% MTX 5%

44%

31%

20%

37%

IDR IDR

AS AS ((Ø Ø 31y31y): ): Pred. 10Pred. 10%, MTX 5% %, MTX 5%

Discordant results: 33 patientsDiscordant results: 33 patients•• 16 TST+/QFT16 TST+/QFT‐‐ : :

younger, more likely AS•• 17 TST17 TST‐‐/QFT+ : /QFT+ :

κ = 0.466 κ = 0.145

TSTTST QFTQFT‐‐ITIT

IDR: IDR:9% 5% older, more likely RA

Chang B, et al. Clin Rheumatol 2011; DOI 10.1007/s10067‐011‐1771‐9

TST+ QFTTST+ QFT‐‐IT+IT+

TST TST vsvs QFTQFT‐‐IT in IBD (n=168) in Switzerland IT in IBD (n=168) in Switzerland low TB incidence, 71% BCGlow TB incidence, 71% BCG‐‐vaccinatedvaccinated

all IBD (n=168) all controls (n=44) ll IBD ( 168)

81% under 81% under immunesuppressiveimmunesuppressive therapytherapy

43%

52%

all IBD (n 168) all controls (n 44)BCG vacc. IBD BCG vacc. Controls

8%9%

all IBD (n=168)

all controls (n=44)

P = 0.0001P = 0.0001

18%23%

TST+QFT‐IT+

Schoepfer AM, et al. Am J Gastroenterol 2008; 103:2799‐806.

QFTQFT--TB Gold correlates better with TBTB Gold correlates better with TB--Risk Risk than the than the TST in 142 Swiss IMID patientsTST in 142 Swiss IMID patients

ve T

est

ve T

est TBTB--RiskRisk

NoNoYesYes 57 1%57 1%

60OR 2.8OR 2.8

ents

with

a p

ositi

ven

ts w

ith a

pos

itiv YesYes

34.9%34.9%32.5%32.5%

57.1%57.1%

20

40 OR 23.8OR 23.8

% P

atie

% P

atie

2.2%2.2%0 2/912/91

RiskRisk--15/4315/43RiskRisk++

26/8026/80RiskRisk--

20/3520/35RiskRisk++

QF TBQF TB--GoldGold++ TSTTST++Matulis G, et al. Ann Rheum Dis 2008; 67:84‐90.

QFTQFT--TB Gold correlates with TB Gold correlates with TBTB--RiskRiskin 142 IMID patients (Switzerland)in 142 IMID patients (Switzerland)

Odds for a positive QF TB-Gold assay strongly increase with increasing prognostic relevance of LTBI risk factors

Matulis G, et al. Ann Rheum Dis 2008; 67:84‐90.

NoNo

YesYes

BCG vaccinatedBCG vaccinated6060

42.9%42.9%

…but not with BCG vaccination status !…but not with BCG vaccination status !

sitiv

e Te

stsi

tive

Test

OR 2.44OR 2.44

2020

4040

10.9%10.9%

20.8%20.8% 23.5%23.5%

atie

nts

with

a p

osat

ient

s w

ith a

pos

OR 0.47OR 0.47

005/24V5/24V-- 12/110V12/110V++ 4/17V4/17V-- 42/98V42/98V++

QFTQFT--IT+IT+patientspatients

TST+TST+patientspatients

% P

a%

Pa


uvuv/mv Regression Analysis/mv Regression Analysis

QF TB-GOLD (n=134) TST (n=115)

Characteristic OR (95%-CI) p-valuep-value for QF vs TST*OR (95%-CI) p-value

BCG vaccination 0.47 (0.15-1.47) 0.20 2.44 (0.74-8.01) 0.14 0.025

MultivariableRisk factor 29.2 (5.91-144) <0.001 4.81 (1.8-12.8) 0.002 0.041

BCG i ti 1 79 (0 49 6 5) 0 37 5 83 (1 46 23 3) 0 013 0 2

UnivariableRisk factor 23.8 (5-110) <0.001 2.77 0.015 0.009(1.22-6.27)

Consistent with higher Consistent with higher SpecifitySpecifity and Sensitivity of and Sensitivity of QFTQFT--IT IT vsvs TST in TST in immunosuppressed IMID patientsimmunosuppressed IMID patients

BCG vaccination 1.79 (0.49-6.5) 0.37 5.83 (1.46-23.3) 0.013 0.2

* using matched-pairs logistic regression


QFTQFT‐‐G and TST in a G and TST in a mostly mostly BCGBCG‐‐naïve, mixed naïve, mixed Italian IMID cohort (n=398)Italian IMID cohort (n=398)

398 IMID398 IMID(RA, AS, PsA, other

393 IMID393 IMID(RA, AS, PsA, other

5 5 IDR (1.2%)IDR (1.2%)

TST & QFTTST & QFT

4 1% BCG i t d4 1% BCG i t d

TST+/QFT+TST+/QFT+(n=39)(n=39)

TST+/QFTTST+/QFT‐‐(n=35)(n=35)

TSTTST‐‐/QFT+/QFT+(n=13)(n=13)

TSTTST‐‐/QFT/QFT‐‐(n=306)(n=306)

Outcome ?Outcome ?

4.1% BCG vaccinated4.1% BCG vaccinated

Bartalesi F, Vicidomini S, Goletti D, et al. Eur Respir J 2009; 33:586‐93.

Concordance TSTConcordance TST‐‐QFT: 87.5% QFT: 87.5% ((κκ = 0.55)= 0.55)Both tests correlated with TB risk factorsBoth tests correlated with TB risk factorsSimilar findings in another Italian study (*)Similar findings in another Italian study (*)

* * Sauzullo I, Mengoni F, Scrive R, et al. Int J Tuberc Lung Dis 2010.

TNFTNFαα--inhibitors attenuate inhibitors attenuate IFNgIFNg--response to mitogenresponse to mitogen

TNFTNF--αα inhibitorsinhibitors(n=84)(n=84)

--8.2 (8.2 (--12.1 to 12.1 to --4.4)4.4)

(multivariate regression analysis)(multivariate regression analysis)

Steroids Steroids (≤10mg/d(≤10mg/d))(n=57)(n=57)

--2.6 (2.6 (--6.5 to 1.3)6.5 to 1.3)

DMARDsDMARDs(n=100)(n=100)

--0.9 (0.9 (--5.0 to 3.1)5.0 to 3.1)

--1010 --55 00 55 1010Decreased responseDecreased response Increased responseIncreased response

IFNIFN--γγ (IU/ml)(IU/ml)

Note: Note: BartalesiBartalesi (2009) found no effect of TNF(2009) found no effect of TNF--αα inhibitors on QFTinhibitors on QFT


60

70

80TNFa-Blockers, no DMARDS

TNFa-Blockers + DMARDS

... but they do not ... but they do not seem to seem to affect validity of QFTaffect validity of QFT--ITIT(i.e. the response to mitogen)(i.e. the response to mitogen)

20

30

40

50

60

% o

f tre

atm

ent g

roup DMARDS, no TNFa-Blockers

MTX +/- Steroids

IDID

0

10

< 0.5 0.5-5.0 5.0-10.0 > 10.0IFN-y (IU/ml)


Are the current cutAre the current cut‐‐off levels for off levels for QuantiFeronQuantiFeron testing too high ?testing too high ?

Is the current QFT cutIs the current QFT cut‐‐off (0.35IU/ml) too high ?off (0.35IU/ml) too high ?

97 97 Japanese RA Japanese RA patients before TNFpatients before TNFαα blockerblockerHRCTHRCT

48 RA patients with 48 RA patients with chestchest CT evidence CT evidence of of

prior TBprior TB

49 RA patients with a clean chest CT scan

CO > 0.35 IU/ml: 5.8%CO > 0.35 IU/ml: 5.8%

CO 0 1 IU/ l 20 8%CO 0 1 IU/ l 20 8%10 (83%)10 (83%) 2(17%)2(17%)

QFT IDR rate 5.2%; unaffected by MTX or Prednisone

Maeda T, et al. J Infect Chemother. 2011 Apr 29. [Epub ahead of print].

CO > 0.1 IU/ml: 20.8%CO > 0.1 IU/ml: 20.8%

12 RA patients (12.4%) with QFT12 RA patients (12.4%) with QFT‐‐2G >0.1IU/ml2G >0.1IU/ml

QFT cutQFT cut‐‐off in RA awaiting TNFoff in RA awaiting TNFαα blocker therapyblocker therapy

49 Japanese RA patients49 Japanese RA patients22 with past TB (history/chest CT+) 22 with past TB (history/chest CT+) vsvs 27 27 without TBwithout TB

Maeda T, Banno S, Maeda S, et al. Mod Rheumatol. 2010 Feb;20(1):18‐23.

A: CutA: Cut‐‐off = 0.35off = 0.35B: CutB: Cut‐‐off = 0.1off = 0.1C: CutC: Cut‐‐off = 0.043off = 0.043

How safe it is to rely on either the How safe it is to rely on either the TST or IGRA in IMID patients TST or IGRA in IMID patients

awaiting TNFawaiting TNFαα blocker therapy ?blocker therapy ?awaiting TNFawaiting TNFαα blocker therapy ?blocker therapy ?

43 RA patients awaiting TNF43 RA patients awaiting TNFαα blocker therapy in Taiwanblocker therapy in Taiwan

8 (18.6%) TST+8 (18.6%) TST+ 35 (81.4%) TST35 (81.4%) TST‐‐

INH (9months)

11stst TST TST (n=43)(n=43)

2/35 TB2/35 TB6 ithd

3 QFT+3 QFT+ 5 QFT5 QFT‐‐

INH (9months)

AntiAnti‐‐TNFTNFαα antibody (antibody (AdalimumabAdalimumab) )

22ndnd TST TST (n=27)(n=27)

6 withdrew


22ndnd QFT QFT (n=8)(n=8)

10 TST+10 TST+ 17 TST17 TST‐‐

1/2 TB1/2 TB 1/1 TB1/1 TB


2 IDR2 IDR

1 QFT+1 QFT+

0/8 TB0/8 TB

Chen DY, Shen GH, Hsieh TY, et al. Arthritis Care Res. 2008; 59:800‐806.

TST TST vsvs QFTQFT‐‐IT in RA and AS in South Korea IT in RA and AS in South Korea high TB incidencehigh TB incidence, 99% BCG, 99% BCG‐‐vaccinatedvaccinated

Chang B, et al. Clin Rheumatol 2011; DOI 10.1007/s10067‐011‐1771‐9

INHP given to 36 QFT+ and 1 QFT IDR/TSTINHP given to 36 QFT+ and 1 QFT IDR/TST++! INHP ! INHP not given to 16 TST+/QFTnot given to 16 TST+/QFT‐‐ patients patients !!INHP given to 36 QFT+ and 1 QFT IDR/TSTINHP given to 36 QFT+ and 1 QFT IDR/TST++! INHP ! INHP not given to 16 TST+/QFTnot given to 16 TST+/QFT‐‐ patients patients !!

none developed TB over 2 yearsnone developed TB over 2 years

Safety of using IGRA for LTBI Screening in RA beforeSafety of using IGRA for LTBI Screening in RA beforeTNFTNFαα blocker therapy (in Newcastle/UK)blocker therapy (in Newcastle/UK)(Low TB incidence, at least 70% BCG vaccinated)(Low TB incidence, at least 70% BCG vaccinated)

101 RA on DMARDs (40101 RA on DMARDs (40% % on steroids)on steroids)

LTBI screening according to GB guidelinesLTBI screening according to GB guidelines(clinical history and X(clinical history and X‐‐ray, but no TST)ray, but no TST)

10 IDR 10 IDR (9.9%)(9.9%)

84 QFT84 QFT‐‐(83%)(83%)

INHPINHP777 7 QFT+QFT+(6.9%)(6.9%)

INHPINHP ??

Pratt A, Nicholl K, Kay L. Rheumatology (Oxford) 2007; 46: 1035–1036.

TNFTNFαα blocker Therapy: 98 RAblocker Therapy: 98 RA

no no TB cases after 18 monthsTB cases after 18 months

4410108484

TT‐‐SPOT.TB SPOT.TB vsvs TST for screening & monitoring TB TST for screening & monitoring TB in rheumatic diseases during infliximab in rheumatic diseases during infliximab therapytherapy(China; 89.7% BCG vaccinated; all on DMARDs) (China; 89.7% BCG vaccinated; all on DMARDs)

58 IMID patients on58 IMID patients on 12 TST+ (20 7%)58 IMID patients on58 IMID patients onInfliximab treatmentInfliximab treatment

(34 (34 SpASpA, 24 RA), 24 RA)

12 TST+ (20.7%)

1 T‐SPOT+ (1.7%)bbefore efore TxTx

46 TST‐/T‐SPOT‐

5 TST /T SPOT

ReRe‐‐testtestafter 1y. after 1y. Active TB during treatment:Active TB during treatment:

0/50/5

on on TxTx

Xie X, Chen JW, Li F, Tian J, Gao JS, Zhang D. Clin Exp Med. 2011;11:155‐61.

5 TST+/T‐SPOT‐

2 TST+/T‐SPOT+

2 TST‐/T‐SPOT+

0/50/52/22/21/21/2

How useful are IGRA and the TST How useful are IGRA and the TST for repeated testing during for repeated testing during TNFTNF bl k h ?bl k h ?TNFTNFαα blocker therapy ?blocker therapy ?

Biphasic emergence of TB among 233 RA patients Biphasic emergence of TB among 233 RA patients ttreated with TNFreated with TNFαα blockers in Chinablockers in China

TST+/QFT+TST+/QFT+(n=37)(n=37)

TSTTST≥10mm≥10mm/QFT/QFT‐‐(n=24)(n=24)

TST 5TST 5‐‐9mm/QFT+9mm/QFT+(n=14)(n=14)

TSTTST‐‐/QFT+/QFT+(n = 8)(n = 8)

TSTTST‐‐/QFT/QFT‐‐(n=150)(n=150)

Months 2Months 2‐‐3 of3 of TNFTNFαα blocker blocker TxTx

INHP INHP (1m prior TNF(1m prior TNFαα TxTx))

No INHPNo INHP

22 ee‐‐pulmonary TB pulmonary TB 22 ee‐‐pulmonary TB pulmonary TB 2 Pulmonary TB2 Pulmonary TB2 Pulmonary TB2 Pulmonary TB

Early TB

Early TB

(TB reactivation?)

(TB reactivation?)

QFT↑/conversionQFT↑/conversion

Chen DY, et al. Ann Rheum Dis 2011, December 2, doi: 10.1136/annrheumdis‐2011‐200489.

Months 20Months 20‐‐24 of24 of TNFTNFαα blocker blocker TxTx

Late TB

Late TB

(new

infection?)

(new

infection?)

All 5: QFT conversionAll 5: QFT conversion 2 pulmonary TB2 pulmonary TB3 3 extrapulmonaryextrapulmonary TBTB2 pulmonary TB2 pulmonary TB3 3 extrapulmonaryextrapulmonary TBTB

High IFNHigh IFNγγ levels or levels or QFT conversion indicate risk to QFT conversion indicate risk to develop develop active TB in active TB in RA patients on TNFRA patients on TNFαα treatmenttreatment

Rising IFNRising IFNγγ response predicts TB!response predicts TB!Rising IFNRising IFNγγ response predicts TB!response predicts TB!3 patients with baseline QFT+ and 3 patients with baseline QFT+ and IU

/ml)

IU/m

l)

IGRA/QFT conversion predicts TB!IGRA/QFT conversion predicts TB!IGRA/QFT conversion predicts TB!IGRA/QFT conversion predicts TB!

active TB active TB earlyearly after TNFafter TNFαα TxTx onsetonset

IFN

IFNγγ(I(I

/ml)

/ml)

Chen DY, et al. Ann Rheum Dis 2011, December 2, doi: 10.1136/annrheumdis‐2011‐200489.

6 patients with baseline QFT6 patients with baseline QFT‐‐ andandactive TB active TB earlyearly after TNFafter TNFαα TxTx (n=1)(n=1)aactive TB ctive TB latelate after after TNFTNFαα TxTx ((n=5)n=5)IF

NIFNγγ(IU/

(IU/

Lack of correlation between TST and QFTLack of correlation between TST and QFT‐‐2G in 2G in BCGBCG‐‐vaccinated RA patients with CT scan+ past TBvaccinated RA patients with CT scan+ past TB

Mod Rheumatol. 2010 Feb;20(1):18‐23.Maeda T, Banno S, Maeda S, et al. (Japan)

How costHow cost‐‐effective are TST and effective are TST and IGRA in IMID patients ?IGRA in IMID patients ?

Hypothetical calculation of cost effectiveness for Hypothetical calculation of cost effectiveness for IGRA and TST in RA patients before TNFIGRA and TST in RA patients before TNFαα therapytherapy

•• Markov model applied for Japan Markov model applied for Japan pp ppp p

•• Hypothetical cohort of 1000 RA patientsHypothetical cohort of 1000 RA patients

Hypothetical cost effectiveness better for QFT Hypothetical cost effectiveness better for QFT strategy in BCGstrategy in BCG‐‐vaccinated and BCGvaccinated and BCG‐‐naïve RAnaïve RA

Kowada A. Mol Diagn Ther. 2010;14:367‐73.

Only when the incidence of TB in RA patients with Only when the incidence of TB in RA patients with TNFaTNFa blockers blockers is < 0.00066 (0.066%) will the TST become more costis < 0.00066 (0.066%) will the TST become more cost‐‐effective !effective !

SummarySummary

Compared to the TST, IGRA exhibit higher sensitivity Compared to the TST, IGRA exhibit higher sensitivity and specificity in IMID treated with or without and specificity in IMID treated with or without immunosuppressive therapyimmunosuppressive therapy

LTBI screening strategies for IMID patients awaiting LTBI screening strategies for IMID patients awaiting TNFTNFαα blocking therapy should include IGRAblocking therapy should include IGRA

Repeated IGRA testing in patients under TNFRepeated IGRA testing in patients under TNFααblocking therapy may be useful in countries withblocking therapy may be useful in countries withblocking therapy may be useful in countries with blocking therapy may be useful in countries with high TB incidencehigh TB incidence

Reducing the current cutReducing the current cut‐‐off of the QFToff of the QFT‐‐IT in IMID IT in IMID patients to 0.1IU/ml may be appropriatepatients to 0.1IU/ml may be appropriate

igra in the face of immune modifiers - uc san diego ... · pdf file3rd global symposium on...

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