igra in the face of immune modifiers - uc san diego ... · pdf file3rd global symposium on...
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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
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
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
Cytokines/EnzymesCytokines/Enzymes•• Interleukins, IFNsInterleukins, IFNs•• ProteasesProteases•• ChemokinesChemokines
Cytokines/EnzymesCytokines/Enzymes•• Interleukins, IFNsInterleukins, IFNs•• ProteasesProteases•• ChemokinesChemokines
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
Matulis G, et al. Ann Rheum Dis 2008; 67:84‐90.
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
Matulis G, et al. Ann Rheum Dis 2008; 67:84‐90.
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
Matulis G, et al. Ann Rheum Dis 2008; 67:84‐90.
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)
Matulis G, et al. Ann Rheum Dis 2008; 67:84‐90.
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
1 QFT+1 QFT+ 7 QFT7 QFT‐‐
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 QFT+2 QFT+ 22 QFT22 QFT‐‐
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