Pathogenesis of Rheumatoid Arthritis. Smolen, J. S. et al. (2012) Nat. Rev. Rheumatol. doi: /nrrheum

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1 1 Pathogenesis of Rheumatoid Arthritis 2 Smolen, J. S. et al. (2012) Nat. Rev. Rheumatol. doi: /nrrheum

Woodrick, R. S. & Ruderman, E. M. (2011) Nat. Rev. Rheumatol.

2 Biologic therapies used in the treatment of rheumatoid arthritis 3 Etanercept Infliximab Adalimumab Golimumab Certolizumab Woodrick, R. S. & Ruderman, E. M. (2011) Nat. Rev. Rheumatol

5 Rheumatoid arthritis Anti-TNF alpha Anti-IL 6 Anti-CTLA4 Anti-CD20 Anti-IL1 JAK inhibitor Ankylosing spondylitis Anti-TNF alpha Psoriasis/psoriatic arthritis Anti-TNF

3 5 Rheumatoid arthritis Anti-TNF alpha Anti-IL 6 Anti-CTLA4 Anti-CD20 Anti-IL1 JAK inhibitor Ankylosing spondylitis Anti-TNF alpha Psoriasis/psoriatic arthritis Anti-TNF alpha Anti-IL12/23 SLE Anti-BAFF Asthma Anti-IgE Chronic spontaneous urticaria Anti-IgE Inflammatory bowel disease Anti-TNF alpha Biologicals revolutionized rheumatology 6

4 7 But 8 Risk of reactivation of latenttb (high in Mab anti-tnf, intermediate with etanercept) Boyman, O. et al. Nat. Rev. Rheumatol. 10(10), (2014)

Risk s Benefits Risk of TB in RA patients 10 Authors, year Locality Comparison group Odds ratio for TB P value or 95% CI Carmona et al., 2003 Askling et al., 2005 Yamada et al.

5 Risk s Benefits Risk of TB in RA patients 10 Authors, year Locality Comparison group Odds ratio for TB P value or 95% CI Carmona et al., 2003 Askling et al., 2005 Yamada et al., 2006 Seong et al, 2007 Gamboa et al., 2006 Wolfe et al., 2004 Spain population Sweden population Japan population Korea population Peru population (NS) USA population 6.2 vs 5.8/100,000 Not significantly Tam et al., 2010 Hong Kong population

6 BSRBR (UK):Risk of TB with anti-tnf therapy 11 Numbers and rates of incident tuberculosis Rate of TB per 100,000 patient years (no. of cases) DMARD n= (5) ETN n= (11) INF n= (11) ADA n=4857 Adjusted* incidence rate ratios compared to ETN (95% CI) (0.9, 5.8) for INF 4.2 (1.8, 9.9) for ADA Switchers included *adjusted for age, gender and entry year TB, tuberculosis; DMARD, disease modifying anti-rheumatic drugs; CI, confidence interval; TNF, tumor necrosis factor; ETN, etanercept; INF, infliximab; ADA, adalimumab. 1. Dixon W, et al. Ann Rheum Dis 2010;69: RATIO (France): Higher Risk of TB in Both RA and AS Patients Treated With Anti-TNF 12 Cumulative frequency of TB 70% 60% 50% 40% 30% 20% 10% 0% 0 6 Adalimumab Etanercept Time from onset of last TNF-i treatment (months) Total Infliximab The risk of TB is higher for patients receiving anti-tnf mabs than for those receiving soluble receptor TNF-i therapy TB, tuberculosis. Tubach F, et al. Arthritis Rheum. 2009;60: Not a head to head comparison. Differences in baseline characteristics among patient groups may exist 12

Higher Incidence of Tuberculosis is Observed in Korean Ankylosing Spondylitis Patients Treated with TNF blockers Incidence Rates of TB in Korea Mean incidence of TB per 100,000 PY AS, ankylosing

7 Higher Incidence of Tuberculosis is Observed in Korean Ankylosing Spondylitis Patients Treated with TNF blockers Incidence Rates of TB in Korea Mean incidence of TB per 100,000 PY AS, ankylosing spondylitis; PY, patient-years; TB, tuberculosis. Adapted from Kim EM, et al. J Rheumatol 2011;38: Biologics Have an Increased Risk of Tuberculosis and Lymphoma Compared to Traditional Diseasemodifying Anti-rheumatic Drugs in Taiwan DMARD vs Biologics in rheumatoid arthritis Traditional DMARDs Biologic DMARDs IRR (95%CI)** Rate/ Rate/ TB *( ) Lymphoma *( ) Serious infection ( ) *P<0.05; **Traditional DMARDs as referent. This data was not adjusted for rheumatoid arthritis disease activity. Not a head-to-head comparison. Differences in baseline characteristics among patient groups may exist. DMARDS, disease-modifying anti-rheumatic drugs; IRR, incidence rate ratio; NNH, number needs to harm; TB, tuberculosis. Adapted from Chiu YM, et al. Int J Rheum Dis 2014;17(Suppl3):9 19.

8 Projected Incremental Tuberculosis Risks in South Asian Countries with TNF inhibitor Therapy Patients (%) Projected incidence of TB on TNF inhibitors in South Asia PHILIPPINES MALAYSIA SINGAPORE THAILAND INDIA VIETNAM NNT (using ETN instead of) Philippines Malaysia Singapore Thailand India Vietnam ADA IFX ADA ETN IFX In South Asia, the estimated number needed to harm is lowest with etanercept Not a head-to-head comparison. Differences in baseline characteristics among patient groups may exist. ADA, adalimumab; ETN, etanercept; IFX, infliximab; NNT, number needed to treat; TB, tuberculosis. Navarra SV, et al. Int J Rheum Dis : Projected Incremental Tuberculosis Risks in North Asian Countries with TNF inhibitor Therapy Patients (%) Projected incidence of TB on TNF inhibitors in North Asia HONG KONG CHINA KOREA MACAU TAIWAN ADA ETN IFX NNT (using ETN instead of) Hong Kong China Korea Macau* Taiwan ADA IFX N/A In North Asia, the estimated number needed to harm is lowest with etanercept Not a head-to-head comparison. Differences in baseline characteristics among patient groups may exist. Infliximab not available in Taiwan. *Macau was not included in the original publication. Data source: ADA, adalimumab; ETN, etanercept; IFX, infliximab; NNT, number needed to treat; TB, tuberculosis. Navarra SV, et al. Int J Rheum Dis :

17 Taiwan=49/10 5 17 WHO Global Tuberculosis Report 2014 ( 10 5 people/year) 18 13237

9 17 Taiwan=49/ WHO Global Tuberculosis Report 2014 ( 10 5 people/year) ( per 10 5 people/year) :

10 Biphasic emergence of active tuberculosis in RA patients receiving TNFα inhibitors Taiwan VGH-TC 19 Chen, DY. et al. Ann Rheum Dis 2012;71: Biphasic emergence of active tuberculosis in RA patients receiving TNFα inhibitors : early TB infection Reactivation 20 Early TB infection No early TB infection Total adalimumab 4 (4.35%) etanercept 0 (0%) Total P=0.023 by Fisher s exact test Data from DY Chen et al. Ann.Rheum.Dis. 71 (2): , 2012

11 Biphasic emergence of active tuberculosis in RA patients receiving TNFα inhibitors : late TB infection New TB infection 21 Late TB infection No TB infection Total adalimumab 2 (2.27%) etanercept 3 (2.13%) Total P=0.656 by Fisher s exact test Data from DY Chen et al. Ann.Rheum.Dis. 71 (2): , 2012 Persistently High Levels of Released IFN-γ or QFT Conversion Strongly Indicate the Development of Active Tuberculosis in Patients Undergoing TNF inhibitor Therapy ESAT-6-stimulated IFNγ release levels (IU/ml) ESAT-6-stimulated IFNγ release levels (IU/ml) *** * * *** Baseline 9 months 18 months 24 months INHP 9 months Anti-TNF treatment TB CFP-10-stimulated IFNγ release levels (IU/ml) TB INHP 2 3 months 0 1 Anti-TNF Rx 3 Anti-TB Rx Anti-TNF Rx Anti-TB Rx 2 6 months Anti-TNF months Anti-TB Rx CFP-10, culture filtrate protein 10; ESAT-6; early secretory antigenic target 6; IFN, interferon; INHP, isoniazid prophylaxis; *P<0.05; **P<0.005; ***P<0.001, versus values at baseline. QFT, QuantiFERON-TB Gold assay; TB, tuberculosis; TST, tuberculin skin test. CFP-10-stimulated IFNγ release levels (IU/ml) Baseline TST+/QFT+ results ESAT-6 CFP-10 ** *** ESAT-6-stimulated IFNγ release levels (IU/ml) ESAT-6-stimulated IFNγ release levels CFP-10-stimulated IFNγ release levels (IU/ml) (IU/ml) Baseline TST /QFT results ESAT-6 CFP-10 Baseline 9 months 18 months24 months 1 TB * TB CFP-10-stimulated IFNγ release levels (IU/ml) Adapted from DY Chen, et al. Ann Rheum Dis 2012;71:

12 How? 23 24

newborn & 1st degree of elementary school High annual incidence of NTM in Taiwan (21.

13 25 Mantoux test is a standard method by intra-dermal injection of two tuberculin units of PPD RT-23, and then measurement of induration diameter after 48-72hrs 5 mm 10 mm TST TB 26 Universal use of BCG vaccination (96%) For newborn & 1st degree of elementary school High annual incidence of NTM in Taiwan (21.5/100,000 in 2002) 42% NTM isolation rate in TCVGH The major challenge of TST is the varying and low specificity in various settings, especially in Taiwan

14 A systemic review and meta-analysis showed that TST result is unreliable in BCG-vaccinated people 27 All TST /672 BCG vaccinated /516 Lee et al., 2006 (22) 103/131 Kang et al., 2005 (30) 49/99 Mori et al., 2004 (85) 75/213 Brock et al., 2001 (68) 10/19 Johnson et al., 1999 (69) 53/54 Not BCG vaccinated /156 Taggart et al., 2006 (86) 78/81 Brock et al., 2001 (68) 15/15 Johnson et al., 1999 (69) 60/ Ann Intern Med 2007; (positive TST result was defined as 5mm) 28 Percentage of patients % (RA) 26% (controls) TST(-) 29.4% (RA) 74% (controls) TST(+) >15 PPD value (mm) RA Controls 25 Ponce de Leon, D et al. Ann Rheum Dis 2005;64:

15 Anti-TNF trial for Taiwanese patients with RA in RA Patients N= 43 Baseline screening: risk factor survey, history of TB exposure, CXR TST Positive N=8 (18.6%) INH Prophylaxis for 9 months TST Negative N=35 (81.4%) No TB (0%) No hepatotoxicity/allergy Active TB infection N= 2 No TB N= % RA patients had TST-positive results at baseline (BCG vaccination +) before anti-tnf therapy in Taiwan (One-step TST test) Chen DY et al. Arthritis & Rheumatism (Arthritis Care & Research) 59(6) :For 132 Taiwanese patients with RA before anti-tnf Rx. Two-step TST could increase positive rate (cutoff 5 mm) by 19.1% 30 Negative Positive 1st TST 101/ % 31/ % 2 step TST 75/132 57/ % within 1-5 wks after 1 st TST 56.8% 43.2% Our results could be explained by Booster phenomenon that was also noted in 29% of RA patients (J Rheumatol 2007;34:474)

16 Summary : TST screening in RA 31 Anergy [false (-) TST] is common in RA patients The use of immunosuppressive agents Immune dysfunction related to RA Two-step TST is necessary in the detection of LTBI for RA patients before starting anti-tnf therapy The application of TST for detecting LTBI is limited in RA patients by the frequent presence of anergy 32 4/43=9302/10 5 Chen DY et al. Arthritis & Rheumatism (Arthritis Care & Research) 59(6)

17 Combined QFT-G assay and TST can aid in detecting LTBI in RA patients receiving adalimumab therapy TST? The application of TST for detecting LTBI is limited in RA patients by the frequent presence of anergy 33 Chen DY et al. Arthritis & Rheumatism 59(6) 2008, Screening protocol for RA patients receiving TNFα inhibitors at VGH-TC Taiwan Chen, DY. et al. Ann Rheum Dis 2012;71:

18 35 Chen, DY. et al. Ann Rheum Dis 2012;71: Biphasic emergence of active tuberculosis in RA patients receiving TNFα inhibitors Taiwan VGH-TC 36 Chen, DY. et al. Ann Rheum Dis 2012;71:

19 In vitro IFN-γ release assays (QFT, T-spot) 37 ESAT-6,CFP-10, TB7.7 (BCG ) ELISA IFN-γ IFN-γ QFT assay has higher specificity (96%) vs. TST in BCG-vaccinated people 38 Sensitivity Specificity TST QFT Ann Intern Med 2008;149:177-84

20 Persistently high levels of released IFN-γ or QFT-G conversion strongly indicate the development of active TB in patients undergoing anti-tnf Rx Taiwan VGH-TC 39 DY Chen et al. Ann.Rheum.Dis. 71 (2): , 2012 DY Chen et al. Ann.Rheum.Dis. 71 (2): , RA patients scheduled for anti-tnf Rx (n=242) Screening of LTBI: TST and QFT assay 40 9 patients excluded due to indeterminate QFT TST+ / QFT+ (n=37) TST+ / QFT - (n=38) TST- / QFT + (n=8) TST- / QFT- (n=150) TST 10 mm (n=24) TST 5-9 mm (n=14) INAH 1 mon before anti-tnf Rx INHP + Anti-TNF Rx Anti-TNF Rx TB (n=2) Rising IFN-γ levels in QFT Continue anti-tnf x 9 mons Decrease IFN-γ levels TB x1 Rising IFN-γ Continue anti-tnf Repeat QFT (-) TB x1 QFT conversion Anti-TB Rx Continue anti-tnf Rx x 15 mon (n=73) Anti-TB Rx Continue anti-tnf Rx x 15 mon (n=156) Anti-TB Rx TB (-) Decrease IFN-γ levels TB (-) x 7 QFT reversion TB (-) x 144 Repeat QFT(-) TB (n=5) QFT conversion

21 41 DY Chen et al. Ann.Rheum.Dis. 71 (2): , step TST (-) (induration diameter < 5mm) 2-step TST (+) (induration 5mm) IGRAs (+) (QFT or T-Spot) 1.Prophylactic Rx 2.Close monitor* 1.Prophylactic Rx 2.Consult TB specialist 3. Close monitor* IGRAs (-) (QFT or T-Spot) 1.Start Biologics 2.Periodic CXR/IGRAs 1.Prophylactic Rx (TST > 10 mm) 2.Close monitor* Baseline IGRAs Indeterminate 1 IGRAs * TB Close monitor: CXR IGRAs Formosian Journal of Rheumatology 2011;25,6-10

22 TRA Recommendation Formosan Journal of Rheumatology 26(1) 8~14, 2012

23 RA ( 10 ) RMP RMP RMP RA TB * # # 46 * Hsueh PR. et al. J Infect 2006;52: # Ke WM. et al. Int J Tuberc Lung Dis. 2013;17:

24 47 Navarra SV et al. Int J Rheum Dis. 2014;17: Risk of TB reactivation in Spain IRR vs. general Population IRR vs. RA with csdmards Before RMP After RMP % compliance 1.8 Undetermined < 100% compliance Gomez-Reino JJ et al. Arthritis Rheum 2007;57:

25 Reasons of decreased TB incidence in patients using biologics Increased awareness Screening for latent TB Treatment for latent TB Introduction of lower TB risk drugs Arkema EV, et al. Ann Rheum Dis 2015;74: About QuantiFERON-TB test

easy steps of QFT In-Tube 51 Indeterminate rates in immune suppressed and immunocompetent populations 52 Population QFT T-SPOT.TB Pearson Chi-Square No. No. % No. No. % (QFT vs T-SPOT.

26 easy steps of QFT In-Tube 51 Indeterminate rates in immune suppressed and immunocompetent populations 52 Population QFT T-SPOT.TB Pearson Chi-Square No. No. % No. No. % (QFT vs T-SPOT.TB) Tested Indet* Indet* Tested Indet* Indet* Overall 17, % 13, % p< Immunosuppressed Immunocompetent 12, %10, % p< , % 2, % p<0.0001

27 QFT indeterminate data 53 Lab A-1* Lab A-2** Lab B Lab C Lab D-1*** Lab D-2* Test numbers Positive N/A 224 N/A N/A N/A N/A Negative N/A 373 N/A N/A N/A N/A Indeterminate 9 (3.7%) 4 (0.67%) 28 (6.8%) 45 (15.68%) 34 (5.52%) 3 (7.7%) * (< 4.42%) ** *** (< 2.14%) 54

28 55 QFT reproducibility within 10 weeks Consistent results: 72.67% Weakly positive results A. Felber, W. Graninger. Tuberculosis 2013:93; 647e653

29 Low titer = frequent conversion? 80% of all subjects with discordant results within 10 weeks had low positive IFN-γ-responses. (mean 0.75 vs IU/ml of persistent positive patients) A low IFN- γ level may alternatively be considered as false positive, especially in those exhibiting NO clinical features or risk factors of TB. A. Felber, W. Graninger. Tuberculosis 2013:93; 647e653 Hong Kong Biologics Registry: Tuberculosis and Non-tuberculosis Serious Infections Event rate of TB (per 100 patient-years) IFX ETN ADA GLM TCZ RTX Total Event rate of Serious/recurrent infections (non-tb) (per 100 patient-years) IFX ETN ADA GLM TCZ RTX Total Events IFX ETN ADA GLM TCZ RTX Total Tuberculosis Serious/recurrent infections (non-tb) Skin rash/allergy Not a head-to-head comparison. Differences in baseline characteristics among patient groups may exist. ADA, adalimumab; ETN, etanercept; GLM, golimumab; IFX, infliximab; RTX, rituximab; TB, tuberculosis; TCZ, tocilizumab. Adapted from Mok CC, et al. Int J Rheum Dis 2014;17Suppl 3:1 8.

30 2015 TRA Recommendation for TB Screening/management before biologics Chen,YH et al. Formosan Journal of Rheumatology 29(1) 1-8 Host-related TB risk factors except rheumatic disease 2015 revised TRA Recommendation per se Chen,YH et al. Formosan Journal of Rheumatology ;29(1),1-8

31 Traditional chemical DMARD-related TB risk factors except rheumatic disease per se 2015 revised TRA Recommendation Risk estimated relative risk (RR) Major risk factors (RR>10) leflumomide 11.7 Minor risk factors (RR<10) cyclosporine 3.8 methotrexate 3.4 corticosteroids 2.4 other (sulfasalazine, azathiorpine, hydroxychloquine) 1.6 Chen,YH et al. Formosan Journal of Rheumatology;29(1),1-8 Risk for TB reactivation among different biologics by meta-analysis Biologics 2015 revised TRA Recommendation LTE studies[44] IR(95%CI) 2013 Cochrane review[19] Odds ratio (95% CI) Cetrolizumab Infliximab Adalimumab Golimumab Tocilizumab Etanercept Abatacept ( ) ( ) ( ) ( ) ( ) ( ) ( ) 4.43( ) 2.82( ) 2.14( ) 3.04( ) Not estimable 1.48( ) 0.50( ) Rituximab 20( ) --- LTE: long-term extension; IR:incidence rate per 100,000 patient-years CI: confidence interval Chen,YH et al. Formosan Journal of Rheumatology ;29(1),1-8

32 2015 TRA Recommendation for TB Screening/management before biologics a.inah 300mg QD x 9M b.inah 300mg QD+rifampin 10mg/kg/day x 3 M c.inah 900mg + rifampentine 900mg QW x 3M d. rifampin 10mg/kg/day x 4M Chen,YH et al. Formosan Journal of Rheumatology 29(1) 1-8 Take Home Message 64

33 Thank you 65

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