1. Screening of Latent Tuberculosis before treatment with TNF  blockers Ori Elkayam M.D Tel Aviv Medical Center

2. Guidelines of the Israeli association of Rheumatology for the prevention of tuberculosis in patients treated with TNF-alpha blocker Screening includes : Tuberculin Skin Test (TST) Chest X-ray Questionnaire about possible exposure to TB Elkayam O, Balbir-Gurman A, Lidgi M, Rahav G, Weiler-Ravel D

3. Risk Factor Questionnaire Did you immigrate from a country with high TB prevalence ? Have you ever been in close contact with TB? Have you been offered to be treated for TB ?

4. Criteria for Tuberculin positivity 15 mm ≤ 10 mm ≤ 5 mm ≤ No risk factor for TB Recent immigrants HIV positive Jail residents, health workers TB on chest X rays Silicosis, DM, CRF, malignancies Children <4 Organ transplants Immunosuppressed* * >15 mg Prednisone for at least 1 month or TNF  blockers

5. Immunocompromised patients Treated with Prednisone Treatments with MTX, Imuran Further studies are needed Prone to infections and malignancies

7. Debate Should TST≥5 mm considered positive for all candidates to anti-TNF  therapy ? Is the diagnosis of latent TB similar for RA patients, PsA and AS?

8. Topics of discussion Milestones of TB in anti-TNFα therapy Era Guidelines for screening of latent TB before anti- TNF  therapy PPD in different rheumatic diseases Prevalence of TB in Israel HIV, TNF  blockers and TB Adverse consequences of over diagnosis of LTB

9. 9 RA1301a Tuberculosis and TNF alpha blockers 70 patients reported to the FDA, including from states with low incidence of TB Extrapulmonary manifestations in 40 pts Fatalities Patients should be evaluated for latent tuberculosis infection with a tuberculin skin test. Keane et al, NEJM 2001;345:1098-104

10. BIOBADASER Treatment of RA with TNF inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. A&R2003 Effectiveness of recommendations to prevent reactivation of LTB in patients treated with TNF antagonists.A&R 2005 Risk of tuberculosis in patients treated with tumor necrosis factor antagonists due to incomplete prevention of reactivation of latent infection. A&R2007

11. BIOBADASER (1) Registry based on the voluntary participation of hospital and community-based rheumatology Units 1540 pts : 1265 RA, 89 PsA, 76 AS 17 pts with TB; 65% extra-pulm, 2 deaths 6 pts: PPD and X rays missing 5 pts:prior X evidence of TB Incidence :1100/100000 A&R2003

12. Spanish Society of Rheumatology Recommendations TST <5 mm Re-test <5 mm Chest X ray Suggestive ≥5 mm Normal Contact INH 9 months

13. BIOBADASER (2) March 2002: data collected using standard forms Since then, data reported by an electronic system. Audit : 18% of the data reported are incomplete 34 TB ( 28 RA)ׁ 32 before March 2002 2 pts after 03/02 fulfilled criteria for LTB Decrease of >70 % in rate of TB A&R 2005

14. BIOBADASER (3) Following March 2002, 5,198 registered. 15 ATB cases were noted (rate 172 per 100,000 patient-years). Recommendations fully followed in 2,655 treatments. Probability of ATB was 7 times higher when recommendations were not followed. Two-step tuberculosis skin test for LTBI was the major failure in complying with recommendations. R2007& A

15. “ The recommendation that TST≥5 mm should be an indication for INH was established because of the high TB risk detected in this population. In populations with lower background rates, other strategies may be proposed “ Gomez-Reino et al

16. Topics of discussion Milestones of TB in anti-TNFα therapy Era Guidelines for screening of latent TB before anti-TNF  therapy PPD in different rheumatic diseases Prevalence of TB in Israel HIV, TNF  blockers and TB Adverse consequences of over diagnosis of LTB

17. Guidelines (USA) Gardam (2003) : TST :0-4 : Major immune suppression +risk factors 5-9 : Epidemiologic risk factors ( Foreign born occupational, abnormal chest X ray, known contact) 10 : all others Winthrop (2005): Refer To CDC definitions of LTB Furst D : CDC recommendations

18. Guidelines (Europe) British Thoracic Society : -Immunosuppressive therapy No value of TST in pts Risk stratification /Chest X ray - No immunosuppressant therapy : TST ≥15 for BCG + TST ≥5 for BCG + Risk stratification

19. Guidelines (Europe) Greece Guidelines: Abnormal X ray TST≥10 French Guidelines: Abnormal X ray History TST≤10 mm

20. Guidelines (Europe) Swiss Guidelines:TST not recommended History of exposure Country of Origin Interferon Gamma assays

21. Topics of discussion Milestones of TB in anti-TNFα therapy Era Guidelines for screening of latent TB before anti-TNF  therapy PPD in different rheumatic diseases Prevalence of TB in Israel HIV, TNF  blockers and TB Adverse consequences of over diagnosis of LTB

22. Attenuated response to PPD in RA 112 RA patients vs 96 healthy controls Similar background : age, sex, BCG vaccine Median PPD : 4.5 in RA vs 11.5 in healthy Negative PPD : 70% in RA vs 26% in healthy

23. PPD in different rheumatic diseases PPDPPD+(%)Steroid (%)AgeN 4.5±730505694 RA 2.9±6.219483821SLE 9.8±8664.53644AS 7.8±6.763155127OA

24. Incidence of MTB in Infliximab treated pts Infliximab treated : -USA : 50/100000 -EU :152/100000 -Spain:1100/100000 -Sweden :100/100000 Rate of TB in RA -USA : 6.2/100000 -Spain : 90/100000 -Sweden: 10/100000

25. Prevalence of TB in Israel (100000) Dept. of TB & AIDS, MOH, Jerusalem #

26. Topics of discussion Milestones of TB in anti-TNF  therapy Era Guidelines for screening of latent TB before anti-TNF  therapy Prevalence of TB in Israel HIV, TNF  blockers and TB PPD in different rheumatic diseases Adverse consequences of over diagnosis of LTB

27. TNF  Blockers, HIV and TB High frequency of extra-pulmonary manifestations HIV impairs TNF  mediated MG apoptotic response to MT HIV + with TST≥5 mm are treated for LTB, independently of CD4 levels

28. Incidence of MTB in Infliximab treated pts vs HIV + Infliximab treated : -USA : 50/100000 -EU :152/100000 -Spain:1100/100000 -Sweden :100/100000 HIV + - South –Africa : 2.2/100 - Swiss : 1.6/100 20 ≤ fold increase of reactivation Rate of TB in RA pts in USA : 6.2/100000 Rate of TB in RA pts in Sweden :10/100000 Rate of TB in RA pts in Spain : 90/100000

29. Topics of discussion Milestones of TB in anti-TNF  therapy Era Guidelines for screening of latent TB before anti-TNF  therapy Prevalence of TB in Israel HIV, TNF  blockers and TB PPD in different rheumatic diseases Adverse consequences of over diagnosis of LTB

30. Adverse consequences of over diagnosis and treatment LTB Drug toxicity Hepatotoxicity Drug multi resistance

31. Multi drug resistance in Southern Israel Overall INH resistance rate :16% In former soviet union :INH resistance of 32% Resistance to any drug observed in 29% overall and 50% of isolates among IFSU. Multi drug-resistant tuberculosis was observed in 8.5% and 17%, respectively.

32. Conclusions Guidelines of diagnosis of LTB should take into consideration : The prevalence of TB in the country The immunosuppressive state of the patients Adverse consequences of over diagnosis of latent TB

33. Conclusions In RA patients :TST≥5 mm In PsA and AS not treated with immunosuppressive drugs : TST ≥10 mm Risk stratification and X chest ray