Screening of Latent Tuberculosis before treatment with TNF  blockers

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 mg Prednisone for at least 1 monthor 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. 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 RA1301a

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 ≥5 mm Re-test <5 mm ≥5 mm Chest X ray Contact Normal INH 9 months Suggestive

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

24. 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 Incidence of MTB in Infliximab treated pts

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 • PPD in different rheumatic diseases • Prevalence of TB in Israel • HIV, TNF  blockers and TB • 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. 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 Incidence of MTB in Infliximab treated pts vs HIV + 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 • PPD in different rheumatic diseases • Prevalence of TB in Israel • HIV, TNF  blockers and TB • 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