Screening of Latent Tuberculosis before treatment with TNF

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

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

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 ?

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

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

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

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

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. 9 RA 1301 a Keane et al, NEJM 2001; 345: 1098 -104

BIOBADASER • Treatment of RA with TNF inhibitors may predispose to significant increase in tuberculosis risk: a multicenter activesurveillance report. A&R 2003 • 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&R 2007

BIOBADASER (1) • Registry based on the voluntary participation of hospital and community-based rheumatology Units • 1540 pts : 1265 RA, 89 Ps. A, 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&R 2003

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

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

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. A&R 2007

“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

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

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

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

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

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

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

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

PPD in different rheumatic diseases N Age Steroid (%) PPD+(%) PPD RA 94 56 50 30 4. 5± 7 SLE 21 38 48 19 2. 9± 6. 2 AS 44 36 4. 5 66 9. 8± 8 OA 27 51 15 63 7. 8± 6. 7

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

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

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

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 CD 4 levels

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

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

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

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.

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

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