screening of latent tuberculosis before treatment with tnf blockers ori elkayam m.d tel aviv...
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Screening of Latent Tuberculosis before treatment with TNF
blockersOri Elkayam M.D
Tel Aviv Medical Center
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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
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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 ?
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Criteria for Tuberculin positivity 5 mm ≤ 10 mm ≤15 mm ≤
HIV positiveRecent immigrants
No risk factor for TB
TB on chest X raysJail residents, health workers
Organ transplants Immunosuppressed*
Silicosis, DM, CRF, malignancies
Children <4
< *15 mg Prednisone for at least 1 month or TNF blockers
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Immunocompromised patients
• Treated with Prednisone
• Treatments with MTX, Imuran
• Further studies are needed
• Prone to infections and malignancies
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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?
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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
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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
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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
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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
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Spanish Society of Rheumatology Recommendations
TST<5 mm
Re-test
<5 mm
Chest X ray
Suggestive
≥5 mm
≥5 mm
Normal Contact
INH 9 months
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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
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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
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“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
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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
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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
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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
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Guidelines (Europe)
• Greece Guidelines: Abnormal X ray
TST≥10
• French Guidelines: Abnormal X ray
History
TST≤10 mm
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Guidelines (Europe)
• Swiss Guidelines:TST not recommended
History of exposure
Country of Origin
Interferon Gamma assays
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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
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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
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PPD in different rheumatic diseases
NAgeSteroid (%)PPD+(%)PPD
RA945650304.5±7
SLE213848192.9±6.2
AS44364.5669.8±8
OA275115637.8±6.7
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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
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Prevalence of TB in Israel (100000)
0
2
4
6
8
10
12
שנת דווח
Dept. of TB & AIDS, MOH, Jerusalem
#
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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
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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
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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
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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
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Adverse consequences of over diagnosis and treatment LTB
• Drug toxicity • Hepatotoxicity
• Drug multi resistance
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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.
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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
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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
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