Transcript EFFECT OF ANTI-TUMOR NECROSIS FACTOR ANTIBODY ON

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≤
15mm≤
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, PsA and AS?
Topics of discussion
• Milestones of TB in anti-TNFα therapy Era
• Guidelines for screening of latent TB before antiTNF 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.
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RA1301a
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
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
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
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)
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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&R2007
“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
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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)
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‫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
• 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 CD4 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
•
≤ 20fold 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 PsA and AS not treated with
immunosuppressive drugs : TST ≤10 mm
• Risk stratification and X chest ray