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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 :

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screening of latent tuberculosis before treatment with tnf blockers

Screening of Latent Tuberculosis before treatment with TNF  blockers

Ori Elkayam M.D

Tel Aviv Medical Center

slide2
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
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
Criteria for Tuberculin positivity

* >15 mg Prednisone for at least 1 monthor TNF blockers

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

biobadaser
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
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

slide12
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

biobadaser 2
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
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

slide15
“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 discussion16
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
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
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 europe19
Guidelines (Europe)
  • Greece Guidelines: Abnormal X ray

TST≥10

  • French Guidelines: Abnormal X ray

History

TST≤10 mm

guidelines europe20
Guidelines (Europe)
  • Swiss Guidelines:TST not recommended

History of exposure

Country of Origin

Interferon Gamma assays

topics of discussion21
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
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
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

Incidence of MTB in Infliximab treated pts
slide25
Prevalence of TB in Israel (100000)

#

Dept. of TB & AIDS, MOH, Jerusalem

topics of discussion26
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
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

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

topics of discussion29
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
Adverse consequences of over diagnosis and treatment LTB
  • Drug toxicity
  • Hepatotoxicity
  • Drug multi resistance
multi drug resistance in southern israel
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
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
conclusions33
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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