Screening of Latent Tuberculosis before treatment with TNF

blockersOri 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 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

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 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

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

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

Re-test

<5 mm

Chest X ray

Suggestive

≥5 mm

≥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.

R2007&A

“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

NAgeSteroid (%)PPD+(%)PPD

RA945650304.5±7

SLE213848192.9±6.2

AS44364.5669.8±8

OA275115637.8±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)

0

2

4

6

8

10

12

שנת דווח

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

• Prevalence of TB in Israel

• HIV, TNF blockers and TB

• PPD in different rheumatic diseases

• 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• 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

• Prevalence of TB in Israel

• HIV, TNF blockers and TB

• PPD in different rheumatic diseases

• 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