TB or not TB ? Mahmoud Abu-Shakra Rheumatic disease Unit Soroka Medical Center Beer-Sheva

The Issue: For patients treated with TNFi agents: When to diagnose LTBI. When to treat with anti-TB agents.

How we diagnose LTBI? LTBI is diagnosed mainly by: Tuberculin Skin Testing (TST) CXR

Skin testing with PPD (TST) Used in screening for M. Tuberculosis infection Low sensitivity and low specificity for active TB Positive test is seen in patients: Have been infected with MT Sensitized by BCG False negative reaction is common in IS patients and those with active TB

Interpretation of TST results: Treatment of LTBI reduces the risk of active TB in > 90% of cases.

Guidelines for positive of skin test reaction (ATS) Induration >15 mm – Persons with no risk factors

> 10 mm Recent arrival from high prevalence countries Resident and employees of high risk categories (prisons, nursing homes,…) Injection drug users Mycobacteriology Lab personnel. Chronic diseases: DM, silicosis, CRF, Lymphoma, leukemia, gastrectomy) Children <4, Children and adolescents exposed to adults in high risk categories

> 5 mm HIV Recent contact to TB Fibrotic changes on CXR consistent with old TB Organ transplant IS therapy equivalent to 15 mg/d prednisone for > 1month

BCG and TST results BCG vaccination induces PPD reactivity, (3-19 mm). Most of the reactivity wane over 10 years. If subjects vaccinated in infancy, TST is the same for vaccinated and non-vaccinated after 5 yrs. If vaccinated at entry to primary school, TST wane more slowly If PPD performed >15 years after BCG, interpret TST as for unvaccinated persons. If there is baseline TST, increase in TST reactivity > 10 mm suggests positivity If there is no baseline, interpret as for unvaccinated

Booster Phenomenon Increased tuberculin reaction upon retesting Results from recall of waned CMI. Anamnestic serologic response Maximal if the interval between 1st and 2nd test is between 1-5 weeks Less frequent if the interval > 90 days

TST and Booster phenomenon Persons in old TB and those who received BCG- TST results may be false negative ( < 2 mm) A 2nd TST in 1-3 weeks is indicated 2-steps TST is important in those who have not had a test in the prior 12 months and who will be subject to regular testing.

> 5 mm IS therapy equivalent to 15 mg/d prednisone for > 1month

What is the risk of TB for patients on > 15 prednisone ? Case-control study of TB cases during 1990-2001 using General Practice Research Database in the UK. 4 controls for each case of first time diagnosis of TB 497 new cases of TB and 1966 controls derived from 16,629,041 PY. Arthritis Care and Research 2006,55:19-26

Variable OR Current use CS 4.9 < 15 mg 2.8 > 15 mg 7.7 Non biologic anti-rheumatic* 2.0 Smoker 1.6 BMI < 20 2.8 DM 3.8 *AZA, gold, cytoxan, Cellcept, sulfasalazine, MTX, cyclosporine, and PCA

Are TNFi immune-suppresser? Most cases of TB among patient treated with TNFi are the result of activation of LTBI and not d/t primary TB. TB associated with TNFi is disseminated (X12) (24%), extra-pulmonary (X3) (56%), and atypical presentation. Median time from TNFi therapy and TB diagnosis was 12 weeks.

TB, TNF and Mice TNF and 55 kDa TNF-r are necessary conditions for protection against murine TB infection. (Immunity, 1995;2:561) In the anti-TNF treated mice: Granuloma formation was delayed 20% lacked epithelioid cells in the liver Less organized, AFB were 10-50 fold higher Extensive necrosis in the lungs. TNF neutralization with mAb results in disease reactivity in mice persistently infected 6 months previously with TB (Inf and Immun. 2001)

Effects of TNF TNF is involved in the regulation of apoptosis of cells infected with M. Tuberculosis TNF promotes the maturation of DC, thereby inducing the transport of MT antigens to the lymph nodes and the priming of the T-cells subsets that traffic the site of infection TNF induced antimicrobial activity of murine macrophages TNF directs the movement of leucocytes (Ann Rheum Dis, 2005;64:24-8)

TNFi and TB in humans Early reports-USA Incidence RA + TNFi 24.4/100000 RA-TNFi 6.1/100000 Jerrold Ellner at Boston- 9 fold increase of TB in TNFi treated in US (NEJM 2001;345:1098)

TB cases in Spain Rate/100,000 OR All Cases (pre) 522 21 (Post) 117 4.7 RA only Pre 564 22.6 post 95 3.8 (Arthrits and Rheum 2005;52:1766)

Risk of TB in RA patients RR of TB in RA Sweden Korea No TNFi 2 9 With TNFi 8 30 J Rheum 2007;34:706 Arthritis and Rheum 2005;52:1986-92

Humira RA clinical Trials Rate/100 PY Pre-screening 1.3 Post Screening 0.15

Risk of TB after screening Spain OR All TB cases 4.7 RA patients 3.8 Lack of compliance with recommendation 7 (Arthitis Care and Res 2007;57:756)

Yes- TNFi are IS The increased risk of TB among TNFi treated is mainly the result of TNFi therapy and not the disease state.

Is Repeated TST indicated? In the START study 7 cases of active TB developed despite negative TST at screening 2 other patients developed TB with positive TST at screening. (one with TST of 6) Arthritis and Rheumatisim 2006;54:1075-86.

Repeated TST following therapy with TNFi- Soroka Data Patients with RA, AS and PsA receiving TNFi therapy and who had not received therapy for LTBI All patients underwent a second TST Conversion was defined as an increase of 6 mm of induration between the screening and the second test. Am J Resp Crit Care Med 1999;159:15-21

Preliminary results 40 patients were assessed. First TST: 25 < 5 mm Second TST: 21 < 5 mm 19 > 5 mm Eight (20%) had an increase of 6 mm between readings with 4 having an increase of 10 mm.

Change in TST reading TST reading 1st TST 2nd TST 0-2 20 1 > 5mm 3 converters 3-4 5 2> 5mm 2 converters > 5 15 3 converters 2 reverters once positive is always positive-incorrect Once positive –no longer useful -correct

Boosting vs. conversion 2 step testing is indicated in this group to avoid interpreting the boost as new infection

Summary The risk of secondary TB following TNFi therapy is more than 15 mg of prednisone Before therapy perform TST If TST > 5 mm diagnose and treat LTBI. If TST <5 mm perform 2nd test 1 week later If TST is negative look for old TB in CXR For patients with negative TST consider annual testing of TST.

Think TB Look for TB associated symptoms Treat recent contact with patients with TB Look for extra-pulmonary and atypical disease. Evaluation should be rigorous including NGT and bronchoscopy