TUBERCULOSIS AND THE TNF-α INHIBITORS Lloyd Friedman, M.D. Yale University Milford Hospital
Outline TNF-α Anti-TNF-α medications Rates of tuberculosis Lower rates with etanercept Screening for latent tuberculosis infection (LTBI) Treatment of LTBI Treatment of active disease Paradoxical response Issues and Recommendations
TNF-α (née cachexin )
The TNFα Inhibitors Infliximab (Remicaide) 1998 Etanercept (Enbrel) 1999 Adalimumab (Humira) 2002 Certolizumab (Cimzia) 2009 Golimumab (Simponi) 2009 Pentoxiphylline Adenosine? Thalidomide
Diseases that Respond to the Rheumatoid Arthritis Psoriatic Arthritis Plaque Psoriasis Ankylosing Spondylitis Juvenile Idiopathic Arthritis Crohn s Disease Ulcerative Colitis Behcet s Disease Sarcoidosis TNFα-Inhibitors
Infliximab Chimeric mab binds to soluble monomeric and trimeric as well as transmembrane TNF RA, psoriatic arthritis, plaque psoriasis ankylosing spondylitis, Crohn s, ulcerative colitis Intravenously every 4-8 weeks Half life 9 days, biological effect 2m
Adalimumab Recombinant human mab binds to soluble monomeric and trimeric as well as transmembrane TNF RA, psoriatic arthritis, ankylosing spondylitis, Crohn s disease, juvenile idiopathic arthritis Subcutaneously every 2 weeks Half life 12-14 days
Etanercept Soluble p75 TNFR2 fusion protein binds to soluble TNF. It also binds to lymphotoxin (TNF-beta). It does not bind to transmembrane TNF. Rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, juvenile idiopathic arthritis (not IBD) Subcutaneous injection 1-2 times/week Half life 4-5 days
Certolizumab pegol Antigen-binding fragment of a human Fab linked to polyethylene glycol RA and Crohn s Subcutaneously every 4 weeks Because it does not contain an Fc portion, it does not induce complement activation, antibody-dependent cellular cytotoxicity, or apoptosis.
Golimumab Human IgG1 kappa anti-tnf monoclonal antibody binds to soluble and transmembrane TNF RA, psoriatic arthritis, ankylosing spondylitis Subcutaneously once a month
Adverse Reactions to the Antibody- Derived TNFα Inhibitors Infections granulomatous and nongranulomatous Injection Site Reactions Infusion Reactions acute and delayed (serum sickness) Neutropenia Cutaneous Reactions Malignancies lymphoma, leukemia, solid tumors Heart Failure - possible Induction of Autoimmunity sarcoidosis, psoriasis, other Demyelinating Disease not proved
TNF-α is vital in the development and maintenance of granulomas
Rates of Tuberculosis
TB risk in Anti-TNF-Treated RA in Sweden Askling. Arth Rheum 2005;52:1986
Tuberculosis Associated with Infliximab 147,000 patients who received infliximab in the USA and Europe 70 cases of TB at a median of 12 weeks 40 (57%) with extrapulmonary disease (17 disseminated) 48 cases after 3 or fewer infusions 55 patients received >1 other immunosuppressive drug Comparison using estimated USA rate in RA patients 24.4 vs 6.2 cases per 100,000 persons/year Keane. NEJM 2001;345:1098
Tuberculosis Associated with Infliximab Pulmonary 22 (31%) Extrapulm (local) 23 (33%) LN (11), perit (4), pleural (2), mening (1), enteric (1), skel (2), gu (2) Extrapulm (dissem) 17 (24%) Not reported 8 (11%) Keane. NEJM 2001;345:1098
Tuberculosis Associated with Infliximab Keane. NEJM 2001;345:1098
Etanercept-related tuberculosis rates are lower than those with infliximab or adalimumab
Risk of TB is Higher with Infliximab and Adalimumab than with Etanercept Tubach.Arth Rheum 2009;60:1884
Granulomatous Infections FDA Reports Infliximab 54 per 100,000 Etanercept 28 per 100,000 Background rate ~ 6 per 100,000 Wallis. CID 2004;39:1254
Granulomatous Infections FDA Reports First 90 days: Infliximab 95 per 100,000 Etanercept 11 per 100,000?New infection vs reactivation. Need to study these curves in LTBI patients Wallis. CID 2004;39:1254
Is screening for LTBI useful for patients on anti-tnf-α drugs?
Patients on infliximab with an initially negative skin test who developed TB TST-neg in 34/47 (72%) Raval. Annals 2007;147:699
Screening: No Difference Between TST and IGRA? Smith. Curr Opin Rheum 2011; 23 epub
Testing for LTBI in candidates for anti-tnf-α drugs IGRA vs TST in pts with risk factors: 14/15 (93%) vs 8/15(53%) Bocchino. EJCMID 2008;27:907
QFT better than TST Ponce de Leon. J Rheum 2008;35:776.
How effective is treatment for LTBI in patients on anti-tnf-α drugs
BTS Recommendations Treatment regimens Isoniazid for 6 months Isoniazid and Rifampin for 3 months Thorax 2005;60:800-805.
BTS Recommendations Patients with a history of untreated LTBI should be treated before starting anti-tnf-α drugs. For those with a normal CXR who are on immunosuppressive therapy, a skin test will not be helpful. If the annual risk of TB is greater than the risk of drug induced hepatitis, the treatment of LTBI should ensue. Patients with a history of adequately treated TB should be monitored clinically every 3 months with CXR and/or sputum if indicated. Thorax 2005;60:800-805.
TB Rates Decreased After Official Recommendations for Prophylaxis Carmona. Arth Rheum 2005;52:1766
CDC Recommendations Test for latent and active TB before starting therapy TST >5 mm is positive A negative skin test does not exclude TB infection consider treating LTBI where circumstances suggest a high probability of LTBI. Start treatment for LTBI before starting TNF therapy consider postponing anti-tnf therapy until the conclusion of treatment for latent or active disease. MMWR 2004; 53:683
Recommended Drug Regimens for LTBI Drug Interval and Duration HIV - HIV + Isoniazid Daily for 9 months A (II) A (II) Twice weekly for 9 months B (II) B (II) Isoniazid Daily for 6 months B (I) C (I) Twice weekly for 6 months B (II) C (I) Rifampin plus Pyrazinamide Daily for 2 months Twice weekly for 2-3 months B (II) C (II) A (I) C (I) Rifampin Daily for 4 months B (II) B (III) A=Preferred, B=Acceptable, C=If A and B cannot be given I = RCT, II= Non RCT, III=Expert opinion Rifabutin can be substituted for rifampin MMWR 2000;49(RR-6).
Tuberculosis developing while on anti-tnf-α drugs and anti-tb drugs 613 patient with RA receiving anti-tnf-α drugs 45 patients with a positive skin test assigned to receive treatment for LTBI (INH for 6m or INH/RIF for 3m) 11 developed active TB all drug sensitive 6 pulmonary, 5 extrapulmonary 8 on infliximab, 3 on adalimumab 36 patients compliant with treatment for LTBI 7 (24.4%) developed active TB (3 were still on LTBI rx) Sichletidis IJTLD 2006;10:1127
Tuberculosis developing while on anti-tnf-α drugs and anti-tb drugs 5 (13.9%) of 36 patients with LTBI developed TB within 3 months (i.e., 13, 889 cases per 100,000) - we can assume that all of these patients developed disease while on their anti-tb drugs. Compares with ~2,000 cases per 100,000 in healthy newly infected close contacts in the first year Sichletidis IJTLD 2006;10:1127
Duration of Therapy for LTBI
IUAT Trial of INH for Stable Fibrotic Lesions 5-year tuberculosis incidence/100 p-y (% reduction) Group Placebo 12 weeks 24 weeks 52 weeks All participants (n=27830) Adherent participants (n=21,635) Fibrotic lesions < 2 cm 2 (n=18,663) Fibrotic lesions > 2 cm 2 (n=8,428) 1.4 1.1 (21) 0.5 (65) 0.4 (75) 1.5 0.9 (31) 0.5 (69) 0.1 (93) 1.2 0.9 (20) 0.4 (66) 0.4 (64) 2.1 1.6 (24) 0.7 (67) 0.2 (89) IUAT. Bull WHO 1982; 60:555-64
Bethel Isoniazid Studies 1957-59 Comstock, GW. How much isoniazid is needed. Int J Tuberc Lung Dis 1999; 3:847-50.
Smear-Negative, Culture-Negative Tuberculosis Hong Kong Chest Service. ARRD 1989;139:871.
Smear-Negative, Culture-Negative Tuberculosis Regimen Duration N Relapse rate Comment INH/RIF daily for 1M, then twice weekly for 3M 4 months 414 5 (1.2%) All subjects were PPD+ Dutt. ARRD 1989; 139:867
CDC Persons with fibrotic lesions/suspected disease: For patients who have a chest radiograph demonstrating old fibrotic lesions thought to represent previous infection with TB and a positive tuberculin skin test (>5mm) without evidence of active disease and no history of treatment for TB, three acceptable regimens can be used for treatment. These regimens include 9 mo of isoniazid, 2 mo of rifampin plus pyrazinamide, and 4 mo of rifampin (with or without isoniazid), provided that infection with drug resistant organisms is judged to be unlikely. MMWR 2000;49(RR-6).
TBTC Study 26 Preliminary Results Daily INH for 9 months versus once weekly INH/RPT for 3 months (outcomes at 33 months) 72% household contacts, 24% new convertors, 2% fibrosis, 2% HIV INH:15/3794 (69% compliance): 0.40% TB I/P: 7/4052 (81% compliance): 0.17% TB and better tolerated
Treatment of active tuberculosis
Treatment of Disease in Patients Already on Anti-TNF-α Agents Use standard antituberculous therapy CDC stop anti-tnf-α agents BTS do not stop anti-tnf-α agents
CDC Recommendations If active TB develops during anti-tnf therapy, discontinue at least until TB regimen has started and the patient is improving. MMWR 2004; 53:683
BTS Recommendations Patients who develop TB while on anti-tnf-α agents should continue the agents while the TB is treated Patients with active TB should who are not on anti TNF-α agents should receive a minimum of 2 months of standard chemotherapy before starting anti TNF-α treatment Thorax 2005;60:800-805.
Paradoxical Response
Paradoxical Response May take a month or more to occur as biologic agent wears off May not respond to treatment with steroids May need to reinstitute the biologic agent
Paradoxical Reaction Garcia Vidal. CID 2005;40:756.
Paradoxical Reaction Wallis. CID 2009;48:1429.
Summary
Issues Testing for LTBI can miss cases Treatment for LTBI may not be effective Active tuberculosis may be insidious and may occur even during treatment of LTBI Etanercept may be safer in patients with LTBI or a history of TB
Practical Recommendations Test with both TST and IGRA. Can do sequentially Treat TST >5 mm or positive IGRA Treat TST <5 and negative IGRA where circumstances suggest a high probability of LTBI fibrotic lesions, recent exposure, endemic area, prisons, ivdu, etc. Start treatment for LTBI before starting anti-tnf-α therapy use INH for 9 months, or consider RIF or INH/RIF for 4 months if you cannot wait that long. Active TB should be excluded in patients with an abnormal chest radiograph or a past history of TB not previously adequately treated. Patients with old TB or LTBI taking infliximab or adalimumab should be screened every month for the first three months by symptoms and with a CXR + sputum Favor etanercept over other agents in patients with LTBI or old TB. Screen carefully for extrapulmonary disease. If TB develops in a patient on TNF-α inhibitors, stop therapy while treating for TB, at least until the TB is well under control. Watch for the development of a paradoxical reaction.