Case reports. Patient 1

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1 REVIEW ARTICLE BJD British Journal of Dermatology Tuberculosis and tumour necrosis factor-a inhibitor therapy: a report of three cases in patients with psoriasis. Comprehensive screening and therapeutic guidelines for clinicians A. Perlmutter,* A. Mittal and A. Menter* *Baylor Research Institute, 3900 Junius Street, Suite 145, Dallas, TX 75246, U.S.A. Baylor University Medical Center, Dallas, TX, U.S.A. Summary Correspondence Alan Menter. amderm@gmail.com Accepted for publication 18 May 2008 Key words guidelines, TNF-a antagonist, treatment, tuberculosis Conflicts of interest A. Menter has received research support and or lecture honoraria from Abbott Laboratories, Amgen Inc, Centocor Inc. and Wyeth Laboratories. A. Mittal and A. Perlmutter: none declared. Tumour necrosis factor (TNF)-a inhibitors, long used in rheumatology and gastroenterology, have made a significant impact on the therapy of psoriasis and psoriatic arthritis. TNF-a is an important cytokine in normal physiological processes such as the immune response to granulomatous infection. Inhibition of this process by TNF-a inhibitors has been reported to increase the susceptibility of patients to granulomatous infections such as Mycobacterium tuberculosis. Despite the numerous reported cases in the literature and appropriate warnings on the labels for the three currently approved TNF-a inhibitors, current guidelines do not address casespecific issues across the full spectrum of tuberculosis. The probability of developing active tuberculosis has been reported to be as much as seven times higher when recommendations are not followed. We report three cases of tuberculosis induced by TNF-a inhibitors despite a rigorous screening policy in our tertiary care psoriasis centre, and suggest tuberculosis-specific guidelines for clinicians using these agents based on a review of the literature. DOI /j x Tumour necrosis factor (TNF)-a inhibitors have been used to treat multiple diseases in more than patients over the past 10 years. There are three currently approved TNF-a inhibitors: etanercept a dimeric protein construct consisting of a human TNF receptor domain fused to a human IgG1 domain; infliximab a chimeric murine human monoclonal anti-tnf-a antibody; and adalimumab a fully humanized monoclonal anti-tnf-a antibody. TNF-a is important in normal physiological processes such as the immune response to granulomatous infection and inhibition of this process thus has the potential to increase the susceptibility of patients to Mycobacterium tuberculosis. Despite numerous cases reported in the literature and appropriate warnings on the labels of the three approved TNF-a inhibitors, current guidelines do not address case-specific issues across the full spectrum of tuberculosis. The probability of developing active tuberculosis has been reported to be up to seven times higher when recommendations are not followed. 1 Although a rigorous screening policy is followed in our tertiary care psoriasis centre, we report three cases of tuberculosis induced by TNF-a inhibitors and suggest tuberculosis-specific guidelines for clinicians using these agents based on a review of the literature. Case reports Patient 1 A 31-year-old Indian man with recalcitrant psoriasis and psoriatic arthritis (PsA) commenced etanercept therapy in August Prior to commencing systemic therapy his purified protein derivative (PPD) and chest X-ray were negative. However, his bacille Calmette Guérin (BCG) vaccination status was unknown. PPD and chest X-rays were negative in 2003 and 2004, respectively. A repeat PPD 1 year later was positive at 15 mm induration, with subsequent negative chest X-ray. Isoniazid therapy was initiated and etanercept therapy discontinued. The patient subsequently consulted a rheumatologist who initiated infliximab therapy which was continued for 9 months until the patient developed general malaise, 8

2 Tuberculosis and TNF-a inhibitor therapy in psoriasis, A. Perlmutter et al. 9 headaches and low-grade fever. Evaluation revealed a mildly elevated C-reactive protein (CRP) and thickening of the proximal jejunum and distal duodenum by abdominal computed tomography (CT) scan. After hospitalization for dehydration newly elevated liver function tests were revealed with a normal total bilirubin. Cerebrospinal fluid studies demonstrated lymphocytic meningitis with elevated protein (white blood cell count 357 cells mm )3, 100% lymphocytes; red blood cell count 0 cells mm )3 ; glucose 66 mg 100 ml )1 ; total protein 97 mg dl )1 ). He was negative for acid-fast bacilli (AFB) by smear, culture and polymerase chain reaction. Mediastinal lymphadenopathy was noted on chest CT with a biopsy demonstrating AFB-positive smear and culture that was pansensitive. Rifampicin, isoniazid, pyrazinamide and ethambutol (RIPE) therapy was initiated for disseminated tuberculosis and presumptive tuberculosis meningitis. Patient 2 This 54-year-old man from Bangladesh presented with generalized psoriasis and mild PsA. Prior therapy included etanercept. An initial PPD was negative. Ciclosporin was initiated and then, subsequently, etanercept because of worsening of his PsA. His ciclosporin was then tapered and discontinued; however, a subsequent strongly positive PPD resulted in discontinuation of all therapy. Successive development of a persistent productive cough, headaches, low-grade fever, hilar adenopathy and pulmonary infiltrates was confirmed as miliary tuberculosis by bronchoscopy. He was started on RIPE therapy. Patient 3 A 65-year-old Caucasian man presented to our clinic with moderate-severe psoriasis and PsA. His PPD was positive at 15 mm induration while his chest X-ray was negative. Isoniazid therapy was instituted. Three months later, etanercept was initiated and continued for 10 months until return of psoriasis activity. Infliximab was subsequently introduced. After the third infusion, he was hospitalized for generalized lethargy, somnolence and cough. Despite his isoniazid prophylaxis, chest X-ray revealed numerous bilateral miliary pulmonary nodules suggestive of tuberculosis. Thoracoscopy with biopsy showed caseating granulomas, positive AFB stains, cultures and deoxyribonucleic acid probe for mycobacterium complex. The patient was started on RIPE therapy. Epidemiology of tuberculosis With approximately 8 million new cases reported globally each year, tuberculosis remains one of the leading causes of death from infectious disease. After 30 years of decline, the number of cases of tuberculosis in the U.S.A. increased by 20% between 1985 and Nine consecutive years of decline followed, the incidence of tuberculosis decreasing by 40% through Although the rate of decline has slowed over the past 5 years, the reported 4Æ8 cases of tuberculosis per population in 2005 still represents an all-time low. 2,3 The onset of the human immunodeficiency virus (HIV) epidemic and the appearance and transmission of multidrug resistant tuberculosis strains have complicated these statistics. Significant disparities in tuberculosis rates persist among foreign-born individuals, racial ethnic minority populations and in certain high-risk states. The prevalence rate among foreign-born people in the U.S.A. is at least eight times higher than among the U.S.-born population, with Hispanic, Black and Asian people having 7 20 times higher incidence rates than Caucasians. Shifting immigration patterns, proximity to the U.S. Mexican border and emerging drug resistance, may all influence tuberculosis incidence. 3 Immigration is likewise a major risk factor in the U.K. with the incidence of tuberculosis remaining high in most ethnic minority groups, especially those from the Indian subcontinent and of African origin. In 1998, 56% of reported cases of tuberculosis were in people not born in the U.K. 4 The increased risk among foreign-born individuals may continue for 20 years after migration. Thus, with continued migration, the percentage of foreign-born individuals with tuberculosis in the developed countries is unlikely to fall. 5 Contemporary tuberculosis screening methods The PPD is a diagnostic tool for tuberculosis endorsed by the American Thoracic Society (ATS) and Centers for Disease Control and Prevention (CDC). Latent tuberculosis infection (LTBI) implies evidence of cell-mediated immunity to tuberculosis without microbiological or clinical evidence of active disease. The CDC recommends screening with the tuberculosis skin test (TST) for populations at increased risk (Table 1). 6 As per CDC and ATS recommendations, the guidelines for interpreting TST results according to patient risk factors are shown in Table 2. 7,8 When reading the PPD, patients on TNF-a antagonists are considered to be immunosuppressed, and are therefore evaluated equivalently to other patients on immunosuppressive medications. A TST reading is based on the presence or absence of induration, evaluated at maximum induration, which occurs h after injection. 8 Although the TST has been a reliable screening tool for almost a century, the introduction of T-cell interferon (IFN)-c release assays (TIGRA) has challenged current standards of preventive treatment. 9 Use of these T-cell-based tests may help to refine diagnostic testing for tuberculosis in patients with inflammatory arthropathies. 10 Two contemporary alternative tuberculosis tests for diagnosing LTBI have been developed and licensed for commercial distribution in many countries: the QuantiFERON Ò -TB Gold test (QFT-G; Cellestis Inc., Valencia, CA, U.S.A.) and the T-SPOT-TB (Oxford Immunotec, Abingdon, U.K.). Both tests measure IFN-c; however, their measurement techniques differ.

3 10 Tuberculosis and TNF-a inhibitor therapy in psoriasis, A. Perlmutter et al. Table 1 Populations at increased risk for tuberculosis High-risk racial or ethnic minorities Those infected with HIV Injecting drug users Those with risk factors known to increase the risk for disease if infection occurs Residents and employees of high-risk congregate settings (e.g. correctional institutions, nursing homes, mental institutions, other long-term residential facilities and shelters for the homeless) Healthcare workers who serve high-risk clients Foreign-born persons, including children, having arrived recently (within 5 years) from countries with a high tuberculosis incidence or prevalence Medically underserved, low-income populations Close contacts (including household or other enclosed environments) of persons known to have tuberculosis Infants, children and adolescents exposed to adults in high-risk categories HIV, human immunodeficiency virus. The QFT-G is approved by the Federal Drug Administration (FDA) and endorsed by the CDC in the U.S.A. as a replacement for the TST, whereas the U.K. National Institute for Health and Clinical Excellence has suggested that TIGRA be used as an adjunct to the TST. 11,12 The QFT-G uses an enzyme-linked immunosorbent assay to detect levels of IFN-c by circulating T cells in the whole blood, with further computer-driven interpretation which eliminates the subjective analysis of the skin test. Both blood tests (QFT-G and T-SPOT) eliminate cross-reactivity with BCG and most nontuberculous mycobacteria (exceptions being M. kansasii, M. szulgai and M. marinum) by using more tuberculous-specific antigens: ESAT-6, CFP-10 and TB7.7. 9,12 Other advantages include one required patient visit and elimination of a potential booster effect. While the use of these tests in immunosuppressed patients is promising, unlike the TST there is a lack of screening data regarding relative sensitivities in these populations, including patients being treated with TNF-a inhibitors Important disadvantages of the QFT-G include availability, cost and lack of epidemiological experience compared with 100 years with the TST. The QFT-G requires that blood be evaluated within 6 h, a significant limitation. 16 Additionally, prospective data are lacking regarding the future risk for active tuberculosis in people with positive results on the TIGRA test. 11 Effects of immunosuppressive therapy on immune response to tuberculosis infection Tuberculosis screening in patients on immunosuppressive therapy is driven by the hypothesis that TNF is important in the maintenance of granuloma formation. 17 One hypothesis Table 2 Interpretation of tuberculin skin test result based on Centers for Disease Control and Prevention American Thoracic Society recommendations 7,8 Induration (mm) Risk factors 15 Persons with no risk factors for tuberculosis 10 Recent immigrant (i.e. within the last 5 years) from high-prevalence countries Injecting drug users Residents and employees of the following high-risk congregate settings: prisons and jails, nursing homes and other long-term care facilities for the elderly, hospitals and other healthcare facilities, residential facilities for patients with AIDS and homeless shelters Laboratory personnel working with mycobacteria Individuals with the following clinical conditions that place them at high risk: silicosis, diabetes mellitus, chronic renal failure, some haematological disorders (e.g. leukaemias and lymphomas), other specific malignancies (e.g. carcinoma of the head, or neck and lungs), weight loss of 10% of ideal body weight, gastrectomy, jejunoileal bypass Children younger than 4 years of age or infants, children and adolescents exposed to adults at high risk 5 HIV-positive individuals Recent contacts of patients with tuberculosis Fibrotic changes on chest radiograph consistent with prior tuberculosis Patients with organ transplants and other immunosuppressed patients (receiving the equivalent of 15 mg daily of prednisone for 1 month or more or taking tumour necrosis factor-a antagonist) AIDS, acquired immune deficiency syndrome; HIV, human immunodeficiency virus. proposes that overexuberant TNF expression in active cavitary disease enhances the proinflammatory response, allowing the infection to cause tissue destruction. 18 Another suggests that TNF inhibitors may accelerate sterilization and enhance antibiotic killing in the setting of immunosuppression. TNF-deficient or TNF receptor-deficient knockout mice show an increased susceptibility to tuberculosis. Reactivation of LTBI in patients treated with TNF agents remains a concern. In contrast to tuberculosis in immunocompetent individuals, tuberculosis associated with TNF-a blockade has a higher rate of extrapulmonary manifestations Infliximab carries a greater potential risk of tuberculosis compared with the other two TNF inhibitors. 23 This is possibly related to higher rates of apoptosis and loss of granuloma integrity due to its antibody-binding properties compared with a receptor-like antagonist. 19 The potency of TNF inhibition may relate to individual dosing schedules and drug concentration rather than the biology of the

4 Tuberculosis and TNF-a inhibitor therapy in psoriasis, A. Perlmutter et al. 11 granuloma. 25 Additionally, reports have shown that both infliximab and adalimumab inhibit T-cell activation and IFN-c production in vitro while etanercept possibly has no effect, thus explaining why infliximab poses a reportedly nine times greater risk of reactivation of LTBI during the first 3 months of treatment than etanercept. 26 Bieber and Kavanaugh report that the median time to onset of tuberculosis with etanercept therapy is 11Æ2 months, with infliximab 75% within 6 weeks and 100% by 7 months, and with adalimumab 3 8 months. 27 Clinical guidelines for tuberculosis testing and treatment in patients being considered for tumour necrosis factor-a inhibitor therapy Use of these agents has also been associated with other life-threatening granulomatous infectious diseases, including candidiasis, histoplasmosis, aspergillosis and listeriosis. Methotrexate, commonly used in conjunction with TNF-a antagonists, has also been independently associated with tuberculosis. 28 A number of observational studies support screening for, and treatment of, LTBI before initiating TNF-a inhibitors. Perez reported an 85% reduction in adalimumab-associated tuberculosis cases and Carmona et al. an 83% reduction in infliximabrelated cases after adopting CDC recommendations. 29,30 In a safety trial with infliximab for rheumatoid arthritis (RA), of 80 patients with a positive TST result who commenced treatment for LTBI followed by infliximab at least 2 weeks later, none developed active tuberculosis. 31 The CDC and ATS recommend 9 months of isoniazid or 4 months of rifampicin prophylaxis for TST reactors. 32 French guidelines 33 recommend at least 3 weeks of tuberculosis prophylaxis before initiating a TNF agent while the BTS guidelines suggest stratifying annual tuberculosis disease risk based on age, ethnicity and location vs. the side-effect profile of tuberculosis chemoprophylaxis to assess whether therapy or observation is indicated. If prophylaxis is indicated, TNF-a inhibitors are commenced concurrently. 34 Without evidence to suggest completion of preventative therapy prior to restarting the TNF-a inhibitor, 2 4 weeks of prophylactic therapy is considered the consensus treatment in patients with a positive PPD and a normal chest X-ray. 25 Tuberculosis treatment is based on identification of the organism by sputum or bronchoscopy washing. For pulmonary disease, the CDC recommends a minimum of monthly sputum specimen collection for microscopic examination and culture until two consecutive specimens are negative. 35 The conversion of sputum smears from positive to negative takes 60 days if receiving appropriate treatment. 36 Once adequate treatment is established, smear negativity could potentially be utilized as a benchmark for re-initiation of TNF-a inhibitor therapy. Designation of drug therapy is largely based on the side-effect profile of the TNF-a inhibitor therapy in relation to patients concomitant disease or condition, e.g. renal failure, hepatitis, children, pregnancy, lactation, etc. Extrapulmonary disease represents a more complex problem, based on the site involved. 24 Follow-up after completion of therapy is generally not required but patients are instructed to seek care promptly for recurrence of signs or symptoms. 35 The risk for tuberculosis relapse in patients previously treated with a course of TNF-a inhibitor therapy with subsequent initiation of one of these agents is unknown. 37 Matsumoto et al. describes a patient with RA diagnosed with peritoneal tuberculosis while being treated with infliximab. Following 9 months of RIPE therapy, infliximab was re-initiated along with maintenance rifampicin isoniazid for 3 months and then isoniazid only, with no signs of recurrence 1 year later. However, the outcome without tuberculosis prophylaxis medication is uncertain. 38 Additionally, during RA clinical trials with etanercept, patients with prior tuberculosis infection or a positive PPD did not show reactivation of tuberculosis over an average of months of treatment. 39 The BTS suggests that for patients with a history of adequately treated previous tuberculosis, TNF therapy may be initiated together with clinical monitoring every 3 months. 34 The BTS stratifies patients with abnormal chest X-rays consistent with prior tuberculosis or histories of prior nonpulmonary tuberculosis without adequate previous treatment into a separate category. Even with active disease excluded, complete chemoprophylaxis without TNF-a inhibitor therapy is favoured based on a higher rate of reactivation in these patients compared with the general population. 34 For patients with active disease, no clear data exist regarding time to initiate TNF-a inhibitor therapy after commencing antituberculous therapy. 25 In a study by Westhovens et al. patients with a history of active tuberculosis were required to have received a full course of antituberculous therapy 2 years prior to the baseline visit; none of the 15 patients with appropriately treated tuberculosis developed active disease during the study. 40 If active pulmonary or nonpulmonary tuberculosis is discovered prior to anti-tnf-a treatment, the BTS warrants supervised (by infectious disease thoracic specialist) standard tuberculosis chemotherapy for at least a 2-month TNF therapy-free interval. 34 The CDC does not have specific recommendations in this regard. If active tuberculosis disease develops during TNF-a inhibitor therapy, CDC guidelines recommend discontinuing the TNF-a inhibitor with the optimal time for resuming treatment not determined. 35 BTS recommends full antituberculous chemotherapy concomitant with continued TNF-a inhibitor treatment when clinically indicated. 34 Suggested guidelines for tumour necrosis factor-a inhibitor therapy While guidelines exist (Tables 3 32,35 and 4 2,34 ), we offer a comprehensive review of the literature and specific guidelines for clinical practice (Table 5). In all scenarios, consultation with a pulmonologist is advised. Patient compliance is crucial.

5 12 Tuberculosis and TNF-a inhibitor therapy in psoriasis, A. Perlmutter et al. Table 3 Summary of Centers for Disease Control and Prevention (CDC) American Thoracic Society (ATS) and British Thoracic Society (BTS) guidelines prior to tumour necrosis factor (TNF) antagonist therapy Screening No immunosuppressives On immunosuppressives LTBI or TB infection PPD positive CXR negative Adequate prior TB treatment Abnormal CXR consistent with prior TB or history of nonpulmonary TB Inadequate prior TB treatment Abnormal CXR consistent with prior TB or history of nonpulmonary TB Active disease ruled out Confirmed active disease CDC ATS Assess risk factors of TB Perform PPD Follow-up CXR if PPD positive As above Patients on TNF agents most likely resemble an immunocompromised population similar to HIV Interpret a TST induration of 5mmasa positive result Interpret negative TST with caution because more likely for false-negative TST result Exclude active TB Start treatment (in accordance with published guidelines) for LTBI before initiating TNF-a antagonist Preferably 9 months of daily INH suggested Optimal time for starting TNF-a therapy is undetermined However, postponing therapy until LTBI treatment is complete might be impractical No specific guidelines The risk for TB relapse in patients previously cured of TB and subsequently treated with TNF-a antagonists is unknown No definitive guidelines regarding the optimal time for initiating TNF antagonist Consider postponing TNF agent until conclusion of treatment for LTBI No definitive guidelines regarding the optimal time for initiating TNF antagonist Assess improvement in patient condition before commencing TNF agent but generally, consider postponing TNF agent until conclusion of treatment for TB BTS Clinical examination Assess prior TB history Perform CXR if normal, then TST may be helpful No TST test Clinical examination Assess prior TB history Perform CXR If CXR is normal, determine risk benefit calculations If chemoprophylaxis risk is greater than the TB risk, repeat CXR within 3 months of starting anti-tnf treatment and further workup if necessary Assess individual risk benefit calculations to determine treatment necessity If TB prophylaxis is initiated, may commence anti-tnf agent concurrently If chemoprophylaxis risk is greater than TB risk, repeat CXR within 3 months of starting anti-tnf treatment Pursue further workup if necessary Initiate anti-tnf-a therapy Clinical monitoring every 3 months Obtain CXR and sputum cultures if respiratory symptoms Initiate anti-tnf agent after completing full course of TB prophylaxis At least 2 months of supervised (by infectious disease specialist pulmonologist) full TB treatment Confirm drug susceptibility (in those with positive cultures) before commencing anti-tnf-a therapy TB, tuberculosis; PPD, purified protein derivative; CXR, chest X-ray; HIV, human immunodeficiency virus; TST, tuberculosis skin test; LTBI, latent TB infection. 1. Screening prior to tumour necrosis factor-a antagonist therapy 1A. Asymptomatic patient not on other immunosuppressive agents Carry out tuberculosis screening as per CDC guidelines, i.e. PPD (Table 3). Chest X-ray (recommended by the BTS) may be an insensitive screening tool for LTBI as it is usually normal but may detect abnormalities indicative of prior tuberculosis or suggesting active tuberculosis. Refer to pulmonologist with positive test. Timing of TNF initiation will depend on diagnosis. Confirmation with the QFT-G or T-SPOT after a positive PPD should be considered, especially in regions with a lower prevalence of tuberculosis and or a BCG-vaccinated population. Once epidemiological evidence further substantiates this test, it may replace our current recommendations. 1B. Asymptomatic patient, on other immunosuppressive agent(s) Consider TIGRA for tuberculosis screening due to increased likelihood of false-negative TST. Same as 1A.

6 Tuberculosis and TNF-a inhibitor therapy in psoriasis, A. Perlmutter et al. 13 Table 4 Summary of Centers for Disease Control and Prevention (CDC) American Thoracic Society (ATS) and British Thoracic Society (BTS) guidelines during tumour necrosis factor (TNF) antagonist therapy During TNF treatment CDC ATS BTS Screening No guidelines regarding PPD screening after starting TNF treatment No guidelines regarding PPD screening after initiating TNF treatment LTBI or TB infection Seroconversion No definitive guidelines No specific guidelines regarding the optimal time for initiating TNF antagonist Consider postponing TNF agent until conclusion of treatment for LTBI Confirmed active disease Initially withhold TNF agents pending the start of anti-tb medication and improvement in the patient s clinical status If possible, consider postponing TNF agent until conclusion of TB treatment May consider uninterrupted TNF therapy along with a full standard course of anti-tb chemotherapy if clinically indicated. In this way, the patient may maintain clinical benefit TB, tuberculosis; LTBI, latent TB infection; PPD, purified protein derivative. 2C. Inadequate prior tuberculosis therapy with abnormal chest X-ray consistent with prior tuberculosis or with history of nonpulmonary tuberculosis (active disease ruled out) Complete course of treatment for LTBI before initiating TNF agent due to an increased likelihood of developing future active disease in these patients. 41 2D. Confirmed active disease A full course of antituberculous treatment is desirable, but not always clinically practical. Withhold TNF-a antagonist therapy until the patient demonstrates adherence to the antituberculous regimen, shows improvement in their condition and until two consecutive sputum cultures are negative. Sputum smear negativity should be utilized as a benchmark for re-initiation of anti-tnf therapy. This usually occurs by 8 weeks in 80% of patients with pulmonary tuberculosis caused by drug-susceptible organisms who are started on standard four-drug therapy. 34 For extrapulmonary tuberculosis, frequency of evaluation will depend on the site involved. 3. Latent tuberculosis infection or tuberculosis during tumour necrosis factor-a antagonist therapy Consider yearly PPD screening with TIGRA due to greater sensitivity in immunosuppressed patients. 3A. PPD conversion 2. High-risk patients prior to initiating tumour necrosis factor antagonist 2A. PPD-positive, chest X-ray-negative patients Refer to pulmonologist to rule out active tuberculosis. Initiate isoniazid therapy once active disease ruled out. Initiate TNF therapy after 4 weeks of isoniazid, possibly 8 12 weeks for infliximab. The BTS risk assessment does not take into account travel, occupational, ethnic or regional risk factors for tuberculosis transmission. Migration, poverty and urban disease transmission patterns pose risks to individuals who are not covered by the aggregate epidemiological picture. 2B. Adequate prior tuberculosis treatment with abnormal chest X-ray consistent with prior tuberculosis or with history of nonpulmonary tuberculosis Without clear epidemiological or statistical evidence it is difficult to determine when to commence TNF therapy following adequate tuberculosis treatment. Monitoring for clinical signs of disease relapse, assessing CRP levels, and keeping a temperature and weight diary for 6 12 months may be helpful. Individuals infected with M. tuberculosis are at greatest risk for developing disease shortly after infection has occurred. 36 Withhold TNF until active disease is ruled out. Re-initiate TNF agent concurrently with tuberculosis prophylaxis in a fully compliant patient demonstrating benefit from treatment. 3B. Active disease It is debatable whether the TNF agent can be restarted prior to receiving a full course of antituberculous treatment. 36 Thus, restarting the TNF agent should mainly be a clinical decision ranging from a minimum of 6 weeks, the time course for a positive smear to turn negative, to the standard of 9 months. Re-initiation is case dependent and important considerations are patient compliance, nondrug resistant tuberculosis by culture and tuberculosis smears having turned negative. Ideally, a full 9 months of tuberculosis therapy is recommended. After completing tuberculosis therapy, monitor for disease relapse with CRP levels and a temperature and weight diary for 6 12 months. In conclusion, despite our rigid policy of screening for tuberculosis, including mandatory PPD evaluations on all patients prior to, and annually during all forms of systemic therapy for psoriasis and PsA (biological agents plus traditional

7 14 Tuberculosis and TNF-a inhibitor therapy in psoriasis, A. Perlmutter et al. Table 5 Guidelines for tuberculosis screening pre-initiation and during treatment with tumour necrosis factor (TNF)-a inhibitors Screening prior to initiating TNF antagonist Screen patients for TB risk factors Interpret TST per published guidelines 4 6 Consider TIGRA for confirmation of positive TST in BCG-vaccinated populations or low-risk communities Screening during TNF therapy Consider yearly PPD screening with TIGRA LTBI or TB prior to TNF antagonist PPD positive CXR negative Adequate prior TB treatment Abnormal CXR consistent with prior TB or history of nonpulmonary TB Inadequate prior TB therapy Abnormal CXR consistent with prior TB or history of nonpulmonary TB Active disease ruled out Confirmed active disease LTBI or TB during TNF therapy Seroconversion Confirmed active disease Recommendations No immunosuppressives Exclude active disease before initiating TNF-a inhibitor INH for 9 months prior to TNF-a inhibitor INH for 4 weeks prior to TNF-a inhibitor adequate in fully compliant patient, possibly 8 12 weeks with infliximab On immunosuppressives See above recommendations Consider TIGRA for TB testing due to increased likelihood of false-negative TST Risk for TB relapse unknown Additional prophylactic therapy Possibly avoid TNF-a inhibitor Close follow-up, monitoring for clinical signs of relapse, CRP levels, weight and temperature diary for 6 12 months Complete course of treatment for LTBI before initiating TNF-a inhibitor These patients have increased likelihood of developing future active disease Case by case basis Withhold TNF-a inhibitor as long as possible May begin TNF-a inhibitor once adequate treatment and smear negativity established by 2 consecutive sputum cultures Withhold TNF-a inhibitor until active disease is ruled out Re-initiate TNF-a inhibitor concurrently with TB prophylaxis in fully compliant patient benefiting from treatment Close monitoring by infectious disease specialist If possible, postpone TNF-a inhibitor until anti-tb treatment completed Should discontinue TNF-a inhibitor until patient has received at least 6 8 weeks anti-tb treatment Clinical decision may range from 6 weeks to 9 months before re-initiating TNF-a inhibitor TB, tuberculosis; TST, tuberculosis skin test; TIGRA, T-cell interferon-c release assay; BCG, bacille Calmette Guérin; LTBI, latent TB infection; PPD, purified protein derivative; CXR, chest X-ray; INH, isoniazid; CRP, C-reactive protein. oral medications), active tuberculosis developed in three patients on TNF-a inhibitor therapy. Two of our three patients were foreign born. The first patient from India developed a positive PPD while on etanercept therapy and subsequently developed active tuberculosis on infliximab therapy in the setting of adequate tuberculosis prophylaxis. The second patient from Bangladesh was on etanercept with a concomitant low-dose tapering of ciclosporin when he became positive, suggesting a possible synergistic effect. The third patient (American-born Caucasian) became positive on etanercept therapy. He completed a 6-month course of isoniazid, was subsequently initiated on infliximab therapy and thereafter developed active pulmonary disease. Shortly after, it was discovered that he had been noncompliant with his antituberculous prophylactic therapy. Thus, we felt it prudent to thoroughly review the literature and current recommendations by national bodies and to offer practical guidelines addressing specific risk benefit issues for physicians utilizing TNF-a inhibitors. As the probability of developing active tuberculosis is up to seven times higher when recommendations are not followed, 1 physician-to-physician interactions and patient compliance are crucial elements in optimizing these guidelines to limit the development of active tuberculosis in patients on TNF-a inhibitory therapy. Acknowledgment We would like to give a special thanks to Dr William Bishai MD PhD (tuberculosis specialist), for his expert assistance and guidance.

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