Pharmacology and therapeutics
The risk of tuberculosis in patients with psoriasis treated with anti-tumor necrosis factor agents Tulin Ergun1, MD, Dilek Seckin1, MD, Emel Baskan Bulbul2, MD, Nahide Onsun3, MD, Ozgen Zuleyha1, MD, Pemra Unalan4, MD, Erkan Alpsoy5, MD, and Sait Karakurt6, MD
1 Department of Dermatology, Marmara University School of Medicine, Istanbul, 2 Department of Dermatology, Uludag University School of Medicine, Bursa, 3 Department of Dermatology, Bezm-i Alem University, 4Department of Family Medicine, Marmara University School of Medicine, Istanbul, 5Department of Dermatology, Akdeniz University School of Medicine, Antalya, and 6Department of Pneumonology, Marmara University School of Medicine, Istanbul, Turkey
Correspondence Zuleyha Ozgen, MD € Marmara Universitesi Hastanesi Dermatoloji ABD. FevziC ß akmak mah. Mimarsinan cad. No:41 34899Ust Kaynarca/Pendik/ ISTANBUL/TURKEY E-mail: [email protected] Conflicts of interest: None.
Abstract Background Tumor necrosis factor-alpha (TNF-a) antagonist treatment is associated with 1.6 to 27 times higher risk of tuberculosis (TB). Objective To find TB incidence of psoriasis patients treated with TNF- a antagonists and define risk factors related with this condition in a country with moderately high risk of TB. Methods Three hundred seventy psoriasis patients treated by anti-TNF agents in four referral centers were included. The data on the characteristics of the patients, TB history, tuberculosis skin test results, anti-TNF agent type and exposure time, localization of TB, and isoniazide prophylaxis state were analyzed. Results Four patients (1.08%) developed TB, three pulmonary and one gastrointestinal, 2– 23 months after initiating anti-TNF agents. Other than the patient with gastrointestinal TB, who was using methotrexate and corticosteroid concomitantly, none had contributing risk factors for TB. Two patients developed pulmonary TB in spite of chemoprophylaxis. Three patients with pulmonary TB completely recovered following antiTB treatment whereas patients with gastroinrestinal TB developed renal failure. Limitations The major limitation of the study is the lack of a diseased control group, which enables us to compare the risk of psoriatics with that of patients having other inflammatory diseases. Conclusion Tuberculosis is a rare but a severe complication of anti-TNF treatment and may develop in spite of chemoprophylaxis. The risk of TB in psoriasis patients in the present study is comparable to literature mostly based on rheumatology patients.
doi: 10.1111/ijd.12628
Introduction According to World Health Organization (WHO) statistics, tuberculosis (TB) is the eighth leading cause of death in the world, and tumor necrosis factor (TNF) antagonist treatment is known to increase the risk of TB infection.1 Patients with TB triggered by anti-TNF agents commonly develop the disease within the first year of treatment, 98% of cases induced by infliximab occurring within the first six months, which corresponds to reactivation of latent TB.2–4 Latent TB infection refers to an individual having evidence of cell-mediated immunity to TB without microbiological, radiographic, or clinical evidence of active disease. These individuals with a positive tuberculin skin test (TST) have an increased risk for TB and require chemoprophylaxis before anti-TNF treatment.5 ª 2015 The International Society of Dermatology
The data regarding TB triggered by anti-TNF agents mostly originate from rheumatology and gastroenterology based studies and registries. However, those patients have several differences compared to psoriatics both in terms of the inherent nature of their disease, comorbidities, and concomitant use of disease-modifying medications. There are relatively limited data on the TB risk of patients with psoriasis using TNF antagonists in endemic regions. Recently, S anchez-Moya and Dauden from Spain reported one of their 144 psoriasis patients using TNF antagonists to develop TB.6 Another study by Sanchez-Moya analyzing Spanish psoriasis registry data revealed four of 793 patients being exposed not only to TNF antagonists but all biologics, including anti-TNF agents, ustekinumab and efalizumab, to develop TB, which has been indicated to be eight times higher compared to the general population.7. In addition to the sparseness of data on the TB risk of International Journal of Dermatology 2015
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patients with psoriasis exposed to TNF antagonists, the contribution of other possible risk factors for TB development, such as old age, chronic lung disease, concomitant use of systemic corticosteroids, or methotrexate, is also lacking. This is important for the interpretation of data extracted from rheumatology-based studies as a significant proportion of patients using TNF antagonists for rheumatological diseases use multiple immunosuppressives, including steroids. In fact, the risk of serious infections was found to be significantly higher in patients with rheumatoid arthritis and Crohn’s disease compared to those with psoriasis (relative risk: 4.6, 5.1, and 1.3, respectively).8 In addition, the concomitant use of steroids, immunosuppressives, and TNF antagonists has been shown to significantly increase TB risk compared to monotherapy with these agents (hazards ratio: 7.4 vs. 2.7) in patients with Crohn’s disease.9 The aim of the current study is to find out TB risk of patients with psoriasis treated with TNF antagonists, to identify other contributing factors to define the vulnerable group, and to find out the effectiveness of TB chemoprophylaxis. Materials and methods This is a cohort study conducted in four referral centers according to the Declaration of Helsinki. The institutional ethics committee of the coordinating center approved the study.
Patients The study included 370 patients with psoriasis treated between 2005 and 2012 by four referral centers. Patients receiving antiTNF agents for at least two months and having a follow-up period of at least six months were included, and relevant data from every patient were analyzed. Patients were screened for TB as proposed by national guidelines, and they were asked about personal and family history of TB, occupation, and previous exposure to TB. All cases, including those who had received TB treatment or prophylaxis in the past, had a chest x-ray, TST with purified protein derivative (PPD), and/or Quantiferon TB-Gold test (when available). In addition, duration and dose of TNF antagonist, concomitantly used immunosuppressives, and existence of psoriatic arthritis and other systemic diseases were recorded. Patients were followed up for adverse events due to anti-TB agents. Liver enzymes were assessed monthly during isoniazide (INH) use. Social security institution database The information related to anti-TB treatment was also obtained from the national health insurance database. As all prescriptions are captured in the database, any patient with psoriasis developing TB and using anti-TB medication could be detected through examining the prescriptions longitudinally. Consequently, all prescriptions of patients with psoriasis International Journal of Dermatology 2015
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between 2007 and 2009 were analyzed for the use of anti-TB medications. Psoriasis was defined according to the code defined in the International Classification of Diseases (ICD-10). As detailed clinical information on patients is not provided, this database was used only to define whether any anti-TNF exposed patient with psoriasis within the country, being followed up in a center other than four study centers, developed TB during the defined time. These data were not statistically analyzed and are described separately in the Results section.
Setting In 2010, the incidence of TB was 28/100,000 in Turkey.10 According to WHO, 25% of the population is estimated to have rin (BCG) latent infection in Turkey. Bacille Calmette–Gue vaccination is routinely performed for newborns, and 64% of the population is vaccinated against TB.11 Local guidelines for TB chemoprophylaxis in patients to be treated with anti-TNF agents have been determined by the Turkish Rheumatological Research and Education Society in its 2005 consensus meeting. Accordingly, all patients who will be treated by antiTNF agents having any of the following conditions receive antiTB chemoprophylaxis before initiation of anti-TNF agents; TST with PPD diameter ≥ 5 mm, abnormal chest x-ray results with calcifications >1 cm, previous untreated exposure to TB, and episode of TB, positive Quantiferon test result.12 Chemoprophylaxis for TB is defined as a 9-month treatment with INH, or if this agent cannot be tolerated, a 4-month treatment with rifampicin, both of which should be started one month before anti-TNF therapy. It is mandatory that all patients receiving anti-TNF therapy are examined by a pneumonologist, and access to these agents is possible only if the prescription, regardless of the indication, is signed by the pneumonologist. Patients are evaluated by the pneumonologist every three months and have a chest x-ray every six months during TNF antagonist use. Consequently, all patients have been followed up personally by both a dermatologist and pneumonologist, which excludes the risk of undiagnosed TB. In addition, patients receive regular calls, every three months, from a nurse in charge of monitoring overall compliance and medication side effects and from local TB control dispensary to check compliance and drug supply for anti-TB. Statistical analysis Categorical variables are presented as absolute numbers and percentages, continuous variables as means standard deviations, minimum and maximum range. Only means are presented as their values essentially overlapped with those of medians. All data were analyzed by the statistical package SPSS for Windows, version 16 (SPSS Inc., Chicago, IL, USA). A chi-squared test for trend was calculated to detect significant differences among categorical variables and t-test for continuous ones. P ≤ 0.05 was accepted to be significant. ª 2015 The International Society of Dermatology
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Anti-TNF and tuberculosis
Results Patient characteristics and tuberculosis screening
Mean age of 370 patients with psoriasis, 172 (46.5%) female and 198 (53.5%) male, was 46.4 1.3 years (range 7–80). Mean follow-up period was 40.8 months (range 6–73 months). Of the 370 patients, 80.8%, 16.8%, and 2.4% had TST, Quantiferon-TB, and missing TST or Quantiferon-TB results, respectively, in addition to chest x-ray in pretreatment screening. Three cases (0.81%) had a positive family history of TB, 12 (3.24%) had fibrotic changes as a sequelae image, consistent with past TB on their chest x-ray, and five (1.35%) had been previously diagnosed and received successful TB treatment (Table 1). There was no association between gender, family history, past TB on chest x-ray, past medical history, and TST measurement/Quantiferon-TB positivity (P > 0.05). Anti-tumor necrosis factor exposure
Among 192 etanercept, 163 infliximab, and 113 adalimumab users, mean treatment duration was 12.7 11.8 months (range: 1–6, median: 9), 13.0 13.1 (range: 1–76, median: 10), and 8.2 7.9 (range: 1–42, median: 6) months, respectively. Chemoprophylaxis status
There were nine (2.4%) missing data for screening and a full-term complete TB chemoprophylaxis. One hundred and six patients having none of the risk conditions for TB Table 1 Demographic features and test results for tuberculosis Characteristics Gender* Females Males TST (mm) ≤5 6–14 ≥15 QTF* Positive Negative Chemoprevention status Yes No
n (%)
172 (46.5) 198 (53.5) 55 (18.4) 140 (46.8) 104 (34.8) 11 (17.7) 51 (82.3) QTF(+) 10 (16.1%) TST(+) 243 (81.2%) QTF( ) 51 (82.3%) QTF(+) 1 (1.6%) TST( ) 55 (18.4%) TST(+) 1 (0.4%)
QTF, Quantiferon; TST, tuberculin skin test. *There is no association between this item and tuberculin skin test measurement. ª 2015 The International Society of Dermatology
Pharmacology and therapeutics
after initial screening did not receive chemoprophylaxis before initiation of anti-TNF agents whereas 253 received anti-TB agents. In spite of having high tuberculin reactivity (PPD = 16 mm), one patient could not receive chemoprophylaxis because of liver cirrhosis. She used etanercept for 58 and infliximab for nine months without any adverse events. Another patient with Quantiferon-TB positivity did not receive chemoprophylaxis as he misunderstood the recommendations and eventually developed TB at the third month of anti-TNF exposure. Except for two patients who received rifampicin, INH was used for chemoprophylaxis and was generally well tolerated. However, two patients had a psoriasis flair and seven developed transient mild–moderate elevations in liver transaminases. Consequently, liver toxicity of INH was seen in 2.3% of patients. Patients developing tuberculosis
Four patients (1.08%) eventually developed TB, three pulmonary and one gastrointestinal. None had a personal or family history of TB. TB was seen in the 2–23 months following the initiation of treatment, and its occurrence was shorter for monoclonal antibodies (2 and 3 months) compared to etanercept (8 and 23 months). Among four patients developing TB, two using etanercept and one using adalimumab developed pulmonary TB. A fourth patient, with coexisting psoriatic arthritis and familial Mediterranean fever, receiving infliximab, methotrexate, and systemic corticosteroid, developed gastrointestinal TB. Accordingly, the incidence rate of TB was 9.9, 5.8, and 13 per 1000 for patients receiving etanercept, infliximab, and adalimumab, respectively. Overall, the cumulative TB incidence rate for all TNF antagonists was 8.9 per 1000. Regarding the TB prophylaxis status of patients developing TB, one patient using etanercept completed nine months of INH prophylaxis, whereas the other developed TB at the eighth month of INH treatment (Table 2). The patient developing TB during adalimumab use did not receive prophylaxis in spite of a positive Quantiferon result because of a misunderstanding. Although local guidelines propose INH to be given one month before initiation of anti-TNF treatment, our first case received INH synchronous with infliximab as she had very severe psoriasis requiring rapid treatment. Eventually, she developed gastrointestinal TB in the second month of infliximab and INH therapy. None of the patients had other risk factors such as cancer, HIV, asthma, and diabetes. TB was diagnosed by clinical features and confirmed by microbiological and radiological findings. Features of patients developing TB are shown in Table 2. All patients received anti-TB treatment and recovered, but the patient with gastrointestinal TB developed renal failure. International Journal of Dermatology 2015
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Table 2 Clinical characteristics of patients developing TB Patient no.
Age, gender Tuberculin skin test (mm) TB prophylaxis Previous anti-TNF exposure, time (months) Anti-TNF type Time to TB (months) Site of TB Concomitant medication Outcome
1
2
3
4
41, female
57, male
55, female
28, male
5
20
11
Quantiferon (+)
+
+
+
Infliximab
Etanercept
Etanercept
Adalimumab
2
8
23
3
Gastrointestinal Methotrexate Corticosteroid Recovered Renal failure
Lungs
Lungs
Lungs
Recovered
Recovered
Recovered
Etanercept, 5
TB, tuberculosis; TNF, tumor necrosis factor.
Social security institution database
All patients having an ICD code for psoriasis between 2007 and 2009 were analyzed. We found 434 patients of whom 374, 54, and six used one, two, or three anti-TNF agents, respectively. Concomitant medications were systemic corticosteroids in 37, methotrexate in 86, and cyclosporine in 21. During that period, the number of patients and cumulative exposure time were 181 and 1494 months for etanercept, 179 and 1705 for infliximab, and 107 and 401 for adalimumab. The number of patients using INH prophylaxis was 74 of 181, 64 of 179, and 33 of 107 for etanercept, infliximab, and adalimumab, respectively. No record for TB treatment other than INH prophylaxis was found during that period. Discussion The current study, performed in a BCG vaccinated population, with an incidence of 28/100,000 for TB, analyzed patients with psoriasis who developed TB during antiTNF treatment and their risk factors. We have seen four cases of TB (1.08%), three pulmonary and one gastrointestinal, all developing within the first 23 months of treatment. As indicated in their labels, there is a relation between TB and anti-TNF agents and various studies docInternational Journal of Dermatology 2015
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umented 1.6–27-fold increase in frequency of TB.3 Several major issues may account for this great variation on the true risk. First is the TB risk of the population and BCG status. According to 2010 WHO health statistics, the TB incidence rate per 100,000 shows great variation in the world and is reported as 9.3, 6.8, 13, 16, and 28 for France, Sweden, United Kingdom, Spain, and Turkey, respectively.11 BCG vaccination is routine in Turkey; 64% of the population is vaccinated against TB, and 25% of the population is estimated to have latent infection.10 Thus, the study population has a relatively moderate risk for TB. The second factor accounting for the differences in TB risk triggered by anti-TNF agents is the screening method (TST vs. interferon-based assays) used. In addition to chest x-ray, we have used TST or/and Quantiferon-TB. TST is a cheap, widely available test, and its use in diagnosis of TB is endorsed by the American Thoracic Society and Centers for Disease Control and Prevention. Although TST has high specificity in non-vaccinated populations (97%), the specificity in BCG-vaccinated populations is low and highly heterogeneous.13,14 Nevertheless, as interferon-based assays eliminate cross-reactivity with BCG and most non-TB mycobacteria, they may aid in identification of latent TB cases who are candidates for prophylactic treatment. In fact, a recent meta-analysis revealed Quantiferon-TB test to have a sensitivity of 76% as well as specificity of 96% and 99% in non-vaccinated and vaccinated populations, respectively.15 As interferonbased studies are more helpful in the differentiation of latent TB from vaccine reactivity, they have replaced TST use within the last few years. Two hundred and fortythree of our 299 (81.2%) patients having TST and 10 of 62 (16.1%) patients having Quantiferon-TB test in screening had prophylactic treatment. These data are comparable with the results of Mariette et al, 16 who have shown replacement of TST with Quantiferon-TB for determining latent TB infection to reduce the need for prophylaxis by half (45.2% vs. 21.4%). These results indicate that TB screening through interferon-based studies decreases unnecessary chemoprophylaxis as preventive treatment itself carries a risk. Another factor influencing the variation in reported TB frequency is the type and duration of anti-TNF. In RATIO registry including 69 TB cases, SIR for TB has been reported to be 18.6, 29.3, and 1.8 for infliximab, adalimumab, and etanercept, respectively.17 Since we had only four patients developing TB, two on etanercept and two on monoclonal antibodies, we cannot drive conclusions. Lalvani and Millington have reported median time to TB development to be 3 and 11.5 months for infliximab and etanercept, respectively,2 which is consistent with our data. ª 2015 The International Society of Dermatology
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Finally, heterogeneity of the patient population, immune status, and use of concomitant systemic corticosteroids and/or immunosuppressives may influence the risk.18,19 Although none of our patients had diabetes, HIV, or asthma, systemic corticosteroid and methotrexate use may have contributed to gastrointestinal TB infection in our infliximab-related case. We compare our TB risk with the results of various studies from regions with a similar background TB risk. Elbek et al.20 reported two of their 240 patients with rheumatological diseases to develop pulmonary TB. The TB incidence was reported as 833/100,000, which is close to ours, 890/100,000. Both of their patients with TB were screened, found to have latent TB, and received INH prophylaxis. Cagatay et al.21 reported that six of their 702 (0.85%) patients developed TB, four pulmonary and two extrapulmonary. All of their patients were screened through chest x-ray and TST according to official guidelines, and 83.0% received prophylactic INH for nine months. When we analyzed the difference between our and their proportions, no statistically significant difference could be found (P > 0.05, 95% CI). This result suggests that the major determinant for TB risk in patients managed through similar screening and prophylaxis guidelines is the background risk of the population rather than the nature of the disease itself. In fact, a higher proportion of our patients developed TB compared to Sanchez-Moya’s 6 (P < 0.05, 95% CI), which may be explained by the higher TB incidence in Turkey compared to Spain.11 Owing to a small number of TB cases, we were unable to make a direct comparison, but the incidence of TB in these populations ranges between 0.69 and 1.08%. These data are somewhat interesting as patients with psoriasis compared to patients with rheumatology and Crohn’s have less common concomitant use of systemic steroids and immunosuppressives and are expected to have a better immune status and thus less of a TB risk.8 The higher TB risk (8.9/1000) of our group compared to both British and Swedish registry data, at which the incidence of TB was reported as 1.5 and 1.5 per 1000 patient-years for infliximab and 0.5 and 1.8 per 1000 patient-years with etanercept, respectively, also supports the importance of population risk as the major determinant for TB.18,22 Two of our patients developed TB in spite of completing nine months of INH treatment. It is well known that prophylaxis decreases the risk of reactivation of TB but does not eliminate it. Patients should be informed about the importance of prophylaxis and encouraged to use their medication properly to improve the success of TB prevention. The most relevant side effect of INH is hepatotoxicity, which was seen in 2.3% of our cases. All were transient, ª 2015 The International Society of Dermatology
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mild to moderate serum transaminase elevations not exceeding 2.5 times of upper limit. Forget and Menzies estimated that hepatotoxicity occurs in 0.92% of patients taking INH therapy.22 Taken together, these data support an acceptable risk/benefit ratio for INH in patients with a TB risk. Although TB mostly affects the lungs, anti-TNFinduced TB tends to affect extrapulmonary sites more commonly. Dixon et al. reported 15 (38%), 25 (62%), and 11 (28%) of 40 cases developed pulmonary, extrapulmonary, and disseminated TB, respectively.23 Only one of four TB patients in the present study had extrapulmonary TB. This may be due to the low number of cases with TB in our study. The most important limitation of this study is the lack of a control group. Moreover, as in other studies, a relatively low number of patients developing TB are unable to identify risk factors. Nevertheless, this is the largest study limited to patients with psoriasis with a relatively long follow-up time. As the study group consists of a homogeneous population in terms of their disease, TB screening, TB prophylaxis, and follow-up guidelines, it provides valuable information. In conclusion, TB is a rare but severe complication of anti-TNF treatment. Although it can be seen in patients with psoriasis with no other risk factors for TB in spite of chemoprophylaxis, failure in adherence to official guidelines for screening and chemoprophylaxis definitely increases the risk. The incidence of TB in patients with psoriasis using TNF inhibitors is comparable to patients with rheumatology. The use of interferon-based assays instead of TST significantly decreases the number of patients requiring prophylaxis and thus improves safety and lowers the cost. Acknowledgments Authors would like to thank the Social Security Institution for providing data of psoriasis patients and Professor Sibel Kalaca from Marmara University School of Medicine, Department of Public Health, for statistical support. References 1 World Health Organisation (WHO). The top 10 causes of death. Available at: http://www.who.int/mediacentre/fs 310 (Accessed June 2011). 2 Lalvani A, Millington KA. Screening for tuberculosis infection prior to initiation of anti-TNF therapy. Autoimmun Rev 2008; 8: 147–152. 3 Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factorneutralizing agent. N Engl J Med 2001; 345: 1098– 1104. International Journal of Dermatology 2015
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4 Wolfe F, Michaud K, Anderson J, et al. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis Rheum 2004; 50: 372–379. 5 Hernandez C, Cetner A, Jordan E, et al. Tuberculosis in the age of biologic therapy. J Am Acad Dermatol 2008; 59: 363–380. 6 Sanchez-Moya A, Dauden E. Incidence of tuberculosis infection in psoriatic patients on anti-TNF therapy: report of a case series with 144 patients. J Eur Acad Dermatol Venereol 2011; 25: 730–733. 7 Sanchez-Moya A, Garcˇa-Doval I, Carretero G, et al. Latent tuberculosis infection and active tuberculosis in patients with psoriasis: a study on the incidence of tuberculosis andthe prevalence of latent tuberculosis disease in patients with moderate-severe psoriasis in _ Spain. BIOBADADERM registry. J Eur Acad Dermatol Venereol 2013; 27: 1366–1374. 8 Burmester GR, Mease P, Dijkmans BA, et al. Adalimumab safety and mortality rates from global clinical trials of six immune-mediated inflammatory diseases. Ann Rheum Dis 2009; 68: 1863–1869. 9 Marehbian J, Arrighi HM, Hass S, et al. Adverse events associated with common therapy regimens for moderateto-severe Crohns disease. Am J Gastroenterol 2009; 104: 2524–2533. 10 WHO Statistical Information System (WHOSIS). 2010 Available at: http://www.who.int/gho/publications/ world_health_statistics/EN_WHS10_Full.pdf [accessed in 2010] 11 World Health Organisation. Tuberculosis. Available at: http://www.who.int/topics/tuberculosis/en/ [accessed 2010]. 12 Keser G, Direskeneli H, Akkocß N, et al. RAED Uzlasßı _ Toplantısı Raporu. 7 Mayıs 2005, Izmir. 13 Pai M, Zwerling A, Menzies D. Systematic review: T-cellbased assays for the diagnosis of latent tuberculosis infection: an update. Ann Intern Med 2008; 149: 177–184. 14 Laffitte E, Janssens JP, Roux-Lombard P, et al. Tuberculosis screening in patients with psoriasis before antitumour necrosis factor therapy: comparison of an interferon-gamma release assay vs. Tuberculin skin test. Br J Dermatol 2009; 161: 797–800.
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15 Mrozec N, Pereira B, Soubrier M, et al. Screening of tuberculosis before biologics. Med Mal Infect 2012; 42: 1–4. 16 Mariette X, Baron G, Tubach F, et al. Influence of replacing tuberculin skin test with ex-vivo interferon gamma release assays on decision to administer prophylactic antituberculosis antibiotics before anti-TNF therapy. Ann Rheum Dis 2012; 71: 1783–1790. 17 Tubach F, Salmon D, Ravaud P, et al. Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: the three-year prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum 2009; 60: 1884– 1894. 18 Askling J, Fored CM, Brandt LM, et al. Risk and case characteristics of tuberculosis in rhematoid arthritis associated with tumor necrosis factor antagonists in Sweden. Arthritis Rheum 2005; 52: 1986–1992. 19 Gomez-Reino JJ, Carmona L, Valverde VR, et al. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum 2003; 48: 2122–2127. 20 Elbek O, Uyar M, Aydˇn N, et al. Increased risk of tuberculosis in patients treated with antitumour necrosis factor alpha. Clin Rheumatol 2009; 28: 421–426. 21 Cagatay T, Aydˇn M, Sunmez S, et al. Follow-up results of 702 patients receiving tumor necrosis factor-alfa antagonists and evaluation of risk of tuberculosis. Rheumatol Int 2010; 30: 1459–1463. 22 Forget EJ, Menzies D. Adverse reactions to first-line antituberculosis drugs. Expert Opin Drug Saf 2006; 5: 231–249. 23 Dixon WG, Hyrich KL, Watson KD, et al. BSRBR Control Centre Consortium, DPM Symmons, on behalf of the BSR Biologics Register. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis 2010; 69: 522–528.
ª 2015 The International Society of Dermatology
The risk of tuberculosis in patients with psoriasis treated with anti-tumor necrosis factor agents Tulin Ergun1, MD, Dilek Seckin1, MD, Emel Baskan Bulbul2, MD, Nahide Onsun3, MD, Ozgen Zuleyha1, MD, Pemra Unalan4, MD, Erkan Alpsoy5, MD, and Sait Karakurt6, MD
1 Department of Dermatology, Marmara University School of Medicine, Istanbul, 2 Department of Dermatology, Uludag University School of Medicine, Bursa, 3 Department of Dermatology, Bezm-i Alem University, 4Department of Family Medicine, Marmara University School of Medicine, Istanbul, 5Department of Dermatology, Akdeniz University School of Medicine, Antalya, and 6Department of Pneumonology, Marmara University School of Medicine, Istanbul, Turkey
Correspondence Zuleyha Ozgen, MD € Marmara Universitesi Hastanesi Dermatoloji ABD. FevziC ß akmak mah. Mimarsinan cad. No:41 34899Ust Kaynarca/Pendik/ ISTANBUL/TURKEY E-mail: [email protected] Conflicts of interest: None.
Abstract Background Tumor necrosis factor-alpha (TNF-a) antagonist treatment is associated with 1.6 to 27 times higher risk of tuberculosis (TB). Objective To find TB incidence of psoriasis patients treated with TNF- a antagonists and define risk factors related with this condition in a country with moderately high risk of TB. Methods Three hundred seventy psoriasis patients treated by anti-TNF agents in four referral centers were included. The data on the characteristics of the patients, TB history, tuberculosis skin test results, anti-TNF agent type and exposure time, localization of TB, and isoniazide prophylaxis state were analyzed. Results Four patients (1.08%) developed TB, three pulmonary and one gastrointestinal, 2– 23 months after initiating anti-TNF agents. Other than the patient with gastrointestinal TB, who was using methotrexate and corticosteroid concomitantly, none had contributing risk factors for TB. Two patients developed pulmonary TB in spite of chemoprophylaxis. Three patients with pulmonary TB completely recovered following antiTB treatment whereas patients with gastroinrestinal TB developed renal failure. Limitations The major limitation of the study is the lack of a diseased control group, which enables us to compare the risk of psoriatics with that of patients having other inflammatory diseases. Conclusion Tuberculosis is a rare but a severe complication of anti-TNF treatment and may develop in spite of chemoprophylaxis. The risk of TB in psoriasis patients in the present study is comparable to literature mostly based on rheumatology patients.
doi: 10.1111/ijd.12628
Introduction According to World Health Organization (WHO) statistics, tuberculosis (TB) is the eighth leading cause of death in the world, and tumor necrosis factor (TNF) antagonist treatment is known to increase the risk of TB infection.1 Patients with TB triggered by anti-TNF agents commonly develop the disease within the first year of treatment, 98% of cases induced by infliximab occurring within the first six months, which corresponds to reactivation of latent TB.2–4 Latent TB infection refers to an individual having evidence of cell-mediated immunity to TB without microbiological, radiographic, or clinical evidence of active disease. These individuals with a positive tuberculin skin test (TST) have an increased risk for TB and require chemoprophylaxis before anti-TNF treatment.5 ª 2015 The International Society of Dermatology
The data regarding TB triggered by anti-TNF agents mostly originate from rheumatology and gastroenterology based studies and registries. However, those patients have several differences compared to psoriatics both in terms of the inherent nature of their disease, comorbidities, and concomitant use of disease-modifying medications. There are relatively limited data on the TB risk of patients with psoriasis using TNF antagonists in endemic regions. Recently, S anchez-Moya and Dauden from Spain reported one of their 144 psoriasis patients using TNF antagonists to develop TB.6 Another study by Sanchez-Moya analyzing Spanish psoriasis registry data revealed four of 793 patients being exposed not only to TNF antagonists but all biologics, including anti-TNF agents, ustekinumab and efalizumab, to develop TB, which has been indicated to be eight times higher compared to the general population.7. In addition to the sparseness of data on the TB risk of International Journal of Dermatology 2015
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Anti-TNF and tuberculosis
patients with psoriasis exposed to TNF antagonists, the contribution of other possible risk factors for TB development, such as old age, chronic lung disease, concomitant use of systemic corticosteroids, or methotrexate, is also lacking. This is important for the interpretation of data extracted from rheumatology-based studies as a significant proportion of patients using TNF antagonists for rheumatological diseases use multiple immunosuppressives, including steroids. In fact, the risk of serious infections was found to be significantly higher in patients with rheumatoid arthritis and Crohn’s disease compared to those with psoriasis (relative risk: 4.6, 5.1, and 1.3, respectively).8 In addition, the concomitant use of steroids, immunosuppressives, and TNF antagonists has been shown to significantly increase TB risk compared to monotherapy with these agents (hazards ratio: 7.4 vs. 2.7) in patients with Crohn’s disease.9 The aim of the current study is to find out TB risk of patients with psoriasis treated with TNF antagonists, to identify other contributing factors to define the vulnerable group, and to find out the effectiveness of TB chemoprophylaxis. Materials and methods This is a cohort study conducted in four referral centers according to the Declaration of Helsinki. The institutional ethics committee of the coordinating center approved the study.
Patients The study included 370 patients with psoriasis treated between 2005 and 2012 by four referral centers. Patients receiving antiTNF agents for at least two months and having a follow-up period of at least six months were included, and relevant data from every patient were analyzed. Patients were screened for TB as proposed by national guidelines, and they were asked about personal and family history of TB, occupation, and previous exposure to TB. All cases, including those who had received TB treatment or prophylaxis in the past, had a chest x-ray, TST with purified protein derivative (PPD), and/or Quantiferon TB-Gold test (when available). In addition, duration and dose of TNF antagonist, concomitantly used immunosuppressives, and existence of psoriatic arthritis and other systemic diseases were recorded. Patients were followed up for adverse events due to anti-TB agents. Liver enzymes were assessed monthly during isoniazide (INH) use. Social security institution database The information related to anti-TB treatment was also obtained from the national health insurance database. As all prescriptions are captured in the database, any patient with psoriasis developing TB and using anti-TB medication could be detected through examining the prescriptions longitudinally. Consequently, all prescriptions of patients with psoriasis International Journal of Dermatology 2015
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between 2007 and 2009 were analyzed for the use of anti-TB medications. Psoriasis was defined according to the code defined in the International Classification of Diseases (ICD-10). As detailed clinical information on patients is not provided, this database was used only to define whether any anti-TNF exposed patient with psoriasis within the country, being followed up in a center other than four study centers, developed TB during the defined time. These data were not statistically analyzed and are described separately in the Results section.
Setting In 2010, the incidence of TB was 28/100,000 in Turkey.10 According to WHO, 25% of the population is estimated to have rin (BCG) latent infection in Turkey. Bacille Calmette–Gue vaccination is routinely performed for newborns, and 64% of the population is vaccinated against TB.11 Local guidelines for TB chemoprophylaxis in patients to be treated with anti-TNF agents have been determined by the Turkish Rheumatological Research and Education Society in its 2005 consensus meeting. Accordingly, all patients who will be treated by antiTNF agents having any of the following conditions receive antiTB chemoprophylaxis before initiation of anti-TNF agents; TST with PPD diameter ≥ 5 mm, abnormal chest x-ray results with calcifications >1 cm, previous untreated exposure to TB, and episode of TB, positive Quantiferon test result.12 Chemoprophylaxis for TB is defined as a 9-month treatment with INH, or if this agent cannot be tolerated, a 4-month treatment with rifampicin, both of which should be started one month before anti-TNF therapy. It is mandatory that all patients receiving anti-TNF therapy are examined by a pneumonologist, and access to these agents is possible only if the prescription, regardless of the indication, is signed by the pneumonologist. Patients are evaluated by the pneumonologist every three months and have a chest x-ray every six months during TNF antagonist use. Consequently, all patients have been followed up personally by both a dermatologist and pneumonologist, which excludes the risk of undiagnosed TB. In addition, patients receive regular calls, every three months, from a nurse in charge of monitoring overall compliance and medication side effects and from local TB control dispensary to check compliance and drug supply for anti-TB. Statistical analysis Categorical variables are presented as absolute numbers and percentages, continuous variables as means standard deviations, minimum and maximum range. Only means are presented as their values essentially overlapped with those of medians. All data were analyzed by the statistical package SPSS for Windows, version 16 (SPSS Inc., Chicago, IL, USA). A chi-squared test for trend was calculated to detect significant differences among categorical variables and t-test for continuous ones. P ≤ 0.05 was accepted to be significant. ª 2015 The International Society of Dermatology
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Anti-TNF and tuberculosis
Results Patient characteristics and tuberculosis screening
Mean age of 370 patients with psoriasis, 172 (46.5%) female and 198 (53.5%) male, was 46.4 1.3 years (range 7–80). Mean follow-up period was 40.8 months (range 6–73 months). Of the 370 patients, 80.8%, 16.8%, and 2.4% had TST, Quantiferon-TB, and missing TST or Quantiferon-TB results, respectively, in addition to chest x-ray in pretreatment screening. Three cases (0.81%) had a positive family history of TB, 12 (3.24%) had fibrotic changes as a sequelae image, consistent with past TB on their chest x-ray, and five (1.35%) had been previously diagnosed and received successful TB treatment (Table 1). There was no association between gender, family history, past TB on chest x-ray, past medical history, and TST measurement/Quantiferon-TB positivity (P > 0.05). Anti-tumor necrosis factor exposure
Among 192 etanercept, 163 infliximab, and 113 adalimumab users, mean treatment duration was 12.7 11.8 months (range: 1–6, median: 9), 13.0 13.1 (range: 1–76, median: 10), and 8.2 7.9 (range: 1–42, median: 6) months, respectively. Chemoprophylaxis status
There were nine (2.4%) missing data for screening and a full-term complete TB chemoprophylaxis. One hundred and six patients having none of the risk conditions for TB Table 1 Demographic features and test results for tuberculosis Characteristics Gender* Females Males TST (mm) ≤5 6–14 ≥15 QTF* Positive Negative Chemoprevention status Yes No
n (%)
172 (46.5) 198 (53.5) 55 (18.4) 140 (46.8) 104 (34.8) 11 (17.7) 51 (82.3) QTF(+) 10 (16.1%) TST(+) 243 (81.2%) QTF( ) 51 (82.3%) QTF(+) 1 (1.6%) TST( ) 55 (18.4%) TST(+) 1 (0.4%)
QTF, Quantiferon; TST, tuberculin skin test. *There is no association between this item and tuberculin skin test measurement. ª 2015 The International Society of Dermatology
Pharmacology and therapeutics
after initial screening did not receive chemoprophylaxis before initiation of anti-TNF agents whereas 253 received anti-TB agents. In spite of having high tuberculin reactivity (PPD = 16 mm), one patient could not receive chemoprophylaxis because of liver cirrhosis. She used etanercept for 58 and infliximab for nine months without any adverse events. Another patient with Quantiferon-TB positivity did not receive chemoprophylaxis as he misunderstood the recommendations and eventually developed TB at the third month of anti-TNF exposure. Except for two patients who received rifampicin, INH was used for chemoprophylaxis and was generally well tolerated. However, two patients had a psoriasis flair and seven developed transient mild–moderate elevations in liver transaminases. Consequently, liver toxicity of INH was seen in 2.3% of patients. Patients developing tuberculosis
Four patients (1.08%) eventually developed TB, three pulmonary and one gastrointestinal. None had a personal or family history of TB. TB was seen in the 2–23 months following the initiation of treatment, and its occurrence was shorter for monoclonal antibodies (2 and 3 months) compared to etanercept (8 and 23 months). Among four patients developing TB, two using etanercept and one using adalimumab developed pulmonary TB. A fourth patient, with coexisting psoriatic arthritis and familial Mediterranean fever, receiving infliximab, methotrexate, and systemic corticosteroid, developed gastrointestinal TB. Accordingly, the incidence rate of TB was 9.9, 5.8, and 13 per 1000 for patients receiving etanercept, infliximab, and adalimumab, respectively. Overall, the cumulative TB incidence rate for all TNF antagonists was 8.9 per 1000. Regarding the TB prophylaxis status of patients developing TB, one patient using etanercept completed nine months of INH prophylaxis, whereas the other developed TB at the eighth month of INH treatment (Table 2). The patient developing TB during adalimumab use did not receive prophylaxis in spite of a positive Quantiferon result because of a misunderstanding. Although local guidelines propose INH to be given one month before initiation of anti-TNF treatment, our first case received INH synchronous with infliximab as she had very severe psoriasis requiring rapid treatment. Eventually, she developed gastrointestinal TB in the second month of infliximab and INH therapy. None of the patients had other risk factors such as cancer, HIV, asthma, and diabetes. TB was diagnosed by clinical features and confirmed by microbiological and radiological findings. Features of patients developing TB are shown in Table 2. All patients received anti-TB treatment and recovered, but the patient with gastrointestinal TB developed renal failure. International Journal of Dermatology 2015
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Table 2 Clinical characteristics of patients developing TB Patient no.
Age, gender Tuberculin skin test (mm) TB prophylaxis Previous anti-TNF exposure, time (months) Anti-TNF type Time to TB (months) Site of TB Concomitant medication Outcome
1
2
3
4
41, female
57, male
55, female
28, male
5
20
11
Quantiferon (+)
+
+
+
Infliximab
Etanercept
Etanercept
Adalimumab
2
8
23
3
Gastrointestinal Methotrexate Corticosteroid Recovered Renal failure
Lungs
Lungs
Lungs
Recovered
Recovered
Recovered
Etanercept, 5
TB, tuberculosis; TNF, tumor necrosis factor.
Social security institution database
All patients having an ICD code for psoriasis between 2007 and 2009 were analyzed. We found 434 patients of whom 374, 54, and six used one, two, or three anti-TNF agents, respectively. Concomitant medications were systemic corticosteroids in 37, methotrexate in 86, and cyclosporine in 21. During that period, the number of patients and cumulative exposure time were 181 and 1494 months for etanercept, 179 and 1705 for infliximab, and 107 and 401 for adalimumab. The number of patients using INH prophylaxis was 74 of 181, 64 of 179, and 33 of 107 for etanercept, infliximab, and adalimumab, respectively. No record for TB treatment other than INH prophylaxis was found during that period. Discussion The current study, performed in a BCG vaccinated population, with an incidence of 28/100,000 for TB, analyzed patients with psoriasis who developed TB during antiTNF treatment and their risk factors. We have seen four cases of TB (1.08%), three pulmonary and one gastrointestinal, all developing within the first 23 months of treatment. As indicated in their labels, there is a relation between TB and anti-TNF agents and various studies docInternational Journal of Dermatology 2015
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umented 1.6–27-fold increase in frequency of TB.3 Several major issues may account for this great variation on the true risk. First is the TB risk of the population and BCG status. According to 2010 WHO health statistics, the TB incidence rate per 100,000 shows great variation in the world and is reported as 9.3, 6.8, 13, 16, and 28 for France, Sweden, United Kingdom, Spain, and Turkey, respectively.11 BCG vaccination is routine in Turkey; 64% of the population is vaccinated against TB, and 25% of the population is estimated to have latent infection.10 Thus, the study population has a relatively moderate risk for TB. The second factor accounting for the differences in TB risk triggered by anti-TNF agents is the screening method (TST vs. interferon-based assays) used. In addition to chest x-ray, we have used TST or/and Quantiferon-TB. TST is a cheap, widely available test, and its use in diagnosis of TB is endorsed by the American Thoracic Society and Centers for Disease Control and Prevention. Although TST has high specificity in non-vaccinated populations (97%), the specificity in BCG-vaccinated populations is low and highly heterogeneous.13,14 Nevertheless, as interferon-based assays eliminate cross-reactivity with BCG and most non-TB mycobacteria, they may aid in identification of latent TB cases who are candidates for prophylactic treatment. In fact, a recent meta-analysis revealed Quantiferon-TB test to have a sensitivity of 76% as well as specificity of 96% and 99% in non-vaccinated and vaccinated populations, respectively.15 As interferonbased studies are more helpful in the differentiation of latent TB from vaccine reactivity, they have replaced TST use within the last few years. Two hundred and fortythree of our 299 (81.2%) patients having TST and 10 of 62 (16.1%) patients having Quantiferon-TB test in screening had prophylactic treatment. These data are comparable with the results of Mariette et al, 16 who have shown replacement of TST with Quantiferon-TB for determining latent TB infection to reduce the need for prophylaxis by half (45.2% vs. 21.4%). These results indicate that TB screening through interferon-based studies decreases unnecessary chemoprophylaxis as preventive treatment itself carries a risk. Another factor influencing the variation in reported TB frequency is the type and duration of anti-TNF. In RATIO registry including 69 TB cases, SIR for TB has been reported to be 18.6, 29.3, and 1.8 for infliximab, adalimumab, and etanercept, respectively.17 Since we had only four patients developing TB, two on etanercept and two on monoclonal antibodies, we cannot drive conclusions. Lalvani and Millington have reported median time to TB development to be 3 and 11.5 months for infliximab and etanercept, respectively,2 which is consistent with our data. ª 2015 The International Society of Dermatology
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Finally, heterogeneity of the patient population, immune status, and use of concomitant systemic corticosteroids and/or immunosuppressives may influence the risk.18,19 Although none of our patients had diabetes, HIV, or asthma, systemic corticosteroid and methotrexate use may have contributed to gastrointestinal TB infection in our infliximab-related case. We compare our TB risk with the results of various studies from regions with a similar background TB risk. Elbek et al.20 reported two of their 240 patients with rheumatological diseases to develop pulmonary TB. The TB incidence was reported as 833/100,000, which is close to ours, 890/100,000. Both of their patients with TB were screened, found to have latent TB, and received INH prophylaxis. Cagatay et al.21 reported that six of their 702 (0.85%) patients developed TB, four pulmonary and two extrapulmonary. All of their patients were screened through chest x-ray and TST according to official guidelines, and 83.0% received prophylactic INH for nine months. When we analyzed the difference between our and their proportions, no statistically significant difference could be found (P > 0.05, 95% CI). This result suggests that the major determinant for TB risk in patients managed through similar screening and prophylaxis guidelines is the background risk of the population rather than the nature of the disease itself. In fact, a higher proportion of our patients developed TB compared to Sanchez-Moya’s 6 (P < 0.05, 95% CI), which may be explained by the higher TB incidence in Turkey compared to Spain.11 Owing to a small number of TB cases, we were unable to make a direct comparison, but the incidence of TB in these populations ranges between 0.69 and 1.08%. These data are somewhat interesting as patients with psoriasis compared to patients with rheumatology and Crohn’s have less common concomitant use of systemic steroids and immunosuppressives and are expected to have a better immune status and thus less of a TB risk.8 The higher TB risk (8.9/1000) of our group compared to both British and Swedish registry data, at which the incidence of TB was reported as 1.5 and 1.5 per 1000 patient-years for infliximab and 0.5 and 1.8 per 1000 patient-years with etanercept, respectively, also supports the importance of population risk as the major determinant for TB.18,22 Two of our patients developed TB in spite of completing nine months of INH treatment. It is well known that prophylaxis decreases the risk of reactivation of TB but does not eliminate it. Patients should be informed about the importance of prophylaxis and encouraged to use their medication properly to improve the success of TB prevention. The most relevant side effect of INH is hepatotoxicity, which was seen in 2.3% of our cases. All were transient, ª 2015 The International Society of Dermatology
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Pharmacology and therapeutics
mild to moderate serum transaminase elevations not exceeding 2.5 times of upper limit. Forget and Menzies estimated that hepatotoxicity occurs in 0.92% of patients taking INH therapy.22 Taken together, these data support an acceptable risk/benefit ratio for INH in patients with a TB risk. Although TB mostly affects the lungs, anti-TNFinduced TB tends to affect extrapulmonary sites more commonly. Dixon et al. reported 15 (38%), 25 (62%), and 11 (28%) of 40 cases developed pulmonary, extrapulmonary, and disseminated TB, respectively.23 Only one of four TB patients in the present study had extrapulmonary TB. This may be due to the low number of cases with TB in our study. The most important limitation of this study is the lack of a control group. Moreover, as in other studies, a relatively low number of patients developing TB are unable to identify risk factors. Nevertheless, this is the largest study limited to patients with psoriasis with a relatively long follow-up time. As the study group consists of a homogeneous population in terms of their disease, TB screening, TB prophylaxis, and follow-up guidelines, it provides valuable information. In conclusion, TB is a rare but severe complication of anti-TNF treatment. Although it can be seen in patients with psoriasis with no other risk factors for TB in spite of chemoprophylaxis, failure in adherence to official guidelines for screening and chemoprophylaxis definitely increases the risk. The incidence of TB in patients with psoriasis using TNF inhibitors is comparable to patients with rheumatology. The use of interferon-based assays instead of TST significantly decreases the number of patients requiring prophylaxis and thus improves safety and lowers the cost. Acknowledgments Authors would like to thank the Social Security Institution for providing data of psoriasis patients and Professor Sibel Kalaca from Marmara University School of Medicine, Department of Public Health, for statistical support. References 1 World Health Organisation (WHO). The top 10 causes of death. Available at: http://www.who.int/mediacentre/fs 310 (Accessed June 2011). 2 Lalvani A, Millington KA. Screening for tuberculosis infection prior to initiation of anti-TNF therapy. Autoimmun Rev 2008; 8: 147–152. 3 Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factorneutralizing agent. N Engl J Med 2001; 345: 1098– 1104. International Journal of Dermatology 2015
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4 Wolfe F, Michaud K, Anderson J, et al. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis Rheum 2004; 50: 372–379. 5 Hernandez C, Cetner A, Jordan E, et al. Tuberculosis in the age of biologic therapy. J Am Acad Dermatol 2008; 59: 363–380. 6 Sanchez-Moya A, Dauden E. Incidence of tuberculosis infection in psoriatic patients on anti-TNF therapy: report of a case series with 144 patients. J Eur Acad Dermatol Venereol 2011; 25: 730–733. 7 Sanchez-Moya A, Garcˇa-Doval I, Carretero G, et al. Latent tuberculosis infection and active tuberculosis in patients with psoriasis: a study on the incidence of tuberculosis andthe prevalence of latent tuberculosis disease in patients with moderate-severe psoriasis in _ Spain. BIOBADADERM registry. J Eur Acad Dermatol Venereol 2013; 27: 1366–1374. 8 Burmester GR, Mease P, Dijkmans BA, et al. Adalimumab safety and mortality rates from global clinical trials of six immune-mediated inflammatory diseases. Ann Rheum Dis 2009; 68: 1863–1869. 9 Marehbian J, Arrighi HM, Hass S, et al. Adverse events associated with common therapy regimens for moderateto-severe Crohns disease. Am J Gastroenterol 2009; 104: 2524–2533. 10 WHO Statistical Information System (WHOSIS). 2010 Available at: http://www.who.int/gho/publications/ world_health_statistics/EN_WHS10_Full.pdf [accessed in 2010] 11 World Health Organisation. Tuberculosis. Available at: http://www.who.int/topics/tuberculosis/en/ [accessed 2010]. 12 Keser G, Direskeneli H, Akkocß N, et al. RAED Uzlasßı _ Toplantısı Raporu. 7 Mayıs 2005, Izmir. 13 Pai M, Zwerling A, Menzies D. Systematic review: T-cellbased assays for the diagnosis of latent tuberculosis infection: an update. Ann Intern Med 2008; 149: 177–184. 14 Laffitte E, Janssens JP, Roux-Lombard P, et al. Tuberculosis screening in patients with psoriasis before antitumour necrosis factor therapy: comparison of an interferon-gamma release assay vs. Tuberculin skin test. Br J Dermatol 2009; 161: 797–800.
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15 Mrozec N, Pereira B, Soubrier M, et al. Screening of tuberculosis before biologics. Med Mal Infect 2012; 42: 1–4. 16 Mariette X, Baron G, Tubach F, et al. Influence of replacing tuberculin skin test with ex-vivo interferon gamma release assays on decision to administer prophylactic antituberculosis antibiotics before anti-TNF therapy. Ann Rheum Dis 2012; 71: 1783–1790. 17 Tubach F, Salmon D, Ravaud P, et al. Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: the three-year prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum 2009; 60: 1884– 1894. 18 Askling J, Fored CM, Brandt LM, et al. Risk and case characteristics of tuberculosis in rhematoid arthritis associated with tumor necrosis factor antagonists in Sweden. Arthritis Rheum 2005; 52: 1986–1992. 19 Gomez-Reino JJ, Carmona L, Valverde VR, et al. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum 2003; 48: 2122–2127. 20 Elbek O, Uyar M, Aydˇn N, et al. Increased risk of tuberculosis in patients treated with antitumour necrosis factor alpha. Clin Rheumatol 2009; 28: 421–426. 21 Cagatay T, Aydˇn M, Sunmez S, et al. Follow-up results of 702 patients receiving tumor necrosis factor-alfa antagonists and evaluation of risk of tuberculosis. Rheumatol Int 2010; 30: 1459–1463. 22 Forget EJ, Menzies D. Adverse reactions to first-line antituberculosis drugs. Expert Opin Drug Saf 2006; 5: 231–249. 23 Dixon WG, Hyrich KL, Watson KD, et al. BSRBR Control Centre Consortium, DPM Symmons, on behalf of the BSR Biologics Register. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis 2010; 69: 522–528.
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