Elevated risk of tuberculosis in patients with rheumatoid arthritis in Japan

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1 ARD Online First, published on July 12, 2006 as /ard Concise report Elevated risk of tuberculosis in patients with rheumatoid arthritis in Japan Toru Yamada, Ayako Nakajima, Eisuke Inoue, Eiichi Tanaka, Masako Hara, Taisuke Tomatsu and Naoyuki Kamatani and Hisashi Yamanaka The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if accepted) to be published in Annals of the Rheumatic Diseases editions and any other BMJPGL products to exploit all subsidiary rights, as set out in our licence ( Authors affiliations Toru Yamada, Ayako Nakajima, Eisuke Inoue, Eiichi Tanaka, Masako Hara, Taisuke Tomatsu and Naoyuki Kamatani and Hisashi Yamanaka Institute of Rheumatology, Tokyo Women s Medical University, Tokyo, Japan Correspondence to: Dr Toru Yamada, Institute of Rheumatology, Tokyo Women s Medical University, Kawada-cho, Shinjuku-ku, Tokyo, , Japan; tyamada@ior.twmu.ac.jp, tyamada@ah.twmu.ac.jp Key words rheumatoid arthritis, tuberculosis, anti-tnf-α, incidence rate, relative risk 1 Copyright Article author (or their employer) Produced by BMJ Publishing Group Ltd (& EULAR) under licence.

2 Abstract Objectives: To determine the risk for tuberculosis infection in patients with rheumatoid arthritis (RA) before the anti-cytokine era in Japan. Patients and methods: A database of a single-institute-based large observational cohort study for RA at the Institute of Rheumatology, Tokyo Women s Medical University was analyzed. Information concerning the past and recent history of tuberculosis infection was collected by patient self-reporting during the month of April and October, The age-adjusted incidence rate and relative risk for tuberculosis infection was investigated. Results: Among 5,044 RA patients, 483 (9.6%) patients claimed to have a past history of tuberculosis infection before October The frequency of past history of tuberculosis increased according to patient age. Four cases of new onset tuberculosis were identified among 5,544 RA patients during one year. The age-adjusted incidence of tuberculosis was 42.4 per 100,000 patients. The relative risk for tuberculosis was 3.21 (95% CI ) and that of male and female was (95% CI ) and 1.41 (95% CI ), respectively. Conclusion: We found an increased risk of tuberculosis infection in Japanese patients with RA especially in male patients prior to the introduction of anti-tnf therapy. This data should form the basis for the risk management of anti-cytokine therapy in Japan. Introduction The introduction of biological agents against tumor necrosis factor alpha (TNFα) 1,2 represents a major advance in the treatment of rheumatoid arthritis (RA). On the other hand, an increased occurrence of tuberculosis is one of the major concerns 3,4. TNFα has a key role in suppressing mycobacterial infections 5, and emerging of active tuberculosis infection is reported soon after the introduction of infliximab 3. In Spain, the incidence of tuberculosis in RA patients after the introduction of anti-tnf agent increased. In Japan the incidence of tuberculosis in the general population is high compared to that evident in the U.S.A. 6 or U.K. 7 and is comparable with that in Spain 8. Therefore, the increase in tuberculosis following the introduction of anti-tnf agents is of grave concern. However, there has been no systematic investigation of the incidence of tuberculosis in patients with RA in Japan so far and this is required to facilitate accurate interpretation of the current problem. 2

3 We have established a large observational cohort survey of RA patients from 2000 in our institute. Using the database in this cohort, we investigated the prevalence and incidence of tuberculosis infection among Japanese patients with RA just before the launch of biological anti-tnf agents in Japan. PATIENTS AND METHODS This report concerns 2 studies analyzing a large observational cohort study for RA at the Institute of Rheumatology, Tokyo Women s Medical University that was commenced in October, A survey is conducted every six months to all RA patients treated at the institute who have given informed consent. Three major domains are included in this survey system: physician s evaluation (swollen and tender joints, the level of disease activity on a visual analogue scale (VAS)), patient s evaluation (pain and general health on a VAS and the Stanford Health Assessment Questionnaire functional index (HAQ disability)) at the each survey and patient s report of events (infection, hospitalization, operation, medication, etc) which occurred within the previous 6 months, and laboratory data. Patients were instructed to complete the questionnaire sheet at home and to mail the completed forms within 2 weeks in a pre-addressed and pre-stamped envelope. For the patients who failed to join the subsequent survey, the questionnaire sheets were mailed to these patients to obtain the information. In study 1, the past history (before October, 2002) of tuberculosis was collected at the 6th survey conducted in April 2003 when the active screening program regarding tuberculosis was started. Questions asked were: Have you ever had tuberculosis? If so, were you treated? If you had extra-pulmonary tuberculosis, please specify the organ. The rate of patients with a past history of tuberculosis was based on the patient s self report. In study 2, the recent onset (within 6 months) of tuberculosis was collected in the questionnaire sheet by the questions: Have you ever had tuberculosis within this 6 months? at two consecutive surveys in April, 2003 (6th survey) and October, 2003 (7th survey). In the case of a patient with a recent onset of tuberculosis, the diagnosis was validated by medical records or by information provided from corresponding hospitals. The age-adjusted incidence rate and relative risk of our cohort data in one year from October, 2002 to September, 2003 was standardized based on the database officially 3

4 reported from The Research Institute of Tuberculosis Japan Anti-Tuberculosis Association ( RESULTS In study 1, among 5,044 RA patients (870 male and 4,174 female), 484 (9.6%) patients claimed to have a past history of tuberculosis infection before October Men (117 patients, 13.3%) exhibited a significantly higher frequency of a past history of tuberculosis than women (367 patients, 8.8 %) (p< ). Pulmonary tuberculosis affected 454 patients and extra-pulmonary tuberculosis affected 52 patients. Twenty-two patients had both pulmonary and extra-pulmonary disease. The locations of extra-pulmonary organs were bones/joints in 10, pleurae and bronchi in 10, cervical lymph nodes in 9, kidney in 6, skin in 5, peritoneum in 4, intestine in 3, eye in 3, uterus in 2, disseminated in 1 patient. One of the patients had both disseminated and bone tuberculosis. Figure 1 shows the percentage of past history of tuberculosis of male and female in each age range. The percentage increased with patient age, and males had higher percentage than females. No statistical difference was found between the groups of patients with or without a past history of tuberculosis concerning the percentage of patients receiving treatment with steroids or DMARDs. In study 2, 4 patients (3 males and 1 female) with recent onset tuberculosis were identified during the period between October, 2002 and September, 2003 among 5,544 (male 970, female 4,574) RA patients who enrolled in one or both surveys in April, 2003 and/or October, Four cases had received treatment with low dose prednisolone (5-10 mg per day) and two cases had received methotrexate (4-6 mg per week). One patient died from acute interstitial pneumonia during the treatment of lung tuberculosis whilst the other 3 patients recovered. The age-adjusted incidence rate of tuberculosis was 42.4 per 100,000 patients (4,836 patient-year) in the RA patients whereas the incidence rate was 25.8 per 100,000 persons in the Japanese general population (Table 1). In males, the incidence rate was per 100,000 patients in RA whereas 34.2 in the general Japanese male population. In females, 13.1 per 100,000 in RA whereas 17.7 in the general Japanese female population. The relative risk for tuberculosis in our RA population was 3.21 (95% CI ) whereas that of male and female patients was (95% CI ) and 1.41 (95% CI ), respectively (Table 1). 4

5 DISCUSSION This study is the first report using a large observational cohort study concerning the incidence of tuberculosis in Japanese RA patients, and presumably the last report just before the dawn of the era of novel biological agents. Our study is not multi-institutional but is based on a single institution and may, thus, not be representative of the general situation within Japan. However, the large number of patients in this study (5,044 patients) actually accounts for approximately 1% of the RA population in Japan, and it is therefore likely that our results at least reflect the current status of tuberculosis infection in Japanese RA patients. We found a 3.2-fold increased risk of tuberculosis in RA patients and a 10-fold increased risk in male, but no increase was detected in female RA statistically. Due to a follow up system for patients who have dropped out from the subsequent survey, this increased risk is not considered to be over-evaluated. In addition, the relative risk in male RA is high regardless of the higher incidence rate of the general male population in Japan. Thus, our study implicated that Japanese male patients with RA have higher risk of tuberculosis even without the use of TNF inhibitors. It is generally believed that autoimmune rheumatic diseases such as systemic lupus erythematosus and RA 11 may be associated with an increased risk of tuberculosis. The increased risk may be attributed to the immunological dysfunction caused by the disease itself, as well as treatment with immunosuppressive agents. However, the reports concerning the risk of tuberculosis in RA patients are somewhat controversial. The incidence of tuberculosis was not increased by conventional immunosuppressive therapy compared to the general population in the U.S.A. 12 (Table 1). On the other hand, an increased relative risk for tuberculosis in RA patients in Sweden (2.0) 13 and Spain (3.68) before anti-tnf era have been reported. In our present report, the magnitude of the relative risk (3.21) for tuberculosis in Japanese RA was similar to the one in Spain. In Spain, increased incidence of tuberculosis occurred after initiation of anti-tnf treatment. However, by the adequate use of guidelines for the treatment with biological agents, especially for the prevention of tuberculosis established in 2001, successful reduction of the incidence of tuberculosis in RA patients treated with anti-tnf was achieved 10,14. Therefore, the acknowledgement of the important association between anti-tnf treatment and tuberculosis, as well as, the rigorous 5

6 implementation of the guidelines for the use of anti-tnf treatment will help protect RA patients from the risk of developing tuberculosis infection as a result of anti-tnf therapy. REFERENCES 1 Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000;343: Maini RN, Breedveld FC, Kalden JR, Smolen JS, Frust D, Weisman MH, et al. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum 2004;50: Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor α - neutralizing agent. N Engl J Med 2001;345: Weisman MH. What are the risks of biologic therapy in rheumatoid arthritis? An update on safety. J Rheumatol 2002;29 Suppl 65: Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis 2003;3: Centers for Disease Control and Prevention (CDC). Reported tuberculosis in the United States, Atlanta (GA): US Department of Health and Human Services, CDC; August Global Tuberculosis Control, WHO Report 2003 p SESPAS (Sociedad Espanola de Salud Publica) SEPAS report: investing in health. In: Cabases JM, Vilalbi JR, Aibar C, editors. Priorities for public health in Spain. Granada (Spain): Escuela Andaluza de Salud Publica; P Carmona L, Hernandez-Garcia C, Vadillo C, Pato E, et al. Indreased risk of tuberculosis in patients with rheumatoid arthritis. J Rheumatol 2003;30: Gomez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD, on behalf of the BIOBADASER Group. 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:

7 11 Bouza E, Moya JG, Munoz P. Infections in systemic lupus erythematosus and rheumatoid arthritis. Infect Dis Clin North A 2001;25: Wolfe F, Michaud K, Anderson J, Urbansky K. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis Rheum 2004;50: Askling J, Fored CM, Brandt L, Baecklund E, Bertilsson L, Cöster L, et al. Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden. Arthritis Rheum 2005;52: Carmona L, Gomez-Reino JJ, Rodriguez-Valverde V, Montero D, Pascual-Gomez E, Mola EM, et al. Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. Arthritis Rheum 2005;52: Figure legend Figure 1. The percentage of past history of tuberculosis in RA patients in each age range. Men had higher percentage of past histories of tuberculosis than women. The numbers of each generation were as follows; age under 20 (male 2; female 12), (m 18; f 32), (m 42; f 318), (m91; f539), (m 225; f 1215), (m 232; f 1098), (m 135; f 465), over 81 (m 11; f 56). 7

8 Table 1. The comparison of the risk of tuberculosis in RA patients and RA patients treated with anti-tnf. general population RA RA after introduction incidence rate relative risk of anti-tnf (per 100,000 person) (95% CI) U.S. 6.4 [1999] [ ] [ ) 12 Germany 8.5 [2001] 7 U.K [2001] 7 Sweden 2.0( ) 13 Spain 21 [2000] [ ] ( ) 9 1,893 [2000] 10 1,113 [2001] 10 Japan 25.8 [2002] 42.4 [2002] 3.21( ) Male ( ) Female ( ) 8

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10 Elevated risk of tuberculosis in patients with rheumatoid arthritis in Japan Toru Yamada, Ayako Nakajima, Eisuke Inoue, Eiichi Tanaka, Masako Hara, Taisuke Tomatsu, Naoyuki Kamatani and Hisashi Yamanaka Ann Rheum Dis published online July 12, 2006 Updated information and services can be found at: alerting service These include: Receive free alerts when new articles cite this article. Sign up in the box at the top right corner of the online article. Topic Collections Articles on similar topics can be found in the following collections Connective tissue disease (4219) Degenerative joint disease (4610) Immunology (including allergy) (5101) Musculoskeletal syndromes (4917) Rheumatoid arthritis (3236) Epidemiology (1356) Notes To request permissions go to: To order reprints go to: To subscribe to BMJ go to: