Clinical efficacy of tocilizumab in patients with active rheumatoid arthritis in real clinical practice

Yasuhiko Hirabayashi 0 1 Tomonori Ishii 0 1 Hideo Harigae 0 1 0 Y. Hirabayashi T. Ishii H. Harigae Department of Rheumatology and Hematology, Tohoku University Graduate School of Medicine , 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8574, Japan 1 Y. Hirabayashi (&) Department of Rheumatology, Hikarigaoka Spellman Hospital , 6-7-1 Higashisendai, Miyagino-ku, Sendai 983-0833, Japan The previous clinical studies have demonstrated tocilizumab monotherapy to be highly eVective in rheumatoid arthritis (RA). The objectives of the present article are to report the eYcacy and safety of tocilizumab in patients with active RA in real clinical practice. In total, 61 patients with RA were treated with tocilizumab. Any comorbidities they had, especially infections, were treated thoroughly before they were given the drug. We provided guidance on infection control and prevention. Mean age of the patients was 60.9 12.4 years, and their mean disease duration 10.9 9.2 years. The patients remained on steroids, methotrexate, and tacrolimus as before, but were taken oV any other drugs they had been using prior to the treatment. Mean of the 28-joint disease activity score using erythrocyte sedimentation rate was 4.75 1.15 initially and fell to 2.21 0.97 after two doses (n = 50). After four doses, the remission rate was 83.8% (31/37). All patients responded well to the therapy and there was no decrease in the eYcacy of tocilizumab during the treatment. Even in the real clinical setting, treatment with tocilizumab can rapidly induce remission in RA in a high proportion of patients and is generally safe and well tolerated. Tocilizumab would seem to be promising as a Wrst-line choice for the treatment of RA. - The characteristic pathophysiology in rheumatoid arthritis (RA) is the destruction of bone and cartilage due to persistent synovitis of unknown etiology. Large quantities of inXammatory cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6) are produced in inXamed synovial membranes, and these are deeply involved in the spread and persistence of the inXammation [1]. The basic concept behind anti-cytokine therapies is to trap these inXammatory cytokines using biological agents such as antibodies or receptors and so block their activity. TNF inhibitors are a recent development in this Weld and have been demonstrated to be useful in the treatment of RA [2]. The progression of bone destruction can be halted by using them in combination with methotrexate (MTX) [3]. However, they may also increase susceptibility to serious infections such as tuberculosis. Even when MTX is used concomitantly, there are also instances of primary nonresponders, mid-treatment secondary non-responders (escape cases), and inadequate responders, indicating that TNF is of little or no relevance to the condition in some patients. Drugs able to overcome the limitations of antiTNF therapy have thus been sought. Tocilizumab (TCZ) is a humanized monoclonal antibody against IL-6 receptors and inhibits binding between IL-6 and IL-6 receptors [4, 5]. It has been shown to be useful against RA in the clinical trials conducted to date. In the SATORI study, it gave signiWcantly higher improvement rates than MTX [6], in the OPTION study, clinical eYcacy was higher with MTX + TCZ than with MTX alone [7], in the SAMURAI study, it was eVective as monotherapy for controlling the progression of bone and joint destruction [8], and in the STREAM study, it provided high levels of eYcacy and continuity of response as long-term monotherapy [9]. Mean 28-joint disease activity score using erythrocyte sedimentation rate (DAS28ESR) at baseline had been elevated in the clinical trials (6.1 in the SATORI and 6.5 in the SAMURAI study), and the remission rate achieved was about 40% at 24 weeks in the SATORI study and 59% at 52 weeks in the SAMURAI study. TCZ was approved for marketing in Japan for use in patients with RA on 16 April 2008. This was the Wrst time that the drug had been approved anywhere so there are still almost no reports of treatment outcomes in real clinical practice. We evaluated our clinical experience with TCZ for therapy of RA. Here, we report the clinical eYcacy and safety of TCZ in the treatment of patients with active RA in real-world settings. Patients and methods The subjects of this analysis were patients who met the 1987 revised criteria for the classiWcation of RA from the American College of Rheumatology (ACR) and who had active disease with the DAS28ESR of 2.6 or over. Patients were included in the analysis if they started treatment with TCZ for the Wrst time in the 11 months between 16 April 2008 (the time of insurance approval in Japan) and 15 March 2009 and they received TCZ at least twice during this time. Their demographics, baseline characteristics, and drug use prior to the treatment are shown in Table 1. The criteria for exclusion from the analysis set were as follows: (i) autoimmune disease comorbidities except Sjgrens syndrome and Hashimotos disease, (ii) functional class IV based on the Steinbrocker criteria, (iii) presence of active infection, (iv) pregnancy, (v) drug poisoning, including alcohol, (vi) lymphocyte count 500 cells/ l, and (vii) positive serum -D-glucan. To reduce adverse events, any comorbidity was treated or controlled as well as possible before giving TCZ. All patients had a thoracic CT scan and were tested for the tuberculin reaction, anti-streptolysin O (ASO), anti-streptokinase (ASK), treponema pallidum haemagglutination (TPHA), hepatitis B surface antigen, anti-hepatitis C virus antibody, and -D-glucan to screen for infections. If tooth plaque or caries were present, we arranged for assessment Table 1 Patient demographics, clinical characteristics, and previous medications at baseline The values shown are mean SD unless otherwise indicated CRP only calculated from data for 60 patients Previous medications denotes drugs used in the 3 months before administration of TCZ Other DMARDs were sodium aurothiomalate, bucillamine, salazosulfapyridine, and mizoribine. These were discontinued on initiating TCZ and treatment by a dentist, including for the presence of apical periodontitis. If chronic rhinorrhea or nasal blockage was seen, the patient was assessed and treated by an otolaryngologist. Patients were asked whether they had hemorrhoids. Handling of previous medications Among the various therapies being used by the patients in the three months before they received TCZ, inXiximab were discontinued at least one-month before and etanercept at least 4 days before the new treatment commenced. Salazosulfapyridine, bucillamine, sodium aurothiomalate, and mizoribine were discontinued upon initiating TCZ. The patients stayed on methotrexate, tacrolimus, and steroids at the same dose levels as before at least until dose 3 of TCZ. There were no users of adalimumab, auranoWn, D-penicillamine, hydroxychloroquine, minocycline, or lobenzarit disodium, nor (...truncated)