Efficacy and Safety of the Selective Cyclooxygenase-2 Inhibitor Celecoxib in the Treatment of Rheumatoid Arthritis and Osteoarthritis in Japan

Background/Aims: Gastrointestinal (GI) disorders are common adverse reactions of nonsteroidal anti-inflammatory drugs (NSAIDs). Loxoprofen is a representative NSAID widely used in East Asia. A selective cyclooxygenase-2 inhibitor, celecoxib, was introduced in Japan in 2007. In this study, we aimed to compare the efficacy and safety of celecoxib with those of loxoprofen in Japanese patients. Methods: We analyzed the data from 12 clinical studies conducted in Japan. These data of Japanese patients were compared with those of the patients in the West that had been published after 2000. Results: The efficacy of celecoxib as an analgesic was comparable to that of loxoprofen, whereas serious GI events, including symptomatic ulcers, were significantly less frequent with celecoxib than with loxoprofen in Japanese patients with rheumatoid arthritis (RA) and osteoarthritis (OA) (p = 0.039). These results were consistent with the findings of the studies conducted in the West. The incidence of serious cardiovascular events was 0.1% in 2,398 subjects on celecoxib, which was not statistically different from the inciPublished online: November 1, 2010 Choitsu Sakamoto, MD, PhD Division of Gastroenterology, Department of Internal Medicine Nippon Medical School, 1-1-5 Sendagi, Bunkyoku Tokyo 113-8603 (Japan) Tel. +81 3 5802 8145, Fax +81 3 5802 8149, E-Mail choitsu @ nms.ac.jp © 2010 S. Karger AG, Basel 0012–2823/11/0832–0108$38.00/0 Accessible online at: www.karger.com/dig D ow nl oa de d by : 54 .1 91 .4 0. 80 9 /1 6/ 20 17 8 :2 1: 56 P M Celecoxib in the Treatment of RA and OA Digestion 2011;83:108–123 109 both COX-1 and COX-2 to varying degrees exert therapeutic effects by inhibiting COX-2. The adverse effects of NSAIDs, particularly in the upper gastrointestinal (GI) tract, are considered to be mainly caused by the inhibition of COX-1 activity, which is involved in gastric mucosal protection [8, 9] . GI injury associated with NSAIDs is a serious clinical problem since NSAID-related ulcer complications have been estimated to lead to 10,000 cases of hospitalization and 16,500 deaths yearly in the United States [10] . Therefore, attempts were made to develop drugs targeted against COX-2 to reduce adverse reactions to NSAIDs, while retaining their anti-inflammatory and analgesic actions. In 1998, celecoxib was approved as the first selective COX-2 inhibitor [11] . Celecoxib is a member of the coxib family, which is a drug family included in the anatomical therapeutic chemical (ATC) classification system; it is characterized by a 3-dimensional structure of molecules designed to afford COX-2 selectivity [11] . Celecoxib has been available in Japan since June 2007 and is indicated for rheumatoid arthritis (RA), osteoarthritis (OA), and inflammation and pain associated with RA or OA. Despite cases of serious NSAID-related ulcer complications in the United States [10] , few studies have reported NSAID-related upper GI injuries in Japan where the main cause of gastroduodenal ulcers is Helicobacter pylori ; the prevalence of infection with H. pylori in Japan is much higher than in the United States [12] . In addition, the types and doses of NSAIDs used for the treatment of patients with RA or OA in Japan are very different from those used in the United States. For example, the maximum prescribed dose of diclofenac in Japan is 100 mg/ day, whereas in the United States it is 200 mg/day. Furthermore, the most frequently prescribed NSAID in Japan is loxoprofen, which is a prodrug that is marketed only in Asia, Mexico, and Brazil, but not in the United States. The lower number of studies on the adverse effects of NSAIDs on gastroduodenal mucosa in Japan can be attributed to differences with regard to upper GI injury and its treatment in Japan and the United States. Therefore, it seems important for us to make it clear how the NSAIDs we usually use are safe or harmful in terms of drug-related gastroduodenal injury. The aim of this study was to review the clinical efficacy and safety data of celecoxib in comparison with those of loxoprofen, which is a widely used form of propionic acid in East Asia, in Japanese trials and to inform doctors about the efficacy and safety of NSAIDs in Japanese patients with RA or OA. Clinical Efficacy of Celecoxib Clinical Efficacy in RA Treatment Twelve phase II and III clinical trials of celecoxib, including 2 placebo-controlled double-blind trials, 2 double-blind loxoprofen-controlled celecoxib trials, and 1 double-blind placeboand loxoprofen-controlled celecoxib trial, were conducted in Japan to evaluate the efficacy and safety of celecoxib in the treatment of patients with RA, OA, and low back pain ( table 1 ). In these trials, a total of 2,410 patients received celecoxib, 1,190 patients loxoprofen, and 414 patients placebo [13–22] . The details of the trials are summarized in table 1 . The efficacy and safety of celecoxib in the treatment of patients with RA were examined in 4 trials, including a double-blind trial including 771 patients with RA to compare the efficacy and safety of 12 weeks’ treatment with celecoxib (200 mg b.i.d.) with those of loxoprofen (60 mg t.i.d.) ( table 1 ) [14] . In this trial, celecoxib was comparable to loxoprofen sodium in the evaluation of both final ‘improvement rate’ as a primary endpoint and ‘time course of percent improvement’ according to the American College of Rheumatology (ACR) Improvement Criteria ( fig. 1 ). In ‘selfassessment of pain by patients’ using the visual analog scale (VAS), the scores revealed that the levels of improvement in patients in the celecoxib treatment group at 2 and 4 weeks after the start of treatment were significantly higher than the corresponding levels in patients in the loxoprofen sodium treatment group, thereby indicating that more rapid improvement can be achieved with celecoxib ( fig. 2 ). These data are consistent with those of a previously published overseas study in which the efficacy of celecoxib (200 mg b.i.d.) in the treatment of patients with RA was compared to that of diclofenac SR (75 mg b.i.d.) [23] . These results showed that the efficacy of celecoxib in the treatment of patients with RA is comparable to that of conventional RA drugs such as loxoprofen sodium and diclofenac. Clinical Efficacy in OA Treatment The efficacy and safety of celecoxib in the treatment of patients with OA were also examined in 4 trials, including a double-blind trial, in 949 patients with OA to compare the efficacy and safety of 4 weeks’ treatment with celecoxib (100 mg b.i.d.) with those of loxoprofen (60 mg t.i.d.) or placebo ( table 1 ) [17] . In this double-blind trial, with regard to the rate of improvement in the final global improvement assessment (the primary endpoint), the level of improvement in the patients in the celecoxib group D ow nl oa de d by : 54 .1 91 .4 0. 80 9 /1 6/ 20 17 8 :2 1: 56 P M Sakamoto /Soen Digestion 2011;83:108–123 110 Table 1. List of 12 clinical trials conducted in Japan to evaluate the efficacy and safety of celecoxib in patients with RA, OA, and low back pain Authors/ year of publication Disease entity Study design Patients n Facilities n Drug dose Patients who received/completed/ discontinued therapy n Term weeks Outcome and method of evaluation