CLINICAL QUESTION: Does celecoxib relieve pain and inflammation in rheumatoid arthritis without the adverse gastrointestinal (GI) effects of traditional non-steroidal anti-inflammatory drugs (NSAIDs)?
BACKGROUND: NSAIDs are widely prescribed to control the pain and inflammation of rheumatoid arthritis. Their use can be limited by the risk of GI toxicity, an adverse event that is thought to be mediated by nonspecific cyclooxygenase (COX) inhibition. Celecoxib, a COX-2-specific inhibitor, offers the possibility of relieving pain and inflammation in rheumatoid arthritis without GI injury.
POPULATION STUDIED: This study included 1149 adult patients with a mean age of 54 years, 73% of whom were women. All met the American College of Rheumatology diagnostic criteria for rheumatoid arthritis for at least 3 months and were in a functional class of I, II, or III. Stable doses of glucocorticoids or disease-modifying antirheumatic drugs were permitted. Concomitant NSAIDs, injectable corticosteroids, anticoagulants, and antiulcer drugs were prohibited.
STUDY DESIGN AND VALIDITY: This was a randomized double-blind placebo-controlled multicenter 12-week trial funded by the manufacturer of celecoxib. Before enrollment, appropriate baseline clinical and laboratory assessments (including Helicobacter pylori antibody testing and upper endoscopy) were conducted. There were 5 treatment arms: patients received placebo, celecoxib (100 mg, 200 mg, or 400 mg twice daily) or naproxen 500 mg twice daily. All patients underwent a second upper GI endoscopy at treatment termination.
OUTCOMES MEASURED: The primary outcome was improvement in signs and symptoms of rheumatoid arthritis using American College of Rheumatology criteria. The incidence of gastroduodenal ulceration (defined as mucosal breaks Ž3 mm in diameter with unequivocal depth) was a secondary outcome.
RESULTS: Forty percent of the patients withdrew from the study; the majority of withdrawals were because of treatment failure. The rate of treatment failure was similar for all 4 active treatment groups (21%-29%) and higher in the placebo group (45%). In general, all celecoxib doses provided efficacy similar to naproxen and superior to placebo. Compared with placebo recipients (29%), there were significantly more responders in the celecoxib groups (39%-44%; P <.05; number needed to treat [NNT] = 8) and the naproxen group (36%; P <.05). Maximal treatment effects with celecoxib were apparent and significant by week 2 and sustained through week 12.
The authors of this study demonstrated that for patients with rheumatoid arthritis, celecoxib offers comparable efficacy to NSAIDs, with fewer endoscopic ulcers. It is unknown if these results will translate into reduced rates of clinically significant GI complications, such as perforations, hemorrhages, and obstructions. However, in the same issue of The Journal of the American Medical Association, a pooled analysis of 8 rofecoxib (another COX-2 inhibitor) trials demonstrated reduced rates of GI complications in osteoarthritis patients.1 An economic analysis of COX-2 inhibitors (based on published costs for these agents and incidence rates for NSAID-induced ulcers) suggests that these agents are probably cost-effective in high-risk patients (those aged 75 years or older or with a history of ulcer or GI bleed).2
On the basis of these findings, we recommend using celecoxib in high-risk patients. Considering the time to maximum benefit of 2 weeks and the relatively large number of nonresponders, it seems reasonable to discontinue celecoxib in patients who have not experienced a benefit after a relatively short therapeutic trial.