Elsevier

The Lancet

Volume 354, Issue 9196, 18–25 December 1999, Pages 2106-2111
The Lancet

Articles
Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison

https://doi.org/10.1016/S0140-6736(99)02332-6Get rights and content

Summary

Background

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclo-oxygenase (COX), which leads to suppression of COX-1-mediated production of gastrointestinal-protective prostaglandins. Gastrointestinal injury is a common outcome. We compared the efficacy, safety, and tolerability of long-term therapy with celecoxib, a COX-1 sparing inhibitor of COX-2, with diclofenac, a non-specific COX inhibitor.

Methods

655 patients with adult-onset rheumatoid arthritis of at least 6 months' duration were randomly assigned oral celecoxib 200 mg twice daily or diclofenac SR 75 mg twice daily for 24 weeks. Anti-inflammatory and analgesic activity and tolerability were assessed at baseline, every 4 weeks, and at week 24. We assessed gastrointestinal safety by upper-gastrointestinal endoscopy within 7 days of the last treatment dose at centres where the procedure was available. Analysis was by intention-to-treat.

Findings

430 patients underwent endoscopy (celecoxib n=212, diclofenac n=218). The two drugs were similar in management of rheumatoid arthritis pain and inflammation. Gastroduodenal ulcers were detected endoscopically in 33 (15%) patients treated with diclofenac and in eight (4%) in the celecoxib group (p<0·001). The rate of withdrawal for any gastrointestinal-related adverse event, most commonly abdominal pain, diarrhoea, and dyspepsia, was nearly three times higher in the diclofenac-treated group than in the celecoxib group (16 vs 6%; p<0·001).

Interpretation

Celecoxib showed sustained anti-inflammatory and analgesic activity similar to diclofenac, with a lower frequency of upper gastrointestinal ulceration or gastrointestinal adverse events, and tolerability was better.

Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs), in the treatment of rheumatoid arthritis, act by inhibiting cyclo-oxygenase (COX); which converts arachidonic acid to prostaglandins.1, 2 A well established limitation of NSAIDs is the risk of clinically important injury to gastrointestinal mucosa, such as ulceration, perforation, and haemorrhage.3, 4

COX exists in two isoforms.5, 6 Cyclo-oxygenase-1 (COX-1), a wide-ranging essential enzyme, produces prostaglandins involved in cytoprotective and regulatory functions in gastrointestinal mucosa, platelets, and renal cells;7 gastric prostaglandins are derived almost exclusively from COX-1.8 Cyclo-oxygenase-2 (COX-2), predominantly a cytokine-induced enzyme, produces prostaglandins that mediate pain and inflammation.9, 10, 11 With the exception of the brain, reproductive organs, and kidney, COX-2 is expressed at low concentrations in most normal tissue, but is upregulated in inflammatory cells such as activated macrophages and synoviocytes.10, 12, 13

All NSAIDs inhibit COX-1 and COX-2, each to varying degrees.14, 15 This observation has led to the hypothesis that the therapeutic effects of NSAIDs are achieved by COX-2 inhibition, but many of the toxic effects, most commonly gastroduodenal injury, result from COX-1 inhibition. By contrast with conventional (ie, non-specific) NSAIDs, celecoxib was designed to inhibit specifically COX-2. Celecoxib inhibits COX-2 selectively in vitro as well as in vivo, and has effective anti-inflammatory and analgesic properties with few gastrointestinal toxic effects in animals and in healthy volunteers.16, 17 To test clinically the hypothesis that celecoxib has anti-inflammatory and analgesic properties through COX-2 inhibition without gastrointestinal toxic effects associated with inhibition of COX-1, we assessed the long-term efficacy, gastrointestinal safety, and overall tolerability of celecoxib compared with diclofenac for management of rheumatoid arthritis. We chose to compare celecoxib with diclofenac because it is a commonly prescribed NSAID believed to have a favourable gastrointestinal safety profile.18

Section snippets

Patients and methods

132 centres in Europe, Israel, South Africa, Australia, and New Zealand took part in this study, in accordance with the Helsinki Declaration. All patients gave written, informed consent.

Results

326 patients received celecoxib and 329 received diclofenac. 212 on celecoxib and 218 on diclofenac underwent upper gastrointestinal endoscopy. 158 patients were withdrawn because of: pre-existing protocol violations (4); protocol non-compliance (8); treatment failure (48); and adverse events (98) (figure 1).

At baseline, the groups were similar for demography, general health, duration of rheumatoid arthritis, history of gastrointestinal disease, and NSAID intolerance (table 1). In general,

Discussion

Celecoxib 200 mg twice daily gave sustained anti-inflammatory and analgesic activity similar to that of diclofenac SR 75 mg twice daily in long-term management of rheumatoid arthritis, but with better gastrointestinal safety and tolerability.

The study population was representative of the general population of patients with rheumatoid arthritis, since those with a history of gastrointestinal complications, such as ulcer or haemorrhage, were not excluded. Screening of study candidates for active

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