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

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.

An endoscopic study of gastroduodenal lesions induced by nonsteroidal anti-inflammatory drugs.

Rheumatoid arthritis (RA) and osteoarthritis (OA) are frequently treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Although NSAIDs are an effective therapy for the pain and inflammation of arthritis, they are associated with serious side effects, particularly ulceration, bleeding, and perforation of the gastrointestinal (GI) tract. In this study, 1826 OA or RA patients who either had been taking NSAIDS for > or =6 months or had been unable to tolerate continuous NSAID use because of adverse GI symptoms or suspected NSAID-related gastroduodenal lesions were examined endoscopically for gastroduodenal lesions and ulcers. At the same time, the patients were asked to rate the severity of any GI symptoms they had been experiencing. Of the total number of patients studied, 817 (44.7%) were OA patients with a mean (+/- SD) age of 55.8+/-12.9 years, and 1009 (55.3%) were RA patients with a mean age of 53.1+/-13.1 years. Clinically significant gastroduodenal lesions were found in 37.1% of patients (n = 678); of these, 24.0% (n = 439) had ulcers. Gastric ulcers were more frequent than duodenal ulcers (14.8% vs 10.2% of patients; P < 0.05), and most gastric ulcers (72.0%) were found in the antrum of the stomach. The prevalence of gastroduodenal ulcers increased with age (P < 0.001), duration of OA (P < 0.001), and duration of current NSAID use (P = 0.019). The prevalence of gastroduodenal ulcers in patients taking NSAIDs for <1 year was 13.8%, compared with a nearly twofold higher prevalence (25.9%) in patients taking NSAIDs for periods of > or =1 year and up to 15 years. The prevalence of gastric ulcers was 32.6% in patients with a history of gastric ulcer but only 13.5% in patients with no GI history (previous gastric ulcer, duodenal ulcer, or upper GI hemorrhage). No relationship was found between the prevalence of gastroduodenal ulcers and sex (men, 22.4%; women, 24.9%) or prevalence of gastroduodenal ulcers and type of arthritic disease (RA, 23.6%; OA, 24.5%). The prevalence of gastroduodenal ulcers increased with the severity of GI symptoms (P = 0.007). These results provide further endoscopic confirmation of the association between NSAID use and gastroduodenal lesions and ulcers and support the contention that safer treatment alternatives to conventional NSAIDs are required.

Double-blind comparison of the efficacy of diclofenac/misoprostol and diclofenac in the treatment of rheumatoid arthritis.

A double-blind, randomised, parallel-group study was conducted in eight countries to compare the efficacy of a fixed combination of diclofenac sodium (50 mg) and misoprostol (200 mcg) with a fixed combination of diclofenac sodium (50 mg) and placebo in treating the signs and symptoms of rheumatoid arthritis (RA). A total of 346 patients with RA who had been stabilised on diclofenac for at least 30 days were randomly assigned to receive either diclofenac/misoprostol BID or TID (n = 177) or diclofenac/placebo BID or TID (n = 169) for 12 weeks. Primary analyses of efficacy, made upon admission and at 4-week intervals, consisted of physician's global assessment of the arthritic condition, patient's global assessment of the arthritic condition, patient's global assessment of joint tenderness/pain, and physician's assessment of joint swelling. In this study, the fixed combination tablet of diclofenac sodium 50 mg/misoprostol 200 mcg administered BID or TID demonstrated no statistically significant difference in efficacy in the treatment of the signs and symptoms of RA compared with diclofenac sodium 50 mg/placebo administered BID or TID.

The gastroduodenal safety and efficacy of the fixed combination of diclofenac and misoprostol in the treatment of osteoarthritis.

A double-blind, randomized, parallel group study was conducted to compare the gastroduodenal safety and antiarthritic efficacy of a fixed combination of diclofenac 50 mg and misoprostol 200 micrograms with that of a combination of diclofenac 50 mg and placebo in patients with osteoarthritis. Three hundred and sixty-one patients with no significant gastroduodenal lesions were enrolled and received study medication two or three times daily for 4 weeks. Post-treatment endoscopic examination of the gastroduodenal mucosa revealed ulcers in 4% of patients in the diclofenac/placebo group compared with none in the diclofenac/misoprostol group (P = 0.015). There were no clinically or statistically significant differences between the two treatment groups in formal assessments of osteoarthritis after either 2 or 4 weeks. It was concluded that diclofenac/misoprostol was associated with significantly less gastroduodenal damage than diclofenac, whilst being as effective as diclofenac alone in the treatment of osteoarthritis.

A double-blind comparison of the gastroduodenal safety and efficacy of diclofenac and a fixed dose combination of diclofenac and misoprostol in the treatment of rheumatoid arthritis.

This double-blind, parallel group study was conducted to evaluate the gastroduodenal safety and antiarthritic efficacy of a fixed combination of diclofenac sodium 50 mg and misoprostol 200 mcg, compared with a combination of diclofenac 50 mg and placebo. Three hundred and thirty-nine patients with rheumatoid arthritis and no significant gastric or duodenal mucosal damage were enrolled and received study medication (diclofenac/misoprostol, 164; diclofenac/placebo, 175) BID or TID for 12 weeks. Posttreatment gastroduodenal endoscopic examinations revealed ulcers in 11% of the diclofenac/placebo group, compared with only 4% of the diclofenac/misoprostol group (p = 0.034). Four-weekly assessments of arthritic condition revealed no clinically or statistically significant treatment differences. It was concluded that diclofenac/misoprostol caused significantly less gastroduodenal damage than diclofenac, but was as effective as diclofenac alone in the treatment of rheumatoid arthritis.

Prevalence of mucosal lesions in the stomach and duodenum due to chronic use of NSAID in patients with rheumatoid arthritis or osteoarthritis, and interim report on prevention by misoprostol of diclofenac associated lesions.

We review preliminary findings of the screening and prophylaxis phases of a study of misoprostol in patients with arthritis receiving nonsteroidal antiinflammatory drugs (NSAID). Endoscopic evaluation of over 1,800 patients with rheumatoid arthritis or osteoarthritis, more than 95% of whom qualified for screening on the basis of continuous NSAID use over the prior 6 months, has revealed clinically significant gastroduodenal lesions in 37% and ulceration in 24%. In the prophylaxis phase, patients without significant lesions were randomized to receive misoprostol or placebo and NSAID therapy with diclofenac for 52 weeks. Product-limit and crude incidence analyses of data from patients thus far enrolled indicate that misoprostol is associated with significant protection against the development of gastroduodenal lesions compared with placebo after 12 or 24 weeks of study. No adverse effect of misoprostol administration on underlying arthritis activity has been observed thus far. Definitive conclusions await completion of the study.

A lung perfusion technique for the detection of antigenic intrapulmonary bronchoconstriction and its mediation.

A guinea pig intraluminal perfusion model was used to assess the effects of antigen challenge of airway reactivity and its pharmacologic modulation. Increases in airway perfusion pressure, following antigen provocation, could be reproduced 60 min later without significant modification of the response. We found no change in lung volume nor observed tissue edema following antigen provocation, and suggest that rises in perfusion pressure are due to decreases in airway caliber. Pharmacologically, the antihistamines, mepyramine and chlorpheniramine, and the antiallergic agent, disodium cromoglygate (DSCG), failed to inhibit antigenic bronchoconstriction. Indeed, mepyramine produced some potentiation of allergic bronchospasm. Compounds reported to inhibit 5-lipoxygenase (phenidone, benoxaprofen, and noradihydroguiaretic acid (NDGA)) or antagonize SRS-A (FPL 55712), produced inhibition of antigen-induced bronchoconstriction. The cyclooxygenase inhibitor, indomethacin, produced biphasic modulation of antigenic bronchoconstriction, potentiation at low doses, and inhibition at high concentrations. Overall, drug-induced modulation of allergic bronchoconstriction suggests that this model more closely resembles the antigenic reactions observed in the parenchymal strip preparation than in the trachea.