Misoprostol prevents NSAID-induced gastroduodenal lesions in patients with osteoarthritis and rheumatoid arthritis. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. Helicobacter pylori infection, ABO blood group, and effect of misoprostol on gastroduodenal mucosa in NSAID-treated patients with rheumatoid arthritis. A group randomized trial to improve safe use of nonsteroidal anti-inflammatory drugs. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. The course of established ankylosing spondylitis and the effects of sulphasalazine over 3 years. Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibitor: efficacy and safety in two placebo-controlled trials in osteoarthritis and rheumatoid arthritis, and studies of gastrointestinal and platelet effects. Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis. A Department of Veterans Affairs Cooperative Study. [Misoprostol in the prevention of gastric erosions caused by nonsteroidal anti-inflammatory agents].
The clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with significant adverse effects on the integrity of the gastrointestinal (GI) mucosa. A unique, double-blind, placebo-controlled, randomized, multicentre study investigated the prophylactic co-therapy with misoprostol, a novel PGE1 analog, for the prevention of the NSAID-induced gastric and duodenal mucosal lesions. The study also investigated whether the co-therapy with misoprostol could interfere with the anti-rheumatic action of the NSAIDs using detailed rheumatological assessments. Patients with osteoarthritis or rheumatoid arthritis had to be free of symptoms and significant erosive and/or haemorrhagic lesions of the upper GI tract. The patients were randomized to co-therapy with misoprostol or its matching placebo. Follow-up endoscopy and symptoms assessment were carried out within 4 weeks and compared to pre-study findings. Misoprostol significantly reduced (p less than 0.01) the incidence of erosive and/or haemorrhagic gastric and duodenal mucosal lesions. Misoprostol also reduced the proportion of patients with epigastric pain (p less than 0.01). Misoprostol was well tolerated and did not interfere with the anti-rheumatic activity of the administered NSAID. We conclude that misoprostol is safe and effective in the protection against NSAID-induced gastric and duodenal mucosal lesions and symptoms. Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a spectrum of toxic effects, notably gastrointestinal (GI) effects, because of inhibition of cyclooxygenase (COX)-1. Whether COX-2-specific inhibitors are associated with fewer clinical GI toxic effects is unknown.
                To determine whether celecoxib, a COX-2-specific inhibitor, is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs.
                The Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind, randomized controlled trial conducted from September 1998 to March 2000.
                Three hundred eighty-six clinical sites in the United States and Canada.
                A total of 8059 patients (>/=18 years old) with osteoarthritis (OA) or rheumatoid arthritis (RA) were enrolled in the study, and 7968 received at least 1 dose of study drug. A total of 4573 patients (57%) received treatment for 6 months.
                Patients were randomly assigned to receive celecoxib, 400 mg twice per day (2 and 4 times the maximum RA and OA dosages, respectively; n = 3987); ibuprofen, 800 mg 3 times per day (n = 1985); or diclofenac, 75 mg twice per day (n = 1996). Aspirin use for cardiovascular prophylaxis (</=325 mg/d) was permitted.
                Incidence of prospectively defined symptomatic upper GI ulcers and ulcer complications (bleeding, perforation, and obstruction) and other adverse effects during the 6-month treatment period.
                For all patients, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76% vs 1.45% (P =.09) and 2. 08% vs 3.54% (P =.02), respectively. For patients not taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.44% vs 1.27% (P =.04) and 1.40% vs 2.91% (P =.02). For patients taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 2.01% vs 2.12% (P =.92) and 4.70% vs 6.00% (P =.49). Fewer celecoxib-treated patients than NSAID-treated patients experienced chronic GI blood loss, GI intolerance, hepatotoxicity, or renal toxicity. No difference was noted in the incidence of cardiovascular events between celecoxib and NSAIDs, irrespective of aspirin use.
                In this study, celecoxib, at dosages greater than those indicated clinically, was associated with a lower incidence of symptomatic ulcers and ulcer complications combined, as well as other clinically important toxic effects, compared with NSAIDs at standard dosages. The decrease in upper GI toxicity was strongest among patients not taking aspirin concomitantly. JAMA. 2000;284:1247-1255 Our aim was to investigate the effect of misoprostol on NSAID-induced gastroduodenal mucosal damage in patients with rheumatoid arthritis. The study included 40 patients, and it was designed as a double-blind, placebo-controlled trial. Misoprostol significantly reduced the gastroduodenal mucosal lesions found at endoscopy (P < 0.05) and prevented the development of ulcers. The cumulative incidence of ulcers at four weeks was 5% in the placebo group and 0% in the misoprostol group. The basal and pentagastrin-stimulated acid output as evaluated after 23 days of treatment with misoprostol was not significantly affected. Forty-one percent of the patients had signs of current Helicobacter pylori infection, 33% had positive serology only, and 26% had no evidence of infection. Most of the patients with current infection belonged to blood group O (P < 0.05). Misoprostol treatment did not affect the occurrence of Helicobacter pylori or the rheumatic disease activity. It is concluded that the protective actions of misoprostol on the gastroduodenal mucosa of NSAID-treated patients are largely mediated by mechanisms other than inhibition of acid secretion. The relationship among active Helicobacter pylori infection, blood group O, and peptic ulcer may be helpful to identify a subpopulation of patients taking NSAIDs at risk of developing peptic ulcers. To determine whether audit/feedback and educational materials improve adherence to recommendations for laboratory monitoring and cytoprotective agents to detect and prevent adverse events caused by nonsteroidal anti-inflammatory agents (NSAIDs).
                Controlled, cluster-randomized trial.
                Physicians commonly prescribing NSAIDs were identified within a large managed care organization and randomized to a control or an intervention group (audit/feedback with peer-derived benchmarks and continuing medical education). Medical records were examined 10 months before and after the intervention for clinical data and receipt of complete blood count (CBC), creatinine testing, and cytoprotective agents (process measures). Primary analysis compared intervention versus control physicians among those who initially performed below a peer-derived benchmark. General estimating equations accounted for patient clustering.
                Of 101 physicians initially randomized, 85 remained eligible (38 internists, 36 family physicians, 11 rheumatologists) postintervention. Mean percent change in performance between intervention and control physicians for CBC monitoring was 16% versus 10%; for creatinine monitoring, 0% versus 17%; and use of cytoprotective agents, -3% versus -1%. None of these changes were significant. Rheumatology specialty, number of NSAID prescriptions and physician visits, and patient risk factors for NSAID-related toxicity were more strongly associated with improved safety practices than the intervention.
                Audit/feedback and educational materials had no observed effect on improving NSAID-related safety practices. Potentially contributing factors include high baseline performance (ceiling effect), dilution of the intervention effect by case mix and provider factors, nonreceipt of intervention materials, and diverse indications for lab tests. To investigate whether concurrent administration of misoprostol reduces the occurrence of serious upper gastrointestinal complications, such as perforation, gastric outlet obstruction, or bleeding, in patients with rheumatoid arthritis who are receiving nonsteroidal anti-inflammatory drugs (NSAIDs).
                6-month randomized, double-blind, placebo-controlled trial.
                664 clinical practices of family medicine, internal medicine, or rheumatology in the United States and Canada.
                8843 men and women (mean age, 68 years) receiving continuous therapy with any of 10 specified NSAIDs for control of symptoms of rheumatoid arthritis. Patients were enrolled between July 1991 and August 1993.
                Patients were randomly assigned to receive 200 micrograms of misoprostol or placebo four times a day.
                Development of serious upper gastrointestinal complications detected by clinical symptoms or findings (not by scheduled endoscopy).
                Serious upper gastrointestinal complications were reduced by 40% (odds ratio, 0.598 [95% CI, 0.364 to 0.982; P = 0.049]) among patients receiving misoprostol (25 of 4404 patients) compared with those receiving placebo (42 of 4439 patients). During the first month, more patients receiving misoprostol (20%) than placebo (15%) withdrew from the study, primarily because of diarrhea and related problems (P < 0.001). Risk factors for serious upper gastrointestinal complications were increasing age, history of peptic ulcer or bleeding, and cardiovascular disease. Patients with all four risk factors would have a 9% risk for a major complication in 6 months.
                In older patients with rheumatoid arthritis, misoprostol reduced serious NSAID-induced upper gastrointestinal complications by 40% compared with placebo. A 3-year placebo-controlled trial of sulphasalazine (SASP) in 89 patients with established AS (including radiological sacroiliitis) showed a reduced frequency of peripheral arthritis in the treated group but did not show any definite benefit in the maintenance of spinal mobility. Adverse effects causing treatment withdrawal occurred in five placebo-treated patients and eight SASP-treated patients, but 22 patients preferred to stop taking daily medication of unproven benefit for the full 3 years. The natural history of established AS suggested two groups of patients: the majority with principally spinal symptoms and infrequent peripheral arthritis or iritis, and a minority who tend to have recurrent extra-spinal problems. To investigate the efficacy and safety of SC-58635 (celecoxib), an antiinflammatory and analgesic agent that acts by selective cyclooxygenase 2 (COX-2) inhibition and is not expected to cause the typical gastrointestinal (GI), renal, and platelet-related side effects associated with inhibition of the COX-1 enzyme.
                Four phase II trials were performed: a 2-week osteoarthritis efficacy trial, a 4-week rheumatoid arthritis efficacy trial, a 1-week endoscopic study of GI mucosal effects, and a 1-week study of effects on platelet function.
                The 2 arthritis trials identified SC-58635 dosage levels that were consistently effective in treating the signs and symptoms of arthritis and were distinguished from placebo on standard arthritis scales. In the upper GI endoscopy study, 19% of subjects receiving naproxen (6 of 32) developed gastric ulcers, whereas no ulcers occurred in subjects receiving SC-58635 or placebo. The study of platelet effects revealed no meaningful effect of SC-58635 on platelet aggregation or thromboxane B2 levels, whereas aspirin caused significant decreases in 2 of 3 platelet aggregation measures and thromboxane B2 levels. In all 4 trials, SC-58635 was well tolerated, with a safety profile similar to that of placebo.
                SC-58635 achieves analgesic and antiinflammatory efficacy in arthritis through selective COX-2 inhibition, without showing any evidence of 2 of the toxic effects of COX-1 inhibition associated with nonsteroidal antiinflammatory drugs. To determine whether sulfasalazine (SSZ) at a dosage of 2,000 mg/day is effective for the treatment of active ankylosing spondylitis (AS) that is not controlled with nonsteroidal antiinflammatory drug therapy.
                Two hundred sixty-four patients with AS were recruited from 15 clinics, randomized (double-blind) to SSZ or placebo treatment, and followed up for 36 weeks. Treatment response was based on morning stiffness, back pain, and physician and patient global assessments.
                While longitudinal analysis revealed a trend favoring SSZ in the middle of treatment, no difference was seen at the end of treatment. Response rates were 38.2% for SSZ and 36.1% for placebo (P = 0.73). The Westergren erythrocyte sedimentation rate declined more with SSZ treatment than with placebo (P < 0.0001). AS patients with associated peripheral arthritis showed improvement that favored SSZ (P = 0.02). Adverse reactions were fewer than expected and were mainly due to nonspecific gastrointestinal complaints.
                SSZ at a dosage of 2,000 mg/day does not seem to be more effective than placebo in the treatment of AS patients with chronic, longstanding disease. SSZ is well tolerated and may be more effective than placebo in the treatment of AS patients with peripheral joint involvement. This effect is more pronounced in treatment of the peripheral arthritis in this subgroup of AS patients. A multicenter, double-blind, placebo-controlled study was carried out to determine whether the synthetic prostaglandin E1 analog misoprostol is effective in preventing gastric and duodenal lesions induced by nonsteroidal anti-inflammatory drugs. Two hundred fifty-six patients under nonsteroidal anti-inflammatory drug treatment (diclofenac, naproxen, piroxicam, ibuprofen, indomethacin, ketoprofen, or tiaprofenic acid) for osteoarthritis, rheumatoid arthritis, or other rheumatic diseases were included in the study. None of the patients had patent gastroduodenal damage at entry (0 to 3 mucosal erosions or subepithelial hemorrhages on endoscopy). Patients were randomly assigned to treatment with misoprostol 400 micrograms/d (M 400), misoprostol 800 micrograms/d (M 800) or a placebo. Results of the follow-up endoscopy on day 28 in the 186 evaluable patients showed that gastric erosions were significantly less common (p < or = 0.02) in the two misoprostol groups (5% and 2% in the M 400 and M 800 groups respectively) than in the placebo group (19%). Similar small numbers of patients in the three groups had gastric subepithelial hemorrhages or duodenal lesions. Three patients developed gastric ulcers in the placebo group, versus none in the misoprostol groups. Misoprostol therapy did not modify the efficacy of the nonsteroidal antiinflammatory agent on pain or other rheumatologic manifestations. Diarrhea occurred in 1%, 10%, and 5% of patients in the M 400, M 800, and placebo groups, respectively. In conclusion, misoprostol given in combination with a nonsteroidal anti-inflammatory agent for 28 days significantly reduced the incidence of gastric erosions in a random sample of patients with a variety of rheumatic diseases. The daily dosage associated with the best risk/benefit ratio may be 400 micrograms/day.
On the basis of the current review, there is scant evidence to guide clinicians about how gastrointestinal or liver comorbidities should influence the choice of pain treatment in patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or other spondyloarthritis. Based upon additional studies that included a mixed population of participants with a range of rheumatic conditions, NSAIDs should be used cautiously in patients with inflammatory arthritis and a history of gastrointestinaI comorbidity as there is consistent evidence that they may be at increased risk.