Relative contribution of mucosal injury and Helicobacter pylori in the development of gastroduodenal lesions in patients taking non-steroidal anti-inflammatory drugs.

BACKGROUND AND AIMS: A past history of peptic ulceration increases the risk of an ulcer developing during non-steroidal anti-inflammatory drug (NSAID) use. Whether this is due to Helicobacter pylori infection or to reactivation of the original lesion is unclear. METHODS: We used multivariate regression analyses of three large similar trials to identify factors that placed patients at high risk of ulcer development or relapse. We compared the efficacy of omeprazole 20 mg daily, misoprostol 200 micro g twice daily, and ranitidine 150 mg twice daily in preventing ulcers and erosions at different sites and in patients who were H pylori positive and negative. RESULTS: Patients with endoscopic lesions (which healed) initially were significantly more likely than those without to develop further erosions or ulcers during treatment (rate ratio 2.12, 1.07-4.17). Risk mounted further with ulcers versus erosions, particularly those that had been slow to heal. There was a highly significant tendency for the relapse lesion to replicate the site and type of the original lesion (mean odds ratios ranging from 3 to 14). Treatment failure was significantly less likely with omeprazole than with placebo, misoprostol, or ranitidine. This advantage was especially evident in H pylori positive patients receiving acid suppression (5.7% v 16.6% for gastric ulcer with omeprazole). CONCLUSIONS: Relapse of lesions in patients taking NSAIDs was highly site and type specific and not adversely affected by H pylori status. This strongly implies that local mucosal factors predispose to ulcer development in patients taking NSAIDs. Identification of the responsible mucosal changes would aid understanding and could promote better treatment.

Influence of sex and Helicobacter pylori on development and healing of gastroduodenal lesions in non-steroidal anti-inflammatory drug users.

BACKGROUND AND AIMS: Factors predisposing to endoscopic ulcer formation or healing with non-steroidal anti-inflammatory drugs (NSAIDs) have not been well defined. METHODS: We used multivariate analysis of data from three large similar trials to identify factors associated with endoscopic lesions and healing. We compared the effectiveness of omeprazole 20 mg and 40 mg daily, misoprostol 200 micro g four times daily, and ranitidine 150 mg twice daily in healing ulcers and erosions at different sites and in patients who were Helicobacter pylori positive and negative. RESULTS: Older age, past ulcer history, rheumatoid arthritis, and H pylori infection were significantly associated with ulcers. Duodenal ulcer was significantly more likely than gastric ulcer with a past ulcer history (odds ratio 1.59, 1.16-2.17), H pylori infection (1.4, 1.04-1.92), and male sex (2.35, 1.75-3.16) while female sex, older age (> or = 60 years: 1.39, 1.03-1.88), and higher NSAID dose (>1 defined daily dose: 1.57, 1.16-2.14) were associated with gastric ulceration. Sex differences were seen in both H pylori positive and negative patients. Gastric and duodenal ulcer healing was significantly faster with omeprazole 20 mg than with misoprostol 200 micro g four times daily or ranitidine 150 mg twice daily although misoprostol was more effective at healing erosions. Gastric ulcer healing was slower with large ulcers (0.37, 0.25-0.54 for >10 mm v 5-10 mm) or a past ulcer history (0.51, 0.34-0.76), and faster with H pylori infection (1.55, 1.06-2.29), especially with acid suppression (72% v 37% at four weeks with ranitidine). CONCLUSIONS: Among NSAID users, H pylori and male sex independently increase the likelihood of duodenal ulceration. H pylori infection does not affect duodenal ulcer healing and enhances gastric ulcer healing by ranitidine and possibly other acid suppressing treatments.

Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group.

BACKGROUND: Misoprostol is effective for ulcers associated with the use of nonsteroidal antiinflammatory drugs (NSAIDs) but is often poorly tolerated because of diarrhea and abdominal pain. We compared the efficacy of omeprazole and misoprostol in healing and preventing ulcers associated with NSAIDs. METHODS: In a double-blind study, we randomly assigned 935 patients who required continuous NSAID therapy and who had ulcers or more than 10 erosions in the stomach or duodenum (or both) to receive 20 mg or 40 mg of omeprazole orally in the morning or 200 microg of misoprostol orally four times daily. Patients were treated for four weeks or, in the absence of healing, eight weeks. Treatment success was defined as the absence of ulcers and the presence of fewer than five erosions at each site and not more than mild dyspepsia. We then randomly reassigned 732 patients in whom treatment was successful to maintenance therapy with 20 mg of omeprazole daily, 200 microg of misoprostol twice daily, or placebo for six months. RESULTS: At eight weeks, treatment was successful in 76 percent of the patients given 20 mg of omeprazole (233 of 308), 75 percent of those given 40 mg of omeprazole (237 of 315), and 71 percent of those given misoprostol (212 of 298). The rates of gastric-ulcer healing were significantly higher with 20 mg of omeprazole (but not 40 mg of omeprazole) than with misoprostol. Healing rates among patients with duodenal ulcers were higher with either dose of omeprazole than with misoprostol, whereas healing rates among patients with erosions alone were higher with misoprostol. More patients remained in remission during maintenance treatment with omeprazole (61 percent) than with misoprostol (48 percent, P=0.001) and with either drug than with placebo (27 percent, P<0.001). There were more adverse events during the healing phase in the misoprostol group than in the groups given 20 mg and 40 mg of omeprazole (59 percent, 48 percent, and 46 percent, respectively). CONCLUSIONS: The overall rates of successful treatment of ulcers, erosions, and symptoms associated with NSAIDs were similar for the two doses of omeprazole and misoprostol. Maintenance therapy with omeprazole was associated with a lower rate of relapse than misoprostol. Omeprazole was better tolerated than misoprostol.

A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group.

BACKGROUND: Suppressing acid secretion is thought o reduce the risk of ulcers associated with regular use of nonsteroidal antiinflammatory drugs (NSAIDs), but the best means of accomplishing this is uncertain. METHODS: We studied 541 patients who required continuous treatment with NSAIDs and who had ulcers or more than 10 erosions in either the stomach or duodenum. Patients were randomly assigned to double-blind treatment with omeprazole, 20 mg or 40 mg orally per day, or ranitidine, 150 mg orally twice a day, for four or eight weeks, depending on when treatment was successful (defined as the resolution of ulcer and the presence of fewer than five erosions in the stomach, and fewer than five erosions in the duodenum, and not more than mild dyspepsia). We randomly assigned 432 patients in whom treatment was successful to maintenance treatment with either 20 mg of omeprazole per day or 150 mg of ranitidine twice a day for six months. RESULTS: At eight weeks, treatment was successful in 80 percent (140 of 174) of the patients in the group given 20 mg of omeprazole per day, 79 percent (148 of 187) of those given 40 mg of omeprazole per day, and 63 percent (110 of 174) of those given ranitidine (P<0.001 for the comparison with 20 mg of omeprazole and P=0.001 for the comparison with 40 mg of omeprazole). The rates of healing of all types of lesions were higher with omeprazole than with ranitidine. During maintenance therapy, the estimated proportion of patients in remission at the end of six months was 72 percent in the omeprazole group and 59 percent in the ranitidine group. The rates of adverse events were similar between groups during both phases. Both medications were well tolerated. CONCLUSIONS: In patients with regular use of NSAIDs, omeprazole healed and prevented ulcers more effectively than did ranitidine.

Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs.

BACKGROUND: Acid suppression with famotidine, a histamine H2-receptor antagonist, provides protection against gastric injury in normal subjects receiving short courses of aspirin or naproxen. The efficacy of famotidine in preventing peptic ulcers in patients receiving long-term therapy with nonsteroidal antiinflammatory drugs (NSAIDs) is not known. METHODS: We studied the efficacy of two doses of famotidine (20 mg and 40 mg, each given orally twice daily), as compared with placebo, in preventing peptic ulcers in 285 patients without peptic ulcers who were receiving long-term NSAID therapy for rheumatoid arthritis (82 percent) or osteoarthritis (18 percent). The patients were evaluated clinically and by endoscopy at base line and after 4, 12, and 24 weeks of treatment. The evaluators were unaware of the treatment assignment. The primary end point was the cumulative incidence of gastric or duodenal ulceration at 24 weeks. RESULTS: The cumulative incidence of gastric ulcers was 20 percent in the placebo group, 13 percent in the group of patients receiving 20 mg of famotidine twice daily (P = 0.24 for the comparison with placebo), and 8 percent in the group receiving 40 mg of famotidine twice daily (P = 0.03 for the comparison with placebo). The proportion of patients in whom duodenal ulcers developed was significantly lower with both doses of famotidine than with placebo (13 percent in the placebo group, 4 percent in the low-dose famotidine group [P = 0.04], and 2 percent in the high-dose famotidine group [P = 0.01]). Both doses of famotidine were well tolerated. CONCLUSIONS: Treatment with high-dose famotidine significantly reduces the cumulative incidence of both gastric and duodenal ulcers in patients with arthritis receiving long-term NSAID therapy.

Ileo-caecal ulceration associated with the use of diclofenac slow release.

A 38-year-old man with seropositive arthropathy on long-standing treatment with diclofenac slow release presented with abdominal pain, diarrhoea and anaemia. Upper gastrointestinal endoscopy and barium series were unremarkable. Five months later he presented with a right iliac fossa mass. Investigations revealed discrete ulceration in the terminal ileum and caecum confirmed at laparotomy. Other possible causes of intestinal ulceration were excluded suggesting a diagnosis of non-steroidal anti-inflammatory drug associated intestinal ulceration.

Patterns of urinary excretion of gold in patients with rheumatoid arthritis undergoing chrysotherapy.

Thirty patients receiving gold therapy for rheumatoid arthritis (RA) were studied for the urinary excretion of gold. Statistical analysis of all the urine specimens passed over a period of four days by each patient showed that a definite rhythm of gold excretion exists for each patient which is possibly related to water excretion but not to creatinine excretion. The study indicates possible reasons for the inability of earlier workers to relate gold excretion to the general body gold status of patients and suggests that as the study of 24 hour excretions of gold may be an insensitive marker of gold excretion, closer examination of individual patient rhythms of gold excretion could possibly provide a more useful method of analysis.

Patterns of gold levels in urine, serum, and saliva in patients with rheumatoid arthritis undergoing chrysotherapy.

Twenty patients undergoing treatment with aurothiomalate for rheumatoid arthritis (RA) were studied for the presence of gold in all urine specimens passed over four days and for gold in the serum of blood drawn by venous section at 10.00, 16.00, and 22.00 hours on a single day of the study. Specimens of saliva collected at the same times as the blood specimens were also analysed for (total) gold content. Eighteen patients showed rhythmic urinary gold excretion. Variations were observed in the serum levels for total, free, and protein bound gold at different times of the day and night together with similar variations in the salivary total gold levels. It was established that a possible relation exists between urinary gold, serum gold, and salivary gold such that at times of higher urinary gold excretion the serum gold levels (total, free, and protein bound) and the total salivary gold levels were decreased. Conversely, at times of lower urinary gold excretion serum and salivary gold levels were increased.

Peripheral joint involvement in polymyalgia rheumatica: a clinical study of 56 cases.

A follow-up study of 56 patients with the provisional diagnosis of polymyalgia rheumatica showed that 12 developed peripheral synovitis during the course of the illness. Five of the 12 were noted to have synovitis on presentation which was characteristically mild, pauci-articular and cleared quickly after commencing prednisolone therapy. The remaining seven had persistent synovitis of peripheral small joints despite an initial brisk response to oral prednisolone. Five of these patients were found to satisfy the ARA criteria for rheumatoid arthritis after a mean follow-up period of 3.5 years. It is suggested that the persistence of peripheral synovitis in patients treated as polymyalgia rheumatica should alert the clinician to the possible development of rheumatoid arthritis.

A controlled trial of tiaprofenic acid against indomethacin in patients with rheumatoid arthritis.

A multicentre double-blind crossover study of tiaprofenic acid 600 mg daily against indomethacin 75 mg daily was carried out in 68 patients with rheumatoid arthritis to compare short-term efficacy and tolerance. There were no significant differences in efficacy between the two treatments, but significantly fewer C.N.S. side-effects were associated with tiaprofenic acid treatment. Five patients withdrew during the course of the study due to side-effects and all were receiving indomethacin.

Free thiomalate levels in patients with rheumatoid arthritis treated with disodium aurothiomalate: relationship to clinical outcome of therapy.

Sixteen patients with seropositive rheumatoid arthritis were treated with 20 mg disodium aurothiomalate (Myocrisin) weekly for six months. Disease activity was assessed before and after treatment. Plasma profiles and urinary excretion of free thiomalate were measured in all patients after the initial injection and again at six months in the 12 patients remaining on therapy. No difference was found in plasma levels or urinary excretion of free thiomalate between patients who responded to treatment or who developed toxic reactions and those who did not.

Circulating thiomalate after administration of disodium aurothiomalate: impurity or active metabolite?

During studies of the metabolism of disodium aurothiomalate in patients with rheumatoid arthritis we have found that its pharmaceutical preparation. Myocrisin, contains 4 to 8% of free thiomalate. To establish whether the free thiomalate previously reported in plasma and urine of patients receiving Myocrisin is a true metabolite or results from this impurity, we prepared aurothiomalate containing 0.1% thiomalate. Intramuscular injection of the purified drug to 2 healthy subjects produced easily detectable levels of thiomalate in both plasma and urine; 7.7 and 9.8% respectively of the doses given were recovered in urine as free thomalate within 4 h. Thus, dissociation of disodium aurothiomalate does occur in vivo, releasing both gold and free thiomalate as potentially active forms.

Popliteal masses masquerading as popliteal cysts.

Two popliteal swellings, thought initially to be synovial cysts associated with arthritic knees, were found to be unrelated tumours of serious significance. In the presence of neurological signs or a large cyst in association with a noninflammed knee joint a disease other than a simple synovial cyst should be considered.