Showing papers in "The Journal of Rheumatology Supplement in 1998"

Mechanism of action of leflunomide in rheumatoid arthritis

Abstract: Leflunomide, a novel drug with proven efficacy in rheumatoid arthritis, is an isoxazol derivative structurally unrelated to other immunomodulatory drugs. Leflunomide is rapidly metabolized to its active form, A77 1726. Two mechanisms of action have been identified for A77 1726: inhibition of dihydroorotate dehydrogenase (DHODH) and inhibition of tyrosine kinases. DHODH inhibition occurs at lower concentrations of A77 1726 than that of tyrosine kinases and is currently considered the major mode of action. Stimulated lymphocytes must increase ribonucleotide levels from 8 to 16-fold before proceeding from the G1 into the S phase. Increased levels of ribonucleotides can only be met by de novo ribonucleotide synthesis. At low levels of ribonucleotides, p53, a "sensor" molecule, gets activated and prevents progression through the cell cycle. Therefore, an inhibitor of de novo uridine monophosphate synthesis would predictably arrest stimulated cells at the G1 phase. In support of this mechanism of action, in vitro mitogen stimulated human peripheral blood lymphocytes treated with A77 1726 undergo arrest at the G1 phase; this inhibition is reversed by uridine.

NSAID induced gastrointestinal complications: the ARAMIS perspective--1997. Arthritis, Rheumatism, and Aging Medical Information System.

Abstract: Gastrointestinal (GI) complications related to nonsteroidal antiinflammatory drug (NSAID) therapy are the most prevalent category of adverse drug reactions. Patients with arthritis are among the most frequent users of NSAID and are therefore particularly at risk for these side effects. To evaluate the nature of NSAID related GI complications and to determine how their frequency can be reduced, a series of studies of such complications in patients with rheumatic disease has been carried out based on data from the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS). We review the literature and present findings from the ARAMIS studies. This report addresses whether GI side effects such as dyspepsia can serve as warning symptoms for serious GI complications and describes the risk factors for these life threatening complications. It also describes differences among NSAID with regard to their GI toxicity and describes a study that investigated whether H2-receptor antagonists and antacids affect the development of serious GI complications. In addition, ongoing research and topics to be addressed in future studies are described.

The burden of rheumatoid arthritis : Facts and figures

Abstract: In the most recent comprehensive economic study in the United States, the cost of arthritis, including rheumatoid arthritis (RA) and osteoarthritis (OA), was $64.8 billion US in 1992. Of the total costs of these diseases, about half were due to expenditures for medical care (direct costs) and about half were due to lost wages (indirect costs). Studies of the cost of RA undercount the true costs of this illness. Overall, costing methods create a bias against illnesses that occur disproportionately among women. The bias arises because the women with these conditions have historically had much lower labor force participation rates than men, and because women earn lower wages than men for similar work. In addition, there are many effects of RA that cannot be easily priced in the marketplace, although they are vital to the person and family affected by this disease. New approaches to therapy, which include earlier and more aggressive intervention, new drugs, and combinations of drugs, appear necessary to provide adequate control of inflammation, so that the longterm damage of RA might be prevented and the considerable costs reduced. The incremental costs, side effects, and benefits of therapies, compared to the average costs of disease, become much more relevant in policy discussions and clinical decision making. The possible adverse effects and costs of treatment must be balanced against the adverse effects and underestimated costs of RA.

Scientific rationale for specific inhibition of COX-2.

Abstract: Cyclooxygenase (COX) is the principal enzyme involved in the production of prostaglandins. Inhibition of COX is also the primary mechanism of action of aspirin and other nonsteroidal antiinflammatory drugs (NSAID). Since prostaglandins are important regulators of cellular function, inhibition of prostaglandin production may lead to adverse effects. Two isoforms of COX have been identified, sequenced, and cloned. COX-1 is constitutively produced and is believed to be involved in regulating normal cellular processes, such as gastrointestinal (GI) cytoprotection, vascular homeostasis, and renal function. In contrast, COX-2 -- the inducible form -- is undetectable in most tissues but is present in inflamed tissue. Evidence therefore suggests that the GI toxicity associated with NSAID use is primarily the result of inhibition of COX-1, and antiinflammatory effects are largely due to inhibition of COX-2. A drug that specifically inhibits COX-2 without affecting COX-1 would, theoretically, reduce inflammation without leading to GI side effects. A variety of biologic assays have been developed to characterize the relative activities of NSAID against COX-1 and COX-2. Such in vitro testing has demonstrated that individual NSAID possess different relative inhibitory effects in various tissues. Several NSAID have been reported to show more potent inhibition of COX-2 than of COX-1 in vitro; however, the clinical relevance of differential inhibition of COX isozymes is as yet unknown. Some clinical studies indicating reduced toxicity for these NSAID may, in fact, be attributable to use of these agents at subtherapeutic doses. As yet, no clinically available NSAID has been shown to have significant in vivo effects on COX-2 while sparing COX-1 activity in humans. However, compounds that may be 100 to 300-fold more effective inhibitors of COX-2 and that therefore may have lower risks for toxicity as well as more potent antiinflammatory effects have been developed, but are not yet available for clinical use.

Early arthritis therapy: rationale and current approach.

Abstract: Rheumatoid arthritis (RA) is a disease that seriously affects patients' quality of life and may lead to disability or even premature death, despite the availability of effective treatments. Evidence suggests that delay of treatment may be the main contributing factor for poor outcome. Delay is caused primarily by the erroneous belief that the course of RA may be controlled in many cases by mild measures such as nonsteroidal antiinflammatory drugs, physiotherapy, and rest. While this may be true in a certain percentage of patients, many patients with RA progress to severe disability. To prevent progression of disease, early treatment of RA, particularly in patients at high risk, seems mandatory. Therefore, early arthritis clinics (EAC) have been established in a number of countries. We discuss the rationale for early intervention and our experiences in Austrian EAC.

New insights in the pathogenesis of rheumatoid arthritis.

Abstract: Recent advances in molecular technology as well as clinical research findings have enabled the identification of distinct cell subsets, cell surface markers, and cell products that contribute to the immune mediated inflammation observed in rheumatoid arthritis (RA). However, the lack of definitive insight into the disease etiology has resulted in various hypotheses about the roles of these cells or molecules in the pathophysiology of RA. This review summarizes arguments for and against the central role played by T cells in the initiation and perpetuation of RA. Although the available data do not exclude a role of any particular inflammatory mechanism, understanding of immunoregulatory functions of various T cell subsets may lead to more targeted and effective interventions.

Clinical experience with leflunomide in rheumatoid arthritis. Leflunomide Investigators' Group.

Abstract: Leflunomide is a novel isoxazol drug with disease modifying properties for the treatment of rheumatoid arthritis (RA). Several Phase II trials have been completed and 3 large Phase III trials are nearing completion. A multicenter Phase II randomized, double blind, placebo controlled, 24 week study of 402 patients with active RA revealed that leflunomide 25 mg once daily was significantly (p < 0.05) superior to placebo in all primary and secondary outcome measures; leflunomide 10 mg daily was also statistically superior to placebo for all outcome measures except tender joint count and score. Significantly (p < 0.05) more patients responded to leflunomide 10 and 25 mg than to placebo. Leflunomide appears to be well tolerated in patients treated for up to 18 months. Gastrointestinal events, weight loss, rash/allergic reactions, and reversible alopecia were the most frequently reported drug related adverse events. Patients treated with leflunomide were not more susceptible to infections than those given placebo. Based upon the results of a population based pharmacokinetic/pharmacodynamic model, leflunomide 20 mg was selected as optimal dose for the Phase III studies; these are 6 to 12 month multicenter, randomized, double blind, controlled trials that include as active comparators methotrexate and sulfasalazine. Once-daily administration of leflunomide is effective in patients with active RA.

Corticosteroid-induced Osteoporosis

Abstract: Corticosteroids are thought to cause bone loss by a combination of inhibitory effects on bone formation and enhanced bone resorption, with the inhibitory effects on bone formation appearing to be most important

Diclofenac/misoprostol: novel findings and their clinical potential.

Abstract: The new class of antiinflammatory and analgesic drugs, the selective cyclooxygenase (COX-2) inhibitors, which promise to be devoid of the types of toxicity associated with nonsteroidal antiinflammatory drugs (NSAID), especially adverse gastrointestinal effects, are under clinical trial but are not yet available for use. All NSAID, including those most recently introduced, exhibit nonselectivity of action, producing therapeutic blood levels that inhibit constitutive COX-1 and deplete tissue protective prostaglandins. Among NSAID, the diclofenac/misoprostol combination (Arthrotec) is unique in possessing an active component, misoprostol, to help prevent NSAID induced gastrointestinal damage. Ulcer damage and associated serious complications probably represent only the tip of the iceberg in relation to clinically significant side effects associated with the use of NSAID. In this context, metaanalysis of 8 large multicenter studies reported here has shown that patients taking NSAID show a mean decrease in hemoglobin over 4 - 12 weeks' assessment, with some 10-20% of patients exhibiting clinically significant decreases (> or = 1 g/dl) early in treatment. Patients taking diclofenac/misoprostol showed significantly less of a decline in hemoglobin and up to 50% fewer clinically significant decreases than patients receiving diclofenac alone. The misoprostol component of diclofenac/misoprostol may also help to restore homeostasis in tissues other than the gut. Inhibition of the activity or release of various tissue damaging agents and inflammatory cytokines, e.g., thromboxane and interleukin 1, are described, as are in vivo animal studies that have revealed synergistic or potentiating analgesic and antiinflammatory activities between misoprostol and NSAID, particularly diclofenac. Clinical studies in postsurgical dental pain in more than 500 patients have now shown enhanced analgesia, with greater relief over a longer period, for the diclofenac/misoprostol combination compared with diclofenac alone. The relevance of these findings to pain and inflammation control in arthritis is discussed. Enhanced control of morning stiffness provided by diclofenac/misoprostol, possibly also the result of misoprostol/diclofenac synergy, is also reported, and the development of an objective system that measures 24 hour ambulatory activity is described. Using this Numact recorder, improved mobility in patients receiving diclofenac 75 mg/misoprostol 200 microg was observed compared with patients treated with diclofenac 75 mg slow release. Further studies are being performed employing magnetic resonance imaging both to assess antiinflammatory effects in joint soft tissue architecture and to assess whether the synergistic stimulatory effects of diclofenac and misoprostol on human osteoarthritic cartilage that have been reported in vitro are clinically evident. A growing body of evidence supports the view that the diclofenac/misoprostol combination provides an improved therapeutic ratio over diclofenac alone, not only by improving gastrointestinal safety but also by enhancing analgesic/antiinflammatory effects.

Diclofenac/misoprostol: the European clinical experience.

Abstract: Objective The fixed combination of diclofenac sodium and misoprostol (Arthrotec) is the only nonsteroidal antiinflammatory drug (NSAID) that contains a gastroprotective component and is available in 2 formulations:(1) an enteric coated core of diclofenac sodium 50 mg surrounded by a mantle of misoprostol 200 microg, and (2) a 75 mg enteric coated diclofenac core also surrounded by a 200 microg mantle of misoprostol. This article reviews the European clinical experience with both formulations in patients with arthritis. Methods Three randomized, blinded, multicenter studies, including one in general practice, evaluated the efficacy of combination diclofenac/misoprostol versus diclofenac or ibuprofen in a total of 1824 patients with rheumatoid arthritis (RA) or osteoarthritis (OA). Four additional studies assessed antiarthritic efficacy and employed endoscopy to compare the gastroduodenal safety of combined diclofenac50/misoprostol with that of diclofenac, naproxen, piroxicam, or indomethacin in 1459 patients with RA, OA, or ankylosing spondylitis. The gastroduodenal safety and antiarthritic efficacy of diclofenac75/misoprostol was compared with that of diclofenac in one endoscopy study involving 514 patients with RA or OA. Results The efficacy and safety data obtained from these European clinical trials show that both formulations diclofenac50/misoprostol and diclofenac75/misoprostol are effective antiinflammatory drugs, with clinical efficacy equivalent to that of diclofenac. Diclofenac50/misoprostol is at least as effective as naproxen, piroxicam, indomethacin, and ibuprofen. Both formulations of the combination were associated with significantly fewer gastroduodenal ulcers compared with diclofenac. In separate studies, the tolerability of diclofenac50/misoprostol (as determined by withdrawal rates) was shown to be equivalent to that of diclofenac, naproxen, piroxicam, and ibuprofen, and the tolerability of diclofenac75/misoprostol was shown to be equivalent to that of diclofenac. The diclofenac50/misoprostol was associated with fewer decreases in hemoglobin concentration compared with diclofenac in the general practice study as well as in hospital patients. Conclusion Diclofenac50/misoprostol and diclofenac75/misoprostol are effective in treating the signs and symptoms of RA and OA and are well tolerated by the majority of patients. Both of these formulations achieve a significant reduction in the incidence of both gastric and duodenal ulcers compared with other NSAID.

Prevention of gastrointestinal complications associated with nonsteroidal antiinflammatory drugs.

Abstract: Nonsteroidal antiinflammatory drugs (NSAID), although used frequently for the treatment of arthritis and musculoskeletal disorders, may produce deleterious effects related to the gastrointestinal (GI) tract, including dyspeptic symptoms, erosions, ulcers, and serious GI complications (i.e., bleeding, perforation, and gastric outlet obstruction). Endoscopic studies with the synthetic prostaglandin E1 analog misoprostol, various acid-reducing agents (e.g., H2 receptor antagonists and proton pump inhibitors), and surface-active drugs such as sucralfate, have been shown to prevent NSAID induced gastric and/or duodenal ulcers. The Misoprostol Ulcer Complication Outcomes Safety Assessment (MUCOSA) trial was a 6 month, randomized, double blind, placebo controlled study to investigate whether concurrent administration of misoprostol would significantly reduce the occurrence of serious upper GI complications in patients with rheumatoid arthritis (RA) who were receiving NSAID. Results showed that overall complications were reduced by 40% (p = 0.049) among patients receiving misoprostol (25 patients with definite serious GI events among 4404 patients treated) compared with those receiving placebo (42 out of 4439 patients). Thus, cotherapy with misoprostol resulted in a statistically significant reduction in the incidence of serious NSAID induced upper GI complications compared with placebo in patients with RA.