Antirheumatic

OBJECTIVES: Although cyclooxygenase-2 inhibitors (coxibs) were developed to cause less gastrointestinal hemorrhage than nonselective nonsterodial antiinflammatory drugs (NSAIDs), there has been concern about their cardiovascular safety. The relative risk of acute myocardial infarction (AMI) was studied among users of celecoxib, rofecoxib, and NSAIDs in Medicare beneficiaries with a comprehensive drug benefit. METHODS: A matched case-control study was conducted of 54,475 patients 65 years of age or older who received their medications through two state-sponsored pharmaceutical benefits programs in the United States. All healthcare use encounters were examined to identify hospitalizations for AMI. Each of the 10,895 cases of AMI were matched to four controls on the basis of age, gender, and the month of index date. A matched logistic regression model was constructed, including indicators for patient demographics, healthcare use, medication use, and cardiovascular risk factors to assess the relative risk of AMI in patients who used rofecoxib compared with persons taking no NSAID, taking celecoxib, or taking NSAIDs. RESULTS: Current use of rofecoxib was associated with an elevated relative risk of AMI compared with celecoxib (OR 1.14; 95% CI, 1.05-1.46; P = 0.011), and with no NSAID (OR, 1.14; 95% CI, 1.00-1.31; P = 0.054). The adjusted relative risk of AMI was also elevated in dose-specific comparasions; rofecoxib < or = 25 mg versus celecoxib < or = 200 mg (OR 1.21; 95% CI, 1.01-1.44; P = 0.036) and rofecoxib > 25 mg versus celecoxib > 200 mg (OR 1.70; 95% CI, 1.07-2.71; P = 0.026). The adjusted relative risks of AMI associated with rofecoxib use of 1 to 30 days (OR, 1.40; 95% CI, 1.12-1.75; P = 0.005) and 31 to 90 days (OR, 1.38; 95% CI, 1.11-1.72; P = 0.003) were higher than > 90 days (OR, 0.96; 95% CI, 0.72-1.25; P = 0.8) compared with celecoxib use of similar duration. Celecoxib was not associated with an increased relative risk of AMI in these comparisions. CONCLUSIONS: In this study, current rofecoxib use was associated with an elevated relative risk of AMI compared with celecoxib use and no NSAID use. Dosages of rofecoxib greater than 25 mg were associated with a higher risk than dosages of 25 mg or less. The risk was elevated in the first 90 days of use, but not thereafter.

BACKGROUND: Oxygen free radicals have been implicated as mediators of tissue damage in patients of rheumatoid arthritis (RA). This study was designed to elucidate plasma oxidant/antioxidant status in rheumatoid arthritis, with the aim of evaluating the importance of antioxidant therapy in the management of this disease. METHODS: The study included 40 patients of rheumatoid arthritis who were randomly divided into two subgroups of 20 each. One group received conventional treatment for 12 weeks and in the other group conventional treatment was supplemented with antioxidants for the same duration. Twenty age- and sex-matched normal individuals constituted the control group. Blood samples of controls and patients were collected at the time of presentation and analyzed for total thiols, glutathione, vitamin C and malondialdehyde (MDA-marker of oxidative stress). The investigations were repeated in the patients after 12 weeks. RESULTS: The blood concentrations of total thiols, glutathione and vitamin C were found to be significantly lower in rheumatoid arthritis patients as compared to healthy controls, while the concentrations of MDA were much higher. There was a statistically significant increase in the posttreatment concentrations of these antioxidants, along with a decrease in the concentrations of MDA. CONCLUSIONS: The antioxidant defense system is compromised in rheumatoid arthritis patients. There is a shift in the oxidant/antioxidant balance in favor of lipid peroxidation, which could lead to the tissue damage observed in the disease. The results suggest the necessity for therapeutic co-administration of antioxidants along with conventional drugs to such patients. However, due to the limited number of cases included in this study, more studies may be required to substantiate the results and arrive at a definite conclusion, in terms of safety and efficacy of adding on antioxidant therapy for the treatment of RA.

Nippon Rinsho. 2002 Dec;60(12):2351-6.
Combination therapy of disease-modifying antirheumatic drugs(DMARDs) in rheumatoid arthritis
Kobayashi S, Kanai Y.
Department of Rheumatology, Juntendo University, School of Medicine.

The early suppression of disease activity during the first 2 years in rheumatoid arthritis (RA) has been reported to be exclusively important to prevent joint destruction and functional decline. Since single disease-modifying antirheumatic drugs(DMARDs) therapy is still disappointing, many rheumatologists today advocated a more aggressive approach using combinations of classic DMARDs. Many clinical trials on combination therapy have been reported and most studies of combination therapy focused on the efficacy of a treatment strategy. Therefore, the possible synergistic action of combination of drugs has not been demonstrated. Among combination of therapy of classical DMARDs, only few trials demonstrated the efficacy of combination therapy. The incidence of adverse effects among 341 RA patients was investigated by our department. The incidence of adverse effect in combination therapy revealed 36.4% which was not statistically different from that in monotherapy(33.6%, p = 0.41). The recent studies on combination therapy on classical DMARDs are not encouraging, however, the combination therapy for patients with early RA, drugs utilizing immunosuppressant, biologics and other newly developed drugs will still have a chance to expect a potent efficacy for RA.

Longterm safety and efficacy of disease modifying antirheumatic drugs (DMARD) have been challenging to assess. There are few studies that have evaluated patient outcome beyond 5 years. As patients may receive several DMARD over the course of their disease a long with nonsteroidal antiinflammatory drugs, corticosteroids, and other drugs for comorbidities, it is difficult to design and implement a trial to define a specific drug's longterm effect. Based on the findings of several key studies, however, it does appear that DMARD are safe when taken longterm, and that they are more likely to be discontinued because of inefficacy than toxicity. Although DMARD are often discontinued because of lack of efficacy, 12 year data suggest that DMARD can provide benefit over this period. The toxicity profiles vary significantly between DMARD. In addition, the time during therapy when the majority of these adverse effects most frequently appear is DMARD-specific. Prospective studies are needed to further clarify longterm safety and efficacy of the newer DMARD.