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Combination Therapy for Rheumatoid Arthritis



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Am Fam Physician. 1999 Oct 1;60(5):1546-1548.

The principle treatments for rheumatoid arthritis are disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids. Although these drugs may alter the clinical course of the disease, the process of joint destruction continues in many patients, leading to permanent disability. Möttönen and colleagues compared the efficacy and tolerability of combination therapy using several DMARDs with the same drugs used as single-drug therapy.

Patients enrolled in the study were between 18 and 65 years of age with symptoms of less than two years' duration. Additional inclusion criteria included active disease with a minimum of three swollen joints and at least three of the following conditions: morning stiffness, more than 10 tender joints and five swollen joints or erythrocyte sedimentation rates and/or C-reactive protein concentrations consistent with rheumatoid arthritis. Patients who had previously used DMARDs, those with marked comorbidities, sensitivities or contraindications to the drugs being studied and patients who had recently taken glucocorticoids were excluded. The 199 patients were randomly assigned to either single-drug or combination therapy.

Combination therapy began with sulfasalazine, in a dosage of 500 mg twice daily; methotrexate, in a dosage of 7.5 mg weekly; hydroxychloroquine, in a dosage of 300 mg daily; and prednisolone, in a dosage of 5 mg daily. If tolerated, this combination was continued for three months. At that time, if clinical improvement was less than 50 percent in two of the three criteria, the dosage of methotrexate was increased to 10 mg weekly and the dosage of prednisolone to 7.5 mg daily. After three months, dosages could be adjusted based on individual response. In this combination therapy group, 94 patients completed six months, 92 completed 12 months and 87 completed 24 months of therapy.

Sulfasalazine in a single dose of 2 g daily was used as the initial drug in the single-therapy group. Prednisolone (in a dosage of up to 10 mg daily) could be used at the discretion of the treating physician. At three months, the dosage of sulfasalazine could be increased to 3 g daily if required. If adverse side effects occurred or patient response was less than 25 percent at six months, methotrexate (in a dosage of 7.5 to 15 mg weekly) was substituted. If this also proved unsatisfactory, subsequent substitutions included azathioprine, with auranofin, hydroxychloroquine, injectable gold and penicillamine as alternatives after azathioprine. Of the 98 patients who started with single-drug therapy, methotrexate was substituted in 51, and 63 patients were also given prednisolone. At six months, 96 patients remained in the single-therapy treatment group. At 12 months, 93 remained, and 91 completed the 24-month study. No patients discontinued therapy because of toxic effects of medications.

Clinical assessment of patients was performed at baseline and at months 1, 3, 4, 5, 6, 9, 12, 18 and 24. Laboratory tests were performed every two weeks for the first three months, then once monthly for one year. During the second year of the study, patients were assessed every two months. Chest radiographs were performed at onset of study and then yearly. Radiographs of the hands and feet were obtained at the beginning of the study and at six, 12 and 24 months.

Based on standardized criteria for remission, 37 percent of those taking combination therapy and 18 percent of patients receiving single-drug therapy were in remission at the end of 24 months. Clinical improvement of at least 50 percent was achieved in 75 percent of the combination-therapy patients at one year compared with 60 percent of those treated with single-drug therapy. At two years, 50 percent clinical improvement was achieved in 71 percent of combination and 58 percent of single-drug treatment patients.

The authors conclude that combination therapy was markedly more effective than single-drug regimens in inducing remission and resulting in clinical improvement. Combination therapy did not appear to be more hazardous and should be considered as initial treatment in selected patients with early, active rheumatoid arthritis.

Möttönen T, et al. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. Lancet. May 8, 1999;353:1568–73.



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