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Combination Therapy for Rheumatoid Arthritis

Am Fam Physician. 2004 Nov 1;70(9):1781-1782.

The 1 percent of the population who are affected by rheumatoid arthritis face reduced life expectancy, significant pain, and functional loss. The goals of treatment are to prevent joint damage, suppress disease activity, and improve quality of life. Because tumor necrosis factor (TNF) plays a crucial role in the pathogenesis of rheumatoid arthritis, TNF-blocking agents such as etanercept have been used to reduce disease activity and slow joint destruction. Klareskog and colleagues studied the combination of etanercept and methotrexate in patients in whom other disease-modifying antirheumatic drug treatments had failed.

They studied nearly 700 adult patients who had active rheumatoid arthritis (American College of Rheumatology [ACR] class I to class III) and who had an unsatisfactory response to at least one disease-modifying drug other than methotrexate. Patients were excluded from the study if they had used methotrexate within six months or had experienced a bad reaction to this drug. Other reasons for exclusion were previous use of TNF antagonists, recent use of disease-modifying drugs or steroids, and any significant comorbid conditions.

The patients were assigned randomly to one of three treatment groups, all of whom received medications and injections that were identical in appearance. Initially, the 228 patients assigned to methotrexate alone received an oral dosage of 7.5 mg per week that increased to 20 mg per week over eight weeks if indicated by joint symptoms. The 223 patients assigned to etanercept alone received a dosage of 25 mg subcutaneously twice weekly. The remaining 231 patients received subcutaneous etanercept and oral methotrexate. All patients received a folic acid supplement twice weekly. Patients were monitored at 24 and 52 weeks for changes in the radiographic appearance of joints, ACR score of disease activity, and disability as measured by the health assessment questionnaire. Patients were assessed clinically and questioned about side effects during the study.

During the first year, 160 patients withdrew from the study, mainly because of side effects. Only six patients in the combination group withdrew because of lack of efficacy, compared with 21 patients in the methotrexate group and 16 patients in the etanercept group. Radiographic scores did not differ significantly among the groups at baseline, but the combination treatment was much more effective in retarding joint damage than methotrexate or etanercept alone.

At one year, 80 percent of the combination treatment group showed no radiologic progression, compared with 68 percent of the etanercept group and 57 percent of the methotrexate group. Patients receiving combination therapy were significantly more likely to achieve gains in ARC scores, measures of disease activity, and quality-of-life assessments than either of the single-treatment groups. At one year, 35 percent of the combination group had achieved remission, compared with 16 percent of the etanercept group and 13 percent of the methotrexate group. Adverse events were common, being reported by more than 80 percent of patients in each group. The types and prevalence of adverse events were comparable across the three treatment groups.

The authors conclude that the combination of etanercept and methotrexate is significantly more effective than either agent alone in retarding the disease process, achieving remission, and improving function and quality of life. They point out that the negative progression scores on the radiographic assessments confirm the controversial report of an earlier study indicating that repair of rheumatologic joint damage is possible.

Klareskog L, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet. February 28, 2004;363:675–81.

editor’s note: After a long period of little progress, new treatments offer real hope to patients with rheumatic diseases. This study challenges family physicians on many levels. The prospect of not just “disease-modifying” but “disease-reversing” therapy is exciting. Family physicians must remain up to date, keep our patients informed of developments, and ensure that they do not persist with outdated or dangerous therapies. Conversely, the new treatments have multiple side effects, significant costs, and unknown long-term effects. Patients, families, and third-party payors face difficult decisions in balancing the pros and cons of the new treatments. Nevertheless, the surge in research on these neglected conditions is welcome. Can we hope that the next generation of physicians will not see patients with the severe joint destruction and damage to other systems that are now common in older patients with rheumatoid arthritis?—a.d.w.

 

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