Disease-modifying antirheumatic drugs such as methotrexate, sulfasalazine and hydroxychloroquine may slow progression of rheumatoid arthritis, but the response to therapy is often inadequate because of toxicity or lack of efficacy. Tumor necrosis factor (TNF), a pro-inflammatory cytokine manufactured in macrophages and T cells, contributes to synovitis and joint destruction. Etanercept, a recombinant human TNF receptor fusion protein, appears to be a useful antagonist of the biologic activity of TNF. In a phase II trial, etanercept has shown promise as an antirheumatic drug. Moreland and associates evaluated the effectiveness of 10-mg and 25-mg injections of this drug, given twice weekly for six months, in patients with rheumatoid arthritis.

The 234 patients in the randomized, double-blind, placebo-controlled study had active rheumatoid arthritis that had failed to respond to disease-modifying antirheumatic drugs. Active disease was defined as 12 or more tender joints, 10 or more swollen joints and at least one of the following: an erythrocyte sedimentation rate of at least 28 mm per hour, a C-reactive protein level greater than 20 mg per L and morning stiffness for at least 45 minutes. Patients were randomly assigned to receive placebo or 10 mg or 25 mg of etanercept subcutaneously twice weekly for 26 weeks. The primary efficacy end points were 20 percent and 50 percent improvement in disease activity at three and six months.

After six months of therapy, 59 percent of the patients who received the 25-mg dose of etanercept and 51 percent of those who received the 10-mg dose had experienced a 20 percent improvement in disease activity. In the placebo group, 11 percent had experienced such an improvement. A 50 percent disease improvement had occurred in 40 percent of the 25-mg group, 24 percent of the 10-mg group and 5 percent of the placebo group.

The clinical response was rapid, often appearing within two weeks of the initiation of therapy. The 25-mg dose was significantly more successful in producing response than the 10-mg dose. Significant improvement occurred in mean tender joint count and morning stiffness, as well as in surrogate biochemical markers, including the erythrocyte sedimentation rate and the C-reactive protein level. Etanercept was well tolerated, with erythematous reactions at the injection site being the most common adverse effect. It was noted that cessation of etanercept therapy after three months was followed by a return of pre-treatment symptoms, suggesting that a lasting effect requires continued administration.

The authors conclude that twice-weekly injections of etanercept, particularly the 25-mg dose, resulted in significant improvement in rheumatoid arthritis. They are encouraged by the magnitude of the responses observed in their study of patients with advanced disease. TNF inhibition appears to be a useful way to control disease activity in rheumatoid arthritis. The authors note that a currently ongoing study of etanercept is evaluating whether the drug arrests the progression of disease and what degree of clinical response is possible in patients with earlier-stage disease.