Tumor necrosis factor, a pro-inflammatory cytokine overproduced in the joints of patients with rheumatoid arthritis, stimulates the production of other inflammatory cytokines. Etanercept is a receptor fusion protein that binds and inactivates tumor necrosis factor. Etanercept has been shown to reduce disease activity in children and adults with chronic rheumatoid arthritis. Over the past decade, the treatment of rheumatoid arthritis has moved toward early, more aggressive therapy with methotrexate. The goal of early therapy is to slow the progression of joint erosion and help preserve function. Bathon and colleagues completed a study comparing the safety and efficacy of methotrexate with that of etanercept in patients with early rheumatoid arthritis.
Study participants were at least 18 years of age, had rheumatoid arthritis for no more than three years and were not previously taking methotrexate or other disease-modifying drugs. Other eligibility criteria included a positive serum rheumatoid factor or at least three bone erosions evident on radiographs of the hands, wrists or feet; at least 10 swollen joints; a minimum of 12 tender or painful joints; and an erythrocyte sedimentation rate of at least 28 mm per hour or a C-reactive protein concentration of at least 2.0 mg per dL.
Patients were randomized to receive 10 or 25 mg of subcutaneous etanercept twice weekly or 7.5 mg of methotrexate weekly. The 7.5-mg dosage was increased to 15 mg by week 4 and to 20 mg by week 8. Participants in all three treatment groups received an oral or subcutaneous placebo. Clinical and laboratory assessments were performed at baseline and week 2, and at months 1, 6, 8, 10 and 12. Disease activity was assessed by the American College of Rheumatology (ACR) scoring system, which defines response to therapy as 20, 50 or 70 percent. A visual analog scale ranging from zero to 10 was used for global assessment of pain. Finally, radiographs of the hands, wrists and feet were obtained at baseline, six months and 12 months. For each patient, 46 joints were examined and scored for erosion using a six-point scale (Sharp score) that ranged from zero (no joint destruction) to 398 (severe joint destruction). The primary end points of the study were the overall clinical response (ACR-N) during the first six months and the Sharp radiologic score at 12 months.
The study included 217 patients in the methotrexate group, 208 in the 10-mg etanercept group and 207 in the 25-mg etanercept group. The mean age of the participants was 50 years, and 75 percent of participants were women. Patients in the etanercept groups showed significant improvement in clinical symptoms after two weeks. During the first six months, the number of patients in the 25-mg etanercept group who had ACR 20, 50 and 70 percent responses was significantly greater than the number in the methotrexate group. The 25-mg etanercept group also had significantly higher ACR-N scores at three, six, nine and 12 months compared with the methotrexate patients. The mean increase in the Sharp radiologic scores at six months was 0.30 in the 25-mg etanercept group compared with 0.68 in the methotrexate group. Overall, 72 percent of the high-dose etanercept participants had no increase in erosion scores compared with 60 percent in the methotrexate group. For the majority of Sharp scores, the results from the 10-mg etanercept group were similar to the results in the methotrexate group. Significantly more patients taking methotrexate experienced adverse events than patients in both etanercept groups (see accompanying table).
The authors conclude that etanercept produces clinical and radiologic benefit in patients with rheumatoid arthritis. They assert that the results of this trial support the concept of early and aggressive treatment of rheumatoid arthritis. The authors note that the combination of methotrexate and etanercept is safe for use, but additional studies are required to determine whether that combination of drugs will work synergistically.
|Event||Methotrexate (%), N = 217||10 mg of etanercept (%), N = 208||25 mg of etanercept (%), N= 207|
|Reaction at injection site||16 (7)||63 (30)*||77 (37)*|
|Upper respiratory tract infection||84 (39)||57 (27)*||72 (35)|
|Headache||59 (27)||52 (25)||46 (22)|
|Nausea||62 (29)||29 (14)*||35 (17)*|
|Rhinitis||30 (14)||36 (17)||31 (15)|
|Diarrhea||27 (12)||26 (12)||30 (14)|
|Bleeding at injection site||21 (10)||30 (14)||29 (14)|
|Skin infection||22 (10)||22 (11)||28 (14)|
|Asthenia||27 (12)||19 (9)||27 (13)|
|Influenza-like syndrome||25 (12)||20 (10)||26 (13)|
|Rash||50 (23)||33 (16)||25 (12)*|
|Dyspepsia||21 (10)||21 (10)||25 (12)|
|Dizziness||23 (11)||10 (5)||24 (12)|
|Back pain||12 (6)||12 (6)||22 (11)|
|Abdominal pain||22 (10)||23 (11)||20 (10)|
|Sinusitis||36 (17)||28 (13)||20 (10)|
|Ecchymosis||22 (10)||17 (8)||18 (9)|
|Alopecia||25 (12)||14 (7)||12 (6)*|
|Mouth ulcer||30 (14)||13 (6)*||10 (5)*|
editor's note: Etanercept will likely become first-line therapy for rheumatoid arthritis and possibly other systemic rheumatologic illnesses. The ease of administration, which is comparable to that of insulin, and the low incidence of side effects should place etanercept and other comparable biologic agents within the prescribing realm of family physicians.—j.t.k.