New studies show that two new biologic therapies slow or halt joint damage in rheumatoid arthritis.
The first study by Bathon, et al (NEJM 343:1586-1593, 2000) compared the efficacy of etanercept (Enbrel®) with methotrexate for reducing disease activity and preventing joint damage in 632 patients with early rheumatoid arthritis (< 3 years). Etanercept is a soluble p75 receptor of tumor necrosis factor (TNF) which inhibits the action of TNF, shown to have an active role in the pathogenesis of rheumatoid arthritis. Patients were randomly assigned to receive either twice-weekly subcutaneous etanercept (10 or 25mg) or weekly oral methotrexate (mean dose, 19mg) for 12 months. Bone erosion and joint space narrowing were measured radiographically at baseline, 6 months, and 12 months and scored using the Sharp scale. Disease activity was assessed at multiple time points using ACR-AUC (area under the curve) and ACR 20/50/70 response criteria.
A significantly more rapid rate of improvement in disease activity was observed during the first 6 months (P<0.05) in patients treated with 25 mg of etanercept when compared to patients receiving methotrexate, but was similar during the latter half of the study. Progression of radiographic joint damage was also slowed more effectively by etanercept compared to methotrexate. The mean increases in erosion scores at 6 months were 0.30 in the etanercept group and 0.68 in the methotrexate group (P=0.001), and at 12 months were 0.47 and 1.03, respectively (P=0.002). Following 1 year of treatment with etanercept, 72% of patients had no progression in erosions compared to 60% of patients treated with methotrexate, (P=0.007). Fewer adverse events (P=0.002) and fewer infections (P=0.006) occurred in the etanercept group.
These data demonstrate that etanercept is efficacious at slowing the progression of disease activity and joint damage in patients with early rheumatoid arthritis and emphasize the importance of early treatment.
The 2nd study by Lipsky, et al (NEJM 343:1594-602, 2000) was a placebo controlled trial in which 428 patients with persistently active rheumatoid arthritis, currently on methotrexate therapy, were randomized to receive infusions of either placebo or infliximab (3 or 10 mg per kilogram of body weight every 4 or 8 weeks) while maintaining the same dose of methotrexate. Infliximab (Remicade®) is a monoclonal antibody to TNFa. Disease activity was measured at baseline and 54 weeks after initiation of treatment using the ACR 20, 50, & 70 response criteria. The van der Heijde modification of the Sharp scoring method was used to assess radiographic joint damage.
The percent of patients achieving ACR 20 responses was significantly greater in all four groups receiving infliximab plus methotrexate (mean 52%, P<0.001) compared with methotrexate alone (17%). The mean increase from baseline in total radiographic score among all patients receiving a combination of infliximab and methotrexate was 0.6, (P<0.001) compared to 7.0 in patients receiving methotrexate alone. 39 to 55% of patients in the combination therapy groups had significant improvement in radiographic scores compared to 14% of patients in the methotrexate alone group. Serious adverse events and the frequency of serious infections were similar in each group.
Therapy with infliximab plus methotrexate significantly improves the signs and symptoms of rheumatoid arthritis as well as prevents the progression of radiographic joint when compared to therapy with methotrexate alone.
Editorial Comment: These two studies provide “proof of concept” that TNF plays a critical role in the joint destruction of RA, since inhibitors of TNF are now shown to profoundly slow or halt damage. The etanercept study confirms that methotrexate is also an effective agent for slowing joint damage. These studies are exciting and reinforce the concept that early treatment will reduce or prevent cumulative joint damage and hopefully long term disability.