New Drugs Cool Rheumatoid Arthritis Flames

VIENNA, June 13 -- Three drugs, two approved and one in the pipeline, are improving care for patients with severe rheumatoid arthritis (RA) according to clinicians here.

The three agents -- rituximab (Rituxan), abatacept (Orencia), and toclizumab (Acterma) -- all reduce signs and symptoms of RA, improve physical function and health status, and slow joint damage progression, said Josef S. Smolen, M.D., of the Medical University of Vienna, and colleagues.

The heterogeneity of the disease is one of the reasons why no single therapy is effective for all patients or for one patient at all times, the authors wrote in a review article published in the online edition of The Lancet.

Disease-modifying anti-rheumatic drugs such as the anti-tumor necrosis factor (TNF) agents etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira), in combination with methotrexate, have significant anti-inflammatory and joint-protecting activity, they noted.

Yet, they noted, the combination of a TNF antagonist and methotrexate is better at protecting against radiographically confirmed progression of joint damage in patients with low disease activity than in patients with highly active disease.

To see if there might be relief for those patients, the investigators reviewed the action, efficacy, and safety of the three newer agents, each of which has a mechanism of action different from that of established anti-arthritis agents.

Rituximab, an anti-CD20 antibody with proven efficacy in the treatment of both rheumatoid arthritis and B-cell non-Hodgkin's lymphoma, is approved in the U.S. and Europe for treatment of rheumatoid arthritis in patients who have failed TNF-inhibitor therapy.

"The rationale for use of rituximab in treatment of this disease comes from the fact that B cells have several functions in disease pathogenesis, including antigen presentation and (auto)antibody and cytokine production," the investigators wrote. "Although rituximab leads to considerable reduction of concentrations of rheumatoid factor, the mechanism of action in rheumatoid arthritis is not clear."

In clinical trials, rituximab was associated with reduction in rheumatoid arthritis symptoms by more than 50% for more than a third of patients. Although the drug rapidly depleted B cells in all clinical trials, with an effect lasting for more than six months in most cases, the disease flares up again as B cells repopulate, and retreatment is necessary to maintain efficacy, the authors noted.

Abatacept is approved in the U.S. for treatment of rheumatoid arthritis patients who have failed all other types of disease-modifying drugs, and in Europe for patients who have failed other disease-modifying drugs, including the TNF inhibitors.

It is a recombinant fusion protein that interferes with T-cell activation by binding to CD28 and competing with this receptor for CD80 and CD86.

In a phase III trial of abatacept 10 mg/kg IV in patients on methotrexate, 68% of 433 patients had a 20% improvement from baseline at six months in American College of Rheumatology criteria (ACR20), 40% had ACR50, and 20% had ACR70 responses, all of which were significantly higher than the responses among the 219 patients who received placebo (P<0.001).

In a second phase III trial, 393 patients with active rheumatoid arthritis and an inadequate response to TNF inhibitors received abatacept (10 mg/kg) or placebo until day 141.

The patients had stopped taking etanercept at least 28 days before, or infliximab at least 60 days before enrollment and had to be stable on disease-modifying antirheumatic drugs, with 75% to 82% continuing methotrexate treatment (about 15 mg a week). These patients also had significantly higher ACR20, 50, and 70 response rates (P<0.001) starting at the second treatment week.

Toclizumab is a humanized anti-interleukin 6 receptor agent that blocks the action of the inflammatory cytokine. The drug is in phase III trials worldwide, and is licensed in Japan as an orphan drug for treatment of Castleman's disease.

In a phase II European trial of toclizumab, 61% of patients had an ACR20 response, 43% had an ACR50 response, and 16% had an ACR70 response at a dose of 8 mg/kg.

"Abatacept, rituximab, and tocilizumab all achieved better clinical results in combination with methotrexate than when used as monotherapy," the authors wrote.

"These findings are in line with similar observations for TNF blockers, which indicated that methotrexate monotherapy has similar clinical effectiveness to monotherapy with TNF inhibitors," they said, "lending support to the pivotal role of methotrexate in general and in combination with biological agents in particular."

The investigators recommended aiming for remission in patients with rheumatoid arthritis, starting with a traditional disease-modifying antirheumatic drug, usually methotrexate.

"At the present time, in patients who continue to show high or moderate disease activity, adding or switching disease-modifying therapy- including addition of a TNF blocker-is typically considered," the authors wrote.

"If active disease prevails despite anti-TNF treatment," they said, "rituximab or abatacept constitute novel alternatives, although abatacept could be administered before use of a TNF inhibitor (such practice is not currently licensed in Europe). The minimum therapeutic aim is low disease activity, but remission should constitute the ultimate goal."