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New Drugs Cool Rheumatoid Arthritis Flames
June 13, 2007
Neil Osterweil, Senior Associate Editor, MedPage Today
Three drugs, two approved and one in the pipeline, are improving care
for patients with severe rheumatoid arthritis (RA) according to
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
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.
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."
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