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BioTech Navigator, August 1997
gold compounds (oral and intramus-
cular), penicillamine, sulfasalazine,
and antimalarial drugs no differ-
ences were found in short-term clini-
cal efficacy for any of the drugs ex-
cept oral gold (which was relatively
less effective).
Since joint erosion occurs
quickly after disease onset, perhaps in
the first year, many rheumatologists
prescribe second-line agents early
(within 2 to 3 months in a patient who
is not responding to NSAID therapy).
Early drug intervention before joint
damage occurs has a better chance of
inducing remission and preventing
permanent joint destruction and dis-
ability. Once the bone and cartilage
become injured and the joint becomes
mechanically abnormal, deterioration
continues regardless of drug therapy.
Another reason second-line agents are
introduced sooner is that first-line
agents have proved more toxic than
previously thought, while many
second-line agents are less toxic than
previously thought.
Drug choice, order, and tim-
ing vary widely depending on the pa-
tient (age, severity of rheumatic dis-
ease, concurrent diseases and thera-
pies, etc.) and the physician
(preference and experience). Weekly
low-dose methotrexate (Rheumatrex/
Lederle) is the most widely used regi-
men. Compared with other agents,
methotrexate has a more rapid onset
of action (significant efficacy within 3
to 4 weeks), appears to be more bene-
ficial in synovitis, and has a good
safety profile. It is probably the best
agent for patients with significant dis-
ease. In the past, routine liver biopsies
were recommended to monitor pa-
tients for liver toxicity, but new re-
ports have shown that the risk of seri-
ous liver disease is only one in 1000
at 5 years.
Methotrexate may also cause
oral ulceration and gastrointestinal
(GI) side effects (GI toxicity can be
reduced with oral folate or leucov-
orin). Less common side effects in-
these mice. IL-1 on the otherhand
stimulates cell types possessing the
IL-1 receptor on their cell surface to
produce collagenase. As mentioned
above, collagenase breaks down colla-
gen.
Although IL-1 and
F
-
have overlapping properties, each has
distinct biologic properties relevant to
the pathogenesis of RA. For example,
depending upon the stage of arthritis,
inhibitors of
F
-
or IL-1 have
marked differences in their ability to
inhibit the arthritis. In some animal
models blocking of
F
-
resulted in
decrease inflammation whereas block-
ing of IL-1 was more important in
preventing cartilage destruction.
These studies have obvious implica-
tions for the treatment of RA.
clude hematologic abnormalities and
pneumonitis (thought to be a hyper-
sensitivity reaction). It is important to
distinguish pulmonary reactions from
the disease itself (RA can be associ-
ated with pulmonary disorders) and
from infectious disease (second-line
agents are immunosuppressants and
thus predispose to infections). Risk
factors for side effects in general in-
clude advanced age, renal or liver
dysfunction, chronic hepatitis B or C,
diabetes mellitus, obesity, reduced
serum albumin concentrations, and
coadministration of trimethoprim-
sulfamethoxazole.
Another second-line agent
with a good safety profile is sul-
fasalazine (sulfapyridine plus salicy-
late, Azulfidine/Kabi Pharmacia).
Widely used in ulcerative colitis, sul-
fasalazine is gaining popularity for
the treatment of RA, especially in Eu-
rope. Penicillamine (Cuprimine/
Merck) and the injectable gold salts --
gold sodium thiomalate
(Myochrysine/Merck) or aurothioglu-
cose (Solganal/Schering) -- were at
one time widely used for RA, but their
use is declining as methotrexate has
proved to be safer and more effective.
Oral gold (auranofin, Ridaura/Con-
nective Therapeutics) is better toler-
ated than the injected form, but it may
be less effective and it appears most
effective in patients with mild to mod-
erate symptoms. The antimalarial
hydroxychloroquine (Plaquenil/
Sanofi Winthrop) is also reserved for
patients with mild, slowly progressive
arthritis. The antimetabolite azathio-
prine (Imuran/Glaxo/Wellcome) is
used mainly for patients with progres-
sive disease that has failed to respond
to either methotrexate or gld. It re-
quires laboratory monitoring for po-
tential bone marrow toxicity, pancre-
atitis, and hepatitis. Cyclophos-
phamide (Cytoxan/Bristol-Myers On-
cology), chlorambucil (Leukeran/
Glaxo/Wellcome), and cyclosporine
(Neoral/Novartis) are effective an-
tirheumatic agents, but serious toxic-
Current treatment for RA.
Drug therapy is the mainstay
of RA treatment. Patients are treated
initially with first-line agents, non-
steroidal anti-inflammatory drugs
(NSAIDs) that act primarily to relieve
symptoms. Eventually, the majority
of RA patients receive second-line
anti-rheumatic agents -- the so called
disease-modifying agents that ap-
pear to have an effect on the underly-
ing disease process. The different
second-line agents are comparable in
efficacy, although each has a distinct
mechanism of action and side effect
profile. For example, the folic acid
antagonist methotrexate is broadly
anti-inflammatory; it reduces inflam-
matory leukotrienes, suppresses cell
mediated immunity, modifies expres-
sion of the gene that codes for colla-
genase, and blocks proliferation of
synovial fibroblasts and endothelial
cells. Cyclosporine, by contrast, is
more selective; it blocks proliferation
of T cells (and thus the release of in-
flammatory cytokines and cytotoxins).
In a meta-analysis of 66 placebo-
controlled trials comparing a variety
of second-line agents -- methotrexate,
