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Johns Hopkins Arthritis Website (http://www.hopkins-arthrtiis.org)

Atorvastatin for the Treatment of Rheumatoid Arthritis

Summarized by Jon Giles, M.D.

In vitro and animal studies have attributed broad anti-inflammatory properties to HMG-CoA
reductase inhibitors (statins); including the ability to modulate adhesion molecule expression,
expression and secretion of pro-inflammatory cytokines, and induction of macrophage apoptosis,
among others. As inflammatory pathways are now recognized as key mediators of the processes
leading to atherosclerosis, these anti-inflammatory abilities may serve to explain how the clinical
benefits of statins observed in clinical trials of cardiovascular disease extend beyond their ability
to lower serum LDL cholesterol concentration. However, few studies have evaluated the anti-
inflammatory properties of statins for the treatment of other immune-modulated diseases other
than atherosclerosis. Here, McCarey et al (Lancet 2004; 363:2015) investigate the use of one
statin, atorvastatin, for the treatment of rheumatoid arthritis (RA).

METHODS In this randomized, double-blind, placebo-controlled trial, subjects with active RA

despite current stable DMARD therapy (defined as 6 swollen joints and two of the following: 6
tender joints, morning stiffness > 30 minutes, or ESR > 28 mm/hr) were recruited from patients
followed at the Glasgow Royal Infirmary (UK). Patients at high risk for coronary events,
receiving lipid lowering medications, or prednisolone > 10 mg/day were excluded.

Subjects were randomized to receive a daily dose of 40 mg of atorvastatin or placebo in addition

to their stable DMARDs. Subjects were evaluated at enrollment, and after 3 and 6 months of
therapy. The primary outcome measure was change in DAS28 score at 6 months. Secondary
outcome measures included changes in serum markers of inflammation, lipids, and endothelial
activation at 6 months.

RESULTS 116 total patients were evenly randomized to receive atorvastatin or placebo.
Median age of participants and median disease duration was 56 and 11.5 years, respectively.
Treatment and placebo groups were balanced in terms of baseline characteristics, with the
notable exception of methotrexate use, with 50% of patients in the treatment group receiving
methotrexate compared to 26% in the placebo group (p=0.0074). No other significant
differences in DMARD use were noted between groups. Of note, about 60% of patients in both
groups were receiving sulfasalazine, only 2 patients of the entire 116 were receiving oral
glucocorticoids (both in the atorvastatin group), and no patients were receiving TNF inhibitors.

In the atorvastatin group, mean DAS28 score at 6 months was 0.50 units lower than mean
baseline score and was significantly different than that of the placebo group (essentially
unchanged at 6 months). Significance was maintained after controlling for differences in
methotrexate use between the groups. Other parameters significantly different from placebo at 6
months included ESR (-5 mm/hr from baseline in the treatment group), swollen joint count (-
2.69 joints from baseline in the treatment group), as well as reductions in serum fibrinogen, IL-6,
and plasma viscosity. As would be expected, treatment with atorvastatin significantly reduced
serum triglycerides, total and LDL cholesterol compared to placebo.

No liver function or CPK elevations were noted in the atorvastatin group and adverse events,
which were minimal, were evenly distributed between groups.

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Johns Hopkins Arthritis Website (http://www.hopkins-arthrtiis.org)
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Johns Hopkins Arthritis Website (http://www.hopkins-arthrtiis.org)

CONCLUSIONS Atorvastatin therapy was associated with significant reductions in both

inflammatory markers and articular signs compared to placebo in patients with active RA despite
DMARD therapy.

EDITORIAL COMMENT This novel trial is the first to test the putative anti-inflammatory
properties of statins in RA. Certainly the overall benefits in terms of improvement in disease
activity are not of the degree to justify the use of statins in place of conventional DMARDs.
However, considering that cardiovascular disease is uniformly responsible for the shortened
lifespan observed in persons with RA, and that statins have proven beneficial in reducing
cardiovascular morbidity and mortality in people with normal (and even supra-normal) serum
LDL cholesterol concentrations, these results could justify the more liberal use of this class of
medications in RA (in whom conventional cardiac risk factors, like elevated serum LDL
cholesterol, are no more prevalent than in the non-RA population). Other classes of medications
with anti-atherogenic properties, such as fibrates and the thiazolidinedione class of insulin
sensitizers, are also known to have anti-inflammatory properties and may prove to have similar
potential as statins for dual applicability in the future.

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