Atorvastatin for Use in Rheumatoid Arthritis
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.
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 Comments: 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.