Fast track — ArticlesTrial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial
Introduction
HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) reduce cardiovascular morbidity and mortality.1, 2, 3 Although statins work in part via lipid modulation, findings of studies indicate they have broader properties, including alteration of inflammatory pathways.4 Ex-vivo activities of statins include suppression of adhesion molecule expression, leucocyte cytokine release, MHC class II expression, lymphocyte and macrophage cognate interactions, and effects on reactive oxygen and nitrogen intermediate production.5 Statins also modify apoptosis in smooth muscle and endothelial cells leading to altered vascular function and neovascularisation.5 These properties offer the potential to modify chronic inflammatory disease states with drugs that show minimal toxic effects in both the short and long term. However, as yet, no clinical data clearly show that statins modulate autoimmune disease activity or indeed modify vascular risk factors in the context of high-grade inflammation.
Rheumatoid arthritis is a chronic inflammatory arthropathy associated with rapid onset of clinically significant functional impairment. It is also associated with accelerated vascular risk with attendant early mortality (pooled standardised mortality ratio 1·7) and excess morbidity.6 We have proposed that cytokine-mediated inflammatory pathways can in part account for this increased vascular risk via accentuation of both classic (lipids) and novel (endothelial function or insulin resistance) pathways.7 Furthermore, statins suppress articular inflammation in vivo in collagen-induced arthritis in mice.8 Moreover, in-vitro cytokine release by rheumatoid arthritis synovial mononuclear cells and by synovial fibroblasts was also reduced by statins.8 Similar anti-inflammatory effects have been reported in neurological models of inflammation.9 Statins therefore have a plausible bioactivity profile in vitro and in vivo that makes them possible therapeutic agents in rheumatoid arthritis to target both vascular risk and synovial inflammation. We therefore undertook a randomised placebo-controlled study to test the clinical efficacy and laboratory effects of these drugs in rheumatoid arthritis.
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Patients
We screened patients attending Glasgow Royal Infirmary and recruited those who gave informed consent for a study approved by North Glasgow University NHS Trust ethics committee. Recruitment was from September, 2001, through November, 2002. Participants were 18–80 years of age, met 1987 American College of Rheumatology (ACR) criteria (no limit on disease duration), and had active inflammatory rheumatoid arthritis despite ongoing disease-modifying antirheumatic drug (DMARD) therapy. We defined
Results
177 patients with rheumatoid arthritis were screened, of whom 116 were randomised to receive either 40 mg atorvastatin or placebo (figure). The median age of the study group was 56 years (IQR 47–66) with median disease duration of 11·5 years (5–20). Atorvastatin and placebo groups were generally comparable, although visual analogue score and patient global assessment were slightly lower in the atorvastatin group at baseline (table 1). By chance, more patients allocated atorvastatin received
Discussion
We have shown marked suppression with atorvastatin of acute-phase variables and a significant reduction in swollen joint count in patients with rheumatoid arthritis presenting with active disease despite existing DMARD therapy. Significantly more patients in the atorvastatin group remained on treatment to completion. Although the magnitude of change is modest, the significant reduction in DAS 28 provides proof of concept that pathways targeted by statins offer therapeutic opportunity in
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