A Double-Blind, Placebo-Controlled, Phase II, Randomized Study of Lovastatin Therapy in the Treatment of Mildly Active Rheumatoid Arthritis

Cynthia Aranow; John Cush; Marcy B. Bolster; Christopher C. Striebich; Maria Dall'era; Meggan Mackay; Ewa Olech; Tracy Frech; Jane Box; Richard Keating; Mary Chester Wasko; William St Clair; Alan Kivitz; Weiquang Huang; PetaGay Ricketts; Beverly Welch; Sherrie Callahan; Meagan Spychala; Karen Boyle; Kate York; Lynette Keyes-Elstein; Ellen Goldmuntz; Betty Diamond; Anne Davidson

Disclosures

Rheumatology. 2020;59(7):1505-1513. 

In This Article

Abstract and Introduction

Abstract

Objectives: 3-hydroxy-3-methylglutaryl coenzyme-A (HMG Co-A) reductase inhibitors (statins) are standard treatment for hyperlipidaemia. In addition to lipid-lowering abilities, statins exhibit multiple anti-inflammatory effects. The objectives of this study were to determine whether treatment of patients with RA with lovastatin decreased CRP or reduced disease activity.

Methods: We conducted a randomized double-blind placebo-controlled 12 week trial of lovastatin vs placebo in 64 RA patients with mild clinical disease activity but an elevated CRP. The primary efficacy end point was the reduction in mean log CRP. Secondary end points included disease activity, RF and anti–CCP antibody titres. Mechanistic end points included levels of serum cytokines. Safety was assessed; hepatic and muscle toxicities were of particular interest.

Results: Baseline features were similar between groups. No significant difference in mean log CRP reduction between the two groups was observed, and disease activity did not change from baseline in either treatment group. Mechanistic analyses did not reveal significant changes in any biomarkers. A post hoc analysis of subjects not using biologic therapy demonstrated a significantly greater proportion achieving ≥20% reduction in CRP from baseline in the lovastatin group compared with placebo (P-value = 0.007). No difference was observed in subjects receiving biologics. Lovastatin was well tolerated with no serious safety concerns.

Conclusion: This study showed no anti-inflammatory or clinical effects on RA disease activity after 12 weeks of treatment with lovastatin. Lovastatin had a modest effect on CRP in subjects not using biologics, suggesting statins may be anti-inflammatory in selected patients.

Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT00302952.

Introduction

3-hydroxy-3-methylglutaryl coenzyme-A (HMG Co-A) reductase inhibitors (statins) lower lipid levels, reduce cardiovascular events and mortality, and have numerous anti-inflammatory and immunomodulatory properties. Statins decrease production of inflammatory chemokines and cytokines by T cells and macrophages, decrease the viability of plasma cells,[1–4] and inhibit endothelial cell activation and angiogenesis.[5–7] In individuals with normal lipid profiles, statins reduce inflammatory markers and improve cardiovascular outcomes.[8,9] These anti-inflammatory effects are attributed to reductions in mevalonate, a cholesterol precursor. Mevalonate is also a precursor for isoprenoid intermediates required for the functioning of guanosine triphosphatases (GTPases), Ras, Rho and Rab, which control cell behaviour through signal transduction pathways. In addition, statins, particularly lovastatin, may sterically inhibit the interaction of lymphocyte function-associated antigen (LFA-1) with its ligand intracellular adhesion molecule (ICAM-1) in a mevalonate-independent manner.[10]

Given these properties, we conducted a prospective trial evaluating the anti-inflammatory effect and efficacy of lovastatin, a statin with potent in vivo and in vitro anti-inflammatory properties, as a non-toxic adjunct therapy in RA patients with mild clinical disease activity. This study examined the short-term effects of exposure to lovastatin on serum CRP, disease activity and a number of RA-related biologic markers.

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