Editorial: Inflammation, Disease‐Modifying Antirheumatic Drugs, Lipids, and Cardiovascular Risk in Rheumatoid Arthritis

Efficient primary prevention requires accurate identification of at-risk patient groups. Management strategies can then be tested in these groups to determine the potential benefit. In the case of cardiovascular disease (CVD) and rheumatoid arthritis (RA), accurately identifying at-risk groups remains a challenging task. The risk of CVD is 2-fold higher in patients with RA compared with that in ageand sex-matched individuals in the general population (1,2), and many of the factors contributing to risk have been identified. These include traditional risk factors such as hypertension, hyperlipidemia, and diabetes as well as the effects of chronic systemic inflammation, a hallmark of RA (3,4). In RA, the application of commonly used CV risk calculators such as the Framingham Risk Score (5) grossly underestimates the risk, by 150% (6,7). The Reynolds’ Risk Score (8), which incorporates a marker of inflammation (i.e., C-reactive protein) along with traditional risk factors, was also shown to underestimate the CV risk in patients with RA. Thus, a fundamental challenge to improving CV risk management in RA is accurate identification of at-risk patients in whom traditional risk factors are not predictive of an increased risk of CV events. How should we best incorporate the inflammation associated with RA to calculate the risk of CV events? Inflammation is considered a major driver of excess CV risk in patients with RA compared with the general population (9). However, validated methods that account for inflammation in the calculations of CV risk in RA have not been developed. Devising such methods is especially difficult, because inflammation in RA is tightly linked with treatment, which also likely affects CV risk. Moreover, inflammation and treatment have been associated with changes in lipid levels. In the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) trial, up to 30% increases in the total cholesterol and low-density lipoprotein (LDL) cholesterol levels were observed after combination treatment with the tumor necrosis factor (TNF) inhibitor etanercept and methotrexate (10). This finding seems counterintuitive to the results of large observational studies showing that TNF inhibitor treatment was associated with a significantly reduced risk of CVD compared with treatment with methotrexate and other nonbiologic diseasemodifying antirheumatic drugs (DMARDs) (11,12). Elevations in the total cholesterol and LDL cholesterol levels are arguably more of a concern with tocilizumab treatment, and increases in these lipid levels were observed across all clinical trials of tocilizumab therapy in RA (13). The interleukin-6 receptor (IL-6R) pathway, the target of tocilizumab, was implicated as part of the causal pathway for CVD in a genetics analysis in 51,000 patients with heart disease and 136,000 control subjects (14,15). The studies suggested that blocking the IL-6R pathway, the mechanism of action for tocilizumab, may reduce the CV risk. With these seemingly contradictory data for tocilizumab, a major unanswered question is whether the elevations in total cholesterol and LDL cholesterol levels associated with tocilizumab (or other DMARDs) are clinically important and related to a higher risk of CV events in patients with RA. In this context, we turn our attention to the findings reported by Rao and colleagues in this issue of Arthritis & Rheumatology (16). In a post hoc analysis of 3,986 adult patients from 5 randomized controlled trials of tocilizumab and extension studies, the authors tested for associations between CV events and changes in a range of laboratory markers and RA disease activity Dr. Liao’s work was supported by the NIH (grant K08-AR060257) and the Harold and Duval Bowen Fund. Dr. Solomon’s work was supported by the NIH (grant K24-AR-055989). Katherine P. Liao, MD, MPH, Daniel H. Solomon, MD, MPH: Brigham and Women’s Hospital, Boston, Massachusetts. Address correspondence to Katherine P. Liao, MD, MPH, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, 75 Francis Street, PBB-B3, Boston, MA 02115. E-mail: kliao@partners.org. Submitted for publication October 1, 2014; accepted in revised form October 14, 2014.