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Editorial: Lipid Changes With Different Antiinflammatory Regimens in Rheumatoid Arthritis: Developing a Pragmatic Approach to Complex Data

Rheumatoid arthritis (RA) is increasingly being considered a syndrome that comprises articular inflammation associated with significant comorbidities, particularly in the cardiovascular (CV) system. Several studies indicate that inflammatory pathways cross-regulate metabolism in RA, thereby altering cholesterol levels. The Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial was performed primarily to inform a strategic approach to the treatment of articular disease in early RA, but offers an intriguing opportunity to simultaneously examine comorbid risk factors. In this issue of Arthritis & Rheumatology, Charles-Schoeman et al describe the lipid changes observed through 2 years of followup across the various treatment arms of the TEAR trial, in patients from whom longitudinal samples were available (1). Their data are of particular interest since there are few randomized studies comparing the effects of biologic and nonbiologic drugs on lipid changes in RA. Several elements of the findings of CharlesSchoeman and colleagues merit discussion. Perhaps most importantly, the results reaffirm the notion that suppression of systemic inflammation, especially early in RA (or when disease activity is particularly high), is associated with elevation in levels of total cholesterol and low-density lipoprotein (LDL) cholesterol regardless of the type of therapy received. While this rise in LDL cholesterol levels has raised concerns based on interpolation from the general population and has led the Food and Drug Administration to mandate CV disease (CVD) end point safety trials for some newer antiinflammatory agents, the increasing perception is that such effects of antiinflammatory therapies are generally predictable, based on the inverse association between high-grade systemic inflammation and circulating cholesterol/LDL cholesterol levels (2). Indeed, our group recently observed that the lowest cholesterol levels in a hospital setting will typically occur in patients manifesting the highest C-reactive protein levels, suggesting that this is a generalizable phenomenon (3). The mechanisms underlying such changes have not been fully established. It has been proposed that LDL particles are in part “scavenged” by the reticuloendothelial system during acute inflammation, leading to enhanced peripheral catabolism and lower levels of LDL cholesterol (2). Scavenger receptors are dysregulated on leukocytes in patients with active inflammatory arthritis. Moreover, in a mechanism-of-action study in RA patients, tofacitinib treatment reduced peripheral cholesterol ester catabolism, thereby increasing cholesterol levels toward those observed in comparator healthy volunteers (4). Such data suggest that the rise in levels of LDL cholesterol upon reduction of inflammation may be driven not by increased hepatic synthesis, but rather largely via modulation of its catabolism and clearance. The above findings are somewhat reassuring. Clearly, however, similar mechanistic data on other antiinflammatory therapies are needed to confirm and extend, or challenge, this paradigm as appropriate. It is not yet established that all modes of antiinflammatory action mediate similar magnitudes of change in lipid metabolism for a given change in systemic inflammation levels. Moreover, the picture becomes even more complex in RA, where there is evidence of 1) compositional changes in high-density lipoprotein (HDL) particles with inflammation (5) and 2) reversal of some of these changes with certain antiinflammatory therapies (6). Thus, interpretation of results that include data only on concentrations of, and not composition of, lipid particles is challenging, and elucidation of likely net effects on Naveed Sattar, FRCP, PhD, Iain B. McInnes, FRCP, PhD: University of Glasgow, Glasgow, UK. Dr. McInnes has received consulting fees, speaking fees, and/or honoraria from Roche, AbbVie, Pfizer, Bristol-Myers Squibb, UCB, and MSD (less than $10,000 each). Address correspondence to Naveed Sattar, FRCP, PhD, or Iain B. McInnes, FRCP, PhD, College of Medical, Veterinary, and Life Sciences, University of Glasgow, 120 University Place, Glasgow G128QQ, UK. E-mail: naveed.sattar@glasgow.ac.uk or iain.mcinnes@ glasgow.ac.uk. Submitted for publication October 23, 2015; accepted in revised form November 5, 2015.