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Changes in lipid levels with inflammation and therapy in RA: a maturing paradigm

Abstract

Dyslipidaemia is commonly observed in patients with active rheumatoid arthritis (RA), with lower total cholesterol levels as well as lower levels of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) reported in these patients than in individuals without RA. This pattern is mirrored in sepsis and other inflammatory states, suggesting systemic inflammation has the general effect of lowering circulating lipid levels. In line with such observations, suppressing inflammation with DMARDs, biologic therapies and small-molecule Janus kinase inhibitors seems to elevate levels of lipid fractions in RA, albeit in a variable manner dependent presumably upon the mechanism of action of the different agents. In addition, limited epidemiological data in patients with RA suggest increased cardiovascular disease (CVD) risk at relatively low cholesterol levels, a pattern contrasting with that observed in the population without RA. Our understanding of the potential mechanisms behind these inflammation-associated lipid changes remains suboptimal and requires further study. In clinical terms, however, use of the total cholesterol to HDL-C ratio as the lipid component of CVD risk scoring in patients with RA would seem appropriate given that these lipid parameters generally change in parallel with inflammation and suppression of inflammation. Whether alternative lipid or lipoprotein measures (or simple markers of inflammation) could improve stratification of CVD risk in RA beyond the established risk factors requires future investigation.

Key Points

  • Plentiful evidence indicates high-grade inflammation is associated with a reduction in circulating levels of lipids, which is at least partially reversible using anti-inflammatory therapies or with resolution of inflammation

  • Evidence, although limited, suggests that lower cholesterol levels, in the context of high levels of inflammation, are associated with increased risk of cardiovascular disease (CVD) in rheumatoid arthritis (RA)

  • Different anti-inflammatory therapies seem to increase the levels of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) to variable degrees, suggesting lipid elevations might be treatment-specific

  • Typically, total cholesterol, LDL-C and HDL-C levels change in the same direction, inversely to changes in inflammation; the total cholesterol:HDL-C ratio seems the most appropriate lipid-associated marker for CVD risk in RA

  • Future studies should determine to what extent treatment-related resolution of inflammation or changes in lipid levels, or other risk factors, independently associate with CVD outcomes; such data are currently lacking

  • Trials that include CVD end points are needed to provide the best evidence for the cardiovascular effects of different treatment modalities in RA; however, such trials are costly and technically challenging

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Figure 1: Trends in hazard ratios for CHD according to triglyceride, HDL-C, and non-HDL cholesterol levels.
Figure 2: Hazard ratios for CVD in RA according to serum levels of total cholesterol and LDL.
Figure 3: Change in serum levels of total cholesterol and HDL-C after TNF blockade in patients with RA.
Figure 4: Effects of JAK inhibition with tofacitinib and TNF blockade with adalimumab on serum LDL-C and HDL-C levels in patients with RA.
Figure 5: Changes in lipid and inflammatory parameters associated with RA and its treatment.
Figure 6: The associations and potential consequences of changes in lipid levels with inflammation and anti-inflammatory therapy.

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J. Robertson and N. Sattar contributed to all stages of the preparation of this manuscript for publication. M. J. Peters and I. B. McInnes made a substantial contribution to discussion of content.

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Correspondence to Naveed Sattar.

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I. B. McInnes has received speakers bureau (honouraria) and grant/research support from the following companies: Abbott, BMS, Pfizer and UCB. N. Sattar has acted as a consultant for and has received speakers bureau (honouraria) from the following companies: Astra Zeneca, MSD, Roche and USB. J. Robertson and M. J. Peters declare no competing interests.

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Robertson, J., Peters, M., McInnes, I. et al. Changes in lipid levels with inflammation and therapy in RA: a maturing paradigm. Nat Rev Rheumatol 9, 513–523 (2013). https://doi.org/10.1038/nrrheum.2013.91

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