Lipids in RA: Is Less Not Necessarily More?
Purpose of Review
In rheumatoid arthritis (RA), lipid levels are dynamic and can fluctuate along with changes in inflammation. A reduction in inflammation, most commonly as a result of disease-modifying anti-rheumatic drug (DMARD) therapy, is associated with increases in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). In this review, we discuss new evidence shedding light on the potential mechanism underlying changes in lipid levels observed with changes in inflammation.
Measured lipid levels in the blood are a result of a balance between synthesis and catabolism or absorption. Recent human studies in active RA show that the catabolic rates of lipids are higher than expected compared to expected rates in the general population. DMARD therapy appears to allow a return to baseline lower catabolic rates, resulting in an apparent increase in lipids.
Increases in lipids observed with control of inflammation and RA treatment suggest a return to homeostasis. Studies are underway to understand the overall impact on cardiovascular risk in RA when lipid levels increase as a result of controlling inflammation.
KeywordsRheumatoid arthritis Lipids Cardiovascular disease Lipid metabolism
We would like to acknowledge Jie Huang for her assistance with creating the figures for this review.
JP and KPL are funded by NIH R01 HL127118 and the Harold and Duval Bowen Fund.
Compliance with Ethical Standards
Conflict of Interest
Dr. Plutzky reports support from Amgen, Sanofi/Aventis, Aegerion, and Esperion, during the conduct of the study.
Dr. Liao has nothing to disclose.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.Navarro-Millan I, et al. Changes in lipoproteins associated with methotrexate or combination therapy in early rheumatoid arthritis: results from the treatment of early rheumatoid arthritis trial. Arthritis Rheum. 2013;65(6):1430–8. https://doi.org/10.1002/art.37916.CrossRefPubMedPubMedCentralGoogle Scholar
- 3.Solomon DH, Karlson EW, Rimm EB, Cannuscio CC, Mandl LA, Manson JE, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation. 2003;107(9):1303–7. https://doi.org/10.1161/01.CIR.0000054612.26458.B2.CrossRefPubMedGoogle Scholar
- 6.Myasoedova E, Crowson CS, Kremers HM, Roger VL, Fitz-Gibbon PD, Therneau TM, et al. Lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease. Ann Rheum Dis. 2011;70(3):482–7. https://doi.org/10.1136/ard.2010.135871.CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Zhang J, Chen L, Delzell E, Muntner P, Hillegass WB, Safford MM, et al. The association between inflammatory markers, serum lipids and the risk of cardiovascular events in patients with rheumatoid arthritis. Ann Rheum Dis. 2014;73(7):1301–8. https://doi.org/10.1136/annrheumdis-2013-204715.CrossRefPubMedGoogle Scholar
- 10.Liao KP, et al. Lipid and lipoprotein levels and trends in rheumatoid arthritis compared to the general population. Arthritis Care Res (Hoboken). 2013.Google Scholar
- 11.Semb AG, Holme I, Kvien TK, Pedersen TR. Intensive lipid lowering in patients with rheumatoid arthritis and previous myocardial infarction: an explorative analysis from the incremental decrease in endpoints through aggressive lipid lowering (IDEAL) trial. Rheumatology (Oxford). 2011;50(2):324–9. https://doi.org/10.1093/rheumatology/keq295.CrossRefGoogle Scholar
- 13.Kirkham BW, Wasko MC, Hsia EC, Fleischmann RM, Genovese MC, Matteson EL, et al. Effects of golimumab, an anti-tumour necrosis factor-alpha human monoclonal antibody, on lipids and markers of inflammation. Ann Rheum Dis. 2013;73(1):161–9. https://doi.org/10.1136/annrheumdis-2012-202089.CrossRefPubMedPubMedCentralGoogle Scholar
- 14.•• Charles-Schoeman C, Fleischmann R, Davignon J, Schwartz H, Turner SM, Beysen C, et al. Potential mechanisms leading to the abnormal lipid profile in patients with rheumatoid arthritis versus healthy volunteers and reversal by tofacitinib. Arthritis Rheumatol. 2015;67(3):616–25. https://doi.org/10.1002/art.38974. This study provided mechanistic data demonstrating that increased cholesterol levels after treatment with tofacitinib may reflect normalization of cholesterol metabolism. CrossRefPubMedPubMedCentralGoogle Scholar
- 16.•• Robertson J, et al. Interleukin-6 blockade raises LDL via reduced catabolism rather than via increased synthesis: a cytokine-specific mechanism for cholesterol changes in rheumatoid arthritis. Ann Rheum Dis. 2017. This study provides mechanistic data demonstrating a normalization of catabolic rate after treatment with the IL-6R antagonist, tocilizumab.Google Scholar
- 18.Charles-Schoeman C, Wang X, Lee YY, Shahbazian A, Navarro-Millán I, Yang S, et al. Association of triple therapy with improvement in cholesterol profiles over two-year follow-up in the treatment of early aggressive rheumatoid arthritis trial. Arthritis Rheumatol. 2016;68(3):577–86. https://doi.org/10.1002/art.39502.CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Liao KP, Playford MP, Frits M, Coblyn JS, Iannaccone C, Weinblatt ME, et al. The association between reduction in inflammation and changes in lipoprotein levels and HDL cholesterol efflux capacity in rheumatoid arthritis. J Am Heart Assoc. 2015;4(2):e001588. https://doi.org/10.1161/JAHA.114.001588.CrossRefPubMedPubMedCentralGoogle Scholar
- 20.McMahon M, Grossman J, FitzGerald J, Dahlin-Lee E, Wallace DJ, Thong BY, et al. Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum. 2006;54(8):2541–9. https://doi.org/10.1002/art.21976.CrossRefPubMedGoogle Scholar
- 21.• Ormseth MJ, Yancey PG, Solus JF, Bridges SL Jr, Curtis JR, Linton MRF, et al. Effect of drug therapy on net cholesterol efflux capacity of high-density lipoprotein-enriched serum in rheumatoid arthritis. Arthritis Rheumatol. 2016;68(9):2099–105. https://doi.org/10.1002/art.39675. This study focused on whether DMARD treatment had differential effects on anti-atherogenic HDL function. Overall, they found that improvements in HDL function were associated with reduced disease activity and not a specific therapy.CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Ronda N, Greco D, Adorni MP, Zimetti F, Favari E, Hjeltnes G, et al. Newly identified antiatherosclerotic activity of methotrexate and adalimumab: complementary effects on lipoprotein function and macrophage cholesterol metabolism. Arthritis Rheumatol. 2015;67(5):1155–64. https://doi.org/10.1002/art.39039.CrossRefPubMedGoogle Scholar
- 25.•• Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119–31. https://doi.org/10.1056/NEJMoa1707914. This study on non-RA patients is the first to directly test and prove the hypothesis that reducing inflammation reduces CVD risk.CrossRefPubMedGoogle Scholar
- 27.Navarro-Millan I, et al. Association of hyperlipidaemia, inflammation and serological status and coronary heart disease among patients with rheumatoid arthritis: data from the National Veterans Health Administration. Ann Rheum Dis. 2015.Google Scholar
- 29.Lipids, Inflammation and CV risk in RA, NCT02714881. ClinicalTrials.gov [cited 2017; Available from: https://www.clinicaltrials.gov/ct2/show/NCT02714881.
- 31.Liao KP, Liu J, Lu B, Solomon DH, Kim SC. Association between lipid levels and major adverse cardiovascular events in rheumatoid arthritis compared to non-rheumatoid arthritis patients. Arthritis Rheumatol. 2015;67(8):2004–10. https://doi.org/10.1002/art.39165.CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Kitas GD, et al. Trial of atorvastatin for the primary prevention of cardiovascular events in patients with rheumatoid arthritis [abstract]. Arthritis Rheum. 2015. 67(S10).Google Scholar