Skip to main content

Advertisement

SpringerLink
Log in

Lipids in RA: Is Less Not Necessarily More?

  • Rheumatoid Arthritis (L Moreland, Section Editor)
  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

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.

Recent Findings

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.

Summary

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Avina-Zubieta JA, Thomas J, Sadatsafavi M, Lehman AJ, Lacaille D. Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis. 2012;71(9):1524–9. https://doi.org/10.1136/annrheumdis-2011-200726.

    Article  PubMed  Google 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.

    Article  PubMed  Google Scholar 

  4. Wilson PW. Evidence of systemic inflammation and estimation of coronary artery disease risk: a population perspective. Am J Med. 2008;121(10 Suppl 1):S15–20. https://doi.org/10.1016/j.amjmed.2008.06.012.

    Article  PubMed  Google Scholar 

  5. Winkleby MA, Feldman HA, Murray DM. Joint analysis of three U.S. community intervention trials for reduction of cardiovascular disease risk. J Clin Epidemiol. 1997;50(6):645–58. https://doi.org/10.1016/S0895-4356(97)00020-6.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Liao KP, Liu J, Lu B, Solomon DH, Kim SC. The association between lipid levels and major adverse cardiovascular events in rheumatoid arthritis compared to non-RA. Arthritis Rheumatol. 2015;67(8):2004–10. https://doi.org/10.1002/art.39165.

    Article  CAS  PubMed  PubMed Central  Google 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.

    Article  CAS  PubMed  Google Scholar 

  9. Myasoedova E, Crowson CS, Kremers HM, Fitz-Gibbon PD, Therneau TM, Gabriel SE. Total cholesterol and LDL levels decrease before rheumatoid arthritis. Ann Rheum Dis. 2010;69(7):1310–4. https://doi.org/10.1136/ard.2009.122374.

    Article  CAS  PubMed  Google 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.

  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.

    Article  CAS  Google Scholar 

  12. Singh JA, Beg S, Lopez-Olivo MA. Tocilizumab for rheumatoid arthritis: a Cochrane systematic review. J Rheumatol. 2011;38(1):10–20. https://doi.org/10.3899/jrheum.100717.

    Article  PubMed  Google 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.

    Article  PubMed  PubMed Central  Google 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Umpleby AM. Hormone Measurement Guidelines: tracing lipid metabolism: the value of stable isotopes. J Endocrinol. 2015;226(3):G1–10. https://doi.org/10.1530/JOE-14-0610.

    Article  CAS  PubMed  Google 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.

  17. Rao VU, Pavlov A, Klearman M, Musselman D, Giles JT, Bathon JM, et al. An evaluation of risk factors for major adverse cardiovascular events during tocilizumab therapy. Arthritis Rheumatol. 2015;67(2):372–80. https://doi.org/10.1002/art.38920.

    Article  CAS  PubMed  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.

    Article  CAS  PubMed  PubMed Central  Google 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.

    Article  PubMed  PubMed Central  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin KE, et al. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med. 2014;371(25):2383–93. https://doi.org/10.1056/NEJMoa1409065.

    Article  CAS  PubMed  PubMed Central  Google 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.

    Article  CAS  PubMed  Google Scholar 

  24. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–207. https://doi.org/10.1056/NEJMoa0807646.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  26. del Rincon I, et al. Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis. Ann Rheum Dis. 2015;74(6):1118–23. https://doi.org/10.1136/annrheumdis-2013-205058.

    Article  PubMed  Google 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.

  28. Solomon DH, Reed GW, Kremer JM, Curtis JR, Farkouh ME, Harrold LR, et al. Disease activity in rheumatoid arthritis and the risk of cardiovascular events. Arthritis Rheumatol. 2015;67(6):1449–55. https://doi.org/10.1002/art.39098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lipids, Inflammation and CV risk in RA, NCT02714881. ClinicalTrials.gov [cited 2017; Available from: https://www.clinicaltrials.gov/ct2/show/NCT02714881.

  30. Clinicaltrials.gov. Treatments against RA and effect on FDG-PET/CT (TARGET), NCT02374021. 2017 [cited 2017 10/13/2017]; Available from: https://clinicaltrials.gov/ct2/show/NCT02374021.

  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.

    Article  CAS  PubMed  PubMed Central  Google 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).

Download references

Acknowledgements

We would like to acknowledge Jie Huang for her assistance with creating the figures for this review.

Funding

JP and KPL are funded by NIH R01 HL127118 and the Harold and Duval Bowen Fund.

Author information

Authors and Affiliations

  1. Division of Cardiology, Brigham and Women’s Hospital, Boston, MA, USA

    Jorge Plutzky

  2. Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, 60 Fenwood Road, Boston, MA, 02115, USA

    Katherine P. Liao

Authors
  1. Jorge Plutzky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katherine P. Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Katherine P. Liao.

Ethics declarations

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

Additional information

This article is part of the Topical Collection on Rheumatoid Arthritis

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Plutzky, J., Liao, K.P. Lipids in RA: Is Less Not Necessarily More?. Curr Rheumatol Rep 20, 8 (2018). https://doi.org/10.1007/s11926-018-0715-7

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11926-018-0715-7

Keywords

Search

Navigation