The elevated risk of cardiovascular disease (CVD) and CVD-related mortality in patients with rheumatoid arthritis (RA) is well-established. An estimated 50% of premature deaths in this population may be attributed to CVD, underscoring the critical importance of managing CVD risk in RA patients.1 While this strategy includes the regular assessment and monitoring of blood lipid levels, these individuals demonstrate an atypical pattern of dyslipidemia and atherogenic changes compared to the general population.

A range of studies have revealed low levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density cholesterol (HDL-C) in RA patients with active disease. A qualitative U-shaped relationship has been identified, with a higher CVD risk in patients with the lowest LDL-C levels compared to those with moderate LDL-C levels. This deviates from the typical link between high LDL-C levels and high CVD risk. “The HDL-C level reduction in RA patients results in a high atherogenic index of TC/HDL-C,” according to a review published in August 2020 in Rheumatology International.2

The mechanistic pathways involved in this “lipid paradox” are not fully understood. “Although the science is still being sorted out, it is believed that inflammation and ramping up of cholesterol catabolism act as a driving forces in this paradox,” explained Seth Shay Martin, MD, MHS, associate professor of medicine at the Johns Hopkins University School of Medicine in Baltimore, Maryland, and director of the Advanced Lipid Disorders Program of the Ciccarone Center at Johns Hopkins.  

Evidence suggests that the lipid paradox and elevated CVD risk in RA aremostly related to the qualitative aspects of lipids, especially the HDL, which loses its antiatherogenic function and finally becomes proatherogenic,” the review authors wrote.2 The resulting proinflammatory HDL is characterized by reduced antioxidant factors, increased proinflammatory proteins and lipid hyperoxide content, and an altered proteome with elevated levels of acute phase proteins and complement system proteins.


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Further in line with the lipid paradox, treatment with both conventional and biologic disease-modifying antirheumatic drugs (DMARDs) have been shown to reduce these inflammatory processes while increasing lipid levels and function.2 “With RA remission on anti-rheumatic drugs, patients may have increased levels of total cholesterol, LDL cholesterol, and HDL cholesterol,” Dr Martin noted. However, these changes are not associated with an increase in CVD risk as would be expected in individuals without RA.2

Selected findings regarding the impact of DMARDs on the lipid profile, atherogenic index, and CVD risk in RA patients are highlighted below.

Hydroxychloroquine has been found to increase HDL levels, possibly due to reduced disease activity or direct effects on lipid metabolism.3

Methotrexate has been linked to a 21% reduction in CV events and a significant increase in TC, LDL-C, and HDL-C cholesterol levels as well as cholesterol efflux capacity.4,2

Other findings have demonstrated increased levels of TC and HDL-C in RA patients after 1 year of combined treatment with methotrexate and prednisolone, with a strong inverse relationship between CRP and HDL-C levels.5

While studies exploring the effects of tumor necrosis factor (TNF)‑alpha inhibitors on lipid profiles in RA have been mixed overall, meta-analyses have reported a modest impact of these agents on levels of TC and HDL-C. These effects do not appear to significantly influence the atherogenic index of these patients, indicating that the “favorable effect of infliximab treatment on cardiovascular comorbidity may relate to other factors such as arterial stiffness and insulin resistance improvement.”2

Treatment with anti‑interleukin‑6 (IL-6) agents have been shown to increase serum TC, HDL-C, and triglyceride levels in clinical trials. Various studies have also found a 15%-20% increase in LDL-C levels with anti-IL-6 therapy, although inconsistent effects on the atherogenic index have been reported.2

RA patients treated with Janus kinase (JAK) inhibitors have shown 21% and 14% increases in LDL-C and HDL-C serum levels, respectively, which were substantially higher than changes observed in patients treated with TNF-alpha inhibitors.2 These increases may be due to a reduction in cholesterol ester fractional catabolic rate following JAK inhibitor therapy.6

Conflicting findings have been noted in studies investigating the lipid profile and atherogenicity index associated with rituximab in RA patients.2 There is a need for further prospective studies to explore these associations.

Additional mechanistic and outcomes studies are also warranted to elucidate the lipid paradox and CVD risk in RA, said Dr Martin. Such research could help to optimize the impact of antirheumatic therapies and lead to improved CV outcomes in RA patients.2 In practice, he emphasizes that “we as clinicians need to take the complete risk factor profile into account and consider that RA is a risk-enhancing factor for atherosclerotic CVD.”

References

  1. Taylor EB, Wolf VL, Dent E, Ryan MJ. Mechanisms of hypertension in autoimmune rheumatic diseases. Br J Pharmacol. 2019; 176(12):1897-1913. doi: 10.1111/bph.14604
  2. Venetsanopoulou AI, Pelechas E, Voulgari PV, Drosos AA. The lipid paradox in rheumatoid arthritis: the dark horse of the augmented cardiovascular risk. Rheumatol Int. 2020;40(8):1181-1191. doi: 10.1007/s00296-020-04616-2
  3. Morris SJ, Wasko MC, Antohe JL, et al. Hydroxychloroquine use associated with improvement in lipid profiles in rheumatoid arthritis patients. Arthritis Care Res (Hoboken). 2011;63(4):530-534. doi: 10.1002/acr.20393
  4. Micha R, Imamura F, Wyler von Ballmoos M, et al. Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease. Am J Cardiol. 2011;108(9):1362-1370. doi: 10.1016/j.amjcard.2011.06.054
  5. Georgiadis AN, Voulgari PV, Argyropoulou MI, et al. Early treatment reduces the cardiovascular risk factors in newly diagnosed rheumatoid arthritis patients. Semin Arthritis Rheum. 2008;38(1):13-19. doi: 10.1016/j.semarthrit.2007.09.008
  6. Charles-Schoeman C, Fleischmann R, Davignon J, 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):616-625. doi: 10.1002/art.38974