Advertisement

Current Rheumatology Reports

, Volume 14, Issue 5, pp 428–437 | Cite as

Lipid Paradox in Rheumatoid Arthritis: Changes With Rheumatoid Arthritis Therapies

  • Matxalen Amezaga Urruela
  • Maria E. Suarez-Almazor
RHEUMATOID ARTHRITIS (LW MORELAND, SECTION EDITOR)

Abstract

Rheumatoid arthritis (RA) is associated with increased cardiovascular (CV) morbidity and mortality, related not only to traditional CV risk factors, but also to a chronic inflammatory state. However, lipid profiles in RA are different from those observed in the general population at risk of CV disease, where there is evidence of a positive relationship between disease and high cholesterol levels. In untreated patients with active RA this relationship is different, with a paradoxical effect resulting in lower levels of cholesterol associated with an increased risk of CV disease. In this review, we summarize the latest evidence on lipid abnormalities in the setting of RA and the interaction between inflammation and lipoproteins, as well as the effect of DMARDs and biologic therapies on lipid profiles and the possible implications for CV outcomes in this population.

Keywords

Rheumatoid arthritis Lipids Cardiovascular risk Markers of inflammation Paradox Therapy Risk factors Lipid profiles Atherosclerosis 

Notes

Acknowledgments

Dr. Suarez-Almazor is the recipient of a K24 award from the National Institute on Arthritis, Musculoskeletal and Skin Disorders (NIAMS K24AR053593). The article’s contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIAMS or NIH.

Disclosure

No potential conflicts of interest relevant to this article were reported.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    John H, Toms TE, Kitas G. Rheumatoid arthritis: is it a coronary heart disease equivalent? Curr Opin Cardiol. 2011;26:327–33.PubMedCrossRefGoogle Scholar
  2. 2.
    Watson DJ, Rhodes T, Gues HA. All cause mortality and vascular events among patients with rheumatoid arthritis, osteoarthritis or no arthritis in the UK General Practice Research Database. J Rheumatol. 2003;30:1196–202.PubMedGoogle Scholar
  3. 3.
    Semb AG, Kvien TK, Aastveit AH, et al. Lipids, myocardial infarction and ischemic stroke in patients with rheumatoid arthritis in the Apolipoprotein- related Mortality RISK (AMORIS) Study. Ann Rheum Dis. 2010;69:1996–2001.PubMedCrossRefGoogle Scholar
  4. 4.
    Del Rincon ID, Williams K, Stern MP, et al. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional risks factors. Arthritis Rheum. 2001;44:2737–45.PubMedCrossRefGoogle Scholar
  5. 5.
    Myasoedova E, Kremers HM, Fits-Gibbon P, et al. Lipid profile improves with the onset of rheumatoid arthritis. Ann Rheum Dis. 2009;68 Suppl 3.Google Scholar
  6. 6.
    Myasoedova E, Crowson CS, Kremers HM, et al. Total cholesterol and LDL levels decrease before rheumatoid arthritis. Ann Rheum Dis. 2010;69:1310–4.PubMedCrossRefGoogle Scholar
  7. 7.
    Park YB, Lee SK, Lee WK, et al. Lipid profiles in untreated patients with rheumatoid arthritis. J Rheumatol. 1999;26:1701–4.PubMedGoogle Scholar
  8. 8.
    Anderson KM, Castelli WP, Levy D. Cholesterol and mortality: 30 years of follow-up from the Framingham study. JAMA. 1987;257:2176–80.PubMedCrossRefGoogle Scholar
  9. 9.
    • Choy E, Sattar N. Interpreting lipid level in the context of high grade inflammatory states with a focus on rheumatoid arthritis: a challenge to conventional cardiovascular risk actions. Ann Rheum Dis. 2009;68:460–569. Th is article explains the relationship between inflammation and lipid profiles, why lipoproteins are altered in patients with RA, and how these changes can translate into clinical relevant CV risk factors.PubMedCrossRefGoogle Scholar
  10. 10.
    Hahn BH, Grossman J, Chen WC, et al. The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: roles of inflammation and dyslipidemia. J Autoimmun. 2007;28:69–75.PubMedCrossRefGoogle Scholar
  11. 11.
    Hahn BH, Grosmman J, Benjamin JA, et al. Altered lipoprotein metabolism in chronic inflammatory states: proinflammatory high-density lipoprotein and accelerated atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Res Ther. 2008;10:213.PubMedCrossRefGoogle Scholar
  12. 12.
    Dahlen GH. Lp (a) lipoprotein in cardiovascular disease. Atherosclerosis. 1994;108:111–26.PubMedCrossRefGoogle Scholar
  13. 13.
    Yoo WH. Dyslipoproteinemia in patients with active rheumatoid arthritis: Effect of disease activity, sex, and menopausal status on lipid profiles. J Rheumatol. 2004;31:1746–53.PubMedGoogle Scholar
  14. 14.
    Toms T, Symmons D, Kitas G. Dyslipidaemia in rheumatoid arthritis: the role of inflammation, drugs, lifestyle and genetic factors. Curr Vasc Pharmacol. 2010;8:301–26.PubMedCrossRefGoogle Scholar
  15. 15.
    Dursunoglu D, Evrengul H, Polat B, et al. Lp (a) lipoprotein and lipids in patients with rheumatoid arthritis: serum levels and relationship to inflammation. Rheumatol Int. 2005;25:241–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Rantapaa-Dahlqvist S, Wallberg-Jonsson S, Dahlen G. Lipoprotein (a), lipids, and lipoproteins in patients with rheumatoid arthritis. Ann Rheum Dis. 1991;50:366–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Peters MJL, Voskuyl AE, Sattar BA, et al. The interplay between inflammation, lipids and cardiovascular risk in rheumatoid arthritis: why ratios may be better. Int J Clin Pract. 2010;64:1440–3.PubMedCrossRefGoogle Scholar
  18. 18.
    Maradit-Kremers H, Nicola PJ, Crowson CS, et al. Cardiovascular death in rheumatoid arthritis: a population-based study. Arthritis Rheum. 2005;52:722–32.PubMedCrossRefGoogle Scholar
  19. 19.
    •• Myasoedova E, Crowson CS, Kremers HM, 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;70:482–7. In this study, concrete evidence of the paradoxical relationship between lower levels of TC and LDLc and increased CV risk in patients with RA is demonstrated, as well as the interplay between inflammation as a CV risk factor.PubMedCrossRefGoogle Scholar
  20. 20.
    Peters MJ, Vis M, van Halm VP, et al. Changes in lipid profile during infliximab and corticosteroid treatment in rheumatoid arthritis. Ann Rheum Dis. 2007;66:958–61.PubMedCrossRefGoogle Scholar
  21. 21.
    Steiner G, Urowitz MB. Lipid profiles in patients with rheumatoid arthritis: mechanisms and the impact of treatment. Semin Arthritis Rheum. 2009;38:372–81.PubMedCrossRefGoogle Scholar
  22. 22.
    Schimmel EK, Yazici Y. Increased lipid levels but unchanged atherogenic index in rheumatoid arthritis patients treated with biologic disease modifying antirheumatic drugs: published experience. Clin Exp Rheumatol. 2009;27:446–51.PubMedGoogle Scholar
  23. 23.
    Park YB, Choi SJ, Kim MY, et al. Effects of anti-rheumatic therapy on serum lipid levels in patients with rheumatoid arthritis: a prospective study. Am J Med. 2002;113:188–93.PubMedCrossRefGoogle Scholar
  24. 24.
    Maxwell SR, Moots RJ, Kendall MJ. Corticosteroids: do they damage the cardiovascular system? Postgrad Med. 1994;70:863–70.CrossRefGoogle Scholar
  25. 25.
    Bruce IN. “Not only.. but also”: factors that contribute to accelerated atherosclerosis and premature coronary heart disease in systemic lupus erythematosus. Rheumatology (Oxford). 2005;44:1492–502.CrossRefGoogle Scholar
  26. 26.
    Hafstrom I, Rohani M, Deneberg S, et al. Effects of low-dose prednisolone on endothelial function, atherosclerosis, and traditional risk factors for atherosclerosis in patients with Rheumatoid arthritis: a randomized study. J Rheumatol. 2007;34:1810–6.PubMedGoogle Scholar
  27. 27.
    Garcia-Gomez C, Nolla JM, Valverde J, et al. High HDL-cholesterol in women with rheumatoid arthritis on low-dose glucocorticoid therapy. Eur J Clin Invest. 2008;38:686–92.PubMedCrossRefGoogle Scholar
  28. 28.
    • Toms T, Panoulas V, Douglas K, et al. Are lipid ratios less susceptible to change with systemic inflammation than individual lipid components in patients with rheumatoid arthritis? Angiology. 2011;62:167–75. This study provides evidence on how, in the setting of inflammation, lipid ratios are less susceptible to changes induced by most antirheumatic drugs. Using these biomarkers as a more reliable method to evaluate lipid abnormalities can assist clinicians in their estimates of CV risk in patients with RA and in the management of traditional risk factors.PubMedCrossRefGoogle Scholar
  29. 29.
    Rho YH, Oeser A, Chung C, et al. Drugs used in the treatment of rheumatoid arthritis: relationship between current use and cardiovascular risk factors. Arch Drug Info. 2009;2:34–40.CrossRefGoogle Scholar
  30. 30.
    •• Chung C, Petri M, Post W, et al. Prevalence of traditional modifiable cardiovascular risk factors in patients with rheumatoid arthritis: comparison with control subjects from the Multi-Ethnic Study of atherosclerosis. Semin Arthritis Rheum. 2012;41:535–44. This paper stresses the importance of controlling traditional CV risk factors in patients with RA. It shows that patients with RA have high rates of undiagnosed diabetes mellitus type 2, hypertension, and elevated LDLc and that fewer than 60 % of them are able to achieve preestablished target goals for each of these conditions.PubMedCrossRefGoogle Scholar
  31. 31.
    Ravindran V, Rachapalli S, Choy EH. Safety of medium to long term glucocorticoid therapy in rheumatoid arthritis: a meta-analysis. Rheumatology (Oxford). 2009;48:807–11.CrossRefGoogle Scholar
  32. 32.
    Loddenkemper K, Bohl N, Perka C, et al. Correlation of different bone markers with bone density in patients with rheumatic diseases on glucocorticoid therapy. Rheumatol Int. 2006;26:331–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Panoulas VF, Douglas KM, Stavropoulos-Kalinoglou A, et al. Long-term exposure to medium-dose glucocorticoid therapy associates with hypertension in patients with rheumatoid arthritis. Rheumatology (Oxford). 2008;47:72–5.CrossRefGoogle Scholar
  34. 34.
    Hoes JN, Jacobs JW, Hulsmans HM, et al. High incidence rate of vertebral fractures during chronic prednisone treatment, in spite of bisphosphonate or alfacalcidol use: extension of the alendronate or alfacalcidol in glucocorticoid-induced osteoporosis-trial. Clin Exp Rheumatol. 2010;28:354–9.PubMedGoogle Scholar
  35. 35.
    Davis 3rd JM, Maradit-Kremers H, Crowson CS, et al. Glucocorticoids and cardiovascular events in rheumatoid arthritis: a population- based cohort study. Arthritis Rheum. 2007;56:820–30.PubMedCrossRefGoogle Scholar
  36. 36.
    Munro R, Morrison E, McDonald AG, et al. Effect of disease modifying agents on the lipid profiles of patients with rheumatoid arthritis. Ann Rheum Dis. 1997;56:374–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Morris SJ, Wasko MC. Antohe Jl, et al. Hydroxychloroquine use is associated with improvement in lipid profiles in rheumatoid arthritis. Arthritis Care Res. 2011;63:530–4.CrossRefGoogle Scholar
  38. 38.
    Cotroneo J, Sleik KM, Rene Rodriguez E, et al. Hydroxychloroquine-induced restrictive cardiomyopathy. Eur J Echocardiogr. 2007;8:247–51.PubMedCrossRefGoogle Scholar
  39. 39.
    Naqvi TZ, Luthringer D, Marchevsky A, et al. Chloroquine induced cardiomyopathy-echocardiographic features. J Am Soc Echocardiogr. 2005;18:383–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Saiki O, Takao R, Naruse Y, et al. Infliximab but not methotrexate induces extra-high levels in VLDL triglyceride in patients with rheumatoid arthritis. J Rheumatol. 2007;34:1997–2004.PubMedGoogle Scholar
  41. 41.
    Westlake S, Colebatch A, Baird J, et al. The effects of methotrexate on cardiovascular disease in patients with rheumatoid arthritis: a systematic literature review. Rheumatology. 2010;48:295–307.CrossRefGoogle Scholar
  42. 42.
    Suissa S, Bernatsky S, Hudson M. Antirheumatic drug use and the risk of acute myocardial infarction. Arthrtisis Rheum. 2006;55:531–6.CrossRefGoogle Scholar
  43. 43.
    Tracey D, Klareskog L, Sasso EH, et al. Tumor necrosis factor antagonist mechanism of action: a comprehensive review. Pharmacol Ther. 2008;117:244–79.PubMedCrossRefGoogle Scholar
  44. 44.
    Nam JL, Winthrop KL, Van Vollenhoven RF, et al. Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA. Ann Rheum Dis. 2010;69:976–86.PubMedCrossRefGoogle Scholar
  45. 45.
    Pollono EN, Lopez-Olivo MA, Lopez JA, et al. A systematic review of the effect of TNF-alpha antagonists on lipid profiles in patients with rheumatoid arthritis. Clin Rheumatol. 2010;29:947–55.PubMedCrossRefGoogle Scholar
  46. 46.
    Van Sijl AM, Peters MJ, Knol DL, et al. The effect on TNF-alpha blocking therapy on lipid levels in rheumatoid arthritis: a meta-analysis. Semin Arthritis Rheum. 2011;41:393–400.PubMedCrossRefGoogle Scholar
  47. 47.
    Daien CI, Duny Y, Barnetche T, et al. Effect of TNF inhibitors on lipid profile in rheumatoid arthritis: a systematic review with meta-analysis. Ann Rheum Dis. 2012. doi: 10.1136/annrheumdis-2011-201148.
  48. 48.
    Gasparyan AY, Ayvazyan L, Cocco G, et al. Adverse cardiovascular effects of antirheumatic drugs: implications for clinical practice and research. Curr Pharm Des. 2012;18:1543–55.PubMedGoogle Scholar
  49. 49.
    Barnabe C, Martin BJ, Ghali WA. Systematic review and metanalysis: anti-tumor necrosis factor alpha therapy and cardiovascular events in rheumatoid arthritis. Arthritis Care Res. 2011;63:522–9.CrossRefGoogle Scholar
  50. 50.
    Sarzi-Puttini P, Atzeni F, Shoenfeld Y, et al. TNF-alpha, rheumatoid arthritis, and heart failure: rheumatological dilemma. Autoimmun Rev. 2005;4:153–61.PubMedCrossRefGoogle Scholar
  51. 51.
    Solomon GE. T-cell agents in the treatment of rheumatoid arthritis. Bull NYU Jt Dis. 2010;68:162–5.Google Scholar
  52. 52.
    Kerekes G, Soltesz P, Der H, et al. Effects of rituximab treatment on endothelial dysfunction, carotid atherosclerosis, and lipid profile in rheumatoid arthritis. Clin Rheumatol. 2009;59:1821–4.Google Scholar
  53. 53.
    Gonzalez-Juanatey C, Llorca J, Vazquez-Rodriguez TR, et al. Short-term improvement of endothelial function in rituximab treated rheumatoid arthritis patients refractory to tumor necrosis factor alpha blocker therapy. Arthritis Rheum. 2008;59:1821–4.PubMedCrossRefGoogle Scholar
  54. 54.
    Novikova D, Popkova T, Nasonov E. The effect of anti-B-cell therapy on the development of atherosclerosis in patients with rheumatoid arthritis. Curr Pharm Des. 2012;18:1512–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Gurcan HM, Keskin DB, Stern JN, et al. A review of the current use of rituximab in autoimmune diseases. Int Immunopharmacol. 2009;9:10–25.PubMedCrossRefGoogle Scholar
  56. 56.
    van Vollenhoven RF, Emery P, Bingham CO, et al. Longterm safety of patients receiving rituximab in rheumatoid arthritis clinical trials. J Rheumatol. 2010;37:558–67.PubMedCrossRefGoogle Scholar
  57. 57.
    Papanicolau DA, Wilder RL, Manolagas SC, et al. The pathophysiologic roles of interleukin 6 in human disease. Ann Intern Med. 1998;128:127–37.Google Scholar
  58. 58.
    Gonzalez-Gay MA, Gonzalez-Juateney C, Lopez-Diaz MJ, et al. HLA-DRB1 and persistent chronic inflammation contribute to cardiovascular events and cardiovascular mortality in patients with rheumatoid arthritis. Arthritis Rheum. 2007;57:125–32.PubMedCrossRefGoogle Scholar
  59. 59.
    Poole CD, Conway P, Currie CJ. An evaluation of the association between C-reactive protein, the change in C-reactive protein over one year, and all cause mortality in chronic immune mediated inflammatory disease managed in UK general practice. Rheumatology (Oxford). 2009;48:78–82.CrossRefGoogle Scholar
  60. 60.
    Oldfield V, Dhillon S, Plosket GL. Tocilizumab: a review of its use in the management of rheumatoid arthritis. Drugs. 2009;69:609–32.PubMedCrossRefGoogle Scholar
  61. 61.
    Singh JA, Beg S, Lopez-Olivo MA. Tocilizumab for rheumatoid arthritis. Cochrane Database Syst Rev. 2010;7:CD008331.PubMedGoogle Scholar
  62. 62.
    Nishimoto N, Ito K, Takagi N. Safety and efficacy profiles of tocilizumab monotherapy in Japanese patients with rheumatoid arthritis: meta-analysis of six initial trials and five long term extensions. Md Rheumatol. 2010;20:222–32.CrossRefGoogle Scholar
  63. 63.
    Kawashiri SY, Kawakami A, Yamasaki S, et al. Effects of the anti-interleukin-6 receptor antibody, tocilizumab, on serum lipid levels in patients with rheumatoid arthritis. Rheumatol Int. 2011;31:451–6.PubMedCrossRefGoogle Scholar
  64. 64.
    Bisoendial RJ, Stroes ES, Kastelein JJ, et al. Targeting cardiovascular risk in rheumatoid arthritis: a dual role for statins. Nat Rev Rheumatol. 2010;6:157–64.PubMedCrossRefGoogle Scholar
  65. 65.
    Vishal T, Bano G, Khajuria V, et al. Pleitropic effects os statins. Ind J Pharmacol. 2003;37:77–85.Google Scholar
  66. 66.
    Semb AG, Holme I, Kvien TK, et al. 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;50:324–9.CrossRefGoogle Scholar
  67. 67.
    De Vera MA, Choi H, Abrahamowicz M, et al. Statin discontinuation and risk of acute myocardial infarction in patients with rheumatoid arthritis: a population-based cohort study. Ann Rheum Dis. 2011;70:1020–4.PubMedCrossRefGoogle Scholar
  68. 68.
    Toms TE, Panoulas VF, Douglas KM, et al. Statin use in rheumatoid arthritis in relation to actual cardiovascular risk: evidence for substantial under treatment of lipid-associated cardiovascular risk? Ann Rheum Dis. 2010;69:683–8.PubMedCrossRefGoogle Scholar
  69. 69.
    El-Barbary A, Hussein M, Rageh E, et al. Effect of atorvastatin on inflammation and modification of vascular risk factors in rheumatoid arthritis. J Rheumatol. 2011;38:229–35.PubMedCrossRefGoogle Scholar
  70. 70.
    McCarey DW, McInnes IB, Madhok R, et al. Trial of atorvastatin in rheumatoid arthritis (TARA): double-blind, randomized placebo-controlled trial. Lancet. 2004;363:2015–21.PubMedCrossRefGoogle Scholar
  71. 71.
    Jick SS, Choi H, Li L, et al. Hyperlipidemia, statin use and the risk of developing rheumatoid arthritis. Ann Rheum Dis. 2009;68:546–51.PubMedCrossRefGoogle Scholar
  72. 72.
    Winiarska M, Bil J, Wilczek E, et al. Statins impair antitumor effects of rituximab by inducing conformational changes of CD20. PLoS Med. 2008;5:e64.PubMedCrossRefGoogle Scholar
  73. 73.
    Arts EE, Jansen TL, Den Broeder A, et al. Statins inhibit the antirheumatic effects of rituximab in rheumatoid arthritis: results from the Dutch Rheumatoid Arthritis Monitoring (DREM) registry. Ann Rheum Dis. 2011;70:877–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Peters MJL, Symmons DPM, McCarey D, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis. 2010;69:325–31.PubMedCrossRefGoogle Scholar
  75. 75.
    Conroy RM, Pyorala K, Fitzgerald AP, et al. Estimation of 10 year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J. 2003;24:987–1003.PubMedCrossRefGoogle Scholar
  76. 76.
    Chung CP, Oeser A, Avalos I, et al. Utility of the Framingham risk score to predict the presence of coronary atherosclerosis in patients with rheumatoid arthritis. Arthritis Res Ther. 2006;8:R186.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Matxalen Amezaga Urruela
    • 1
  • Maria E. Suarez-Almazor
    • 2
  1. 1.Department of General Internal Medicine and Ambulatory TreatmentBaylor College of Medicine and The University of Texas M.D. Anderson Cancer CenterHoustonUSA
  2. 2.Section of Rheumatology & Section of Clinical Research and Education, General Internal Medicine, Department of General Internal Medicine and Ambulatory TreatmentThe University of Texas M.D. Anderson Cancer CenterHoustonUSA

Personalised recommendations