The lipid paradox in rheumatoid arthritis: the dark horse of the augmented cardiovascular risk

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation that, if left untreated, can cause joint destruction and physical impairments. The inflammatory process is systematic, and it is associated with increased morbidity and mortality. Over the last years, mortality presents a decreasing trend; still, there is a high burden of cardiovascular disease (CVD) in RA that seems to be related to coronary atherosclerosis. Chronic inflammation, physical inactivity, and drugs used to treat RA are some of the reasons. Thus, the management of CVD risk is essential and involves the patient's stratification using distinct parameters that include assessment of the blood lipid profile. However, 'dyslipidemia' in RA patients follows a different pattern under the impact of inflammatory processes, while therapies that target the underlying disease change the levels of specific lipid components. In this review, we explore the relationship between blood lipids and inflammation in the so-called ΄lipid paradox΄ in RA, and we present the existing knowledge over the influence of antirheumatic drugs on the lipid profile of RA patients.

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Abbreviations

ACPA:

Anti-cyclic citrullinated protein antibodies

apo A-I:

Apolipoprotein A-I

ABCA1:

ATP-binding cassette transporter A1

ABCG1:

ATP-binding cassette transporter G1 (ABCG1)

apo A-II:

Apolipoprotein A-II

apo B-48:

Apolipoprotein B-48

apo B:

Apolipoprotein B-100

b:

Biological

CETP:

Cholesteryl ester transfer protein

CHD:

Coronary heart disease

CHOL:

Cholesterol

CRP:

C-reactive protein

CVD:

Cardiovascular disease

Cs:

Conventional synthetic

DAS-28:

Disease Activity Score-28 for Rheumatoid Arthritis

DMARDs:

Disease-modifying antirheumatic drugs

ESR:

Erythrocyte sedimentation rate

EULAR:

European League Against Rheumatism

HDL:

High-density lipoproteins

HDL-C:

High-density lipoprotein cholesterol

HCQ:

Hydroxychloroquine

IDL:

Intermediate-density lipoproteins

IL-6:

Interleukin-6

JAK inhibitors:

Janus kinase inhibitors

LDL:

Low-density lipoproteins

LDL-C:

Low-density lipoprotein cholesterol

LDL-C:

Low-density lipoprotein cholesterol

LDLR:

LDL receptor

LCAT:

Lecithin cholesterol acyltransferase

Lp(a):

Lipoprotein(a)

LPL:

Lipoprotein lipase

FCR:

Fractional catabolic rate

FFA:

Free fatty acids

MTX:

Methotrexate

Ox-LDL:

Oxidized LDL

PON:

Paraoxonase

RA:

Rheumatoid arthritis

RF:

Rheumatoid factor

RChT:

Reverse cholesterol transport

RTX:

Rituximab

SR-B1:

Class-B-scavenger receptor B1

TC:

Total cholesterol

TGs:

Triglycerides

TNF-a:

Tumor necrosis factor-alpha

VLDL:

Very low-density lipoproteins

References

  1. 1.

    Alamanos Y, Voulgari PV, Drosos AA (2006) Incidence and prevalence of rheumatoid arthritis, based on the 1987 American College of Rheumatology criteria: a systematic review. Semin Arthritis Rheum 36:182–188. https://doi.org/10.1016/j.semarthrit.2006.08.006

    Article  PubMed  Google Scholar 

  2. 2.

    Alamanos Y, Drosos AA (2005) Epidemiology of adult rheumatoid arthritis. Autoimmun Rev 4:130–136. https://doi.org/10.1016/j.autrev.2004.09.002

    Article  PubMed  Google Scholar 

  3. 3.

    Crowson CS, Liao KP, Davis JM, Solomon DH, Matteson EL, Knutson KL et al (2013) Rheumatoid arthritis and cardiovascular disease. Am Heart J166:622–628. https://doi.org/10.1016/j.ahj.2013.07.010

    CAS  Article  Google Scholar 

  4. 4.

    Avina-Zubieta JA, Thomas J, Sadatsafavi M, Lehman AJ, Lacaille D (2012) Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis 71:1524–1529. https://doi.org/10.1136/annrheumdis-2011-200726

    Article  PubMed  Google Scholar 

  5. 5.

    Chuang YW, Yu MC, Lin CL, Yu TM, Shu KH, Huang ST, Kao CH (2016) Risk of peripheral arterial occlusive disease in patients with rheumatoid arthritis. A nationwide population-based cohort study. Thromb Haemost 115:439–445. https://doi.org/10.1160/TH15-07-0600

    Article  PubMed  Google Scholar 

  6. 6.

    Stamatelopoulos KS, Kitas GD, Papamichael CM, Kyrkou K, Zampeli E, Fragiadaki K et al (2010) Subclinical peripheral arterial disease in rheumatoid arthritis. Atherosclerosis 212:305–309. https://doi.org/10.1016/j.atherosclerosis.2010.05.007

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Agca R, Heslinga SC, Rollefstad S, Heslinga M, McInnes IB, Peters MJ et al (2017) EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis 76:17–28. https://doi.org/10.1136/annrheumdis-2016-209775

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Peters MJ, Voskuyl AE, Sattar N, Dijkmans BA, Smulders YM, Nurmohamed MT (2010) The interplay between inflammation, lipids and cardiovascular risk in rheumatoid arthritis: why ratios may be better. Int J Clin Pract 64:1440–1443. https://doi.org/10.1111/j.1742-1241.2009.02220.x

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Myasoedova E, Crowson CS, Kremers HM, Roger VL, Fitz-Gibbon PD, Therneau TM et al (2011) Lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease. Ann Rheum Dis 70:482–487. https://doi.org/10.1136/ard.2010.135871

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Myasoedova E (2017) Lipids and lipid changes with synthetic and biologic disease-modifying antirheumatic drug therapy in rheumatoid arthritis: implications for cardiovascular risk. Curr Opin Rheumatol 29:277–284. https://doi.org/10.1097/BOR.0000000000000378

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Feingold KR, Grunfeld C (2018) Introduction to lipids and lipoproteins. Source endotext. MDText.com Inc., South Dartmouth

    Google Scholar 

  12. 12.

    Rodrigo VB, Alfonso VB (2013) Overview about lipid structure lipid metabolism, Rodrigo Valenzuela Baez. IntechOpenRijeka

    Google Scholar 

  13. 13.

    Mahley RW, Innerarity TL, Rall SC, Weisgraber KH (1984) Plasma lipoproteins: apolipoprotein structure and function. J Lipid Res 25:1277–1294

    CAS  PubMed  Google Scholar 

  14. 14.

    Canbay A, Bechmann L, Gerken G (2007) Lipid metabolism in the liver. Z Gastroenterol 45:35–41. https://doi.org/10.1055/s-2006-927368

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Nguyen P, Leray V, Diez M, Serisier S, Bloc'hJ Le, Siliart B et al (2008) Liver lipid metabolism. J Anim Physiol Anim Nutr (Berl) 92:272–283. https://doi.org/10.1111/j.1439-0396.2007.00752.x

    CAS  Article  Google Scholar 

  16. 16.

    Navab M, Hama SY, Anantharamaiah GM, Hassan K, Hough GP, Watson AD et al (2000) Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3. J Lipid Res 41:1495–1508

    CAS  PubMed  Google Scholar 

  17. 17.

    Wu MF, Xu KZ, Guo YG, Yu J, Wu Y, Lin LM (2019) Lipoprotein(a) and atherosclerotic cardiovascular disease: current understanding and future perspectives. Cardiovasc Drugs Ther 33:739–748. https://doi.org/10.1007/s10557-019-06906-9

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Jagpal A, Navarro-Millán I (2018) Cardiovascular co-morbidity in patients with rheumatoid arthritis: a narrative review of risk factors, cardiovascular risk assessment and treatment. BMC Rheumatol 2:10. https://doi.org/10.1186/s41927-018-0014-y

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Stavropoulos-Kalinoglou A, Metsios GS, Panoulas VF, Douglas KMJ, Nevill AM, Jamurtas AZ et al (2009) Associations of obesity with modifiable risk factors for the development of cardiovascular disease in patients with rheumatoid arthritis. Ann Rheum Dis 68:242–245. https://doi.org/10.1136/ard.2008.095596

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Panoulas VF, Metsios GS, Pace AV, John H, Treharne GJ, Banks MJ et al (2008) Hypertension in rheumatoid arthritis. Rheumatology 47:1286–1298. https://doi.org/10.1093/rheumatology/ken159

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Toms TE, Symmons DP, Kitas GD (2010) Dyslipidaemia in rheumatoid arthritis: the role of inflammation, drugs, lifestyle and genetic factors. Curr Vasc Pharmacol 8:301–326. https://doi.org/10.2174/157016110791112269

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Osman R, L'Allier PL, Elgharib N, Tardif JC (2006) Critical appraisal of C-reactive protein throughout the spectrum of cardiovascular disease. Vasc Health Risk Manag 2:221–237.

    CAS  Article  Google Scholar 

  23. 23.

    Goodson NJ, Symmons DP, Scott DG, Bunn D, Lunt M, Silman AJ (2005) Baseline levels of C-reactive protein and prediction of death from cardiovascular disease in patients with inflammatory polyarthritis: a ten-year follow-up study of a primary care-based inception cohort. Arthritis Rheum 52:2293–2299. https://doi.org/10.1002/art.21204

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Gonzalez-Gay MA, Gonzalez-Juanatey C, Pineiro A, Garcia-Porrua C, Testa A, Llorca J (2005) High-grade C-reactive protein elevation correlates with accelerated atherogenesis in patients with rheumatoid arthritis. J Rheumatol 32:1219–1223

    CAS  PubMed  Google Scholar 

  25. 25.

    Zhang J, Chen L, Delzell E, Muntner P, Hillegass WB, Safford MM et al (2014) The association between inflammatory markers, serum lipids and the risk of cardiovascular events in patients with rheumatoid arthritis. Ann Rheum Dis 73:1301–1308. https://doi.org/10.1136/annrheumdis-2013-204715

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Goodson NJ, Wiles NJ, Lunt M, Barrett EM, Silman AJ, Symmons DP (2002) Mortality in early inflammatory polyarthritis: cardiovascular mortality is increased in seropositive patients. Arthritis Rheum 46:2010–2019. https://doi.org/10.1002/art.10419

    Article  PubMed  Google Scholar 

  27. 27.

    Farragher TM, Goodson NJ, Naseem H, Silman AJ, Thomson W, Symmons D et al (2008) Association of the HLA-DRB1 gene with premature death, particularly from cardiovascular disease, in patients with rheumatoid arthritis and inflammatory polyarthritis. Arthritis Rheum 58:359–369. https://doi.org/10.1002/art.23149

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Gasparyan AY, Ayvazyan L, Blackmore H, Kitas GD (2011) Writing a narrative biomedical review: considerations for authors, peer reviewers, and editors. Rheumatol Int 31:1409–1417. https://doi.org/10.1007/s00296-011-1999-3

    Article  PubMed  Google Scholar 

  29. 29.

    Baker JD (2016) The purpose, process, and methods of writing a literature review. AORN J 103:265–269. https://doi.org/10.1016/j.aorn.2016.01.016

    Article  PubMed  Google Scholar 

  30. 30.

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

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Georgiadis AN, Papavasiliou EC, Lourida ES, Alamanos Y, Kostara C, Tselepis AD et al (2006) Atherogenic lipid profile is a feature characteristic of patients with early rheumatoid arthritis: effect of early treatment: a prospective, controlled study. Arthritis Res Ther 8:R82. https://doi.org/10.1186/ar1952

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Georgiadis AN, Voulgari PV, Argyropoulou MI, Alamanos Y, Elisaf M, Tselepis AD et al (2008) Early treatment reduces the cardiovascular risk factors in newly diagnosed rheumatoid arthritis patients. Semin Arthritis Rheum 38:13–19. https://doi.org/10.1016/j.semarthrit.2007.09.008

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Myasoedova E, Crowson CS, Kremers HM, Fitz-Gibbon PD, Therneau TM et al (2010) Total cholesterol and LDL levels decrease before rheumatoid arthritis. Ann Rheum Dis 69:1310–1314. https://doi.org/10.1136/ard.2009.122374

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ et al (2009) Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 373:1175–1182. https://doi.org/10.1016/S0140-6736(09)60447-5

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Van Lenten BJ, Reddy ST, Navab M, Fogelman AM (2006) Understanding changes in high density lipoproteins during the acute phase response. Arterioscler Thromb Vasc Biol 26:1687–1688. https://doi.org/10.1161/01.ATV.0000232522.47018.a6

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Jamnitski A, Levels JH, van den Oever IA, Nurmohamed MT (2013) High-density lipoprotein profiling changes in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors: a cohort study. J Rheumatol 40:825–830. https://doi.org/10.3899/jrheum.121358

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Navarro-Millán I, Charles-Schoeman C, Yang S, Bathon JM, Bridges SL Jr, Chen L (2013) Changes in lipoproteins associated with methotrexate or combination therapy in early rheumatoid arthritis: results from the treatment of early rheumatoid arthritis trial. Arthritis Rheum 65:1430–1438. https://doi.org/10.1002/art.37916

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Liao KP, Playford MP, Frits M, Coblyn JS, Lannaccone C, Weinblatt ME et al (2015) The association between reduction in inflammation and changes in lipoprotein levels and HDL cholesterol efflux capacity in rheumatoid arthritis. J Am Heart Assoc 30:4. https://doi.org/10.1161/JAHA.114.001588

    CAS  Article  Google Scholar 

  39. 39.

    Hashizume M, Mihara M (2012) Atherogenic effects of TNF-α and IL-6 via up-regulation of scavenger receptors. Cytokine 58:424–430. https://doi.org/10.1016/j.cyto.2012.02.010

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Lubrano V, Gabriele M, Puntoni MR, Longo V, Pucci L (2015) Relationship among IL-6, LDL cholesterol and lipid peroxidation. Cell Mol Biol Lett 20:310–322. https://doi.org/10.1515/cmble-2015-0020

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Umpreby AM (2015) Hormone measurement guidelines: tracing lipid metabolism: the value of stable isotopes. J Endocrinol 226:G1–10. https://doi.org/10.1530/JOE-14-0610

    CAS  Article  Google Scholar 

  42. 42.

    Strang AC, BisoendialRJ KRS, Schulte DM et al (2013) Pro-atherogenic lipid changes and decreased hepatic LDL receptor expression by tocilizumab in rheumatoid arthritis. Atherosclerosis 229:174–181. https://doi.org/10.1016/j.atherosclerosis.2013.04.031

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Charles-Schoeman C, Fleischmann R, Davignon J, Schwartz H, Turner SM, Beysen C et al (2015) Potential mechanisms leading to the abnormal lipid profile in patients with rheumatoid arthritis versus healthy volunteers and reversal by tofacitinib. Arthritis Rheumatol 67:616–625. https://doi.org/10.1002/art.38974

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Robertson J, Porter D, Sattar N, Packard CJ, Caslake M, McInnes I et al (2017) 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 76:1949–1952. https://doi.org/10.1136/annrheumdis-2017-211708

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Chistiakov DA, Bobryshev YV, Orekhov AN (2016) Macrophage-mediated cholesterol handling in atherosclerosis. J Cell Mol Med 20:17–28. https://doi.org/10.1111/jcmm.12689

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Lourida ES, Georgiadis AN, Papavasiliou EC, Papathanasiou AI, Drosos AA, Tselepis AD (2007) Patients with early rheumatoid arthritis exhibit elevated autoantibody titers against mildly oxidized low-density lipoprotein and exhibit decreased activity of the lipoprotein-associated phospholipase A2. Arthritis Res Ther 9:R19. https://doi.org/10.1186/ar2129

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Gabriel SE (2005) Cardiovascular death in rheumatoid arthritis: a population-based study. Arthritis Rheum 52:722–732. https://doi.org/10.1002/art.20878

    Article  PubMed  Google Scholar 

  48. 48.

    Toms TE, Panoulas VF, Douglas KM, Nightingale P, Smith JP, Griffiths H et al (2011) Are lipid ratios less susceptible to change with systemic inflammation than individual lipid components in patients with rheumatoid arthritis? Angiology 62:167–175. https://doi.org/10.1177/0003319710373749

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Del Rincon I, Polak JF, O’Leary DH, Battafarano DF, Erikson JM, Restrepo JF et al (2015) Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis. Ann Rheum Dis 74:1118–1123. https://doi.org/10.1136/annrheumdis-2013-205058

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Ambrosino P, Lupoli R, Di Minno A, Tasso M, Peluso R, Di Minno MN (2015) Subclinical atherosclerosis in patients with rheumatoid arthritis. A meta-analysis of literature studies. Thromb Haemost 113:916–930. https://doi.org/10.1160/TH14-11-0921

    Article  PubMed  Google Scholar 

  51. 51.

    Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C et al (2017) Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377:1119–1131. https://doi.org/10.1056/NEJMoa1707914

    CAS  Article  Google Scholar 

  52. 52.

    Van Lenten BJ, Hama SY, de Beer FC, Stafforini DM, McIntyre TM, Prescott SM et al (1995) Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures. J Clin Invest 96:2758–2767. https://doi.org/10.1172/JCI118345

    Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Van Lenten BJ, Wagner AC, Nayak DP, Hama S, Navab M, Fogelman A (2001) High-density lipoprotein loses its anti-inflammatory properties during acute influenza a infection. Circulation 103:2283–2288. https://doi.org/10.1161/01.cir.103.18.2283

    Article  PubMed  Google Scholar 

  54. 54.

    Ansell BJ, Navab M, Hama S, Kamranpour N, Fonarow G, Hough G, Rahmani S et al (2003) Inflammatory/antiinflammatory properties of high-density lipoprotein distinguish patients form control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment. Circulation 108:2751–2756. https://doi.org/10.1161/01.CIR.0000103624.14436.4B

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Mackness MI, Durrington PN, Mackness B (2004) The role of paraoxonase 1 activity in cardiovascular disease: potential for therapeutic intervention. Am J Cardiovasc Drugs 4:211–217. https://doi.org/10.2165/00129784-200404040-00002

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Hayek T, Oiknine J, Brook JG, Aviram M (1994) Role of HDL apolipoprotein E in cellular cholesterol efflux: studies in apo E knockout transgenic mice. Biochem Biophys Res Commun 205:1072–1078. https://doi.org/10.1006/bbrc.1994.2775

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Navab M, Ananthramaiah GM, Reddy ST, Van Lenten BJ, Ansell BJ, Hama S et al (2005) The double jeopardy of HDL. Ann Med 37(3):173–178. https://doi.org/10.1080/07853890510007322

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Charles-Schoeman C, Lee YY, Grijalva V, Amjadi S, FitzGerald J, Ranganath VK et al (2012) Cholesterol efflux by high density lipoproteins is impaired in patients with active rheumatoid arthritis. Ann Rheum Dis 71:1157–1162. https://doi.org/10.1136/annrheumdis-2011-200493

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Popa C, van Tits LJ, Barrera P, Lemmers HL, van den Hoogen FH, van Riel PL et al (2009) Anti-inflammatory therapy with tumour necrosis factor alpha inhibitors improves high-density lipoprotein cholesterol antioxidative capacity in rheumatoid arthritis patients. Ann Rheum Dis 68:868–872. https://doi.org/10.1136/ard.2008.092171

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Watanabe J, Charles-Schoeman C, Miao Y, Elashoff D, Lee YY, Katselis G, Lee TD, Reddy ST (2012) Proteomic profiling following immunoaffinity captre of high-density lipoprotein: association of acute-phase proteins and complement factors with proinflammatory high-density lipoprotein in rheumatoid arthritis. Arthritis Rheum 64:1828–1837. https://doi.org/10.1002/art.34363

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    McInnes IB, Thompson L, Giles JT, Bathon JM, Salmon JE, Beaulieu AD et al (2015) Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: measure, a randomised, placebo-controlled study. Ann Rheum Dis 74:694–702. https://doi.org/10.1136/annrheumdis-2013-204345

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Davis JM, Kremers ΜH, Crowson CS, Nicola PJ, Ballman KV, Therneau TM et al (2007) Glucocorticoids and cardiovascular events in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum 56:820–830. https://doi.org/10.1002/art.22418

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Zampeli E, Protogerou A, Stamatelopoulos K, Fragiadaki K, Katsiari CG, Kyrkou K, Papamichael CM et al (2012) Predictors of new atherosclerotic carotid plaque development in patients with rheumatoid arthritis: a longitudinal study. Arthritis Res Ther 14:R44. https://doi.org/10.1186/ar3757

    Article  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Hafstrom I, Rohani M, Deneberg S, Wornert M, Jogestrand T, Frostegard J (2007) 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 34:1810–1816

    PubMed  Google Scholar 

  65. 65.

    Morris SJ, Wasko MCM, Antohe JL, Sartorius JA, Kirchner HL, Dancea S et al (2011) Hydroxychloroquine use associated with improvement in lipid profiles in rheumatoid arthritis patients. Arthritis Care Res 63:530–534. https://doi.org/10.1002/acr.20393

    CAS  Article  Google Scholar 

  66. 66.

    Micha R, Imamura F, Ballmoos MW, Solomon DH, Hernán MA, RidkerPM, et al (2011) Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease. Am J Cardiol 108:1362–1370. https://doi.org/10.1016/j.amjcard.2011.06.054

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Reiss AB, Carsons SE, Anwar K, Rao S, Edelman SD, Zhang H et al (2008) Atheroprotective effects of methotrexate on reverse cholesterol transport proteins and foam cell transformation in human THP-1 monocyte/macrophages. Arthritis Rheum 58:3675–3683. https://doi.org/10.1002/art.24040

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68.

    RhoYH OeserA, Chung CP, Milne GL, Stein CM (2009) Drugs used in the treatment of rheumatoid arthritis: relationship between current use and cardiovascular risk factors. Arch Drug Inf 2:34–40. https://doi.org/10.1111/j.1753-5174.2009.00019.x

    CAS  Article  Google Scholar 

  69. 69.

    Ormseth MJ, Yancey PG, Solus JF (2016) Effect of drug therapy on net cholesterol efflux capacity of high-density lipoprotein-enriched serum in rheumatoid arthritis. Arthritis Rheumatol 68:2099–2105.

    CAS  Article  Google Scholar 

  70. 70.

    O’Neill F, Charakida M, Topham E, McLoughlin E, Patel N, Sutill E et al (2017) Anti-inflammatory treatment improves high-density lipoprotein function in rheumatoid arthritis. Heart 103:766–773. https://doi.org/10.1136/heartjnl-2015-308953

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Park YB, Choi HK, Kim MY (2002) Effects of antirheumatic therapy on serum lipid levels in patients with rheumatoid arthritis: a prospective study. Am J Med 113:188–193. https://doi.org/10.1016/S0002-9343(02)01186-5

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    RondaN GD, Adorni MP (2015) Newly identified antiatherosclerotic activity of methotrexate and adalimumab: complementary effects on lipoprotein function and macrophage cholesterol metabolism. Arthritis Rheumatol 67:1155–1164. https://doi.org/10.1002/art.39039

    CAS  Article  Google Scholar 

  73. 73.

    Rodriguez-Jimenez NA, Garcia-Gonzalez CE, Ayala-Lopez KP (2014) Modifications in lipid levels are independent of serum TNF-alpha in rheumatoid arthritis: results of an observational 24-week cohort study comparing patients receiving etanercept plus methotrexate or methotrexate as monotherapy. Biomed Res Int. https://doi.org/10.1155/2014/510305

    Article  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Charles-Schoeman C, Wang X, Lee YY (2016) 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 68:577–586. https://doi.org/10.1002/art.39502

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Popa C, van den Hoogen FHJ, Radstake TRDJ, Netea MG, Eijsbouts AE et al (2007) Modulation of lipoprotein plasma concentrations during long-term anti-TNF therapy in patients with active rheumatoid arthritis. Ann Rheum Dis 66:1503–1507. https://doi.org/10.1136/ard.2006.066191

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Wijbrandts CA, Leuven SI, Boom HD, Gerlag DM, Stroes EG, Kastelein JJ et al (2009) Sustained changes in lipid profile and macrophage migration inhibitory factor levels after anti-tumor necrosis factor therapy in rheumatoid arthritis. Ann Rheum Dis 68:1316–1321. https://doi.org/10.1136/ard.2007.086728

    CAS  Article  PubMed  Google Scholar 

  77. 77.

    Kiortsis DN, Mavridis AK, Filippatos TD, Vasakos S, Nikas SN, Drosos AA (2006) Effects of infliximab treatment on lipoprotein profile in patients with rheumatoid arthritis and ankylosing spondylitis. J Rheumatol 33:921–923

    CAS  PubMed  Google Scholar 

  78. 78.

    Bergström U, Jovinge S, Persson J, Jacobsson L (2018) Effects of treatment with adalimumab on blood lipid levels and atherosclerosis in patients with rheumatoid arthritis. Curr Ther Res Clin Exp 89:1–6. https://doi.org/10.1016/j.curtheres.2018.07.001

    Article  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Seriolo B, Paolino S, Sulli A, Fasciolo D, Cutolo M (2006) Effects of anti-TNF-alpha treatment on lipid profile in patients with active rheumatoid arthritis. Ann N Y Acad Sci 1069:414–419. https://doi.org/10.1196/annals.1351.039

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Daïen CI, Duny Y, Barnetche T, Daurès JP, Combe B, Morel J (2012) Effect of TNF inhibitors on lipid profile in rheumatoid arthritis: a systematic review with meta-analysis. Ann Rheum Dis 71:862–868. https://doi.org/10.1136/annrheumdis-2011-201148

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    Van Sijl AM, Peters MJ, Knol DL, de Vet RH, Sattar N, Dijkmans BA et al (2011) The effect of TNF-α blocking therapy on lipid levels in rheumatoid arthritis: a meta-analysis. Semin Arthritis Rheum 41:393–400. https://doi.org/10.1016/j.semarthrit.2011.04.003

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    Di Minno MN, Ambrosino P, Peluso R, Di Minno A, Lupoli R, Dentali F, CaRRDs Study Group (2014) Lipid profile changes in patients with rheumatic diseases receiving a treatment with TNF-α blockers: a meta-analysis of prospective studies. Ann Med 6:73–83

    Article  Google Scholar 

  83. 83.

    Cacciapaglia F, Anelli MG, Rinaldi A, Serafino L, Covelli M, Scioscia C et al (2014) Lipid profile of rheumatoid arthritis patients treated with anti-tumor necrosis factor-alpha drugs changes according to disease activity and predicts clinical response. Drug Dev Res 75(Suppl 1):S77–80. https://doi.org/10.1002/ddr.21203

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Végh E, Kerekes G, Pusztai A, Hamar A, Szamosi S, Váncsa A et al (2020) Effects of 1-year anti-TNF-α therapy on vascular function in rheumatoid arthritis and ankylosing spondylitis. Rheumatol Int 40:427–436. https://doi.org/10.1007/s00296-019-04497-0

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Kiortsis DN, Mavridis AK, Vasakos S, Nikas SN, Drosos AA (2005) Effects of infliximab treatment on insulin resistance in patients with rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis 64:765–766. https://doi.org/10.1136/ard.2004.026534

    CAS  Article  PubMed  Google Scholar 

  86. 86.

    Hashizume M, Yoshida H, Koike N, Suzuki M, Mihara M (2010) Overproduced interleukin 6 decreases blood lipid levels via upregulation of very-low-density lipoprotein receptor. Ann Rheum Dis 69:741–746. https://doi.org/10.1136/ard.2008.104844

    CAS  Article  PubMed  Google Scholar 

  87. 87.

    Cacciapaglia F, Anelli MG, Rinaldi A, Fornaro M, Lopalco G, Scioscia C et al (2018) Lipids and atherogenic indices fluctuation in rheumatoid arthritis patients on long-term tocilizumab treatment. Mediat Inflamm. https://doi.org/10.1155/2018/2453265

    Article  Google Scholar 

  88. 88.

    Kawashiri SY, Kawakami A, Yamasaki S, Imazato T, Iwamoto N, Fujikawa K et al (2011) Effects of the anti-interleukin-6 receptor antibody, tocilizumab, on serum lipid levels in patients with rheumatoid arthritis. Rheumatol Int 31:451–456. https://doi.org/10.1007/s00296-009-1303-y

    CAS  Article  PubMed  Google Scholar 

  89. 89.

    Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD et al (2012) Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 367:495–507. https://doi.org/10.1056/NEJMoa1109071

    CAS  Article  PubMed  Google Scholar 

  90. 90.

    Chen DY, Chen YM, Hsieh TY, Hsieh CW, Lin CC, Lan JL (2015) Significant effects of biologic therapy on lipid profiles and insulin resistance in patients with rheumatoid arthritis. Arthritis Res Ther 17:52. https://doi.org/10.1186/s13075-015-0559-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Charles-Schoeman C, Gonzalez-Gay MA, Kaplan I, Boy M, Geier J, Luo Z et al (2016) Effects of tofacitinib and other DMARDs on lipid profiles in rheumatoid arthritis: implications for the rheumatologist. Semin Arthritis Rheum 46:71–80. https://doi.org/10.1016/j.semarthrit.2016.03.004

    CAS  Article  PubMed  Google Scholar 

  92. 92.

    Novikova DS, Popkova TV, Lukina GV, Luchikhina EL, Karateev DE, Volkov AV et al (2016) The effects of rituximab on lipids, arterial stiffness and carotid intima-media thickness in rheumatoid arthritis. J Korean Med Sci 31:202–207.

    CAS  Article  Google Scholar 

  93. 93.

    Kerekes G, Soltész P, Dér H, Veres K, Szabó Z, Végvári A et al (2009) Effects of rituximab treatment on endothelial dysfunction, carotid atherosclerosis, and lipid profile in rheumatoid arthritis. Clin Rheumatol 28:705–710. https://doi.org/10.1007/s10067-009-1095-1

    Article  PubMed  Google Scholar 

  94. 94.

    Mathieu S, Pereira B, Dubost JJ, Lusson JR, Soubrier M (2012) No significant change in arterial stiffness in RA after 6 months and 1 year of rituximab treatment. Rheumatology (Oxford) 51:1107–1111. https://doi.org/10.1093/rheumatology/kes006

    CAS  Article  Google Scholar 

  95. 95.

    Ridker PM, Cook NR (2013) Statins: new American guidelines for prevention of cardiovascular disease. Lancet 382:1762–1765. https://doi.org/10.1016/S0140-6736(13)62388-0

    Article  PubMed  Google Scholar 

  96. 96.

    Kitas GD, Nightingale P, Armitage J, Sattar N, Belch JJ, Symmons DPM (2019) A multicenter, randomized, placebo-controlled trial of atorvastatin for the primary prevention of cardiovascular events in patients with rheumatoid arthritis. Arthritis Rheumatol 71:1437–1449. https://doi.org/10.1002/art.40892

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97.

    An J, Alemao E, Reynolds K, Kawabata H, Solomon DH, Liao KP et al (2016) Cardiovascular outcomes associated with lowering low-density lipoprotein cholesterol in rheumatoid arthritis and matched nonrheumatoid arthritis. J Rheumatol 43:1989–1996. https://doi.org/10.3899/jrheum.160110

    CAS  Article  PubMed  Google Scholar 

  98. 98.

    Jafri K, Taylor L, Nezamzadeh M, Baker JF, Mehta NN, Bartels C et al (2015) Management of hyperlipidemia among patients with rheumatoid arthritis in the primary care setting. BMC Musculoskelet Disord 16:237. https://doi.org/10.1186/s12891-015-0700-5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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All authors made substantial contributions and approved the final version of the manuscript. (AIV and EP: drafting; PVV: review; AAD: conception and design of the work, review).

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Venetsanopoulou, A.I., Pelechas, E., Voulgari, P.V. et al. The lipid paradox in rheumatoid arthritis: the dark horse of the augmented cardiovascular risk. Rheumatol Int 40, 1181–1191 (2020). https://doi.org/10.1007/s00296-020-04616-2

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Keywords

  • Rheumatoid arthritis
  • Cardiovascular disease
  • Dyslipidemia
  • Inflammation
  • Lipid paradox
  • Lipoprotein metabolism