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Cardiovascular effects of approved drugs for rheumatoid arthritis

A Publisher Correction to this article was published on 16 April 2021

This article has been updated

Abstract

The risk of cardiovascular disease is increased in patients with rheumatoid arthritis compared with the general population owing to the influence of traditional and non-traditional risk factors. Inflammation has a pivotal contribution and can accelerate the atherosclerotic process. Although dampening inflammation with DMARDs should theoretically abrogate this process, evidence suggests that these drugs can also promote atherosclerosis directly and indirectly, hence adding to an increased cardiovascular burden. However, the extent and direction of the effects largely differ across drugs. Understanding how these drugs influence endothelial damage and vascular repair mechanisms is key to understanding these outcomes. NSAIDs and glucocorticoids can increase the cardiovascular risk. Conversely, conventional, biologic and targeted DMARDs control inflammation and reduce this risk, although some of these drugs can also aggravate traditional factors or thrombotic events. Given these data, the fundamental objective for clinicians should be disease control, in an individualized approach that considers the most appropriate drug for each patient, taking into account joint and cardiovascular outcomes. This Review provides a comprehensive analysis of the effects of DMARDs and other approved drugs on cardiovascular involvement in rheumatoid arthritis, from a clinical and mechanistic perspective, with a roadmap to inform the research agenda.

Key points

  • Effective disease control with anti-rheumatic drugs in rheumatoid arthritis is expected to reduce cardiovascular risk in the same way that it reduces disease activity, by dampening inflammation.

  • Treatment with DMARDs can promote adverse vascular outcomes and trigger paradoxical effects on traditional risk factors, thus functioning as a double-edged sword in terms of cardiovascular risk management.

  • Overall, the use of conventional synthetic DMARDs, with the exception of methotrexate, is associated with some detrimental cardiovascular effects, depending on the dosages and length of usage.

  • Biologic DMARDs can reduce the cardiovascular burden, but can also have paradoxical effects on traditional cardiovascular risk factors; to what extent these effects translate into cardiovascular risk is unclear.

  • Targeted synthetic DMARDs might confer a slightly higher risk of thrombotic events than standard of care therapy in some patients, but evidence is limited and long-term clinical studies are needed.

  • Further efforts should focus on improving knowledge on vascular repair mechanisms, running prospective long-term trials, handling confounding by indication bias and providing critical appraisal of treatment targets.

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Fig. 1: The role of inflammation in promoting atherosclerosis in rheumatoid arthritis.
Fig. 2: DMARDs: double-edged swords in cardiovascular disease in RA.
Fig. 3: Effect of DMARDs on atherosclerosis progression.

Change history

References

  1. 1.

    Maradit-Kremers, H. et al. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum. 52, 402–411 (2005).

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Solomon, D. H. et al. Patterns of cardiovascular risk in rheumatoid arthritis. Ann. Rheum. Dis. 65, 1608–1612 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    del Rincón, I. D., Williams, K., Stern, M. P., Freeman, G. L. & Escalante, A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum. 44, 2737–2745 (2001).

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Peters, M. J. L. et al. Does rheumatoid arthritis equal diabetes mellitus as an independent risk factor for cardiovascular disease? A prospective study. Arthritis Rheum. 61, 1571–1579 (2009).

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Avina-Zubieta, J. A., Thomas, J., Sadatsafavi, M., Lehman, A. J. & Lacaille, D. Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann. Rheum. Dis. 71, 1524–1529 (2012).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Schieir, O., Tosevski, C., Glazier, R. H., Hogg-Johnson, S. & Badley, E. M. Incident myocardial infarction associated with major types of arthritis in the general population: a systematic review and meta-analysis. Ann. Rheum. Dis. 76, 1396–1404 (2017).

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Holmqvist, M., Ljung, L. & Askling, J. Mortality following new-onset rheumatoid arthritis: has modern rheumatology had an impact? Ann. Rheum. Dis. 77, 85–91 (2018).

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    van den Oever, I. A. M., Sattar, N. & Nurmohamed, M. T. Thromboembolic and cardiovascular risk in rheumatoid arthritis: role of the haemostatic system. Ann. Rheum. Dis. 73, 954–957 (2014).

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Gonzalez-Gay, M. A., Gonzalez-Juanatey, C., Vazquez-Rodriguez, T. R., Martin, J. & Llorca, J. Endothelial dysfunction, carotid intima-media thickness, and accelerated atherosclerosis in rheumatoid arthritis. Semin. Arthritis Rheum. 38, 67–70 (2008).

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Södergren, A. et al. Atherosclerosis in early rheumatoid arthritis: very early endothelial activation and rapid progression of intima media thickness. Arthritis Res. Ther. 12, R158 (2010).

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Mason, J. C. & Libby, P. Cardiovascular disease in patients with chronic inflammation: mechanisms underlying premature cardiovascular events in rheumatologic conditions. Eur. Heart J. 36, 482–489 (2015).

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Wallberg-Jonsson, S., Ohman, M. L. & Dahlqvist, S. R. Cardiovascular morbidity and mortality in patients with seropositive rheumatoid arthritis in Northern Sweden. J. Rheumatol. 24, 445–451 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Jean, S. et al. Temporal trends in prevalence, incidence, and mortality for rheumatoid arthritis in Quebec, Canada: a population-based study. Clin. Rheumatol. 36, 2667–2671 (2017).

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Gonzalez, A. et al. The widening mortality gap between rheumatoid arthritis patients and the general population. Arthritis Rheum. 56, 3583–3587 (2007).

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Lacaille, D., Avina-Zubieta, J. A., Sayre, E. C. & Abrahamowicz, M. Improvement in 5-year mortality in incident rheumatoid arthritis compared with the general population — closing the mortality gap. Ann. Rheum. Dis. 76, 1057–1063 (2017).

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Nikiphorou, E. et al. Cardiovascular risk factors and outcomes in early rheumatoid arthritis: a population-based study. Heart 106, 1566–1572 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    van Boheemen, L. et al. Cardiovascular risk in persons at risk of developing rheumatoid arthritis. PLoS ONE 15, e0237072 (2020).

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Myasoedova, E. et al. Total cholesterol and LDL levels decrease before rheumatoid arthritis. Ann. Rheum. Dis. 69, 1310–1314 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    van Halm, V. P. et al. Lipids and inflammation: serial measurements of the lipid profile of blood donors who later developed rheumatoid arthritis. Ann. Rheum. Dis. 66, 184–188 (2007).

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Kerola, A. M. et al. Cardiovascular comorbidities antedating the diagnosis of rheumatoid arthritis. Ann. Rheum. Dis. 72, 1826–1829 (2013).

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    López-Mejías, R. et al. Identification of a 3′-untranslated genetic variant of RARB associated with carotid intima-media thickness in rheumatoid arthritis: a genome-wide association study. Arthritis Rheumatol. 71, 351–360 (2019).

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    López-Mejías, R. et al. Cardiovascular risk assessment in patients with rheumatoid arthritis: the relevance of clinical, genetic and serological markers. Autoimmun. Rev. 15, 1013–1030 (2016).

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Kerola, A. M., Kauppi, M. J., Kerola, T. & Nieminen, T. V. M. How early in the course of rheumatoid arthritis does the excess cardiovascular risk appear? Ann. Rheum. Dis. 71, 1606–1615 (2012).

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    van den Oever, I. A. M., van Sijl, A. M. & Nurmohamed, M. T. Management of cardiovascular risk in patients with rheumatoid arthritis: evidence and expert opinion. Ther. Adv. Musculoskelet. Dis. 5, 166–181 (2013).

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Solomon, D. H. et al. Explaining the cardiovascular risk associated with rheumatoid arthritis: traditional risk factors versus markers of rheumatoid arthritis severity. Ann. Rheum. Dis. 69, 1920–1925 (2010).

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Gonzalez-Gay, M. A. et al. HLA-DRB1 and persistent chronic inflammation contribute to cardiovascular events and cardiovascular mortality in patients with rheumatoid arthritis. Arthritis Rheum. 57, 125–132 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Turesson, C., McClelland, R. L., Christianson, T. J. H. & Matteson, E. L. Severe extra-articular disease manifestations are associated with an increased risk of first ever cardiovascular events in patients with rheumatoid arthritis. Ann. Rheum. Dis. 66, 70–75 (2006).

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Symmons, D. P. M. & Gabriel, S. E. Epidemiology of CVD in rheumatic disease, with a focus on RA and SLE. Nat. Rev. Rheumatol. 7, 399–408 (2011).

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Gonzalez, A. et al. Do cardiovascular risk factors confer the same risk for cardiovascular outcomes in rheumatoid arthritis patients as in non-rheumatoid arthritis patients? Ann. Rheum. Dis. 67, 64–69 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Liao, K. P. & Solomon, D. H. Traditional cardiovascular risk factors, inflammation and cardiovascular risk in rheumatoid arthritis. Rheumatology 52, 45–52 (2013).

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Crowson, C. S. et al. Impact of risk factors associated with cardiovascular outcomes in patients with rheumatoid arthritis. Ann. Rheum. Dis. 77, 48–54 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Arts, E. E., Fransen, J., Den Broeder, A. A., van Riel, P. L. C. M. & Popa, C. D. Low disease activity (DAS28≤3.2) reduces the risk of first cardiovascular event in rheumatoid arthritis: a time-dependent Cox regression analysis in a large cohort study. Ann. Rheum. Dis. 76, 1693–1699 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Mehta, N. N., Torigian, D. A., Gelfand, J. M., Saboury, B. & Alavi, A. Quantification of atherosclerotic plaque activity and vascular inflammation using [18-F] fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). J. Vis. Exp. https://doi.org/10.3791/3777 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Geraldino-Pardilla, L. et al. Arterial inflammation detected with 18 F-fluorodeoxyglucose-positron emission tomography in rheumatoid arthritis. Arthritis Rheumatol. 70, 30–39 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Ahmed, A. et al. Brief report: proatherogenic cytokine microenvironment in the aortic adventitia of patients with rheumatoid arthritis. Arthritis Rheumatol. 68, 1361–1366 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Sattar, N., McCarey, D. W., Capell, H. & McInnes, I. B. Explaining how ‘high-grade’ systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation 108, 2957–2963 (2003).

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Libby, P. Role of inflammation in atherosclerosis associated with rheumatoid arthritis. Am. J. Med. 121, S21–S31 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Skeoch, S. & Bruce, I. N. Atherosclerosis in rheumatoid arthritis: is it all about inflammation? Nat. Rev. Rheumatol. 11, 390–400 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Legein, B., Temmerman, L., Biessen, E. A. L. & Lutgens, E. Inflammation and immune system interactions in atherosclerosis. Cell. Mol. Life Sci. 70, 3847–3869 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Hansson, G. K. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 352, 1685–1695 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Sakakura, K. et al. Pathophysiology of atherosclerosis plaque progression. Heart Lung Circ. 22, 399–411 (2013).

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Hansson, G. K., Libby, P. & Tabas, I. Inflammation and plaque vulnerability. J. Intern. Med. 278, 483–493 (2016).

    Google Scholar 

  43. 43.

    Karra, R. et al. Molecular evidence for arterial repair in atherosclerosis. Proc. Natl Acad. Sci. USA 102, 16789–16794 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Zenovich, A. G. & Taylor, D. A. Atherosclerosis as a disease of failed endogenous repair. Front. Biosci. 13, 3621–3636 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Lüscher, T. F. Novel mechanisms of atherosclerosis and cardiovascular repair. Eur. Heart J. 37, 1709–1711 (2016).

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Dimmeler, S. & Zeiher, A. M. Vascular repair by circulating endothelial progenitor cells: the missing link in atherosclerosis? J. Mol. Med. 82, 671–677 (2004).

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    England, B. R., Thiele, G. M., Anderson, D. R. & Mikuls, T. R. Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications. BMJ 361, k1036 (2018).

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Smolen, J. S. et al. Rheumatoid arthritis. Nat. Rev. Dis. Prim. 4, 18001 (2018).

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Smolen, J. S. et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann. Rheum. Dis. 76, 960–977 (2017).

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Combe, B. et al. 2016 update of the EULAR recommendations for the management of early arthritis. Ann. Rheum. Dis. 76, 948–959 (2017).

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Smolen, J. S. et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann. Rheum. Dis. 79, 685–699 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Lindhardsen, J. et al. The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study. Ann. Rheum. Dis. 70, 929–934 (2011).

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Meune, C. et al. Trends in cardiovascular mortality in patients with rheumatoid arthritis over 50 years: a systematic review and meta-analysis of cohort studies. Rheumatology 48, 1308–1313 (2009).

    Google Scholar 

  54. 54.

    Solomon, S. D. et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N. Engl. J. Med. 352, 1071–1080 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Roubille, C. et al. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann. Rheum. Dis. 74, 480–489 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Nissen, S. E. et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N. Engl. J. Med. 376, 1389–1390 (2017).

    Google Scholar 

  57. 57.

    MacDonald, T. M. et al. Randomized trial of switching from prescribed non-selective non-steroidal anti-inflammatory drugs to prescribed celecoxib: the Standard care vs. Celecoxib Outcome Trial (SCOT). Eur. Heart J. 38, 1843–1850 (2016).

    Google Scholar 

  58. 58.

    Ghosh, R., Alajbegovic, A. & Gomes, A. V. NSAIDs and cardiovascular diseases: role of reactive oxygen species. Oxid. Med. Cell. Longev. 2015, 1–25 (2015).

    Google Scholar 

  59. 59.

    Costello, R. E. et al. Glucocorticoid use is associated with an increased risk of hypertension. Rheumatology 60, 132–139 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Xie, W., Yang, X., Ji, L. & Zhang, Z. Incident diabetes associated with hydroxychloroquine, methotrexate, biologics and glucocorticoids in rheumatoid arthritis: a systematic review and meta-analysis. Semin. Arthritis Rheum. 50, 598–607 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    del Rincón, I., Battafarano, D. F., Restrepo, J. F., Erikson, J. M. & Escalante, A. Glucocorticoid dose thresholds associated with all-cause and cardiovascular mortality in rheumatoid arthritis. Arthritis Rheumatol. 66, 264–272 (2014).

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    van Sijl, A. M., Boers, M., Voskuyl, A. E. & Nurmohamed, M. T. Confounding by indication probably distorts the relationship between steroid use and cardiovascular disease in rheumatoid arthritis: results from a prospective cohort study. PLoS ONE 9, e87965 (2014).

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Verhoeven, F., Prati, C., Maguin-Gaté, K., Wendling, D. & Demougeot, C. Glucocorticoids and endothelial function in inflammatory diseases: focus on rheumatoid arthritis. Arthritis Res. Ther. 18, 258 (2016).

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Choi, H. K., Hernán, M. A., Seeger, J. D., Robins, J. M. & Wolfe, F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 359, 1173–1177 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Westlake, S. L. et al. The effect of methotrexate on cardiovascular disease in patients with rheumatoid arthritis: a systematic literature review. Rheumatology 49, 295–307 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Micha, R. et al. Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease. Am. J. Cardiol. 108, 1362–1370 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Reiss, A. B. et al. Atheroprotective effects of methotrexate on reverse cholesterol transport proteins and foam cell transformation in human THP-1 monocyte/macrophages. Arthritis Rheum. 58, 3675–3683 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Ronda, N. et al. Newly identified antiatherosclerotic activity of methotrexate and adalimumab: complementary effects on lipoprotein function and macrophage cholesterol metabolism. Arthritis Rheumatol. 67, 1155–1164 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Johnston, A., Gudjonsson, J. E., Sigmundsdottir, H., Runar Ludviksson, B. & Valdimarsson, H. The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules. Clin. Immunol. 114, 154–163 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Whittle, S. L. Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review. Rheumatology 43, 267–271 (2003).

    Google Scholar 

  71. 71.

    Ridker, P. M. et al. Low-dose methotrexate for the prevention of atherosclerotic events. N. Engl. J. Med. 380, 752–762 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Singh, G. F. Arthritis, rheumatism and aging medical information system post-marketing surveillance program. J. Rheumatol. 28, 1174–1179 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Kerr, G. et al. Associations of hydroxychloroquine use with lipid profiles in rheumatoid arthritis: pharmacologic implications. Arthritis Care Res. 66, 1619–1626 (2014).

    CAS  Google Scholar 

  74. 74.

    Rempenault, C. et al. Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: a systematic review and meta-analysis. Ann. Rheum. Dis. 77, 98–103 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Robert, N., Wong, G. W. & Wright, J. M. Effect of cyclosporine on blood pressure. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD007893.pub2 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Kockx, M. et al. Low-density lipoprotein receptor-dependent and low-density lipoprotein receptor-independent mechanisms of cyclosporin A-induced dyslipidemia. Arterioscler. Thromb. Vasc. Biol. 36, 1338–1349 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Kockx, M. & Kritharides, L. Cyclosporin A-induced hyperlipidemia. in Lipoproteins - Role in Health and Diseases (eds Frank, S. & Kostner, G.) (IntechOpen, 2012).

  78. 78.

    Diederich, D., Skopec, J., Diederich, A. & Dai, F. X. Cyclosporine produces endothelial dysfunction by increased production of superoxide. Hypertension 23, 957–961 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Woywodt, A. et al. Circulating endothelial cells are a novel marker of cyclosporine-induced endothelial damage. Hypertension 41, 720–723 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Renner, B. et al. Cyclosporine induces endothelial cell release of complement-activating microparticles. J. Am. Soc. Nephrol. 24, 1849–1862 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Kellner, H., Bornholdt, K. & Hein, G. Leflunomide in the treatment of patients with early rheumatoid arthritis — results of a prospective non-interventional study. Clin. Rheumatol. 29, 913–920 (2010).

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Chu, M. & Zhang, C. Inhibition of angiogenesis by leflunomide via targeting the soluble ephrin-A1/EphA2 system in bladder cancer. Sci. Rep. 8, 1539 (2018).

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Capell, H. A. et al. Combination therapy with sulfasalazine and methotrexate is more effective than either drug alone in patients with rheumatoid arthritis with a suboptimal response to sulfasalazine: results from the double-blind placebo-controlled MASCOT study. Ann. Rheum. Dis. 66, 235–241 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Suarez-Almazor et al. Sulfasalazine for treating rheumatoid arthritis. Cochrane Database Syst. Rev. 1998, CD000958 (1998).

    Google Scholar 

  85. 85.

    van Halm, V. P., Nurmohamed, M. T., Twisk, J. W. R., Dijkmans, B. A. C. & Voskuyl, A. E. Disease-modifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study. Arthritis Res. Ther. 8, R151 (2006).

    PubMed  PubMed Central  Google Scholar 

  86. 86.

    MacMullan, P. A. et al. Sulfasalazine and its metabolites inhibit platelet function in patients with inflammatory arthritis. Clin. Rheumatol. 35, 447–455 (2016).

    PubMed  PubMed Central  Google Scholar 

  87. 87.

    Myasoedova, E. 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 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Jacobsson, L. T. H. et al. Treatment with TNF blockers and mortality risk in patients with rheumatoid arthritis. Ann. Rheum. Dis. 66, 670–675 (2007).

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Ljung, L., Askling, J., Rantapää-Dahlqvist, S., Jacobsson, L. & ARTIS Study Group. The risk of acute coronary syndrome in rheumatoid arthritis in relation to tumour necrosis factor inhibitors and the risk in the general population: a national cohort study. Arthritis Res. Ther. 16, R127 (2014).

    PubMed  PubMed Central  Google Scholar 

  90. 90.

    Petitpain, N. et al. Arterial and venous thromboembolic events during anti-TNF therapy: A study of 85 spontaneous reports in the period 2000–2006. Biomed. Mater. Eng. 19, 355–364 (2009).

    PubMed  PubMed Central  Google Scholar 

  91. 91.

    Davies, R. et al. Venous thrombotic events are not increased in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register. Ann. Rheum. Dis. 70, 1831–1834 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Ursini, F. et al. Anti-TNF-alpha agents and endothelial function in rheumatoid arthritis: a systematic review and meta-analysis. Sci. Rep. 7, 5346 (2017).

    PubMed  PubMed Central  Google Scholar 

  93. 93.

    Popa, C. et al. 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 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Liao, K. P. 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. 4, e001588 (2015).

    PubMed  PubMed Central  Google Scholar 

  95. 95.

    Popa, C. et al. Modulation of lipoprotein plasma concentrations during long-term anti-TNF therapy in patients with active rheumatoid arthritis. Ann. Rheum. Dis. 66, 1503–1507 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Dixon, W. G. et al. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor α therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum. 56, 2905–2912 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Sarzi-Puttini, P., Atzeni, F., Shoenfeld, Y. & Ferraccioli, G. TNF-α, rheumatoid arthritis, and heart failure: a rheumatological dilemma. Autoimmun. Rev. 4, 153–161 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Emery, P. et al. Safety and tolerability of subcutaneous sarilumab and intravenous tocilizumab in patients with rheumatoid arthritis. Rheumatology 58, 849–858 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Jones, G. et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann. Rheum. Dis. 69, 88–96 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Cacciapaglia, F. et al. Lipids and atherogenic indices fluctuation in rheumatoid arthritis patients on long-term tocilizumab treatment. Mediators Inflamm. 2018, 2453265 (2018).

    PubMed  PubMed Central  Google Scholar 

  101. 101.

    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. 76, 1949–1952 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Ursini, F. et al. The effect of non-TNF-targeted biologics on vascular dysfunction in rheumatoid arthritis: a systematic literature review. Autoimmun. Rev. 18, 501–509 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Singh, S. et al. Comparative risk of cardiovascular events with biologic and synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a systematic review and meta-analysis. Arthritis Care Res. 72, 561–576 (2020).

    CAS  Google Scholar 

  104. 104.

    Mathieu, S., Pereira, B., Dubost, J.-J., Lusson, J.-R. & Soubrier, M. No significant change in arterial stiffness in RA after 6 months and 1 year of rituximab treatment. Rheumatology 51, 1107–1111 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Raterman, H. G. et al. HDL protein composition alters from proatherogenic into less atherogenic and proinflammatory in rheumatoid arthritis patients responding to rituximab. Ann. Rheum. Dis. 72, 560–565 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Nurmohamed, M. et al. The impact of biologics and tofacitinib on cardiovascular risk factors and outcomes in patients with rheumatic disease: a systematic literature review. Drug. Saf. 41, 473–488 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Gottenberg, J.-E. et al. Comparative effectiveness of rituximab, abatacept, and tocilizumab in adults with rheumatoid arthritis and inadequate response to TNF inhibitors: prospective cohort study. BMJ 364, l67 (2019).

    PubMed  PubMed Central  Google Scholar 

  108. 108.

    Henry, J. et al. Doses of rituximab for retreatment in rheumatoid arthritis: influence on maintenance and risk of serious infection. Rheumatology 57, 538–547 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Winthrop, K. L. et al. Long-term safety of rituximab in patients with rheumatoid arthritis: results of a five-year observational study. Arthritis Care Res. 71, 993–1003 (2019).

    CAS  Google Scholar 

  110. 110.

    Xie, F. et al. Tocilizumab and the risk of cardiovascular disease: direct comparison among biologic disease-modifying antirheumatic drugs for rheumatoid arthritis patients. Arthritis Care Res. 71, 1004–1018 (2019).

    CAS  Google Scholar 

  111. 111.

    Sharif, K. et al. Anterior ST-elevation myocardial infarction induced by rituximab infusion: A case report and review of the literature. J. Clin. Pharm. Ther. 42, 356–362 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Kyaw, T., Tipping, P., Bobik, A. & Toh, B.-H. Opposing roles of B lymphocyte subsets in atherosclerosis. Autoimmunity 50, 52–56 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Kyaw, T. et al. B1a B lymphocytes are atheroprotective by secreting natural IgM that increases IgM deposits and reduces necrotic cores in atherosclerotic lesions. Circ. Res. 109, 830–840 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Mathieu, S. et al. Effects of 6 months of abatacept treatment on aortic stiffness in patients with rheumatoid arthritis. Biologics 7, 259–264 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Benucci, M. et al. Factors correlated with the improvement of endothelial dysfunction during Abatacept therapy in patients with rheumatoid arthritis. J. Inflamm. Res. 7, 247–252 (2018).

    Google Scholar 

  116. 116.

    Charles-Schoeman, C. et al. Remodeling of the HDL proteome with treatment response to abatacept or adalimumab in the AMPLE trial of patients with rheumatoid arthritis. Atherosclerosis 275, 107–114 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Ursini, F. et al. Abatacept improves whole-body insulin sensitivity in rheumatoid arthritis: an observational study. Medicine 94, e888 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Kang, E. H. et al. Comparative cardiovascular risk of abatacept and tumor necrosis factor inhibitors in patients with rheumatoid arthritis with and without diabetes mellitus: a multidatabase cohort study. J. Am. Heart Assoc. 7, e007393 (2018).

    PubMed  PubMed Central  Google Scholar 

  119. 119.

    Jin, Y., Kang, E. H., Brill, G., Desai, R. J. & Kim, S. C. Cardiovascular (CV) risk after initiation of abatacept versus TNF inhibitors in rheumatoid arthritis patients with and without baseline CV disease. J. Rheumatol. 45, 1240–1248 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Vicenová, B., Vopálenský, V., Burýsek, L. & Pospísek, M. Emerging role of interleukin-1 in cardiovascular diseases. Physiol. Res. 58, 481–498 (2009).

    PubMed  PubMed Central  Google Scholar 

  121. 121.

    Arend, W. P. & Dayer, J. M. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum. 33, 305–315 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Schiff, M. H. et al. The safety of anakinra in high-risk patients with active rheumatoid arthritis: six-month observations of patients with comorbid conditions. Arthritis Rheum. 50, 1752–1760 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Ikonomidis, I. et al. Inhibition of interleukin-1 by anakinra improves vascular and left ventricular function in patients with rheumatoid arthritis. Circulation 117, 2662–2669 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Ikonomidis, I. et al. Increased benefit of interleukin-1 inhibition on vascular function, myocardial deformation, and twisting in patients with coronary artery disease and coexisting rheumatoid arthritis. Circ. Cardiovasc. Imaging 7, 619–628 (2014).

    PubMed  PubMed Central  Google Scholar 

  125. 125.

    Ikonomidis, I. et al. Lowering interleukin-1 activity with anakinra improves myocardial deformation in rheumatoid arthritis. Heart 95, 1502–1507 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Ljung, L. et al. Interleukin-1 receptor antagonist is associated with both lipid metabolism and inflammation in rheumatoid arthritis. Clin. Exp. Rheumatol. 25, 617–620 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Winthrop, K. L. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat. Rev. Rheumatol. 13, 234–243 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    O’Shea, J. Targeting the Jak/STAT pathway for immunosuppression. Ann. Rheum. Dis. 63 (Suppl. 2), ii67–ii71 (2004).

    PubMed  PubMed Central  Google Scholar 

  130. 130.

    Riese, R. J., Krishnaswami, S. & Kremer, J. Inhibition of JAK kinases in patients with rheumatoid arthritis: scientific rationale and clinical outcomes. Best Pract. Res. Clin. Rheumatol. 24, 513–526 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Charles-Schoeman, C. et al. Effects of tofacitinib and other DMARDs on lipid profiles in rheumatoid arthritis: implications for the rheumatologist. Semin. Arthritis Rheum. 46, 71–80 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Robertson, J., Peters, M. J., McInnes, I. B. & Sattar, N. Changes in lipid levels with inflammation and therapy in RA: a maturing paradigm. Nat. Rev. Rheumatol. 9, 513–523 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Souto, A. et al. Lipid profile changes in patients with chronic inflammatory arthritis treated with biologic agents and tofacitinib in randomized clinical trials: a systematic review and meta-analysis. Arthritis Rheumatol. 67, 117–127 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Atzeni, F., Svenungsson, E. & Nurmohamed, M. T. Do DMARDs and biologic agents protect from cardiovascular disease in patients with inflammatory arthropathies? Autoimmun. Rev. 18, 102401 (2019).

    PubMed  PubMed Central  Google Scholar 

  135. 135.

    Charles-Schoeman, 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. 67, 616–625 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Kerekes, G. et al. Rheumatoid arthritis and metabolic syndrome. Nat. Rev. Rheumatol. 10, 691–696 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Myasoedova, E. 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. 70, 482–487 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    McInnes, I. B. et al. Open-label tofacitinib and double-blind atorvastatin in rheumatoid arthritis patients: a randomised study. Ann. Rheum. Dis. 73, 124–131 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Charles-Schoeman, C. et al. Risk factors for major adverse cardiovascular events in phase III and long-term extension studies of tofacitinib in patients with rheumatoid arthritis. Arthritis Rheumatol. 71, 1450–1459 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Kremer, J. M. et al. Effects of baricitinib on lipid, apolipoprotein, and lipoprotein particle profiles in a phase iib study of patients with active rheumatoid arthritis. Arthritis Rheumatol. 69, 943–952 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Smolen, J. S. et al. Safety profile of baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment. J. Rheumatol. 46, 7–18 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Taylor, P. C. et al. Lipid profile and effect of statin treatment in pooled phase II and phase III baricitinib studies. Ann. Rheum. Dis. 77, 988–995 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Choy, E. H. S. et al. The effect of JAK1/JAK2 inhibition in rheumatoid arthritis: efficacy and safety of baricitinib. Clin. Exp. Rheumatol. 37, 694–704 (2019).

    PubMed  PubMed Central  Google Scholar 

  144. 144.

    Serhal, L. & Edwards, C. J. Upadacitinib for the treatment of rheumatoid arthritis. Expert. Rev. Clin. Immunol. 15, 13–25 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Kume, K. et al. Tofacitinib improves atherosclerosis despite up-regulating serum cholesterol in patients with active rheumatoid arthritis: a cohort study. Rheumatol. Int. 37, 2079–2085 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Szekanecz, Z. et al. Autoimmune atherosclerosis in 3D: how it develops, how to diagnose and what to do. Autoimmun. Rev. 15, 756–769 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Yang, X., Wan, M., Cheng, Z., Wang, Z. & Wu, Q. Tofacitinib inhibits ox-LDL-induced adhesion of THP-1 monocytes to endothelial cells. Artif. Cells Nanomed. Biotechnol. 47, 2775–2782 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Wang, Z. et al. Tofacitinib ameliorates atherosclerosis and reduces foam cell formation in apoE deficient mice. Biochem. Biophys. Res. Commun. 490, 194–201 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Oh, Y.-B. et al. Inhibition of Janus activated kinase-3 protects against myocardial ischemia and reperfusion injury in mice. Exp. Mol. Med. 45, e23 (2013).

    PubMed  PubMed Central  Google Scholar 

  150. 150.

    Taylor, P. C., Abdul Azeez, M. & Kiriakidis, S. Filgotinib for the treatment of rheumatoid arthritis. Expert Opin. Investig. Drugs 26, 1181–1187 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Cohen, S. B. et al. Thu0167 safety profile of upadacitinib in rheumatoid arthritis: integrated analysis from the select phase 3 clinical program. in Poster Presentations 357–357 (BMJ Publishing Group Ltd and European League Against Rheumatism, 2019).

  152. 152.

    Taylor, P. C. et al. Cardiovascular safety during treatment with baricitinib in rheumatoid arthritis. Arthritis Rheumatol. 71, 1042–1055 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Xie, W. et al. Impact of Janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials. Ann. Rheum. Dis. 78, 1048–1054 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154.

    Charles-Schoeman, C. et al. Cardiovascular safety findings in patients with rheumatoid arthritis treated with tofacitinib, an oral Janus kinase inhibitor. Semin. Arthritis Rheum. 46, 261–271 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    van Vollenhoven, R. F. et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N. Engl. J. Med. 367, 508–519 (2012).

    PubMed  PubMed Central  Google Scholar 

  156. 156.

    Lee, Y. H. & Song, G. G. Impact of Janus kinase inhibitors on the risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials. Ann. Rheum. Dis. 79, e122 (2020).

    PubMed  PubMed Central  Google Scholar 

  157. 157.

    Cohen, S. B. et al. Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials. Ann. Rheum. Dis. 76, 1253–1262 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Mease, P. et al. Incidence of venous and arterial thromboembolic events reported in the tofacitinib rheumatoid arthritis, psoriasis and psoriatic arthritis development programmes and from real-world data. Ann. Rheum. Dis. 79, 1400–1413 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159.

    Genovese, M. et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 8.4 years: an updated integrated safety analysis. Ann. Rheum. Dis. 79, 638 (2020).

    Google Scholar 

  160. 160.

    Cohen, S. B. et al. Safety profile of upadacitinib in rheumatoid arthritis: integrated analysis from the SELECT phase III clinical programme. Ann. Rheum. Dis. 80, 304–311 (2021).

    CAS  Google Scholar 

  161. 161.

    Genovese, M. C. et al. THU0202 Integrated safety analysis of filgotinib treatment for rheumatoid arthritis from 7 clinical trials. Ann. Rheum. Dis. 79, 324–325 (2020).

    Google Scholar 

  162. 162.

    Scott, I. C., Hider, S. L. & Scott, D. L. Thromboembolism with Janus Kinase (JAK) inhibitors for rheumatoid arthritis: how real is the risk? Drug. Saf. 41, 645–653 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 163.

    Harigai, M. Growing evidence of the safety of JAK inhibitors in patients with rheumatoid arthritis. Rheumatology 58, i34–i42 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Desai, R. J., Pawar, A., Weinblatt, M. E. & Kim, S. C. Comparative risk of venous thromboembolism in rheumatoid arthritis patients receiving tofacitinib versus those receiving tumor necrosis factor inhibitors: an observational cohort study. Arthritis Rheumatol. 71, 892–900 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

    Xie, W., Xiao, S., Huang, Y., Sun, X. & Zhang, Z. Effect of tofacitinib on cardiovascular events and all-cause mortality in patients with immune-mediated inflammatory diseases: a systematic review and meta-analysis of randomized controlled trials. Ther. Adv. Musculoskelet. Dis. 11, 1759720X19895492 (2019).

    PubMed  PubMed Central  Google Scholar 

  166. 166.

    EMA. EMA confirms Xeljanz to be used with caution in patients at high risk of blood clots. https://www.ema.europa.eu/en/news/ema-confirms-xeljanz-be-used-caution-patients-high-risk-blood-clots (European Medicines Agency, 2019).

  167. 167.

    FDA. FDA approves boxed warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib. https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-boxed-warning-about-increased-risk-blood-clots-and-death-higher-dose-arthritis-and (2021).

  168. 168.

    Genovese, M. C. et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis over a median of 3 years of treatment: an updated integrated safety analysis. Lancet Rheum. 2, E347–E357 (2020).

    Google Scholar 

  169. 169.

    Harigai, M. et al. Safety profile of baricitinib in Japanese patients with active rheumatoid arthritis with over 1.6 years median time in treatment: an integrated analysis of phases 2 and 3 trials. Mod. Rheumatol. 30, 36–43 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

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C.D.P. and G.S. researched data for the article. F.A., J.R-C., and G.S. wrote the article and M.T.N. and G.S. provided substantial contributions to discussions of content. F.A., J.R-C., Z.S. and G.S. reviewed and edited the manuscript before submission.

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Correspondence to Fabiola Atzeni.

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Glossary

Venous thromboembolic events

Events caused by the formation of a clot (thrombus) that obstructs the flow of blood in a venous vessel. At the clinical level, venous events can be deep vein thrombosis or pulmonary embolisms.

Arterial thromboembolic events

Events caused by the formation of a clot (thrombus) that obstructs the flow of blood in an arterial vessel. At the clinical level, arterial events can be classified as myocardial infarction, sudden cardiac death, ischaemic stroke and peripheral artery disease with occlusions (that is, those usually considered within the umbrella term ‘major adverse cardiovascular event’).

Reverse cholesterol transport

Mechanism of transport by which high-density lipoproteins transfer excess cholesterol from the peripheral tissues to the liver for redistribution to other compartments (including other lipoproteins) or elimination.

Major adverse cardiovascular events

(MACEs). A composite end point frequently used in cardiovascular research that includes fatal and non-fatal cardiovascular events, such as myocardial infarction (or ischaemic coronary disease), stroke or cardiovascular death; however, the exact definitions of MACE components can vary across studies.

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Atzeni, F., Rodríguez-Carrio, J., Popa, C.D. et al. Cardiovascular effects of approved drugs for rheumatoid arthritis. Nat Rev Rheumatol 17, 270–290 (2021). https://doi.org/10.1038/s41584-021-00593-3

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