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Cardiovascular disease risk and pathogenesis in systemic lupus erythematosus

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Abstract

Systemic lupus erythematosus (SLE) often features extensive cardiovascular (CV) comorbidity and patients with SLE are at significantly increased risk of CV event occurrence and CV-related mortality. While the specific mechanisms leading to this increased cardiovascular disease (CVD) risk remain to be fully characterized, this heightened risk cannot be fully explained by traditional CV risk factors and is likely driven by immunologic and inflammatory features of SLE. Widespread innate and adaptive immune dysregulation characterize SLE, and factors including excessive type I interferon burden, inappropriate formation and ineffective clearance of neutrophil extracellular traps, and autoantibody formation have been linked to clinical and metabolic features impacting CV risk in SLE and may represent pathogenic drivers of SLE–related CVD. Indeed, functional and phenotypic aberrations in almost every immune cell type are present in SLE and may impact CVD progression. As understanding of the contribution of SLE–specific factors to CVD in SLE improves, improved screening and monitoring of CV risk alongside development of therapeutic treatments aimed at prevention of CVD in SLE patients are required and remain the focus of several ongoing studies and lines of inquiry.

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References

  1. Moghaddam B, Marozoff S, Li L, Sayre EC, Zubieta JAA (2021) All-cause and cause-specific mortality in systemic lupus erythematosus: a population-based study. Rheumatology (Oxford). https://doi.org/10.1093/rheumatology/keab362

    Article  Google Scholar 

  2. Lee YH, Choi SJ, Ji JD, Song GG (2016) Overall and cause-specific mortality in systemic lupus erythematosus: an updated meta-analysis. Lupus 25:727–734. https://doi.org/10.1177/0961203315627202

    Article  CAS  PubMed  Google Scholar 

  3. Fors Nieves CE, Izmirly PM (2016) Mortality in systemic lupus erythematosus: an updated review. Curr Rheumatol Rep 18:21. https://doi.org/10.1007/s11926-016-0571-2

    Article  PubMed  Google Scholar 

  4. Ajeganova S, Hafstrom I, Frostegard J (2021) Patients with SLE have higher risk of cardiovascular events and mortality in comparison with controls with the same levels of traditional risk factors and intima-media measures, which is related to accumulated disease damage and antiphospholipid syndrome: a case-control study over 10 years. Lupus Sci Med 8 https://doi.org/10.1136/lupus-2020-000454

  5. Tselios K, Gladman DD, Sheane BJ, Su J, Urowitz M (2019) All-cause, cause-specific and age-specific standardised mortality ratios of patients with systemic lupus erythematosus in Ontario, Canada over 43 years (1971–2013). Ann Rheum Dis 78:802–806. https://doi.org/10.1136/annrheumdis-2018-214802

    Article  PubMed  Google Scholar 

  6. Bjornadal L, Yin L, Granath F, Klareskog L, Ekbom A (2004) Cardiovascular disease a hazard despite improved prognosis in patients with systemic lupus erythematosus: results from a Swedish population based study 1964–95. J Rheumatol 31:713–719

    PubMed  Google Scholar 

  7. Tektonidou MG, Kravvariti E, Konstantonis G, Tentolouris N, Sfikakis PP, Protogerou A (2017) Subclinical atherosclerosis in systemic lupus erythematosus: comparable risk with diabetes mellitus and rheumatoid arthritis. Autoimmun Rev 16:308–312. https://doi.org/10.1016/j.autrev.2017.01.009

    Article  PubMed  Google Scholar 

  8. Roman MJ, Moeller E, Davis A, Paget SA, Crow MK, Lockshin MD, Sammaritano L, Devereux RB, Schwartz JE, Levine DM, Salmon JE (2006) Preclinical carotid atherosclerosis in patients with rheumatoid arthritis. Ann Intern Med 144:249–256. https://doi.org/10.7326/0003-4819-144-4-200602210-00006

    Article  PubMed  Google Scholar 

  9. Roman MJ, Shanker BA, Davis A, Lockshin MD, Sammaritano L, Simantov R, Crow MK, Schwartz JE, Paget SA, Devereux RB, Salmon JE (2003) Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 349:2399–2406. https://doi.org/10.1056/NEJMoa035471

    Article  CAS  PubMed  Google Scholar 

  10. Salmon JE, Roman MJ (2008) Subclinical atherosclerosis in rheumatoid arthritis and systemic lupus erythematosus. Am J Med 121:S3-8. https://doi.org/10.1016/j.amjmed.2008.06.010

    Article  PubMed  PubMed Central  Google Scholar 

  11. Cavender MA, Steg PG, Smith SC Jr, Eagle K, Ohman EM, Goto S, Kuder J, Im K, Wilson PW, Bhatt DL, Investigators RR (2015) Impact of diabetes mellitus on hospitalization for heart failure, cardiovascular events, and death: outcomes at 4 years from the Reduction of Atherothrombosis for Continued Health (REACH) registry. Circulation 132:923–931. https://doi.org/10.1161/CIRCULATIONAHA.114.014796

    Article  PubMed  Google Scholar 

  12. Yazdany J, Pooley N, Langham J, Nicholson L, Langham S, Embleton N, Wang X, Desta B, Barut V, Hammond E (2020) Systemic lupus erythematosus; stroke and myocardial infarction risk: a systematic review and meta-analysis. Rmd Open 6 https://doi.org/10.1136/rmdopen-2020-001247

  13. Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA Jr, Jansen-McWilliams L, D’Agostino RB, Kuller LH (1997) Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 145:408–415. https://doi.org/10.1093/oxfordjournals.aje.a009122

    Article  CAS  PubMed  Google Scholar 

  14. Chen J, Tang Y, Zhu M, Xu A (2016) Heart involvement in systemic lupus erythematosus: a systemic review and meta-analysis. Clin Rheumatol 35:2437–2448. https://doi.org/10.1007/s10067-016-3373-z

    Article  PubMed  Google Scholar 

  15. Stojan G, Li J, Budoff M, Arbab-Zadeh A, Petri MA (2020) High-risk coronary plaque in SLE: low-attenuation non-calcified coronary plaque and positive remodelling index. Lupus Sci Med 7 https://doi.org/10.1136/lupus-2020-000409

  16. Carlucci PM, Purmalek MM, Dey AK, Temesgen-Oyelakin Y, Sakhardande S, Joshi AA, Lerman JB, Fike A, Davis M, Chung JH, Playford MP, Naqi M, Mistry P, Gutierrez-Cruz G, Dell’Orso S, Naz F, Salahuddin T, Natarajan B, Manna Z, Tsai WL, Gupta S, Grayson P, Teague H, Chen MY, Sun HW, Hasni S, Mehta NN, Kaplan MJ (2018) Neutrophil subsets and their gene signature associate with vascular inflammation and coronary atherosclerosis in lupus. JCI Insight 3 https://doi.org/10.1172/jci.insight.99276

  17. Kao AH, Lertratanakul A, Elliott JR, Sattar A, Santelices L, Shaw P, Birru M, Avram Z, Thompson T, Sutton-Tyrrell K, Ramsey-Goldman R, Manzi S (2013) Relation of carotid intima-media thickness and plaque with incident cardiovascular events in women with systemic lupus erythematosus. Am J Cardiol 112:1025–1032. https://doi.org/10.1016/j.amjcard.2013.05.040

    Article  PubMed  PubMed Central  Google Scholar 

  18. Gustafsson JT, Herlitz Lindberg M, Gunnarsson I, Pettersson S, Elvin K, Ohrvik J, Larsson A, Jensen-Urstad K, Svenungsson E (2017) Excess atherosclerosis in systemic lupus erythematosus,-a matter of renal involvement: case control study of 281 SLE patients and 281 individually matched population controls. PLoS ONE 12:e0174572. https://doi.org/10.1371/journal.pone.0174572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hermansen ML, Lindhardsen J, Torp-Pedersen C, Faurschou M, Jacobsen S (2017) The risk of cardiovascular morbidity and cardiovascular mortality in systemic lupus erythematosus and lupus nephritis: a Danish nationwide population-based cohort study. Rheumatology (Oxford) 56:709–715. https://doi.org/10.1093/rheumatology/kew475

    Article  Google Scholar 

  20. Esdaile JM, Abrahamowicz M, Grodzicky T, Li Y, Panaritis C, du Berger R, Cote R, Grover SA, Fortin PR, Clarke AE, Senecal JL (2001) Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum 44:2331–2337. https://doi.org/10.1002/1529-0131(200110)44:10%3c2331::aid-art395%3e3.0.co;2-i

    Article  CAS  PubMed  Google Scholar 

  21. Knockaert DC (2007) Cardiac involvement in systemic inflammatory diseases. Eur Heart J 28:1797–1804. https://doi.org/10.1093/eurheartj/ehm193

    Article  PubMed  Google Scholar 

  22. Libby P (2006) Inflammation and cardiovascular disease mechanisms. Am J Clin Nutr 83:456S-S460. https://doi.org/10.1093/ajcn/83.2.456S

    Article  CAS  PubMed  Google Scholar 

  23. Golia E, Limongelli G, Natale F, Fimiani F, Maddaloni V, Pariggiano I, Bianchi R, Crisci M, D’Acierno L, Giordano R, Di Palma G, Conte M, Golino P, Russo MG, Calabro R, Calabro P (2014) Inflammation and cardiovascular disease: from pathogenesis to therapeutic target. Curr Atheroscler Rep 16:435. https://doi.org/10.1007/s11883-014-0435-z

    Article  CAS  PubMed  Google Scholar 

  24. Berg AH, Scherer PE (2005) Adipose tissue, inflammation, and cardiovascular disease. Circ Res 96:939–949. https://doi.org/10.1161/01.RES.0000163635.62927.34

    Article  CAS  PubMed  Google Scholar 

  25. Manzi S, Selzer F, Sutton-Tyrrell K, Fitzgerald SG, Rairie JE, Tracy RP, Kuller LH (1999) Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus. Arthritis Rheum 42:51–60. https://doi.org/10.1002/1529-0131(199901)42:1%3c51::AID-ANR7%3e3.0.CO;2-D

    Article  CAS  PubMed  Google Scholar 

  26. Endemann DH, Schiffrin EL (2004) Endothelial dysfunction. J Am Soc Nephrol 15:1983–1992. https://doi.org/10.1097/01.ASN.0000132474.50966.DA

    Article  CAS  PubMed  Google Scholar 

  27. Widmer RJ, Lerman A (2014) Endothelial dysfunction and cardiovascular disease. Glob Cardiol Sci Pract 2014:291–308. https://doi.org/10.5339/gcsp.2014.43

    Article  PubMed  PubMed Central  Google Scholar 

  28. da Rosa Franchi Santos LF, Stadtlober NP, Costa Dall’Aqua LG, Scavuzzi BM, Guimaraes PM, Flauzino T, BatistiLozovoy MA, Mayumi Iriyoda TV, VissociReiche EM, Dichi I, Maes M, ColadoSimao A (2018) Increased adhesion molecule levels in systemic lupus erythematosus: relationships with severity of illness, autoimmunity, metabolic syndrome and cortisol levels. Lupus 27:380–8. https://doi.org/10.1177/0961203317723716

    Article  PubMed  Google Scholar 

  29. Lee WF, Wu CY, Yang HY, Lee WI, Chen LC, Ou LS, Huang JL (2019) Biomarkers associating endothelial dysregulation in pediatric-onset systemic lupus erythematous. Pediatr Rheumatol Online J 17:69. https://doi.org/10.1186/s12969-019-0369-7

    Article  PubMed  PubMed Central  Google Scholar 

  30. Yeboah J, Folsom AR, Burke GL, Johnson C, Polak JF, Post W, Lima JA, Crouse JR, Herrington DM (2009) Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: the multi-ethnic study of atherosclerosis. Circulation 120:502–509. https://doi.org/10.1161/CIRCULATIONAHA.109.864801

    Article  PubMed  PubMed Central  Google Scholar 

  31. Mak A, Liu Y, Ho RCM (2011) Endothelium-dependent but not endothelium-independent flow-mediated dilation is significantly reduced in patients with systemic lupus erythematosus without vascular events: a metaanalysis and metaregression. J Rheumatol 38:1296–1303. https://doi.org/10.3899/jrheum.101182

    Article  PubMed  Google Scholar 

  32. Mak A, Kow NY, Schwarz H, Gong LL, Tay SH, Ling LH (2017) Endothelial dysfunction in systemic lupus erythematosus - a case-control study and an updated meta-analysis and meta-regression. Scientific reports 7 https://doi.org/10.1038/s41598-017-07574-1

  33. Mendoza-Pinto C, Rojas-Villarraga A, Molano-Gonzalez N, Garcia-Carrasco M, Munguia-Realpozo P, Etchegaray-Morales I, Morales-Sanchez H, Berra-Romani R, Cervera R (2020) Endothelial dysfunction and arterial stiffness in patients with systemic lupus erythematosus: a systematic review and meta-analysis. Atherosclerosis 297:55–63. https://doi.org/10.1016/j.atherosclerosis.2020.01.028

    Article  CAS  PubMed  Google Scholar 

  34. Rajagopalan S, Somers EC, Brook RD, Kehrer C, Pfenninger D, Lewis E, Chakrabarti A, Richardson BC, Shelden E, McCune WJ, Kaplan MJ (2004) Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity. Blood 103:3677–3683. https://doi.org/10.1182/blood-2003-09-3198

    Article  CAS  PubMed  Google Scholar 

  35. Lee PY, Li Y, Richards HB, Chan FS, Zhuang H, Narain S, Butfiloski EJ, Sobel ES, Reeves WH, Segal MS (2007) Type I interferon as a novel risk factor for endothelial progenitor cell depletion and endothelial dysfunction in systemic lupus erythematosus. Arthritis Rheum 56:3759–3769. https://doi.org/10.1002/art.23035

    Article  CAS  PubMed  Google Scholar 

  36. Geng L, Wang S, Li X, Wang D, Chen H, Chen J, Sun Y, Chen W, Yao G, Gao X, Chen W, Shi S, Feng X, Sun L (2018) Association between Type I interferon and depletion and dysfunction of endothelial progenitor cells in C57BL/6 mice deficient in both apolipoprotein E and Fas ligand. Curr Res Transl Med 66:71–82. https://doi.org/10.1016/j.retram.2018.02.002

    Article  PubMed  Google Scholar 

  37. Thacker SG, Duquaine D, Park J, Kaplan MJ (2010) Lupus-prone New Zealand Black/New Zealand White F1 mice display endothelial dysfunction and abnormal phenotype and function of endothelial progenitor cells. Lupus 19:288–299. https://doi.org/10.1177/0961203309353773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Thacker SG, Zhao W, Smith CK, Luo W, Wang H, Vivekanandan-Giri A, Rabquer BJ, Koch AE, Pennathur S, Davidson A, Eitzman DT, Kaplan MJ (2012) Type I interferons modulate vascular function, repair, thrombosis, and plaque progression in murine models of lupus and atherosclerosis. Arthritis Rheum 64:2975–2985. https://doi.org/10.1002/art.34504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, Pannier B, Vlachopoulos C, Wilkinson I, Struijker-Boudier H, European Network for Non-invasive Investigation of Large A (2006) Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 27:2588–605. https://doi.org/10.1093/eurheartj/ehl254

    Article  PubMed  Google Scholar 

  40. Vlachopoulos C, Aznaouridis K, Stefanadis C (2010) Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol 55:1318–1327. https://doi.org/10.1016/j.jacc.2009.10.061

    Article  PubMed  Google Scholar 

  41. Mitchell GF, Hwang SJ, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, Vita JA, Levy D, Benjamin EJ (2010) Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation 121:505–511. https://doi.org/10.1161/CIRCULATIONAHA.109.886655

    Article  PubMed  PubMed Central  Google Scholar 

  42. Willum-Hansen T, Staessen JA, Torp-Pedersen C, Rasmussen S, Thijs L, Ibsen H, Jeppesen J (2006) Prognostic value of aortic pulse wave velocity as index of arterial stiffness in the general population. Circulation 113:664–670. https://doi.org/10.1161/CIRCULATIONAHA.105.579342

    Article  PubMed  Google Scholar 

  43. Shang Q, Tam LS, Li EK, Yip GW, Yu CM (2008) Increased arterial stiffness correlated with disease activity in systemic lupus erythematosus. Lupus 17:1096–1102. https://doi.org/10.1177/0961203308092160

    Article  CAS  PubMed  Google Scholar 

  44. Sacre K, Escoubet B, Pasquet B, Chauveheid MP, Zennaro MC, Tubach F, Papo T (2014) Increased arterial stiffness in systemic lupus erythematosus (SLE) patients at low risk for cardiovascular disease: a cross-sectional controlled study. PLoS ONE 9:e94511. https://doi.org/10.1371/journal.pone.0094511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Roldan PC, Greene ER, Qualls CR, Sibbitt WL Jr, Roldan CA (2019) Progression of atherosclerosis versus arterial stiffness with age within and between arteries in systemic lupus erythematosus. Rheumatol Int 39:1027–1036. https://doi.org/10.1007/s00296-019-04267-y

    Article  PubMed  Google Scholar 

  46. Barnes JN, Nualnim N, Sugawara J, Sommerlad SM, Renzi CP, Tanaka H (2011) Arterial stiffening, wave reflection, and inflammation in habitually exercising systemic lupus erythematosus patients. Am J Hypertens 24:1194–1200. https://doi.org/10.1038/ajh.2011.143

    Article  CAS  PubMed  Google Scholar 

  47. Montalban-Mendez C, Soriano-Maldonado A, Vargas-Hitos JA, Saez-Uran LM, Rosales-Castillo A, Morillas-de-Laguno P, Gavilan-Carrera B, Jimenez-Alonso J (2018) Cardiorespiratory fitness and age-related arterial stiffness in women with systemic lupus erythematosus. Eur J Clin Invest 48 https://doi.org/10.1111/eci.12885

  48. Soriano-Maldonado A, Morillas-de-Laguno P, Sabio JM, Gavilan-Carrera B, Rosales-Castillo A, Montalban-Mendez C, Saez-Uran LM, Callejas-Rubio JL, Vargas-Hitos JA (2018) Effects of 12-week aerobic exercise on arterial stiffness, inflammation, and cardiorespiratory fitness in women with systemic lupus erythematosus: non-randomized controlled trial. J Clin Med 7 https://doi.org/10.3390/jcm7120477

  49. Urowitz MB, Gladman D, Ibanez D, Fortin P, Sanchez-Guerrero J, Bae S, Clarke A, Bernatsky S, Gordon C, Hanly J, Wallace D, Isenberg D, Ginzler E, Merrill J, Alarcon G, Steinsson K, Petri M, Dooley MA, Bruce I, Manzi S, Khamashta M, Ramsey-Goldman R, Zoma A, Sturfelt G, Nived O, Maddison P, Font J, van Vollenhoven R, Aranow C, Kalunian K, Stoll T, Buyon J (2007) Clinical manifestations and coronary artery disease risk factors at diagnosis of systemic lupus erythematosus: data from an international inception cohort. Lupus 16:731–735. https://doi.org/10.1177/0961203307081113

    Article  CAS  PubMed  Google Scholar 

  50. Urowitz MB, Gladman D, Ibanez D, Fortin P, Sanchez-Guerrero J, Bae S, Clarke A, Bernatsky S, Gordon C, Hanly J, Wallace D, Isenberg D, Ginzler E, Merrill J, Alarcon GS, Steinsson K, Petri M, Dooley MA, Bruce I, Manzi S, Khamashta M, Ramsey-Goldman R, Zoma A, Sturfelt G, Nived O, Maddison P, Font J, van Vollenhoven R, Aranow C, Kalunian K, Stoll T, Systemic Lupus International Collaborating C (2008) Accumulation of coronary artery disease risk factors over three years: data from an international inception cohort. Arthritis Rheum 59:176–80. https://doi.org/10.1002/art.23353

    Article  CAS  PubMed  Google Scholar 

  51. Borba EF, Bonfa E (1997) Dyslipoproteinemias in systemic lupus erythematosus: influence of disease, activity, and anticardiolipin antibodies. Lupus 6:533–539. https://doi.org/10.1177/096120339700600610

    Article  CAS  PubMed  Google Scholar 

  52. Tselios K, Koumaras C, Gladman DD, Urowitz MB (2016) Dyslipidemia in systemic lupus erythematosus: just another comorbidity? Semin Arthritis Rheum 45:604–610. https://doi.org/10.1016/j.semarthrit.2015.10.010

    Article  CAS  PubMed  Google Scholar 

  53. Borba EF, Bonfa E, Vinagre CG, Ramires JA, Maranhao RC (2000) Chylomicron metabolism is markedly altered in systemic lupus erythematosus. Arthritis Rheum 43:1033–1040. https://doi.org/10.1002/1529-0131(200005)43:5%3c1033::AID-ANR11%3e3.0.CO;2-B

    Article  CAS  PubMed  Google Scholar 

  54. de Carvalho JF, Borba EF, Viana VS, Bueno C, Leon EP, Bonfa E (2004) Anti-lipoprotein lipase antibodies: a new player in the complex atherosclerotic process in systemic lupus erythematosus? Arthritis Rheum 50:3610–3615. https://doi.org/10.1002/art.20630

    Article  CAS  PubMed  Google Scholar 

  55. McMahon M, Grossman J, Skaggs B, Fitzgerald J, Sahakian L, Ragavendra N, Charles-Schoeman C, Watson K, Wong WK, Volkmann E, Chen W, Gorn A, Karpouzas G, Weisman M, Wallace DJ, Hahn BH (2009) Dysfunctional proinflammatory high-density lipoproteins confer increased risk of atherosclerosis in women with systemic lupus erythematosus. Arthritis Rheum 60:2428–2437. https://doi.org/10.1002/art.24677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Smith CK, Vivekanandan-Giri A, Tang C, Knight JS, Mathew A, Padilla RL, Gillespie BW, Carmona-Rivera C, Liu X, Subramanian V, Hasni S, Thompson PR, Heinecke JW, Saran R, Pennathur S, Kaplan MJ (2014) Neutrophil extracellular trap-derived enzymes oxidize high-density lipoprotein: an additional proatherogenic mechanism in systemic lupus erythematosus. Arthritis Rheumatol 66:2532–2544. https://doi.org/10.1002/art.38703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Frostegard J, Svenungsson E, Wu R, Gunnarsson I, Lundberg IE, Klareskog L, Horkko S, Witztum JL (2005) Lipid peroxidation is enhanced in patients with systemic lupus erythematosus and is associated with arterial and renal disease manifestations. Arthritis Rheum 52:192–200. https://doi.org/10.1002/art.20780

    Article  CAS  PubMed  Google Scholar 

  58. Ronda N, Favari E, Borghi MO, Ingegnoli F, Gerosa M, Chighizola C, Zimetti F, Adorni MP, Bernini F, Meroni PL (2014) Impaired serum cholesterol efflux capacity in rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis 73:609–615. https://doi.org/10.1136/annrheumdis-2012-202914

    Article  PubMed  Google Scholar 

  59. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F, American Heart A, National Heart L, Blood I (2005) Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 112:2735–2752. https://doi.org/10.1161/CIRCULATIONAHA.105.169404

    Article  PubMed  Google Scholar 

  60. Malik S, Wong ND, Franklin SS, Kamath TV, L’Italien GJ, Pio JR, Williams GR (2004) Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. Circulation 110:1245–1250. https://doi.org/10.1161/01.CIR.0000140677.20606.0E

    Article  PubMed  Google Scholar 

  61. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT (2002) The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 288:2709–2716. https://doi.org/10.1001/jama.288.21.2709

    Article  PubMed  Google Scholar 

  62. Parker B, Ahmad Y, Shelmerdine J, Edlin H, Yates AP, Teh LS, Bruce IN (2011) An analysis of the metabolic syndrome phenotype in systemic lupus erythematosus. Lupus 20:1459–1465. https://doi.org/10.1177/0961203311416695

    Article  CAS  PubMed  Google Scholar 

  63. Mok CC, Poon WL, Lai JP, Wong CK, Chiu SM, Wong CK, Lun SW, Ko GT, Lam CW, Lam CS (2010) Metabolic syndrome, endothelial injury, and subclinical atherosclerosis in patients with systemic lupus erythematosus. Scand J Rheumatol 39:42–49. https://doi.org/10.3109/03009740903046668

    Article  CAS  PubMed  Google Scholar 

  64. Esposito K, Giugliano D (2004) The metabolic syndrome and inflammation: association or causation? Nutr Metab Cardiovasc Dis 14:228–232. https://doi.org/10.1016/s0939-4753(04)80048-6

    Article  CAS  PubMed  Google Scholar 

  65. Maury E, Brichard SM (2010) Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Mol Cell Endocrinol 314:1–16. https://doi.org/10.1016/j.mce.2009.07.031

    Article  CAS  PubMed  Google Scholar 

  66. El Magadmi M, Ahmad Y, Turkie W, Yates AP, Sheikh N, Bernstein RM, Durrington PN, Laing I, Bruce IN (2006) Hyperinsulinemia, insulin resistance, and circulating oxidized low density lipoprotein in women with systemic lupus erythematosus. J Rheumatol 33:50–56

    PubMed  Google Scholar 

  67. Chung CP, Avalos I, Oeser A, Gebretsadik T, Shintani A, Raggi P, Stein CM (2007) High prevalence of the metabolic syndrome in patients with systemic lupus erythematosus: association with disease characteristics and cardiovascular risk factors. Ann Rheum Dis 66:208–214. https://doi.org/10.1136/ard.2006.054973

    Article  CAS  PubMed  Google Scholar 

  68. Chung CP, Oeser A, Solus JF, Gebretsadik T, Shintani A, Avalos I, Sokka T, Raggi P, Pincus T, Stein CM (2008) Inflammation-associated insulin resistance: differential effects in rheumatoid arthritis and systemic lupus erythematosus define potential mechanisms. Arthritis Rheum 58:2105–2112. https://doi.org/10.1002/art.23600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sanchez-Perez H, Tejera-Segura B, de Vera-Gonzalez A, Gonzalez-Delgado A, Olmos JM, Hernandez JL, Corrales A, Lopez-Mejias R, Gonzalez-Gay MA, Ferraz-Amaro I (2017) Insulin resistance in systemic lupus erythematosus patients: contributing factors and relationship with subclinical atherosclerosis. Clin Exp Rheumatol 35:885–892

    PubMed  Google Scholar 

  70. Miyake CNH, Gualano B, Dantas WS, Pereira RT, Neves W, Zambelli VO, Shinjo SK, Pereira RM, Silva ER, Sa-Pinto AL, Borba E, Roschel H, Bonfa E, Benatti FB (2018) Increased insulin resistance and glucagon levels in mild/inactive systemic lupus erythematosus patients despite normal glucose tolerance. Arthritis Care Res (Hoboken) 70:114–124. https://doi.org/10.1002/acr.23237

    Article  CAS  Google Scholar 

  71. Fantuzzi G (2008) Adiponectin and inflammation: consensus and controversy. J Allergy Clin Immunol 121:326–330. https://doi.org/10.1016/j.jaci.2007.10.018

    Article  CAS  PubMed  Google Scholar 

  72. Tsokos GC, Lo MS, Costa Reis P, Sullivan KE (2016) New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol 12:716–730. https://doi.org/10.1038/nrrheum.2016.186

    Article  CAS  PubMed  Google Scholar 

  73. Pan L, Lu MP, Wang JH, Xu M, Yang SR (2020) Immunological pathogenesis and treatment of systemic lupus erythematosus. World J Pediatr 16:19–30. https://doi.org/10.1007/s12519-019-00229-3

    Article  PubMed  Google Scholar 

  74. Gupta S, Kaplan MJ (2021) Bite of the wolf: innate immune responses propagate autoimmunity in lupus. J Clin Invest 131 https://doi.org/10.1172/JCI144918

  75. Villanueva E, Yalavarthi S, Berthier CC, Hodgin JB, Khandpur R, Lin AM, Rubin CJ, Zhao W, Olsen SH, Klinker M, Shealy D, Denny MF, Plumas J, Chaperot L, Kretzler M, Bruce AT, Kaplan MJ (2011) Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol 187:538–552. https://doi.org/10.4049/jimmunol.1100450

    Article  CAS  PubMed  Google Scholar 

  76. Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C, De Ravin SS, Smith CK, Malech HL, Ledbetter JA, Elkon KB, Kaplan MJ (2016) Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med 22:146–153. https://doi.org/10.1038/nm.4027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rahman S, Sagar D, Hanna RN, Lightfoot YL, Mistry P, Smith CK, Manna Z, Hasni S, Siegel RM, Sanjuan MA, Kolbeck R, Kaplan MJ, Casey KA (2019) Low-density granulocytes activate T cells and demonstrate a non-suppressive role in systemic lupus erythematosus. Ann Rheum Dis 78:957–966. https://doi.org/10.1136/annrheumdis-2018-214620

    Article  CAS  PubMed  Google Scholar 

  78. van den Hoogen LL, van der Linden M, Meyaard L, Fritsch-Stork RDE, van Roon JA, Radstake TR (2020) Neutrophil extracellular traps and low-density granulocytes are associated with the interferon signature in systemic lupus erythematosus, but not in antiphospholipid syndrome. Ann Rheum Dis 79:e135. https://doi.org/10.1136/annrheumdis-2019-215781

    Article  CAS  PubMed  Google Scholar 

  79. Pieterse E, Rother N, Garsen M, Hofstra JM, Satchell SC, Hoffmann M, Loeven MA, Knaapen HK, van der Heijden OWH, Berden JHM, Hilbrands LB, van der Vlag J (2017) Neutrophil extracellular traps drive endothelial-to-mesenchymal transition. Arterioscler Thromb Vasc Biol 37:1371–1379. https://doi.org/10.1161/ATVBAHA.117.309002

    Article  CAS  PubMed  Google Scholar 

  80. Mistry P, Nakabo S, O’Neil L, Goel RR, Jiang K, Carmona-Rivera C, Gupta S, Chan DW, Carlucci PM, Wang X, Naz F, Manna Z, Dey A, Mehta NN, Hasni S, Dell’Orso S, Gutierrez-Cruz G, Sun HW, Kaplan MJ (2019) Transcriptomic, epigenetic, and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus. Proc Natl Acad Sci U S A 116:25222–25228. https://doi.org/10.1073/pnas.1908576116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Carmona-Rivera C, Zhao W, Yalavarthi S, Kaplan MJ (2015) Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythematosus through the activation of matrix metalloproteinase-2. Ann Rheum Dis 74:1417–1424. https://doi.org/10.1136/annrheumdis-2013-204837

    Article  CAS  PubMed  Google Scholar 

  82. Moore S, Juo HH, Nielsen CT, Tyden H, Bengtsson AA, Lood C (2020) Role of neutrophil extracellular traps regarding patients at risk of increased disease activity and cardiovascular comorbidity in systemic lupus erythematosus. J Rheumatol 47:1652–1660. https://doi.org/10.3899/jrheum.190875

    Article  CAS  PubMed  Google Scholar 

  83. Ding X, Xiang W, He X (2020) IFN-I Mediates dysfunction of endothelial progenitor cells in atherosclerosis of systemic lupus erythematosus. Front Immunol 11:581385. https://doi.org/10.3389/fimmu.2020.581385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Bashant KR, Aponte AM, Randazzo D, Rezvan Sangsari P, Wood AJ, Bibby JA, West EE, Vassallo A, Manna ZG, Playford MP, Jordan N, Hasni S, Gucek M, Kemper C, Conway Morris A, Morgan NY, Toepfner N, Guck J, Mehta NN, Chilvers ER, Summers C, Kaplan MJ (2021) Proteomic, biomechanical and functional analyses define neutrophil heterogeneity in systemic lupus erythematosus. Ann Rheum Dis 80:209–218. https://doi.org/10.1136/annrheumdis-2020-218338

    Article  CAS  PubMed  Google Scholar 

  85. Buie JJ, Renaud LL, Muise-Helmericks R, Oates JC (2017) IFN-alpha negatively regulates the expression of endothelial nitric oxide synthase and nitric oxide production: implications for systemic lupus erythematosus. J Immunol 199:1979–1988. https://doi.org/10.4049/jimmunol.1600108

    Article  CAS  PubMed  Google Scholar 

  86. Lood C, Amisten S, Gullstrand B, Jonsen A, Allhorn M, Truedsson L, Sturfelt G, Erlinge D, Bengtsson AA (2010) Platelet transcriptional profile and protein expression in patients with systemic lupus erythematosus: up-regulation of the type I interferon system is strongly associated with vascular disease. Blood 116:1951–1957. https://doi.org/10.1182/blood-2010-03-274605

    Article  CAS  PubMed  Google Scholar 

  87. Nhek S, Clancy R, Lee KA, Allen NM, Barrett TJ, Marcantoni E, Nwaukoni J, Rasmussen S, Rubin M, Newman JD, Buyon JP, Berger JS (2017) Activated platelets induce endothelial cell activation via an interleukin-1beta pathway in systemic lupus erythematosus. Arterioscler Thromb Vasc Biol 37:707–716. https://doi.org/10.1161/ATVBAHA.116.308126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Duffau P, Seneschal J, Nicco C, Richez C, Lazaro E, Douchet I, Bordes C, Viallard JF, Goulvestre C, Pellegrin JL, Weil B, Moreau JF, Batteux F, Blanco P (2010) Platelet CD154 potentiates interferon-alpha secretion by plasmacytoid dendritic cells in systemic lupus erythematosus. Sci Transl Med 2:47ra63. https://doi.org/10.1126/scitranslmed.3001001

    Article  CAS  PubMed  Google Scholar 

  89. Li J, Fu Q, Cui H, Qu B, Pan W, Shen N, Bao C (2011) Interferon-alpha priming promotes lipid uptake and macrophage-derived foam cell formation: a novel link between interferon-alpha and atherosclerosis in lupus. Arthritis Rheum 63:492–502. https://doi.org/10.1002/art.30165

    Article  CAS  PubMed  Google Scholar 

  90. Ghazarian M, Revelo XS, Nohr MK, Luck H, Zeng K, Lei H, Tsai S, Schroer SA, Park YJ, Chng MHY, Shen L, D’Angelo JA, Horton P, Chapman WC, Brockmeier D, Woo M, Engleman EG, Adeyi O, Hirano N, Jin T, Gehring AJ, Winer S, Winer DA (2017) Type I interferon responses drive intrahepatic T cells to promote metabolic syndrome. Sci Immunol 2 https://doi.org/10.1126/sciimmunol.aai7616

  91. Diao Y, Mohandas R, Lee P, Liu Z, Sautina L, Mu W, Li S, Wen X, Croker B, Segal MS (2016) Effects of long-term Type I interferon on the arterial wall and smooth muscle progenitor cells differentiation. Arterioscler Thromb Vasc Biol 36:266–273. https://doi.org/10.1161/ATVBAHA.115.306767

    Article  CAS  PubMed  Google Scholar 

  92. Navratil JS, Manzi S, Kao AH, Krishnaswami S, Liu CC, Ruffing MJ, Shaw PS, Nilson AC, Dryden ER, Johnson JJ, Ahearn JM (2006) Platelet C4d is highly specific for systemic lupus erythematosus. Arthritis Rheum 54:670–674. https://doi.org/10.1002/art.21627

    Article  CAS  PubMed  Google Scholar 

  93. Petri MA, Conklin J, O’Malley T, Dervieux T (2019) Platelet-bound C4d, low C3 and lupus anticoagulant associate with thrombosis in SLE. Lupus Sci Med 6:e000318. https://doi.org/10.1136/lupus-2019-000318

    Article  PubMed  PubMed Central  Google Scholar 

  94. Svenungsson E, Gustafsson JT, Grosso G, Rossides M, Gunnarsson I, Jensen-Urstad K, Larsson A, Ekdahl KN, Nilsson B, Bengtsson AA, Lood C (2020) Complement deposition, C4d, on platelets is associated with vascular events in systemic lupus erythematosus. Rheumatology (Oxford) 59:3264–3274. https://doi.org/10.1093/rheumatology/keaa092

    Article  CAS  Google Scholar 

  95. Moore KJ, Tabas I (2011) Macrophages in the pathogenesis of atherosclerosis. Cell 145:341–355. https://doi.org/10.1016/j.cell.2011.04.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Ma WT, Gao F, Gu K, Chen DK (2019) The role of monocytes and macrophages in autoimmune diseases: a comprehensive review. Front Immunol 10:1140. https://doi.org/10.3389/fimmu.2019.01140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Smith CK, Seto NL, Vivekanandan-Giri A, Yuan W, Playford MP, Manna Z, Hasni SA, Kuai R, Mehta NN, Schwendeman A, Pennathur S, Kaplan MJ (2017) Lupus high-density lipoprotein induces proinflammatory responses in macrophages by binding lectin-like oxidised low-density lipoprotein receptor 1 and failing to promote activating transcription factor 3 activity. Ann Rheum Dis 76:602–611. https://doi.org/10.1136/annrheumdis-2016-209683

    Article  CAS  PubMed  Google Scholar 

  98. Rho YH, Solus J, Raggi P, Oeser A, Gebretsadik T, Shintani A, Stein CM (2011) Macrophage activation and coronary atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Care Res (Hoboken) 63:535–541. https://doi.org/10.1002/acr.20365

    Article  CAS  Google Scholar 

  99. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464:1357–1361. https://doi.org/10.1038/nature08938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Warnatsch A, Ioannou M, Wang Q, Papayannopoulos V (2015) Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science 349:316–320. https://doi.org/10.1126/science.aaa8064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Liu Y, Carmona-Rivera C, Moore E, Seto NL, Knight JS, Pryor M, Yang ZH, Hemmers S, Remaley AT, Mowen KA, Kaplan MJ (2018) Myeloid-specific deletion of peptidylarginine deiminase 4 mitigates atherosclerosis. Front Immunol 9:1680. https://doi.org/10.3389/fimmu.2018.01680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Farrera C, Fadeel B (2013) Macrophage clearance of neutrophil extracellular traps is a silent process. J Immunol 191:2647–2656. https://doi.org/10.4049/jimmunol.1300436

    Article  CAS  PubMed  Google Scholar 

  103. Wolf D, Ley K (2019) Immunity and inflammation in atherosclerosis. Circ Res 124:315–327. https://doi.org/10.1161/CIRCRESAHA.118.313591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Saigusa R, Winkels H, Ley K (2020) T cell subsets and functions in atherosclerosis. Nat Rev Cardiol 17:387–401. https://doi.org/10.1038/s41569-020-0352-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK (1986) Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 6:131–138. https://doi.org/10.1161/01.atv.6.2.131

    Article  CAS  PubMed  Google Scholar 

  106. Winkels H, Ehinger E, Vassallo M, Buscher K, Dinh HQ, Kobiyama K, Hamers AAJ, Cochain C, Vafadarnejad E, Saliba AE, Zernecke A, Pramod AB, Ghosh AK, Anto Michel N, Hoppe N, Hilgendorf I, Zirlik A, Hedrick CC, Ley K, Wolf D (2018) Atlas of the immune cell repertoire in mouse atherosclerosis defined by single-cell RNA-sequencing and mass cytometry. Circ Res 122:1675–1688. https://doi.org/10.1161/CIRCRESAHA.117.312513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Fernandez DM, Rahman AH, Fernandez NF, Chudnovskiy A, Amir ED, Amadori L, Khan NS, Wong CK, Shamailova R, Hill CA, Wang Z, Remark R, Li JR, Pina C, Faries C, Awad AJ, Moss N, Bjorkegren JLM, Kim-Schulze S, Gnjatic S, Ma’ayan A, Mocco J, Faries P, Merad M, Giannarelli C (2019) Single-cell immune landscape of human atherosclerotic plaques. Nat Med 25:1576–1588. https://doi.org/10.1038/s41591-019-0590-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Eid RE, Rao DA, Zhou J, Lo SF, Ranjbaran H, Gallo A, Sokol SI, Pfau S, Pober JS, Tellides G (2009) Interleukin-17 and interferon-gamma are produced concomitantly by human coronary artery-infiltrating T cells and act synergistically on vascular smooth muscle cells. Circulation 119:1424–1432. https://doi.org/10.1161/CIRCULATIONAHA.108.827618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Suarez-Fueyo A, Bradley SJ, Tsokos GC (2016) T cells in systemic lupus erythematosus. Curr Opin Immunol 43:32–38. https://doi.org/10.1016/j.coi.2016.09.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Schwartz DM, Burma AM, Kitakule MM, Luo Y, Mehta NN (2020) T cells in autoimmunity-associated cardiovascular diseases. Front Immunol 11:588776. https://doi.org/10.3389/fimmu.2020.588776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zhou X, Nicoletti A, Elhage R, Hansson GK (2000) Transfer of CD4(+) T cells aggravates atherosclerosis in immunodeficient apolipoprotein E knockout mice. Circulation 102:2919–2922. https://doi.org/10.1161/01.cir.102.24.2919

    Article  CAS  PubMed  Google Scholar 

  112. Wilhelm AJ, Rhoads JP, Wade NS, Major AS (2015) Dysregulated CD4+ T cells from SLE-susceptible mice are sufficient to accelerate atherosclerosis in LDLr-/- mice. Ann Rheum Dis 74:778–785. https://doi.org/10.1136/annrheumdis-2013-203759

    Article  CAS  PubMed  Google Scholar 

  113. Clement M, Charles N, Escoubet B, Guedj K, Chauveheid MP, Caligiuri G, Nicoletti A, Papo T, Sacre K (2015) CD4+CXCR3+ T cells and plasmacytoid dendritic cells drive accelerated atherosclerosis associated with systemic lupus erythematosus. J Autoimmun 63:59–67. https://doi.org/10.1016/j.jaut.2015.07.001

    Article  CAS  PubMed  Google Scholar 

  114. Li W, Deng C, Yang H, Wang G (2019) The regulatory T cell in active systemic lupus erythematosus patients: a systemic review and meta-analysis. Front Immunol 10:159. https://doi.org/10.3389/fimmu.2019.00159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Yang J, Chu Y, Yang X, Gao D, Zhu L, Yang X, Wan L, Li M (2009) Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum 60:1472–1483. https://doi.org/10.1002/art.24499

    Article  PubMed  Google Scholar 

  116. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238. https://doi.org/10.1038/nature04753

    Article  CAS  PubMed  Google Scholar 

  117. Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317:256–260. https://doi.org/10.1126/science.1145697

    Article  CAS  PubMed  Google Scholar 

  118. Xie JJ, Wang J, Tang TT, Chen J, Gao XL, Yuan J, Zhou ZH, Liao MY, Yao R, Yu X, Wang D, Cheng Y, Liao YH, Cheng X (2010) The Th17/Treg functional imbalance during atherogenesis in ApoE(-/-) mice. Cytokine 49:185–193. https://doi.org/10.1016/j.cyto.2009.09.007

    Article  CAS  PubMed  Google Scholar 

  119. Zhu M, Mo H, Li D, Luo X, Zhang L (2013) Th17/Treg imbalance induced by increased incidence of atherosclerosis in patients with systemic lupus erythematosus (SLE). Clin Rheumatol 32:1045–1052. https://doi.org/10.1007/s10067-013-2237-z

    Article  PubMed  Google Scholar 

  120. Venigalla RK, Tretter T, Krienke S, Max R, Eckstein V, Blank N, Fiehn C, Ho AD, Lorenz HM (2008) Reduced CD4+, CD25- T cell sensitivity to the suppressive function of CD4+, CD25high, CD127 -/low regulatory T cells in patients with active systemic lupus erythematosus. Arthritis Rheum 58:2120–2130. https://doi.org/10.1002/art.23556

    Article  PubMed  Google Scholar 

  121. Monk CR, Spachidou M, Rovis F, Leung E, Botto M, Lechler RI, Garden OA (2005) MRL/Mp CD4+, CD25- T cells show reduced sensitivity to suppression by CD4+, CD25+ regulatory T cells in vitro: a novel defect of T cell regulation in systemic lupus erythematosus. Arthritis Rheum 52:1180–1184. https://doi.org/10.1002/art.20976

    Article  CAS  PubMed  Google Scholar 

  122. Adamo L, Rocha-Resende C, Mann DL (2020) The emerging role of B lymphocytes in cardiovascular disease. Annu Rev Immunol 38:99–121. https://doi.org/10.1146/annurev-immunol-042617-053104

    Article  CAS  PubMed  Google Scholar 

  123. Gruber S, Hendrikx T, Tsiantoulas D, Ozsvar-Kozma M, Goderle L, Mallat Z, Witztum JL, Shiri-Sverdlov R, Nitschke L, Binder CJ (2016) Sialic acid-binding immunoglobulin-like lectin G promotes atherosclerosis and liver inflammation by suppressing the protective functions of B-1 cells. Cell Rep 14:2348–2361. https://doi.org/10.1016/j.celrep.2016.02.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Sage AP, Tsiantoulas D, Baker L, Harrison J, Masters L, Murphy D, Loinard C, Binder CJ, Mallat Z (2012) BAFF receptor deficiency reduces the development of atherosclerosis in mice–brief report. Arterioscler Thromb Vasc Biol 32:1573–1576. https://doi.org/10.1161/ATVBAHA.111.244731

    Article  CAS  PubMed  Google Scholar 

  125. Kyaw T, Cui P, Tay C, Kanellakis P, Hosseini H, Liu E, Rolink AG, Tipping P, Bobik A, Toh BH (2013) BAFF receptor mAb treatment ameliorates development and progression of atherosclerosis in hyperlipidemic ApoE(-/-) mice. PLoS ONE 8:e60430. https://doi.org/10.1371/journal.pone.0060430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Tsiantoulas D, Bot I, Ozsvar-Kozma M, Goderle L, Perkmann T, Hartvigsen K, Conrad DH, Kuiper J, Mallat Z, Binder CJ (2017) Increased plasma IgE accelerate atherosclerosis in secreted IgM deficiency. Circ Res 120:78–84. https://doi.org/10.1161/CIRCRESAHA.116.309606

    Article  CAS  PubMed  Google Scholar 

  127. Tay C, Liu YH, Hosseini H, Kanellakis P, Cao A, Peter K, Tipping P, Bobik A, Toh BH, Kyaw T (2016) B-cell-specific depletion of tumour necrosis factor alpha inhibits atherosclerosis development and plaque vulnerability to rupture by reducing cell death and inflammation. Cardiovasc Res 111:385–397. https://doi.org/10.1093/cvr/cvw186

    Article  CAS  PubMed  Google Scholar 

  128. Enghard P, Humrich JY, Chu VT, Grussie E, Hiepe F, Burmester GR, Radbruch A, Berek C, Riemekasten G (2010) Class switching and consecutive loss of dsDNA-reactive B1a B cells from the peritoneal cavity during murine lupus development. Eur J Immunol 40:1809–1818. https://doi.org/10.1002/eji.200940050

    Article  CAS  PubMed  Google Scholar 

  129. Menon M, Blair PA, Isenberg DA, Mauri C (2016) A regulatory feedback between plasmacytoid dendritic cells and regulatory B cells is aberrant in systemic lupus erythematosus. Immunity 44:683–697. https://doi.org/10.1016/j.immuni.2016.02.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Svenungsson E, Engelbertsen D, Wigren M, Gustafsson JT, Gunnarsson I, Elvin K, Jensen-Urstad K, Fredrikson GN, Nilsson J (2015) Decreased levels of autoantibodies against apolipoprotein B-100 antigens are associated with cardiovascular disease in systemic lupus erythematosus. Clin Exp Immunol 181:417–426. https://doi.org/10.1111/cei.12651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Anania C, Gustafsson T, Hua X, Su J, Vikstrom M, de Faire U, Heimburger M, Jogestrand T, Frostegard J (2010) Increased prevalence of vulnerable atherosclerotic plaques and low levels of natural IgM antibodies against phosphorylcholine in patients with systemic lupus erythematosus. Arthritis Res Ther 12:R214. https://doi.org/10.1186/ar3193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Bouillet L, Baudet AE, Deroux A, Sidibe A, Dumestre-Perard C, Mannic T, Treillard B, Arboleas MA, Chiquet CA, Gulino-Debrac DG, Vilgrain IY (2013) Auto-antibodies to vascular endothelial cadherin in humans: association with autoimmune diseases. Lab Invest 93:1194–1202. https://doi.org/10.1038/labinvest.2013.106

    Article  CAS  PubMed  Google Scholar 

  133. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, PG DEG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA, (2006) International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4:295–306. https://doi.org/10.1111/j.1538-7836.2006.01753.x

    Article  CAS  PubMed  Google Scholar 

  134. Yalavarthi S, Gould TJ, Rao AN, Mazza LF, Morris AE, Nunez-Alvarez C, Hernandez-Ramirez D, Bockenstedt PL, Liaw PC, Cabral AR, Knight JS (2015) Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies: a newly identified mechanism of thrombosis in the antiphospholipid syndrome. Arthritis Rheumatol 67:2990–3003. https://doi.org/10.1002/art.39247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Petri MA, Barr E, Magder LS (2019) Development of a systemic lupus erythematosus cardiovascular risk equation. Lupus Sci Med 6:e000346. https://doi.org/10.1136/lupus-2019-000346

    Article  PubMed  PubMed Central  Google Scholar 

  136. Gustafsson JT, Svenungsson E (2014) Definitions of and contributions to cardiovascular disease in systemic lupus erythematosus. Autoimmunity 47:67–76. https://doi.org/10.3109/08916934.2013.856005

    Article  CAS  PubMed  Google Scholar 

  137. Ikonomidis I, Makavos G, Katsimbri P, Boumpas DT, Parissis J, Iliodromitis E (2019) Imaging risk in multisystem inflammatory diseases. JACC Cardiovasc Imaging 12:2517–2537. https://doi.org/10.1016/j.jcmg.2018.06.033

    Article  PubMed  Google Scholar 

  138. Figueroa AL, Abdelbaky A, Truong QA, Corsini E, MacNabb MH, Lavender ZR, Lawler MA, Grinspoon SK, Brady TJ, Nasir K, Hoffmann U, Tawakol A (2013) Measurement of arterial activity on routine FDG PET/CT images improves prediction of risk of future CV events. JACC Cardiovasc Imaging 6:1250–1259. https://doi.org/10.1016/j.jcmg.2013.08.006

    Article  PubMed  Google Scholar 

  139. Robson PM, Dey D, Newby DE, Berman D, Li D, Fayad ZA, Dweck MR (2017) MR/PET imaging of the cardiovascular system. JACC Cardiovasc Imaging 10:1165–1179. https://doi.org/10.1016/j.jcmg.2017.07.008

    Article  PubMed  PubMed Central  Google Scholar 

  140. Adamson PD, Vesey AT, Joshi NV, Newby DE, Dweck MR (2015) Salt in the wound: (18)F-fluoride positron emission tomography for identification of vulnerable coronary plaques. Cardiovasc Diagn Ther 5:150–155. https://doi.org/10.3978/j.issn.2223-3652.2015.03.01

    Article  PubMed  PubMed Central  Google Scholar 

  141. McMahon M, Skaggs BJ, Grossman JM, Sahakian L, Fitzgerald J, Wong WK, Lourenco EV, Ragavendra N, Charles-Schoeman C, Gorn A, Karpouzas GA, Taylor MB, Watson KE, Weisman MH, Wallace DJ, Hahn BH (2014) A panel of biomarkers is associated with increased risk of the presence and progression of atherosclerosis in women with systemic lupus erythematosus. Arthritis Rheumatol 66:130–139. https://doi.org/10.1002/art.38204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Skaggs BJ, Grossman J, Sahakian L, Perry L, FitzGerald J, Charles-Schoeman C, Gorn A, Taylor M, Moriarty J, Ragavendra N, Weisman M, Wallace DJ, Hahn BH, McMahon M (2021) A panel of biomarkers associates with increased risk for cardiovascular events in women with systemic lupus erythematosus. ACR Open Rheumatol 3:209–220. https://doi.org/10.1002/acr2.11223

    Article  PubMed  PubMed Central  Google Scholar 

  143. Bruce IN (2005) ‘Not only...but also’: factors that contribute to accelerated atherosclerosis and premature coronary heart disease in systemic lupus erythematosus. Rheumatology (Oxford) 44:1492–1502. https://doi.org/10.1093/rheumatology/kei142

    Article  CAS  Google Scholar 

  144. Wajed J, Ahmad Y, Durrington PN, Bruce IN (2004) Prevention of cardiovascular disease in systemic lupus erythematosus–proposed guidelines for risk factor management. Rheumatology (Oxford) 43:7–12. https://doi.org/10.1093/rheumatology/keg436

    Article  CAS  Google Scholar 

  145. Iudici M, Fasano S, Gabriele Falcone L, Pantano I, La Montagna G, Migliaresi S, Valentini G (2016) Low-dose aspirin as primary prophylaxis for cardiovascular events in systemic lupus erythematosus: a long-term retrospective cohort study. Rheumatology (Oxford) 55:1623–1630. https://doi.org/10.1093/rheumatology/kew231

    Article  CAS  Google Scholar 

  146. Fasano S, Pierro L, Pantano I, Iudici M, Valentini G (2017) Longterm hydroxychloroquine therapy and low-dose aspirin may have an additive effectiveness in the primary prevention of cardiovascular events in patients with systemic lupus erythematosus. J Rheumatol 44:1032–1038. https://doi.org/10.3899/jrheum.161351

    Article  CAS  PubMed  Google Scholar 

  147. Tselios K, Gladman DD, Su J, Urowitz MB (2016) Does renin-angiotensin system blockade protect lupus nephritis patients from atherosclerotic cardiovascular events? A case-control study. Arthritis Care Res (Hoboken) 68:1497–1504. https://doi.org/10.1002/acr.22857

    Article  CAS  Google Scholar 

  148. Fanouriakis A, Kostopoulou M, Alunno A, Aringer M, Bajema I, Boletis JN, Cervera R, Doria A, Gordon C, Govoni M, Houssiau F, Jayne D, Kouloumas M, Kuhn A, Larsen JL, Lerstrom K, Moroni G, Mosca M, Schneider M, Smolen JS, Svenungsson E, Tesar V, Tincani A, Troldborg A, van Vollenhoven R, Wenzel J, Bertsias G, Boumpas DT (2019) 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis 78:736–745. https://doi.org/10.1136/annrheumdis-2019-215089

    Article  CAS  PubMed  Google Scholar 

  149. Yu HH, Chen PC, Yang YH, Wang LC, Lee JH, Lin YT, Chiang BL (2015) Statin reduces mortality and morbidity in systemic lupus erythematosus patients with hyperlipidemia: a nationwide population-based cohort study. Atherosclerosis 243:11–18. https://doi.org/10.1016/j.atherosclerosis.2015.08.030

    Article  CAS  PubMed  Google Scholar 

  150. Reiss AB, Arain HA, Kasselman LJ, Renna HA, Zhen J, Voloshyna I, DeLeon J, Carsons SE, Petri M (2019) Human lupus plasma pro-atherogenic effects on cultured macrophages are not mitigated by statin therapy: a mechanistic LAPS substudy. Medicina (Kaunas) 55 https://doi.org/10.3390/medicina55090514

  151. Petri MA, Kiani AN, Post W, Christopher-Stine L, Magder LS (2011) Lupus Atherosclerosis Prevention Study (LAPS). Ann Rheum Dis 70:760–765. https://doi.org/10.1136/ard.2010.136762

    Article  CAS  PubMed  Google Scholar 

  152. Schanberg LE, Sandborg C, Barnhart HX, Ardoin SP, Yow E, Evans GW, Mieszkalski KL, Ilowite NT, Eberhard A, Imundo LF, Kimura Y, von Scheven E, Silverman E, Bowyer SL, Punaro M, Singer NG, Sherry DD, McCurdy D, Klein-Gitelman M, Wallace C, Silver R, Wagner-Weiner L, Higgins GC, Brunner HI, Jung L, Soep JB, Reed AM, Provenzale J, Thompson SD, Prevention A, in Pediatric Lupus Erythematosus I, (2012) Use of atorvastatin in systemic lupus erythematosus in children and adolescents. Arthritis Rheum 64:285–296. https://doi.org/10.1002/art.30645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA (2010) Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis 69:20–28. https://doi.org/10.1136/ard.2008.101766

    Article  CAS  PubMed  Google Scholar 

  154. Ponticelli C, Moroni G (2017) Hydroxychloroquine in systemic lupus erythematosus (SLE). Expert Opin Drug Saf 16:411–419. https://doi.org/10.1080/14740338.2017.1269168

    Article  CAS  PubMed  Google Scholar 

  155. Virdis A, Tani C, Duranti E, Vagnani S, Carli L, Kuhl AA, Solini A, Baldini C, Talarico R, Bombardieri S, Taddei S, Mosca M (2015) Early treatment with hydroxychloroquine prevents the development of endothelial dysfunction in a murine model of systemic lupus erythematosus. Arthritis Res Ther 17:277. https://doi.org/10.1186/s13075-015-0790-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Gomez-Guzman M, Jimenez R, Romero M, Sanchez M, Zarzuelo MJ, Gomez-Morales M, O’Valle F, Lopez-Farre AJ, Algieri F, Galvez J, Perez-Vizcaino F, Sabio JM, Duarte J (2014) Chronic hydroxychloroquine improves endothelial dysfunction and protects kidney in a mouse model of systemic lupus erythematosus. Hypertension 64:330–337. https://doi.org/10.1161/HYPERTENSIONAHA.114.03587

    Article  CAS  PubMed  Google Scholar 

  157. Miranda S, Billoir P, Damian L, Thiebaut PA, Schapman D, Le Besnerais M, Jouen F, Galas L, Levesque H, Le Cam-Duchez V, Joannides R, Richard V, Benhamou Y (2019) Hydroxychloroquine reverses the prothrombotic state in a mouse model of antiphospholipid syndrome: role of reduced inflammation and endothelial dysfunction. PLoS ONE 14:e0212614. https://doi.org/10.1371/journal.pone.0212614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Carmona-Rivera C, Carlucci PM, Moore E, Lingampalli N, Uchtenhagen H, James E, Liu Y, Bicker KL, Wahamaa H, Hoffmann V, Catrina AI, Thompson P, Buckner JH, Robinson WH, Fox DA, Kaplan MJ (2017) Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis. Sci Immunol 2 https://doi.org/10.1126/sciimmunol.aag3358

  159. Cornwell MG, Luttrell-Williams ES, Golpanian M, El Bannoudi H, Myndzar K, Izmirly P, Belmont HM, Katz S, Smilowitz NR, Engel A, Clancy R, Ruggles K, Buyon JP, Berger JS (2021) Hydroxychloroquine is associated with lower platelet activity and improved vascular health in systemic lupus erythematosus. Lupus Sci Med 8 https://doi.org/10.1136/lupus-2021-000475

  160. Yang DH, Leong PY, Sia SK, Wang YH, Wei JC (2019) Long-term hydroxychloroquine therapy and risk of coronary artery disease in patients with systemic lupus erythematosus. J Clin Med 8 https://doi.org/10.3390/jcm8060796

  161. Haugaard JH, Dreyer L, Ottosen MB, Gislason G, Kofoed K, Egeberg A (2021) Use of hydroxychloroquine and risk of major adverse cardiovascular events in patients with lupus erythematosus: a Danish nationwide cohort study. J Am Acad Dermatol 84:930–937. https://doi.org/10.1016/j.jaad.2020.12.013

    Article  CAS  PubMed  Google Scholar 

  162. Liu D, Li X, Zhang Y, Kwong JS, Li L, Zhang Y, Xu C, Li Q, Sun X, Tian H, Li S (2018) Chloroquine and hydroxychloroquine are associated with reduced cardiovascular risk: a systematic review and meta-analysis. Drug Des Devel Ther 12:1685–1695. https://doi.org/10.2147/DDDT.S166893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Sun L, Liu M, Li R, Zhao Q, Liu J, Yang Y, Zhang L, Bai X, Wei Y, Ma Q, Zhou J, Yuan Z, Wu Y (2016) Hydroxychloroquine, a promising choice for coronary artery disease? Med Hypotheses 93:5–7. https://doi.org/10.1016/j.mehy.2016.04.045

    Article  CAS  PubMed  Google Scholar 

  164. Slobodnick A, Shah B, Krasnokutsky S, Pillinger MH (2018) Update on colchicine, 2017. Rheumatology (Oxford) 57:i4–i11. https://doi.org/10.1093/rheumatology/kex453

    Article  CAS  Google Scholar 

  165. Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, Pinto FJ, Ibrahim R, Gamra H, Kiwan GS, Berry C, Lopez-Sendon J, Ostadal P, Koenig W, Angoulvant D, Gregoire JC, Lavoie MA, Dube MP, Rhainds D, Provencher M, Blondeau L, Orfanos A, L’Allier PL, Guertin MC, Roubille F (2019) Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 381:2497–2505. https://doi.org/10.1056/NEJMoa1912388

    Article  CAS  PubMed  Google Scholar 

  166. Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, The SHK, Xu XF, Ireland MA, Lenderink T, Latchem D, Hoogslag P, Jerzewski A, Nierop P, Whelan A, Hendriks R, Swart H, Schaap J, Kuijper AFM, van Hessen MWJ, Saklani P, Tan I, Thompson AG, Morton A, Judkins C, Bax WA, Dirksen M, Alings M, Hankey GJ, Budgeon CA, Tijssen JGP, Cornel JH, Thompson PL, LoDoCo2 Trial I (2020) Colchicine in patients with chronic coronary disease. N Engl J Med 383:1838–1847. https://doi.org/10.1056/NEJMoa2021372

    Article  CAS  PubMed  Google Scholar 

  167. Abel D, Ardoin SP, Gorelik M (2021) The potential role of colchicine in preventing coronary vascular disease in childhood-onset lupus: a new view on an old drug. Pediatr Rheumatol Online J 19:15. https://doi.org/10.1186/s12969-021-00504-6

    Article  PubMed  PubMed Central  Google Scholar 

  168. Han Y, Xie H, Liu Y, Gao P, Yang X, Shen Z (2019) Effect of metformin on all-cause and cardiovascular mortality in patients with coronary artery diseases: a systematic review and an updated meta-analysis. Cardiovasc Diabetol 18:96. https://doi.org/10.1186/s12933-019-0900-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Wang H, Li T, Chen S, Gu Y, Ye S (2015) Neutrophil extracellular trap mitochondrial DNA and its autoantibody in systemic lupus erythematosus and a proof-of-concept trial of metformin. Arthritis Rheumatol 67:3190–3200. https://doi.org/10.1002/art.39296

    Article  CAS  PubMed  Google Scholar 

  170. Yin Y, Choi SC, Xu Z, Perry DJ, Seay H, Croker BP, Sobel ES, Brusko TM, Morel L (2015) Normalization of CD4+ T cell metabolism reverses lupus. Sci Transl Med 7:274ra18. https://doi.org/10.1126/scitranslmed.aaa0835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Sun F, Wang HJ, Liu Z, Geng S, Wang HT, Wang X, Li T, Morel L, Wan W, Lu L, Teng X, Ye S (2020) Safety and efficacy of metformin in systemic lupus erythematosus: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Rheumatol 2:e210–e216. https://doi.org/10.1016/S2665-9913(20)30004-7

    Article  Google Scholar 

  172. Aprahamian TR, Bonegio RG, Weitzner Z, Gharakhanian R, Rifkin IR (2014) Peroxisome proliferator-activated receptor gamma agonists in the prevention and treatment of murine systemic lupus erythematosus. Immunology 142:363–373. https://doi.org/10.1111/imm.12256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Zhao W, Thacker SG, Hodgin JB, Zhang H, Wang JH, Park JL, Randolph A, Somers EC, Pennathur S, Kretzler M, Brosius FC 3rd, Kaplan MJ (2009) The peroxisome proliferator-activated receptor gamma agonist pioglitazone improves cardiometabolic risk and renal inflammation in murine lupus. J Immunol 183:2729–2740. https://doi.org/10.4049/jimmunol.0804341

    Article  CAS  PubMed  Google Scholar 

  174. Juarez-Rojas JG, Medina-Urrutia AX, Jorge-Galarza E, Caracas-Portilla NA, Posadas-Sanchez R, Cardoso-Saldana GC, Goycochea-Robles MV, Silveira LH, Lino-Perez L, Mas-Oliva J, Perez-Mendez O, Posadas-Romero C (2012) Pioglitazone improves the cardiovascular profile in patients with uncomplicated systemic lupus erythematosus: a double-blind randomized clinical trial. Lupus 21:27–35. https://doi.org/10.1177/0961203311422096

    Article  CAS  PubMed  Google Scholar 

  175. Mohammadi S, Saghaeian-Jazi M, Sedighi S, Memarian A (2017) Immunomodulation in systemic lupus erythematosus: induction of M2 population in monocyte-derived macrophages by pioglitazone. Lupus 26:1318–1327. https://doi.org/10.1177/0961203317701842

    Article  CAS  PubMed  Google Scholar 

  176. Zhao W, Berthier CC, Lewis EE, McCune WJ, Kretzler M, Kaplan MJ (2013) The peroxisome-proliferator activated receptor-gamma agonist pioglitazone modulates aberrant T cell responses in systemic lupus erythematosus. Clin Immunol 149:119–132. https://doi.org/10.1016/j.clim.2013.07.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Hasni S, Temesgen-Oyelakin Y, Davis M, Gupta S, Poncio E, Naqi M, Wang X, Oliveira C, Claybaugh D, Dey A, Lu S, Carlucci P, Manna Z, Shi Y, Ochoa I, Thomas D, Heller T, Gadina M, Chu J, Purmalek M, Li X, Playford M, Mehta N, Kaplan M (2021) The peroxisome proliferator-activated receptor-y (PPAR) agonist pioglitazone improves vascular and metabolic dysfunction in patients with systemic lupuse erythematosus (SLE) [abstract]. Arthritis Rheumatol 73

  178. Knight JS, Zhao W, Luo W, Subramanian V, O’Dell AA, Yalavarthi S, Hodgin JB, Eitzman DT, Thompson PR, Kaplan MJ (2013) Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus. J Clin Invest 123:2981–2993. https://doi.org/10.1172/JCI67390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Knight JS, Subramanian V, O’Dell AA, Yalavarthi S, Zhao W, Smith CK, Hodgin JB, Thompson PR, Kaplan MJ (2015) Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice. Ann Rheum Dis 74:2199–2206. https://doi.org/10.1136/annrheumdis-2014-205365

    Article  CAS  PubMed  Google Scholar 

  180. Knight JS, Luo W, O’Dell AA, Yalavarthi S, Zhao W, Subramanian V, Guo C, Grenn RC, Thompson PR, Eitzman DT, Kaplan MJ (2014) Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis. Circ Res 114:947–956. https://doi.org/10.1161/CIRCRESAHA.114.303312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Rohrbach AS, Slade DJ, Thompson PR, Mowen KA (2012) Activation of PAD4 in NET formation. Front Immunol 3:360. https://doi.org/10.3389/fimmu.2012.00360

    Article  PubMed  PubMed Central  Google Scholar 

  182. Liu X, Arfman T, Wichapong K, Reutelingsperger CPM, Voorberg J, Nicolaes GAF (2021) PAD4 takes charge during neutrophil activation: impact of PAD4 mediated NET formation on immune-mediated disease. J Thromb Haemost 19:1607–1617. https://doi.org/10.1111/jth.15313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Furumoto Y, Smith CK, Blanco L, Zhao W, Brooks SR, Thacker SG, Abdalrahman Z, Sciume G, Tsai WL, Trier AM, Nunez L, Mast L, Hoffmann V, Remaley AT, O’Shea JJ, Kaplan MJ, Gadina M (2017) Tofacitinib ameliorates murine lupus and its associated vascular dysfunction. Arthritis Rheumatol 69:148–160. https://doi.org/10.1002/art.39818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Hasni SA, Gupta S, Davis M, Poncio E, Temesgen-Oyelakin Y, Carlucci PM, Wang X, Naqi M, Playford MP, Goel RR, Li X, Biehl AJ, Ochoa-Navas I, Manna Z, Shi Y, Thomas D, Chen J, Biancotto A, Apps R, Cheung F, Kotliarov Y, Babyak AL, Zhou H, Shi R, Stagliano K, Tsai WL, Vian L, Gazaniga N, Giudice V, Lu S, Brooks SR, MacKay M, Gregersen P, Mehta NN, Remaley AT, Diamond B, O’Shea JJ, Gadina M, Kaplan MJ (2021) Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus. Nat Commun 12:3391. https://doi.org/10.1038/s41467-021-23361-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Verden A, Dimbil M, Kyle R, Overstreet B, Hoffman KB (2018) Analysis of spontaneous postmarket case reports submitted to the FDA regarding thromboembolic adverse events and JAK inhibitors. Drug Saf 41:357–361. https://doi.org/10.1007/s40264-017-0622-2

    Article  CAS  PubMed  Google Scholar 

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  1. Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 10 Center Drive, 12N248C, Bethesda, MD, 20892, USA

    Christopher B. Oliveira & Mariana J. Kaplan

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This article is a contribution to the special issue on: Inflammation in vascular diseases - Guest Editors: Mariana Kaplan & Peter Grayson

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Oliveira, C.B., Kaplan, M.J. Cardiovascular disease risk and pathogenesis in systemic lupus erythematosus. Semin Immunopathol 44, 309–324 (2022). https://doi.org/10.1007/s00281-022-00922-y

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