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Atherosclerosis in Rheumatoid Arthritis: Promoters and Opponents

Abstract

Substantial epidemiological data identified cardiovascular (CV) diseases as a main cause of mortality in patients with rheumatoid arthritis (RA). In light of this, RA patients may benefit from additional CV risk screening and more intensive prevention strategies. Nevertheless, current algorithms for CV risk stratification still remain tailored on general population and are burdened by a significant underestimation of CV risk in RA patients. Acute CV events in patients with RA are largely related to an accelerated atherosclerosis. As pathophysiological features of atherosclerosis overlap those occurring in the inflamed RA synovium, the understanding of those common pathways represents an urgent need and a leading challenge for CV prevention in patients with RA. Genetic background, metabolic status, gut microbiome, and systemic inflammation have been also suggested as additional key pro-atherosclerotic factors. The aim of this narrative review is to update the current knowledge about pathophysiology of atherogenesis in RA patients and potential anti-atherosclerotic effects of disease-modifying anti-rheumatic drugs.

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References

  1. Meune C, Touze E, Trinquart L, Allanore Y (2010) High risk of clinical cardiovascular events in rheumatoid arthritis: levels of associations of myocardial infarction and stroke through a systematic review and meta-analysis. Arch Cardiovasc Dis 103:253–261

    Article  PubMed  Google Scholar 

  2. Baghdadi LR, Woodman RJ, Shanahan EM, Mangoni AA (2015) The impact of traditional cardiovascular risk factors on cardiovascular outcomes in patients with rheumatoid arthritis: a systematic review and meta-analysis. PLoS One 10:e0117952

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Ambrosino P, Lupoli R, Di Minno A, Tasso M, Peluso R and Di Minno MN (2015) Subclinical atherosclerosis in patients with rheumatoid arthritis: a meta-analysis of literature studies. Thromb Haemost Vol. 113, pp. 916–930

    Article  PubMed  Google Scholar 

  4. Bartoloni E, Alunno A, Bistoni O, Gerli R (2010) How early is the atherosclerotic risk in rheumatoid arthritis? Autoimmun Rev 9:701–707

    Article  CAS  PubMed  Google Scholar 

  5. Lazzerini PE, Capecchi PL, Acampa M, Galeazzi M, Laghi-Pasini F (2014) Arrhythmic risk in rheumatoid arthritis: the driving role of systemic inflammation. Autoimmun Rev 13:936–944

    Article  PubMed  Google Scholar 

  6. Udachkina HV, Novikova DS, Popkova TV, Kirillova IG, Markelova EI, Luchikhina EL, Lukina GV et al (2018) Calcification of coronary arteries in early rheumatoid arthritis prior to anti-rheumatic therapy. Rheumatol Int 38:211–217

    Article  PubMed  Google Scholar 

  7. Wahlin B, Meedt T, Jonsson F, Henein MY, Wallberg-Jonsson S (2016) Coronary artery calcification is related to inflammation in rheumatoid arthritis: a long-term follow-up study. Biomed Res Int 2016:1261582

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Peters MJ, Symmons DP, McCarey D, Dijkmans BA, Nicola P, Kvien TK, McInnes IB et al (2010) EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis 69:325–331

    Article  CAS  PubMed  Google Scholar 

  9. Crowson CS, Gabriel SE, Semb AG, van Riel P, Karpouzas G, Dessein PH, Hitchon C et al (2017) Rheumatoid arthritis-specific cardiovascular risk scores are not superior to general risk scores: a validation analysis of patients from seven countries. Rheumatology (Oxford) 56:1102–1110

    Article  CAS  Google Scholar 

  10. Ozen G, Sunbul M, Atagunduz P, Direskeneli H, Tigen K, Inanc N (2016) The 2013 ACC/AHA 10-year atherosclerotic cardiovascular disease risk index is better than SCORE and QRisk II in rheumatoid arthritis: is it enough? Rheumatology (Oxford) 55:513–522

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Crowson CS, Rollefstad S, Ikdahl E, Kitas GD, van Riel P, Gabriel SE, Matteson EL et al (2018) Impact of risk factors associated with cardiovascular outcomes in patients with rheumatoid arthritis. Ann Rheum Dis 77:48–54

    Article  CAS  PubMed  Google Scholar 

  13. Karpouzas GA, Malpeso J, Choi TY, Li D, Munoz S, Budoff MJ (2014) Prevalence, extent and composition of coronary plaque in patients with rheumatoid arthritis without symptoms or prior diagnosis of coronary artery disease. Ann Rheum Dis 73:1797–1804

    Article  PubMed  Google Scholar 

  14. van den Oever IA, Sattar N, Nurmohamed MT (2014) Thromboembolic and cardiovascular risk in rheumatoid arthritis: role of the haemostatic system. Ann Rheum Dis 73:954–957

    Article  PubMed  CAS  Google Scholar 

  15. McCoy SS, Crowson CS, Maradit-Kremers H, Therneau TM, Roger VL, Matteson EL, Gabriel SE (2013) Longterm outcomes and treatment after myocardial infarction in patients with rheumatoid arthritis. J Rheumatol 40:605–610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lopez-Mejias R, Castaneda S, Gonzalez-Juanatey C, Corrales A, Ferraz-Amaro I, Genre F, Remuzgo-Martinez S et al (2016) Cardiovascular risk assessment in patients with rheumatoid arthritis: the relevance of clinical, genetic and serological markers. Autoimmun Rev 15:1013–1030

    Article  PubMed  Google Scholar 

  17. Gonzalez-Gay MA, Gonzalez-Juanatey C, Lopez-Diaz MJ, Pineiro A, Garcia-Porrua C, Miranda-Filloy JA, Ollier WE et al (2007) HLA-DRB1 and persistent chronic inflammation contribute to cardiovascular events and cardiovascular mortality in patients with rheumatoid arthritis. Arthritis Rheum 57:125–132

    Article  CAS  PubMed  Google Scholar 

  18. Farragher TM, Goodson NJ, Naseem H, Silman AJ, Thomson W, Symmons D, Barton A (2008) Association of the HLA-DRB1 gene with premature death, particularly from cardiovascular disease, in patients with rheumatoid arthritis and inflammatory polyarthritis. Arthritis Rheum 58:359–369

    Article  PubMed  PubMed Central  Google Scholar 

  19. Paakkanen R, Lokki ML, Seppanen M, Tierala I, Nieminen MS, Sinisalo J (2012) Proinflammatory HLA-DRB1*01-haplotype predisposes to ST-elevation myocardial infarction. Atherosclerosis 221:461–466

    Article  CAS  PubMed  Google Scholar 

  20. Shimane K, Kochi Y, Yamada R, Okada Y, Suzuki A, Miyatake A, Kubo M et al (2009) A single nucleotide polymorphism in the IRF5 promoter region is associated with susceptibility to rheumatoid arthritis in the Japanese population. Ann Rheum Dis 68:377–383

    Article  CAS  PubMed  Google Scholar 

  21. Rodriguez-Rodriguez L, Gonzalez-Juanatey C, Palomino-Morales R, Vazquez-Rodriguez TR, Miranda-Filloy JA, Fernandez-Gutierrez B, Llorca J et al (2011) TNFA -308 (rs1800629) polymorphism is associated with a higher risk of cardiovascular disease in patients with rheumatoid arthritis. Atherosclerosis 216:125–130

    Article  CAS  PubMed  Google Scholar 

  22. Vallve JC, Paredes S, Girona J, Uliaque K, Ribalta J, Hurt-Camejo E, Masana L (2008) Tumor necrosis factor-alpha -1031 T/C polymorphism is associated with smaller and more proatherogenic low density lipoprotein particles in patients with rheumatoid arthritis. J Rheumatol 35:1697–1703

    CAS  PubMed  Google Scholar 

  23. Panoulas VF, Nikas SN, Smith JP, Douglas KM, Nightingale P, Milionis HJ, Treharne GJ et al (2008) Lymphotoxin 252A>G polymorphism is common and associates with myocardial infarction in patients with rheumatoid arthritis. Ann Rheum Dis 67:1550–1556

    Article  CAS  PubMed  Google Scholar 

  24. Garcia-Bermudez M, Gonzalez-Juanatey C, Lopez-Mejias R, Teruel M, Corrales A, Miranda-Filloy JA, Castaneda S et al (2012) Study of association of CD40-CD154 gene polymorphisms with disease susceptibility and cardiovascular risk in Spanish rheumatoid arthritis patients. PLoS One 7:e49214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lopez-Mejias R, Genre F, Remuzgo-Martinez S, Robustillo-Villarino M, Garcia-Bermudez M, Llorca J, Corrales A et al (2015) Protective role of the interleukin 33 rs3939286 gene polymorphism in the development of subclinical atherosclerosis in rheumatoid arthritis patients. PLoS One 10:e0143153

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Lopez-Mejias R, Garcia-Bermudez M, Gonzalez-Juanatey C, Castaneda S, Miranda-Filloy JA, Gomez-Vaquero C, Fernandez-Gutierrez B et al (2012) NFKB1-94ATTG ins/del polymorphism (rs28362491) is associated with cardiovascular disease in patients with rheumatoid arthritis. Atherosclerosis 224:426–429

    Article  CAS  PubMed  Google Scholar 

  27. Lopez-Mejias R, Garcia-Bermudez M, Gonzalez-Juanatey C, Castaneda S, Perez-Esteban S, Miranda-Filloy JA, Gomez-Vaquero C et al (2011) Lack of association between IL6 single nucleotide polymorphisms and cardiovascular disease in Spanish patients with rheumatoid arthritis. Atherosclerosis 219:655–658

    Article  CAS  PubMed  Google Scholar 

  28. Garcia-Bermudez M, Lopez-Mejias R, Genre F, Castaneda S, Llorca J, Gonzalez-Juanatey C, Corrales A et al (2014) Interferon regulatory factor 5 genetic variants are associated with cardiovascular disease in patients with rheumatoid arthritis. Arthritis Res Ther. 16:R146

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Garcia-Bermudez M, Gonzalez-Juanatey C, Rodriguez-Rodriguez L, Vazquez-Rodriguez TR, Miranda-Filloy JA, Fernandez-Gutierrez B, Llorca J et al (2011) Lack of association between LEP rs2167270 (19 G>A) polymorphism and disease susceptibility and cardiovascular disease in patients with rheumatoid arthritis. Clin Exp Rheumatol 29:293–298

    CAS  PubMed  Google Scholar 

  30. Rodriguez-Rodriguez L, Garcia-Bermudez M, Gonzalez-Juanatey C, Vazquez-Rodriguez TR, Miranda-Filloy JA, Fernandez-Gutierrez B, Llorca J et al (2011) Lack of association between ADIPOQ rs266729 and ADIPOQ rs1501299 polymorphisms and cardiovascular disease in rheumatoid arthritis patients. Tissue Antigens 77:74–78

    Article  CAS  PubMed  Google Scholar 

  31. Rodriguez-Rodriguez L, Garcia-Bermudez M, Gonzalez-Juanatey C, Vazquez-Rodriguez TR, Miranda-Filloy JA, Fernandez-Gutierrez B, Llorca J et al (2011) Lack of association between RETN rs1862513 polymorphism and cardiovascular disease in rheumatoid arthritis patients. Clin Exp Rheumatol 29:19–25

    PubMed  Google Scholar 

  32. Cavalcanti CA, Silva Jde A, Pita Wde B, Veit TD, Monticielo OA, Xavier RM, Brenol JC et al (2016) Vitamin D receptor polymorphisms and expression profile in rheumatoid arthritis Brazilian patients. Mol Biol Rep 43:41–51

    Article  CAS  PubMed  Google Scholar 

  33. Sabry D, Kaddafy SR, Abdelaziz AA, Nassar AK, Rayan MM, Sadek SM, Abou-Elalla AA (2018) Association of SIRT-1 gene polymorphism and vitamin D level in Egyptian patients with rheumatoid arthritis. J Clin Med Res 10:189–195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Song GG, Bae SC, Lee YH (2016) Vitamin D receptor FokI, BsmI, and TaqI polymorphisms and susceptibility to rheumatoid arthritis : a meta-analysis. Z Rheumatol 75:322–329

    Article  CAS  PubMed  Google Scholar 

  35. Leonard D, Svenungsson E, Dahlqvist J, Alexsson A, Arlestig L, Taylor KE, Sandling JK et al (2018) Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis. Ann Rheum Dis

  36. Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11:98–107

    Article  CAS  PubMed  Google Scholar 

  37. Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867

    Article  CAS  PubMed  Google Scholar 

  38. Oh YS, Lee YJ, Park EY, Jun HS (2011) Interleukin-6 treatment induces beta-cell apoptosis via STAT-3-mediated nitric oxide production. Diabetes Metab Res Rev 27:813–819

    Article  CAS  PubMed  Google Scholar 

  39. Wang C, Guan Y, Yang J (2010) Cytokines in the progression of pancreatic beta-cell dysfunction. Int J Endocrinol 2010:515136

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. de la Rosa Arias I, Escudero-Contreras A, Rodriguez-Cuenca S, Ruiz-Ponce M, Jimenez-Gomez Y, Ruiz-Limon P, Perez-Sanchez C et al. (2018) Defective glucose and lipid metabolism in rheumatoid arthritis is determined by chronic inflammation in metabolic tissues. Journal of internal medicine

  41. Ruscitti P, Ursini F, Cipriani P, Ciccia F, Liakouli V, Carubbi F, Guggino G et al (2017) Prevalence of type 2 diabetes and impaired fasting glucose in patients affected by rheumatoid arthritis: results from a cross-sectional study. Medicine 96:e7896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gremese E, Ferraccioli G (2011) The metabolic syndrome: the crossroads between rheumatoid arthritis and cardiovascular risk. Autoimmun Rev 10:582–589

    Article  CAS  PubMed  Google Scholar 

  43. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, McCormick LL et al (2011) The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35:871–882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ardestani A, Lupse B, Kido Y, Leibowitz G, Maedler K (2018) mTORC1 signaling: a double-edged sword in diabetic beta cells. Cell Metab 27:314–331

    Article  CAS  PubMed  Google Scholar 

  45. Bartolome A, Kimura-Koyanagi M, Asahara S, Guillen C, Inoue H, Teruyama K, Shimizu S et al (2014) Pancreatic beta-cell failure mediated by mTORC1 hyperactivity and autophagic impairment. Diabetes 63:2996–3008

    Article  PubMed  Google Scholar 

  46. Nagai S, Kurebayashi Y, Koyasu S (2013) Role of PI3K/Akt and mTOR complexes in Th17 cell differentiation. Ann N Y Acad Sci 1280:30–34

    Article  CAS  PubMed  Google Scholar 

  47. Niu X, Chen G (2014) Clinical biomarkers and pathogenic-related cytokines in rheumatoid arthritis. J Immunol Res 2014:698192

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Zuniga LA, Shen WJ, Joyce-Shaikh B, Pyatnova EA, Richards AG, Thom C, Andrade SM et al (2010) IL-17 regulates adipogenesis, glucose homeostasis, and obesity. J Immunol 185:6947–6959

    Article  CAS  PubMed  Google Scholar 

  49. Fischer JA, Hueber AJ, Wilson S, Galm M, Baum W, Kitson C, Auer J et al (2015) Combined inhibition of tumor necrosis factor alpha and interleukin-17 as a therapeutic opportunity in rheumatoid arthritis: development and characterization of a novel bispecific antibody. Arthritis Rheumatol 67:51–62

    Article  CAS  PubMed  Google Scholar 

  50. Kang KY, Kim YK, Yi H, Kim J, Jung HR, Kim IJ, Cho JH et al (2013) Metformin downregulates Th17 cells differentiation and attenuates murine autoimmune arthritis. Int Immunopharmacol 16:85–92

    Article  CAS  PubMed  Google Scholar 

  51. Chung CP, Oeser A, Solus JF, Avalos I, Gebretsadik T, Shintani A, Raggi P et al (2008) Prevalence of the metabolic syndrome is increased in rheumatoid arthritis and is associated with coronary atherosclerosis. Atherosclerosis 196:756–763

    Article  CAS  PubMed  Google Scholar 

  52. Ruscitti P, Cipriani P, Masedu F, Romano S, Berardicurti O, Liakouli V, Carubbi F et al (2017) Increased cardiovascular events and subclinical atherosclerosis in rheumatoid arthritis patients: 1 year prospective single centre study. PLoS One 12:e0170108

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Hallajzadeh J, Safiri S, Mansournia MA, Khoramdad M, Izadi N, Almasi-Hashiani A, Pakzad R et al (2017) Metabolic syndrome and its components among rheumatoid arthritis patients: a comprehensive updated systematic review and meta-analysis. PLoS One 12:e0170361

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Parra-Salcedo F, Contreras-Yanez I, Elias-Lopez D, Aguilar-Salinas CA, Pascual-Ramos V (2015) Prevalence, incidence and characteristics of the metabolic syndrome (MetS) in a cohort of Mexican Mestizo early rheumatoid arthritis patients treated with conventional disease modifying anti-rheumatic drugs: the complex relationship between MetS and disease activity. Arthritis Res Ther. 17:34

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Muller R, Kull M, Polluste K, Aart A, Eglit T, Lember M, Kallikorm R (2017) The metabolic profile in early rheumatoid arthritis: a high prevalence of metabolic obesity. Rheumatol Int 37:21–27

    Article  CAS  PubMed  Google Scholar 

  56. Tournadre A, Pereira B, Dutheil F, Giraud C, Courteix D, Sapin V, Frayssac T et al (2017) Changes in body composition and metabolic profile during interleukin 6 inhibition in rheumatoid arthritis. J Cachexia Sarcopenia Muscle 8:639–646

    Article  PubMed  PubMed Central  Google Scholar 

  57. Liberale L, Bonaventura A, Vecchie A, Matteo C, Dallegri F, Montecucco F and Carbone F (2017) The role of adipocytokines in coronary atherosclerosis. Curr Atheroscler Rep. Vol. 19, p. 10

  58. Menzaghi C, Trischitta V (2018) The adiponectin paradox for all-cause and cardiovascular mortality. Diabetes 67:12–22

    Article  CAS  PubMed  Google Scholar 

  59. Gonzalez-Gay MA, Garcia-Unzueta MT, Berja A, Gonzalez-Juanatey C, Miranda-Filloy JA, Vazquez-Rodriguez TR, de Matias JM et al (2009) Anti-TNF-alpha therapy does not modulate leptin in patients with severe rheumatoid arthritis. Clin Exp Rheumatol 27:222–228

    CAS  PubMed  Google Scholar 

  60. Gomez-Banuelos E, Navarro-Hernandez RE, Corona-Meraz F, Madrigal-Ruiz PM, Martin-Marquez BT, Pizano-Martinez OE, Aguilar-Arreola J et al (2015) Serum leptin and serum leptin/serum leptin receptor ratio imbalance in obese rheumatoid arthritis patients positive for anti-cyclic citrullinated peptide antibodies. Arthritis Res Ther. 17:335

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Batun-Garrido JAJ, Salas-Magana M, Juarez-Rojop IE (2018) Association between leptin and IL-6 concentrations with cardiovascular risk in patients with rheumatoid arthritis. Clin Rheumatol 37:631–637

    Article  PubMed  Google Scholar 

  62. Senolt L, Pavelka K, Housa D, Haluzik M (2006) Increased adiponectin is negatively linked to the local inflammatory process in patients with rheumatoid arthritis. Cytokine 35:247–252

    Article  CAS  PubMed  Google Scholar 

  63. Rho YH, Chung CP, Solus JF, Raggi P, Oeser A, Gebretsadik T, Shintani A et al (2010) Adipocytokines, insulin resistance, and coronary atherosclerosis in rheumatoid arthritis. Arthritis Rheum 62:1259–1264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Gonzalez-Gay MA, Gonzalez-Juanatey C, Rodriguez-Rodriguez L, Miranda-Filloy JA, Martin J, Llorca J (2011) Lack of association between adipokines and ghrelin and carotid intima-media thickness in patients with severe rheumatoid arthritis. Clin Exp Rheumatol 29:358–359

  65. Dessein PH, Woodiwiss AJ, Norton GR, Tsang L, Solomon A (2013) Independent associations of total and high molecular weight adiponectin with cardiometabolic risk and surrogate markers of enhanced early atherogenesis in black and white patients with rheumatoid arthritis: a cross-sectional study. Arthritis Res Ther. 15:R128

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Dessein PH, Tsang L, Solomon A, Woodiwiss AJ, Millen AM, Norton GR (2014) Adiponectin and atherosclerosis in rheumatoid arthritis. Mediators Inflamm 2014:358949

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Qian J, Xu L, Sun X, Wang Y, Xuan W, Zhang Q, Zhao P et al (2018) Adiponectin aggravates bone erosion by promoting osteopontin production in synovial tissue of rheumatoid arthritis. Arthritis Res Ther. 20:26

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Gonzalez-Gay MA, Vazquez-Rodriguez TR, Garcia-Unzueta MT, Berja A, Miranda-Filloy JA, de Matias JM, Gonzalez-Juanatey C et al (2010) Visfatin is not associated with inflammation or metabolic syndrome in patients with severe rheumatoid arthritis undergoing anti-TNF-alpha therapy. Clin Exp Rheumatol 28:56–62

    CAS  PubMed  Google Scholar 

  69. Robinson C, Tsang L, Solomon A, Woodiwiss AJ, Gunter S, Mer M, Hsu HC et al (2018) Nesfatin-1 and visfatin expression is associated with reduced atherosclerotic disease risk in patients with rheumatoid arthritis. Peptides 102:31–37

    Article  CAS  PubMed  Google Scholar 

  70. Migita K, Maeda Y, Miyashita T, Kimura H, Nakamura M, Ishibashi H, Eguchi K (2006) The serum levels of resistin in rheumatoid arthritis patients. Clin Exp Rheumatol 24:698–701

    CAS  PubMed  Google Scholar 

  71. Senolt L, Housa D, Vernerova Z, Jirasek T, Svobodova R, Veigl D, Anderlova K et al (2007) Resistin in rheumatoid arthritis synovial tissue, synovial fluid and serum. Ann Rheum Dis 66:458–463

    Article  CAS  PubMed  Google Scholar 

  72. Gonzalez-Gay MA, Garcia-Unzueta MT, Gonzalez-Juanatey C, Miranda-Filloy JA, Vazquez-Rodriguez TR, De Matias JM, Martin J et al (2008) Anti-TNF-alpha therapy modulates resistin in patients with rheumatoid arthritis. Clin Exp Rheumatol 26:311–316

    CAS  PubMed  Google Scholar 

  73. Dessein PH, Norton GR, Woodiwiss AJ, Solomon A (2013) Independent relationship between circulating resistin concentrations and endothelial activation in rheumatoid arthritis. Ann Rheum Dis 72:1586–1588

    Article  PubMed  Google Scholar 

  74. Gonzalez-Gay MA, Gonzalez-Juanatey C, Rodriguez-Rodriguez L, Miranda-Filloy JA, Martin J, Llorca J (2011) Lack of association between adipokines and ghrelin and carotid intima-media thickness in patients with severe rheumatoid arthritis. Clin Exp Rheumatol 29:358–359

    CAS  PubMed  Google Scholar 

  75. Abella V, Scotece M, Conde J, Pino J, Gonzalez-Gay MA, Gomez-Reino JJ, Mera A et al (2017) Leptin in the interplay of inflammation, metabolism and immune system disorders. Nat Rev Rheumatol 13:100–109

    Article  CAS  PubMed  Google Scholar 

  76. Cao H, Lin J, Chen W, Xu G, Sun C (2016) Baseline adiponectin and leptin levels in predicting an increased risk of disease activity in rheumatoid arthritis: a meta-analysis and systematic review. Autoimmunity 49:547–553

    Article  CAS  PubMed  Google Scholar 

  77. Procaccini C, De Rosa V, Galgani M, Carbone F, La Rocca C, Formisano L and Matarese G (2013) Role of adipokines signaling in the modulation of T cells function. Front Immunol. Vol. 4, p. 332

  78. Wang M, Wei J, Li H, Ouyang X, Sun X, Tang Y, Chen H et al (2018) Leptin upregulates peripheral CD4(+)CXCR5(+)ICOS(+) T cells via increased IL-6 in rheumatoid arthritis patients. J Interf Cytokine Res: Off J Int Soc Interf Cytokine Res 38:86–92

    Article  CAS  Google Scholar 

  79. Sun X, Wei J, Tang Y, Wang B, Zhang Y, Shi L, Guo J et al (2017) Leptin-induced migration and angiogenesis in rheumatoid arthritis is mediated by reactive oxygen species. FEBS Open Bio 7:1899–1908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Frommer KW, Zimmermann B, Meier FM, Schroder D, Heil M, Schaffler A, Buchler C et al (2010) Adiponectin-mediated changes in effector cells involved in the pathophysiology of rheumatoid arthritis. Arthritis Rheum 62:2886–2899

    Article  CAS  PubMed  Google Scholar 

  81. Zhang MY, Dini AA, Yang XK, Li LJ, Wu GC, Leng RX, Pan HF et al (2017) Association between serum/plasma adiponectin levels and immune-mediated diseases: a meta-analysis. Arch Dermatol Res 309:625–635

    Article  CAS  PubMed  Google Scholar 

  82. Krumbholz G, Junker S, Meier FMP, Rickert M, Steinmeyer J, Rehart S, Lange U et al (2017) Response of human rheumatoid arthritis osteoblasts and osteoclasts to adiponectin. Clin Exp Rheumatol 35:406–414

    PubMed  Google Scholar 

  83. Brentano F, Schorr O, Ospelt C, Stanczyk J, Gay RE, Gay S, Kyburz D (2007) Pre-B cell colony-enhancing factor/visfatin, a new marker of inflammation in rheumatoid arthritis with proinflammatory and matrix-degrading activities. Arthritis Rheum 56:2829–2839

    Article  CAS  PubMed  Google Scholar 

  84. Hosseinzadeh-Attar MJ, Golpaie A, Foroughi M, Hosseinpanah F, Zahediasl S, Azizi F (2016) The relationship between visfatin and serum concentrations of C-reactive protein, interleukin 6 in patients with metabolic syndrome. J Endocrinol Investig 39:917–922

    Article  CAS  Google Scholar 

  85. Lee YH, Bae SC (2018) Circulating adiponectin and visfatin levels in rheumatoid arthritis and their correlation with disease activity: a meta-analysis. Int J Rheum Dis 21:664–672

    Article  CAS  PubMed  Google Scholar 

  86. Boyer JF, Gourraud PA, Cantagrel A, Davignon JL, Constantin A (2011) Traditional cardiovascular risk factors in rheumatoid arthritis: a meta-analysis. Joint, Bone, Spine: Rev Rhum 78:179–183

    Article  Google Scholar 

  87. Toms TE, Panoulas VF, Douglas KM, Griffiths H, Sattar N, Smith JP, Symmons DP et al (2010) Statin use in rheumatoid arthritis in relation to actual cardiovascular risk: evidence for substantial undertreatment of lipid-associated cardiovascular risk? Ann Rheum Dis 69:683–688

    Article  CAS  PubMed  Google Scholar 

  88. Charles-Schoeman C, Lee YY, Grijalva V, Amjadi S, FitzGerald J, Ranganath VK, Taylor M et al (2012) Cholesterol efflux by high density lipoproteins is impaired in patients with active rheumatoid arthritis. Ann Rheum Dis 71:1157–1162

    Article  CAS  PubMed  Google Scholar 

  89. McMahon M, Grossman J, FitzGerald J, Dahlin-Lee E, Wallace DJ, Thong BY, Badsha H et al (2006) Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 54:2541–2549

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  91. Myasoedova E, Crowson CS, Kremers HM, Fitz-Gibbon PD, Therneau TM, Gabriel SE (2010) Total cholesterol and LDL levels decrease before rheumatoid arthritis. Ann Rheum Dis 69:1310–1314

    Article  CAS  PubMed  Google Scholar 

  92. van Halm VP, Nielen MM, Nurmohamed MT, van Schaardenburg D, Reesink HW, Voskuyl AE, Twisk JW et al (2007) Lipids and inflammation: serial measurements of the lipid profile of blood donors who later developed rheumatoid arthritis. Ann Rheum Dis 66:184–188

    Article  PubMed  CAS  Google Scholar 

  93. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y et al (2004) Neutrophil extracellular traps kill bacteria. Science 303:1532–1535

    Article  CAS  PubMed  Google Scholar 

  94. Bonaventura A, Liberale L, Carbone F, Vecchie A, Diaz-Canestro C, Camici GG, Montecucco F et al (2018) The pathophysiological role of neutrophil extracellular traps in inflammatory diseases. Thromb Haemost 118:6–27

    Article  PubMed  Google Scholar 

  95. Gupta S, Kaplan MJ (2016) The role of neutrophils and NETosis in autoimmune and renal diseases. Nat Rev Nephrol 12:402–413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Puga I, Cols M, Barra CM, He B, Cassis L, Gentile M, Comerma L et al (2011) B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat Immunol 13:170–180

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Sangaletti S, Tripodo C, Chiodoni C, Guarnotta C, Cappetti B, Casalini P, Piconese S et al (2012) Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity. Blood 120:3007–3018

    Article  CAS  PubMed  Google Scholar 

  98. Corsiero E, Pratesi F, Prediletto E, Bombardieri M and Migliorini P (2016) NETosis as source of autoantigens in rheumatoid arthritis. Frontiers in immunology. Vol. 7, p. 485

  99. Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A, Gizinski A, Yalavarthi S, Knight JS, Friday S et al (2013) NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med 5:178ra140

    Article  CAS  Google Scholar 

  100. Koushik S, Joshi N, Nagaraju S, Mahmood S, Mudeenahally K, Padmavathy R, Jegatheesan SK et al (2017) PAD4: pathophysiology, current therapeutics and future perspective in rheumatoid arthritis. Expert Opin Ther Targets 21:433–447

    Article  CAS  PubMed  Google Scholar 

  101. Sur Chowdhury C, Giaglis S, Walker UA, Buser A, Hahn S, Hasler P (2014) Enhanced neutrophil extracellular trap generation in rheumatoid arthritis: analysis of underlying signal transduction pathways and potential diagnostic utility. Arthritis Res Ther. 16:R122

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Wang W, Jian Z, Guo J, Ning X (2014) Increased levels of serum myeloperoxidase in patients with active rheumatoid arthritis. Life Sci 117:19–23

    Article  CAS  PubMed  Google Scholar 

  103. Perez-Sanchez C, Ruiz-Limon P, Aguirre MA, Jimenez-Gomez Y, de la Rosa Arias I, Abalos-Aguilera MC, Rodriguez-Ariza A et al (2017) Diagnostic potential of NETosis-derived products for disease activity, atherosclerosis and therapeutic effectiveness in rheumatoid arthritis patients. J Autoimmun 82:31–40

    Article  CAS  PubMed  Google Scholar 

  104. Christensen AD, Haase C, Cook AD and Hamilton JA (2016) K/BxN serum-transfer arthritis as a model for human inflammatory arthritis. Frontiers in immunology. Vol. 7, p. 213

  105. Huang X, Li J, Dorta-Estremera S, Di Domizio J, Anthony SM, Watowich SS, Popkin D et al (2015) Neutrophils regulate humoral autoimmunity by restricting interferon-gamma production via the generation of reactive oxygen species. Cell Rep 12:1120–1132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Jorch SK, Kubes P (2017) An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med 23:279–287

    Article  CAS  PubMed  Google Scholar 

  107. Maicas N, Ferrandiz ML, Brines R, Ibanez L, Cuadrado A, Koenders MI, van den Berg WB et al (2011) Deficiency of Nrf2 accelerates the effector phase of arthritis and aggravates joint disease. Antioxid Redox Signal 15:889–901

    Article  CAS  PubMed  Google Scholar 

  108. Rohrbach AS, Hemmers S, Arandjelovic S, Corr M, Mowen KA (2012) PAD4 is not essential for disease in the K/BxN murine autoantibody-mediated model of arthritis. Arthritis Res Ther 14:R104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Seri Y, Shoda H, Suzuki A, Matsumoto I, Sumida T, Fujio K, Yamamoto K (2015) Peptidylarginine deiminase type 4 deficiency reduced arthritis severity in a glucose-6-phosphate isomerase-induced arthritis model. Sci Rep 5:13041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  111. Maki-Petaja KM, Elkhawad M, Cheriyan J, Joshi FR, Ostor AJ, Hall FC, Rudd JH et al (2012) Anti-tumor necrosis factor-alpha therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis. Circulation 126:2473–2480

    Article  PubMed  CAS  Google Scholar 

  112. Maki-Petaja KM, Hall FC, Booth AD, Wallace SM, Yasmin BPW, Harish S et al (2006) Rheumatoid arthritis is associated with increased aortic pulse-wave velocity, which is reduced by anti-tumor necrosis factor-alpha therapy. Circulation 114:1185–1192

    Article  CAS  PubMed  Google Scholar 

  113. Rose S, Sheth NH, Baker JF, Ogdie A, Raper A, Saboury B, Werner TJ et al (2013) A comparison of vascular inflammation in psoriasis, rheumatoid arthritis, and healthy subjects by FDG-PET/CT: a pilot study. Am J Cardiovasc Dis 3:273–278

    PubMed  PubMed Central  Google Scholar 

  114. Skeoch S, Cristinacce PLH, Williams H, Pemberton P, Xu D, Sun J, James J et al (2017) Imaging atherosclerosis in rheumatoid arthritis: evidence for increased prevalence, altered phenotype and a link between systemic and localised plaque inflammation. Sci Rep 7:827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Qi H, Yang S, Zhang L (2017) Neutrophil extracellular traps and endothelial dysfunction in atherosclerosis and thrombosis. Front Immunol 8:928

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Palmai-Pallag T, Bachrati CZ (2014) Inflammation-induced DNA damage and damage-induced inflammation: a vicious cycle. Microbes Infect 16:822–832

    Article  CAS  PubMed  Google Scholar 

  117. Sobhy IS, Miyake A, Shinya T, Galis I (2017) Oral secretions affect HIPVs induced by generalist (Mythimna loreyi) and specialist (Parnara guttata) herbivores in rice. J Chem Ecol 43:929–943

    Article  CAS  PubMed  Google Scholar 

  118. Zhang Y, Guan L, Yu J, Zhao Z, Mao L, Li S, Zhao J (2016) Pulmonary endothelial activation caused by extracellular histones contributes to neutrophil activation in acute respiratory distress syndrome. Respir Res 17:155

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Massberg S, Grahl L, von Bruehl ML, Manukyan D, Pfeiler S, Goosmann C, Brinkmann V et al (2010) Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 16:887–896

    Article  CAS  PubMed  Google Scholar 

  120. McDonald B, Davis RP, Kim SJ, Tse M, Esmon CT, Kolaczkowska E, Jenne CN (2017) Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice. Blood 129:1357–1367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Stakos DA, Kambas K, Konstantinidis T, Mitroulis I, Apostolidou E, Arelaki S, Tsironidou V et al (2015) Expression of functional tissue factor by neutrophil extracellular traps in culprit artery of acute myocardial infarction. Eur Heart J 36:1405–1414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Mangold A, Alias S, Scherz T, Hofbauer T, Jakowitsch J, Panzenbock A, Simon D et al (2015) Coronary neutrophil extracellular trap burden and deoxyribonuclease activity in ST-elevation acute coronary syndrome are predictors of ST-segment resolution and infarct size. Circ Res 116:1182–1192

    Article  CAS  PubMed  Google Scholar 

  123. Knight JS, Luo W, O'Dell AA, Yalavarthi S, Zhao W, Subramanian V, Guo C et al (2014) Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis. Circ Res 114:947–956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Warnatsch A, Ioannou M, Wang Q, Papayannopoulos V (2015) Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science 349:316–320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Ge L, Zhou X, Ji WJ, Lu RY, Zhang Y, Zhang YD, Ma YQ et al (2015) Neutrophil extracellular traps in ischemia-reperfusion injury-induced myocardial no-reflow: therapeutic potential of DNase-based reperfusion strategy. Am J Physiol Heart Circ Physiol 308:H500–H509

    Article  CAS  PubMed  Google Scholar 

  126. Ruiz-Limon P, Ortega R, de la Rosa Arias I, Abalos-Aguilera MDC, Perez-Sanchez C, Jimenez-Gomez Y, Peralbo-Santaella E et al (2017) Tocilizumab improves the proatherothrombotic profile of rheumatoid arthritis patients modulating endothelial dysfunction, NETosis, and inflammation. Transl Res 183:87–103

    Article  CAS  PubMed  Google Scholar 

  127. Aggarwal R, Liao K, Nair R, Ringold S, Costenbader KH (2009) Anti-citrullinated peptide antibody assays and their role in the diagnosis of rheumatoid arthritis. Arthritis Rheum 61:1472–1483

    Article  PubMed  PubMed Central  Google Scholar 

  128. Arandjelovic S, McKenney KR, Leming SS, Mowen KA (2012) ATP induces protein arginine deiminase 2-dependent citrullination in mast cells through the P2X7 purinergic receptor. J Immunol 189:4112–4122

    Article  CAS  PubMed  Google Scholar 

  129. Spinelli FR, Pecani A, Conti F, Mancini R, Alessandri C, Valesini G (2016) Post-translational modifications in rheumatoid arthritis and atherosclerosis: focus on citrullination and carbamylation. J Int Med Res 44:81–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Giles JT, Fert-Bober J, Park JK, Bingham CO, 3rd, Andrade F, Fox-Talbot K, Pappas D et al. (2012) Myocardial citrullination in rheumatoid arthritis: a correlative histopathologic study. Arthritis Res Ther. Vol. 14, p. R39

    Article  Google Scholar 

  131. del Rincon ID, Williams K, Stern MP, Freeman GL and Escalante A (2001) High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum Vol. 44, pp. 2737–2745

  132. Sokolove J, Brennan MJ, Sharpe O, Lahey LJ, Kao AH, Krishnan E, Edmundowicz D et al (2013) Brief report: citrullination within the atherosclerotic plaque: a potential target for the anti-citrullinated protein antibody response in rheumatoid arthritis. Arthritis Rheum 65:1719–1724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Geraldino-Pardilla L, Giles JT, Sokolove J, Zartoshti A, Robinson WH, Budoff M, Detrano R et al (2017) Association of anti-citrullinated peptide antibodies with coronary artery calcification in rheumatoid arthritis. Arthritis care Res. 69:1276–1281

    Article  CAS  Google Scholar 

  134. Sohn DH, Rhodes C, Onuma K, Zhao X, Sharpe O, Gazitt T, Shiao R et al (2015) Local joint inflammation and histone citrullination in a murine model of the transition from preclinical autoimmunity to inflammatory arthritis. Arthritis Rheumatol. 67:2877–2887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Cambridge G, Acharya J, Cooper JA, Edwards JC, Humphries SE (2013) Antibodies to citrullinated peptides and risk of coronary heart disease. Atherosclerosis 228:243–246

    Article  CAS  PubMed  Google Scholar 

  136. Shi J, Knevel R, Suwannalai P, van der Linden MP, Janssen GM, van Veelen PA, Levarht NE et al (2011) Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc Natl Acad Sci U S A 108:17372–17377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Shi J, van de Stadt LA, Levarht EW, Huizinga TW, Toes RE, Trouw LA and van Schaardenburg D (2013) Anti-carbamylated protein antibodies are present in arthralgia patients and predict the development of rheumatoid arthritis. Arthritis Rheum Vol. 65, pp. 911–915

  138. Holzer M, Gauster M, Pfeifer T, Wadsack C, Fauler G, Stiegler P, Koefeler H et al (2011) Protein carbamylation renders high-density lipoprotein dysfunctional. Antioxid Redox Signal 14:2337–2346

    Article  CAS  PubMed  Google Scholar 

  139. Speer T, Owala FO, Holy EW, Zewinger S, Frenzel FL, Stahli BE, Razavi M et al (2014) Carbamylated low-density lipoprotein induces endothelial dysfunction. Eur Heart J 35:3021–3032

    Article  CAS  PubMed  Google Scholar 

  140. Jaisson S, Pietrement C, Gillery P (2011) Carbamylation-derived products: bioactive compounds and potential biomarkers in chronic renal failure and atherosclerosis. Clin Chem 57:1499–1505

    Article  CAS  PubMed  Google Scholar 

  141. Spinelli FR, Pecani A, Ciciarello F, Colasanti T, Di Franco M, Miranda F, Conti F et al (2017) Association between antibodies to carbamylated proteins and subclinical atherosclerosis in rheumatoid arthritis patients. BMC Musculoskelet Disord 18:214

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Shamriz O, Mizrahi H, Werbner M, Shoenfeld Y, Avni O, Koren O (2016) Microbiota at the crossroads of autoimmunity. Autoimmun Rev 15:859–869

    Article  CAS  PubMed  Google Scholar 

  143. McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365:2205–2219

    Article  CAS  PubMed  Google Scholar 

  144. Scher JU, Ubeda C, Equinda M, Khanin R, Buischi Y, Viale A, Lipuma L et al (2012) Periodontal disease and the oral microbiota in new-onset rheumatoid arthritis. Arthritis Rheum 64:3083–3094

    Article  PubMed  PubMed Central  Google Scholar 

  145. Zhang X, Zhang D, Jia H, Feng Q, Wang D, Liang D, Wu X et al (2015) The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med 21:895–905

    Article  CAS  PubMed  Google Scholar 

  146. Jie Z, Xia H, Zhong SL, Feng Q, Li S, Liang S, Zhong H et al (2017) The gut microbiome in atherosclerotic cardiovascular disease. Nat Commun 8:845

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Carbone F, Liberale L, Bonaventura A, Cea M, Montecucco F (2016) Targeting inflammation in primary cardiovascular prevention. Curr Pharm Des 22:5662–5675

    Article  CAS  PubMed  Google Scholar 

  148. Zhang J, Chen L, Delzell E, Muntner P, Hillegass WB, Safford MM, Millan IY et al (2014) The association between inflammatory markers, serum lipids and the risk of cardiovascular events in patients with rheumatoid arthritis. Ann Rheum Dis 73:1301–1308

    Article  CAS  PubMed  Google Scholar 

  149. Arida A, Protogerou AD, Konstantonis G, Fragiadaki K, Kitas GD, Sfikakis PP (2017) Atherosclerosis is not accelerated in rheumatoid arthritis of low activity or remission, regardless of antirheumatic treatment modalities. Rheumatology (Oxford) 56:934–939

    Article  CAS  Google Scholar 

  150. Arts EE, Fransen J, den Broeder AA, Popa CD, van Riel PL (2015) The effect of disease duration and disease activity on the risk of cardiovascular disease in rheumatoid arthritis patients. Ann Rheum Dis 74:998–1003

    Article  CAS  PubMed  Google Scholar 

  151. Myasoedova E, Chandran A, Ilhan B, Major BT, Michet CJ, Matteson EL, Crowson CS (2016) The role of rheumatoid arthritis (RA) flare and cumulative burden of RA severity in the risk of cardiovascular disease. Ann Rheum Dis 75:560–565

    Article  CAS  PubMed  Google Scholar 

  152. Soulaidopoulos S, Nikiphorou E, Dimitroulas T, Kitas GD (2018) The role of statins in disease modification and cardiovascular risk in rheumatoid arthritis. Front Med (Lausanne) 5:24

    Article  Google Scholar 

  153. El-Barbary AM, Hussein MS, Rageh EM, Hamouda HE, Wagih AA, Ismail RG (2011) Effect of atorvastatin on inflammation and modification of vascular risk factors in rheumatoid arthritis. J Rheumatol 38:229–235

    Article  CAS  PubMed  Google Scholar 

  154. Hermann F, Forster A, Chenevard R, Enseleit F, Hurlimann D, Corti R, Spieker LE et al (2005) Simvastatin improves endothelial function in patients with rheumatoid arthritis. J Am Coll Cardiol 45:461–464

    Article  CAS  PubMed  Google Scholar 

  155. Ikdahl E, Rollefstad S, Hisdal J, Olsen IC, Pedersen TR, Kvien TK, Semb AG (2016) Sustained improvement of arterial stiffness and blood pressure after long-term rosuvastatin treatment in patients with inflammatory joint diseases: results from the RORA-AS study. PLoS One 11:e0153440

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Maki-Petaja KM, Booth AD, Hall FC, Wallace SM, Brown J, McEniery CM, Wilkinson IB (2007) Ezetimibe and simvastatin reduce inflammation, disease activity, and aortic stiffness and improve endothelial function in rheumatoid arthritis. J Am Coll Cardiol 50:852–858

    Article  CAS  PubMed  Google Scholar 

  157. McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakov O, Ford I, Capell HA et al (2004) Trial of atorvastatin in rheumatoid arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet 363:2015–2021

    Article  CAS  PubMed  Google Scholar 

  158. Rollefstad S, Ikdahl E, Hisdal J, Olsen IC, Holme I, Hammer HB, Smerud KT et al (2015) Rosuvastatin-induced carotid plaque regression in patients with inflammatory joint diseases: the rosuvastatin in rheumatoid arthritis, ankylosing spondylitis and other inflammatory joint diseases study. Arthritis Rheumatol. 67:1718–1728

    Article  CAS  PubMed  Google Scholar 

  159. Tam LS, Li EK, Shang Q, Tomlinson B, Lee VW, Lee KK, Li M et al (2011) Effects of rosuvastatin on subclinical atherosclerosis and arterial stiffness in rheumatoid arthritis: a randomized controlled pilot trial. Scand J Rheumatol 40:411–421

    Article  CAS  PubMed  Google Scholar 

  160. Van Doornum S, McColl G, Wicks IP (2004) Atorvastatin reduces arterial stiffness in patients with rheumatoid arthritis. Ann Rheum Dis 63:1571–1575

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Steiner G, Urowitz MB (2009) Lipid profiles in patients with rheumatoid arthritis: mechanisms and the impact of treatment. Semin Arthritis Rheum 38:372–381

    Article  CAS  PubMed  Google Scholar 

  162. Akiyama M, Mawatari T, Nakashima Y, Miyahara H, Yamada H, Okazaki K, Fukushi J et al (2015) Prevalence of dyslipidemia in Japanese patients with rheumatoid arthritis and effects of atorvastatin treatment. Clin Rheumatol 34:1867–1875

    Article  PubMed  Google Scholar 

  163. Semb AG, Holme I, Kvien TK, Pedersen TR (2011) Intensive lipid lowering in patients with rheumatoid arthritis and previous myocardial infarction: an explorative analysis from the incremental decrease in endpoints through aggressive lipid lowering (IDEAL) trial. Rheumatology (Oxford) 50:324–329

    Article  CAS  Google Scholar 

  164. Sheng X, Murphy MJ, Macdonald TM, Wei L (2012) Effectiveness of statins on total cholesterol and cardiovascular disease and all-cause mortality in osteoarthritis and rheumatoid arthritis. J Rheumatol 39:32–40

    Article  CAS  PubMed  Google Scholar 

  165. De Vera MA, Choi H, Abrahamowicz M, Kopec J, Lacaille D (2012) Impact of statin discontinuation on mortality in patients with rheumatoid arthritis: a population-based study. Arthritis Care Res 64:809–816

    Article  CAS  Google Scholar 

  166. Semb AG, Kvien TK, DeMicco DA, Fayyad R, Wun CC, LaRosa JC, Betteridge J et al (2012) Effect of intensive lipid-lowering therapy on cardiovascular outcome in patients with and those without inflammatory joint disease. Arthritis Rheum 64:2836–2846

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  168. Huang CY, Lin TT, Yang YH, Lin LY, Tsai CT, Hwang JJ, Chen PC et al (2018) Effect of statin therapy on the prevention of new-onset acute coronary syndrome in patients with rheumatoid arthritis. Int J Cardiol 253:1–6

    Article  PubMed  Google Scholar 

  169. Li GM, Zhao J, Li B, Zhang XF, Ma JX, Ma XL, Liu J (2018) The anti-inflammatory effects of statins on patients with rheumatoid arthritis: a systemic review and meta-analysis of 15 randomized controlled trials. Autoimmun Rev 17:215–225

    Article  CAS  PubMed  Google Scholar 

  170. Lv S, Liu Y, Zou Z, Li F, Zhao S, Shi R, Bian R et al (2015) The impact of statins therapy on disease activity and inflammatory factor in patients with rheumatoid arthritis: a meta-analysis. Clin Exp Rheumatol 33:69–76

    PubMed  Google Scholar 

  171. Oesterle A, Laufs U, Liao JK (2017) Pleiotropic effects of statins on the cardiovascular system. Circ Res 120:229–243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Chang Y, Wei W (2015) Angiotensin II in inflammation, immunity and rheumatoid arthritis. Clin Exp Immunol 179:137–145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Kawakami Y, Matsuo K, Murata M, Yudoh K, Nakamura H, Shimizu H, Beppu M et al. (2012) Expression of angiotensin II receptor-1 in human articular chondrocytes. Arthritis Vol 2012, p 648537

  174. Walsh DA, Catravas J, Wharton J (2000) Angiotensin converting enzyme in human synovium: increased stromal [(125)I]351A binding in rheumatoid arthritis. Ann Rheum Dis 59:125–131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Flammer AJ, Sudano I, Hermann F, Gay S, Forster A, Neidhart M, Kunzler P et al (2008) Angiotensin-converting enzyme inhibition improves vascular function in rheumatoid arthritis. Circulation 117:2262–2269

    Article  CAS  PubMed  Google Scholar 

  176. Perry ME, Chee MM, Ferrell WR, Lockhart JC, Sturrock RD (2008) Angiotensin receptor blockers reduce erythrocyte sedimentation rate levels in patients with rheumatoid arthritis. Ann Rheum Dis 67:1646–1647

    Article  CAS  PubMed  Google Scholar 

  177. Ridker PM, Luscher TF (2014) Anti-inflammatory therapies for cardiovascular disease. Eur Heart J 35:1782–1791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Mangoni AA, Zinellu A, Sotgia S, Carru C, Piga M and Erre GL (2017) Protective effects of methotrexate against proatherosclerotic cytokines: a review of the evidence. Mediators Inflamm. Vol. 2017, p. 9632846

  179. Kim HJ, Kim MJ, Lee CK, Hong YH (2015) Effects of methotrexate on carotid intima-media thickness in patients with rheumatoid arthritis. J Korean Med Sci 30:1589–1596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Woodman RJ, Baghdadi LR, Shanahan ME, Mangoni AA (2017) The temporal relationship between arterial stiffening and blood pressure is modified by methotrexate treatment in patients with rheumatoid arthritis. Front Physiol 8:593

    Article  PubMed  PubMed Central  Google Scholar 

  181. Yasar Bilge NS, Kasifoglu N, Kasifoglu T, Sahin F, Gonullu E, Korkmaz C (2016) The role of methotrexate and low-dose prednisolone on adiponectine levels and insulin resistance in patients with rheumatoid arthritis naive to disease-modifying antirheumatic drugs. Int J Rheum Dis 19:665–671

    Article  CAS  PubMed  Google Scholar 

  182. Low AS, Symmons DP, Lunt M, Mercer LK, Gale CP, Watson KD, Dixon WG et al (2017) Relationship between exposure to tumour necrosis factor inhibitor therapy and incidence and severity of myocardial infarction in patients with rheumatoid arthritis. Ann Rheum Dis 76:654–660

    Article  CAS  PubMed  Google Scholar 

  183. Bissell LA, Hensor EM, Kozera L, Mackie SL, Burska AN, Nam JL, Keen H et al (2016) Improvement in insulin resistance is greater when infliximab is added to methotrexate during intensive treatment of early rheumatoid arthritis-results from the IDEA study. Rheumatology (Oxford) 55:2181–2190

    Article  CAS  Google Scholar 

  184. Kotani K, Miyamoto M, Ando H (2017) The effect of treatments for rheumatoid arthritis on endothelial dysfunction evaluated by flow-mediated vasodilation in patients with rheumatoid arthritis. Curr Vasc Pharmacol 15:10–18

    Article  CAS  PubMed  Google Scholar 

  185. Manfredi AA, Baldini M, Camera M, Baldissera E, Brambilla M, Peretti G, Maseri A et al (2016) Anti-TNFalpha agents curb platelet activation in patients with rheumatoid arthritis. Ann Rheum Dis 75:1511–1520

    Article  CAS  PubMed  Google Scholar 

  186. Voloshyna I, Seshadri S, Anwar K, Littlefield MJ, Belilos E, Carsons SE, Reiss AB (2014) Infliximab reverses suppression of cholesterol efflux proteins by TNF-alpha: a possible mechanism for modulation of atherogenesis. Biomed Res Int. 2014:312647

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Bergstrom U, Grundtman C, Lundberg IE, Jacobsson LT, Nilsson K, Turesson C (2014) Effects of adalimumab treatment on endothelial cell activation markers in the skeletal muscle of patients with rheumatoid arthritis. Clin Exp Rheumatol 32:883–890

    PubMed  Google Scholar 

  188. Vassilopoulos D, Gravos A, Vlachopoulos C, Kandili A, Ioakeimidis N, Pectasides D, Stefanadis C (2015) Adalimumab decreases aortic stiffness independently of its effect in disease activity in patients with rheumatoid arthritis. Clin Rheumatol 34:359–364

    Article  PubMed  Google Scholar 

  189. Heathfield SK, Parker B, Zeef LA, Bruce IN, Alexander MY (2013) Certolizumab pegol attenuates the pro-inflammatory state in endothelial cells in a manner that is atheroprotective. Clin Exp Rheumatol 31:225–233

    PubMed  Google Scholar 

  190. Charles-Schoeman C, Wang X, Lee YY, Shahbazian A, Navarro-Millan I, Yang S, Chen L et al (2016) Association of triple therapy with improvement in cholesterol profiles over two-year follow up in the treatment of early aggressive rheumatoid arthritis trial. Arthritis Rheumatol 68:577–586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Deodhar A, Bitman B, Yang Y, Collier DH (2016) The effect of etanercept on traditional metabolic risk factors for cardiovascular disease in patients with rheumatoid arthritis. Clin Rheumatol 35:3045–3052

    Article  PubMed  PubMed Central  Google Scholar 

  192. Totoson P, Maguin-Gate K, Prigent-Tessier A, Monnier A, Verhoeven F, Marie C, Wendling D et al (2016) Etanercept improves endothelial function via pleiotropic effects in rat adjuvant-induced arthritis. Rheumatology (Oxford) 55:1308–1317

    Article  CAS  Google Scholar 

  193. Charles-Schoeman C, Wicker P, Gonzalez-Gay MA, Boy M, Zuckerman A, Soma K, Geier J et al (2016) Cardiovascular safety findings in patients with rheumatoid arthritis treated with tofacitinib, an oral Janus kinase inhibitor. Semin Arthritis Rheum 46:261–271

    Article  CAS  PubMed  Google Scholar 

  194. Kim SC, Solomon DH, Rogers JR, Gale S, Klearman M, Sarsour K, Schneeweiss S (2017) Cardiovascular safety of tocilizumab versus tumor necrosis factor inhibitors in patients with rheumatoid arthritis: a multi-database cohort study. Arthritis Rheumatol 69:1154–1164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Kume K, Amano K, Yamada S, Kanazawa T, Ohta H, Hatta K, Amano K et al (2017) Tofacitinib improves atherosclerosis despite up-regulating serum cholesterol in patients with active rheumatoid arthritis: a cohort study. Rheumatol Int 37:2079–2085

    Article  CAS  PubMed  Google Scholar 

  196. Gabay C, McInnes IB, Kavanaugh A, Tuckwell K, Klearman M, Pulley J, Sattar N (2016) Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis. Ann Rheum Dis 75:1806–1812

    Article  PubMed  CAS  Google Scholar 

  197. Wang Z, Wang S, Wang Z, Yun T, Wang C, Wang H (2017) Tofacitinib ameliorates atherosclerosis and reduces foam cell formation in apoE deficient mice. Biochem Biophys Res Commun 490:194–201

    Article  CAS  PubMed  Google Scholar 

  198. Dayer JM, Oliviero F, Punzi L (2017) A brief history of IL-1 and IL-1 Ra in rheumatology. Front Pharmacol 8:293

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  199. Herder C, de Las Heras Gala T, Carstensen-Kirberg M, Huth C, Zierer A, Wahl S, Sudduth-Klinger J et al. (2017) Circulating levels of interleukin 1-receptor antagonist and risk of cardiovascular disease: meta-analysis of six population-based cohorts. Arterioscler Thromb Vasc Biol Vol. 37, pp. 1222–1227

    Article  CAS  PubMed  Google Scholar 

  200. Peiro C, Lorenzo O, Carraro R, Sanchez-Ferrer CF (2017) IL-1beta inhibition in cardiovascular complications associated to diabetes mellitus. Front Pharmacol 8:363

  201. Ruscitti P, Cipriani P, Liakouli V, Carubbi F, Berardicurti O, Di Benedetto P, Ciccia F et al. (2018) The emerging role of IL-1 inhibition in patients affected by rheumatoid arthritis and diabetes. Rev Recent Clin Trials

  202. Di KB, Bahcivan E, Eser Faki H, Uney K (2018) Combined treatment with interlukin-1 and tumor necrosis factor-alpha antagonists improve type 2 diabetes in rats. Can J Physiol Pharmacol

  203. Szekanecz Z, Kerekes G, Vegh E, Kardos Z, Barath Z, Tamasi L, Shoenfeld Y (2016) Autoimmune atherosclerosis in 3D: how it develops, how to diagnose and what to do. Autoimmun Rev 15:756–769

    Article  CAS  PubMed  Google Scholar 

  204. Ormseth MJ, Solus JF, Vickers KC, Oeser AM, Raggi P, Stein CM (2015) Utility of select plasma microRNA for disease and cardiovascular risk assessment in patients with rheumatoid arthritis. J Rheumatol 42:1746–1751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by a grant from the European Commission (FP7-INNOVATION I HEALTH-F2-2013-602114; Athero-B Cell: Targeting and exploiting B cell function for treatment in cardiovascular disease), a grant from the Italian Ministry of Health to the Italian Cardiovascular Network and a grant from the Fondazione CARIGE to Prof. F. Montecucco.

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Correspondence to Maurizio Cutolo.

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Carbone, F., Bonaventura, A., Liberale, L. et al. Atherosclerosis in Rheumatoid Arthritis: Promoters and Opponents. Clinic Rev Allerg Immunol 58, 1–14 (2020). https://doi.org/10.1007/s12016-018-8714-z

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  • DOI: https://doi.org/10.1007/s12016-018-8714-z

Keywords

  • Rheumatoid arthritis
  • Atherosclerosis
  • Neutrophil extracellular traps
  • Microbiome
  • Single nucleotide polymorphisms
  • Adipocytokines