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Associations of Rheumatoid Factor, Rheumatoid Arthritis, and Interleukin-6 Inhibitor with the Prognosis of Ischemic Stroke: a Prospective Multicenter Cohort Study and Mendelian Randomization Analysis

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Abstract

Rheumatoid factor (RF), an established diagnostic biomarker for rheumatoid arthritis (RA), is associated with cardiovascular diseases, but its impact on clinical outcomes of ischemic stroke remains unclear. We aimed to investigate the observational associations between serum RF and prognosis of ischemic stroke, and further examined the genetic associations of RA and its therapeutic strategy, interleukin-6 (IL-6) inhibitor, with prognosis of ischemic stroke. We measured serum RF levels in 3474 Chinese ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke. The primary outcome was the composite outcome of death or major disability (modified Rankin Scale score ≥3) at 3 months after stroke onset. Mendelian randomization (MR) analyses were performed to examine the associations of genetically predicted RA and IL-6 inhibition with prognosis of ischemic stroke. During 3 months of follow-up, 866 patients (25.43%) experienced death or major disability. After multivariate adjustment, RF-positive was significantly associated with a high risk of primary outcome (OR, 1.47; 95% CI, 1.08–2.00; P =0.016) compared with RF-negative. The two-sample MR analyses suggested that genetically predicted RA was associated with an increased risk of primary outcome (OR, 1.09; 95% CI, 1.01–1.18; P=0.021), while genetically predicted IL-6 inhibition was associated with a decreased risk of primary outcome (OR, 0.88; 95% CI, 0.77–0.99; P=0.041). We found that positive RF was associated with increased risks of adverse outcomes after atherosclerotic ischemic stroke, and genetically predicted RA and IL-6 inhibition increased and decreased the risks of adverse outcomes after ischemic stroke, respectively.

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Data Availability

CATIS data are available to researchers on reasonable request by directly contacting the corresponding authors. All summary statistics used in the two-sample Mendelian randomization analyses are available online from each genome-wide association study. Statistical code is available on the request by directly contacting the corresponding authors.

References

  1. Ma Q, Li R, Wang L, et al. Temporal trend and attributable risk factors of stroke burden in China, 1990–2019: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 2021;6(12):e897–906.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Pan Y, Li Z, Li J, et al. Residual risk and its risk factors for ischemic stroke with adherence to guideline-based secondary stroke prevention. J Stroke. 2021;23(1):51–60.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69(9):1580–8.

    Article  PubMed  Google Scholar 

  4. Tan EM, Smolen JS. Historical observations contributing insights on etiopathogenesis of rheumatoid arthritis and role of rheumatoid factor. J Exp Med. 2016;213(10):1937–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kato H, Yamakawa M, Ogino T. Complement mediated vascular endothelial injury in rheumatoid nodules: a histopathological and immunohistochemical study. J Rheumatol. 2000;27(8):1839–47.

    CAS  PubMed  Google Scholar 

  6. Majka DS, Vu TT, Pope RM, et al. Association of rheumatoid factors with subclinical and clinical atherosclerosis in African American women: the multiethnic study of atherosclerosis. Arthritis Care Res (Hoboken). 2017;69(2):166–74.

    Article  CAS  PubMed  Google Scholar 

  7. Edwards CJ, Syddall H, Goswami R, et al. The autoantibody rheumatoid factor may be an independent risk factor for ischaemic heart disease in men. Heart. 2007;93(10):1263–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Holmqvist ME, Wedren S, Jacobsson LT, et al. Rapid increase in myocardial infarction risk following diagnosis of rheumatoid arthritis amongst patients diagnosed between 1995 and 2006. J Intern Med. 2010;268(6):578–85.

    Article  CAS  PubMed  Google Scholar 

  9. Myasoedova E, Crowson CS, Nicola PJ, et al. The influence of rheumatoid arthritis disease characteristics on heart failure. J Rheumatol. 2011;38(8):1601–6.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lee DH, Sheen SH, Lee DG, et al. Association between ischemic stroke and seropositive rheumatoid arthritis in Korea: a nationwide longitudinal cohort study. PloS One. 2021;16(5):e0251851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Quisi A, Alici G. The relationship between serum rheumatoid factor level and no-reflow phenomenon in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. J Clin Lab Anal. 2018;32(9):e22598.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Tomasson G, Aspelund T, Jonsson T, Valdimarsson H, Felson DT, Gudnason V. Effect of rheumatoid factor on mortality and coronary heart disease. Ann Rheum Dis. 2010;69(9):1649–54.

    Article  CAS  PubMed  Google Scholar 

  13. Zhu Z, Chen L, Guo D, et al. Serum rheumatoid factor levels at acute phase of ischemic stroke are associated with poststroke cognitive impairment. J Stroke Cerebrovasc Dis. 2019;28(4):1133–40.

    Article  PubMed  Google Scholar 

  14. Södergren A, Stegmayr B, Ohman M-L, Wållberg-Jonsson S. Increased incidence of stroke and impaired prognosis after stroke among patients with seropositive rheumatoid arthritis. Clin Exp Rheumatol. 2009;27(4):641–4.

    PubMed  Google Scholar 

  15. Vallbracht I, Rieber J, Oppermann M, Forger F, Siebert U, Helmke K. Diagnostic and clinical value of anti-cyclic citrullinated peptide antibodies compared with rheumatoid factor isotypes in rheumatoid arthritis. Ann Rheum Dis. 2004;63(9):1079–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kishimoto T, Kang S. IL-6 Revisited: from rheumatoid arthritis to CAR T cell therapy and COVID-19. Annu Rev Immunol. 2022;40:323–48.

    Article  PubMed  Google Scholar 

  17. Lee K, Lim CY. Mendelian randomization analysis in observational epidemiology. J Lipid Atheroscler. 2019;8(2):67–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Okada Y, Wu D, Trynka G, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014;506(7488):376–81.

    Article  CAS  PubMed  Google Scholar 

  19. Folkersen L, Fauman E, Sabater-Lleal M, et al. Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease. PLoS Genet. 2017;13(4):e1006706.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Soderholm M, Pedersen A, Lorentzen E, et al. Genome-wide association meta-analysis of functional outcome after ischemic stroke. Neurology. 2019;92(12):e1271–83.

    Article  PubMed  PubMed Central  Google Scholar 

  21. He J, Zhang Y, Xu T, et al. Effects of immediate blood pressure reduction on death and major disability in patients with acute ischemic stroke: the CATIS randomized clinical trial. JAMA. 2014;311(5):479–89.

    Article  CAS  PubMed  Google Scholar 

  22. Brott T, Adams HP Jr, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989;20(7):864–70.

    Article  CAS  PubMed  Google Scholar 

  23. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24(1):35–41.

    Article  PubMed  Google Scholar 

  24. Pickering TG, Hall JE, Appel LJ, et al. Recommendations for blood pressure measurement in humans: an AHA scientific statement from the Council on High Blood Pressure Research Professional and Public Education Subcommittee. J Clin Hypertens (Greenwich). 2005;7(2):102–9.

    Article  PubMed  Google Scholar 

  25. Joint Committee for Developing Chinese guidelines on Prevention and Treatment of Dyslipidemia in Adults. Chinese guidelines on prevention and treatment of dyslipidemia in adults. Zhonghua Xin Xue Guan Bing Za Zhi. 2007;35:390–419.

    Google Scholar 

  26. Bath PM, Lees KR, Schellinger PD, et al. Statistical analysis of the primary outcome in acute stroke trials. Stroke. 2012;43(4):1171–8.

    Article  PubMed  Google Scholar 

  27. Murphy D, Sinha-Royle E, Bellis K, Harrington C, Hutchinson D. Nodular rheumatoid arthritis (RA): A distinct disease subtype, initiated by cadmium inhalation inducing pulmonary nodule formation and subsequent RA-associated autoantibody generation. Med Hypotheses. 2019;122:48–55.

    Article  CAS  PubMed  Google Scholar 

  28. Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013;37(7):658–65.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Hemani G, Zheng J, Elsworth B, et al. The MR-Base platform supports systematic causal inference across the human phenome. eLife. 2018;7:e34408.

  30. Chen YR, Hsieh FI, Lien LM, et al. Rheumatoid arthritis significantly increased recurrence risk after ischemic stroke/transient ischemic attack. J Neurol. 2018;265(8):1810–8.

    Article  CAS  PubMed  Google Scholar 

  31. Nguyen-Oghalai TU, Wu H, McNearney TA, Granger CV, Ottenbacher KJ. Functional outcome after stroke in patients with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Rheum. 2008;59(7):984–8.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kwan J, Horsfield G, Bryant T, et al. IL-6 is a predictive biomarker for stroke associated infection and future mortality in the elderly after an ischemic stroke. Exp Gerontol. 2013;48(9):960–5.

    Article  CAS  PubMed  Google Scholar 

  33. Pawluk H, Grzesk G, Kolodziejska R, et al. Effect of IL-6 and hsCRP serum levels on functional prognosis in stroke patients undergoing IV-thrombolysis: retrospective analysis. Clin Interv Aging. 2020;15:1295–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gale RJ, Nikoloutsopoulos A, Bradley J, Roberts-Thomson PJ. Immune complex activation of neutrophils and enhancement of the activation by rheumatoid factor and complement. J Rheumatol. 1985;12(1):21–6.

    CAS  PubMed  Google Scholar 

  35. Han S, Kim NR, Kang JW, Eun JS, Kang YM. Radial BMD and serum CTX-I can predict the progression of carotid plaque in rheumatoid arthritis: a 3-year prospective cohort study. Arthritis Res Ther. 2021;23(1):258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Suss P, Rothe T, Hoffmann A, Schlachetzki JCM, Winkler J. The joint-brain axis: insights from rheumatoid arthritis on the crosstalk between chronic peripheral inflammation and the brain. Front Immunol. 2020;11:612104.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Tam LH, Shang Q, Li EK, et al. Effect of treat-to-target strategies aiming at remission of arterial stiffness in early rheumatoid arthritis: a randomized controlled study. J Rheumatol. 2018;45(9):1229–39.

    Article  CAS  PubMed  Google Scholar 

  38. Akhmedov A, Crucet M, Simic B, et al. TNFalpha induces endothelial dysfunction in rheumatoid arthritis via LOX-1 and arginase 2: reversal by monoclonal TNFalpha antibodies. Cardiovasc Res. 2022;118(1):254–66.

    Article  CAS  PubMed  Google Scholar 

  39. Wang J, He L, Li W, Lv S. A role of IL-17 in rheumatoid arthritis patients complicated with atherosclerosis. Front Pharmacol. 2022;13:828933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nishioku T, Furusho K, Tomita A, et al. Potential role for S100A4 in the disruption of the blood-brain barrier in collagen-induced arthritic mice, an animal model of rheumatoid arthritis. Neuroscience. 2011;189:286–92.

    Article  CAS  PubMed  Google Scholar 

  41. Armstead WM, Hekierski H, Pastor P, Yarovoi S, Higazi AA, Cines DB. Release of IL-6 after stroke contributes to impaired cerebral autoregulation and hippocampal neuronal necrosis through NMDA receptor activation and upregulation of ET-1 and JNK. Transl Stroke Res. 2019;10(1):104–11.

    Article  CAS  PubMed  Google Scholar 

  42. Pulito-Cueto V, Remuzgo-Martínez S, Genre F, et al. Anti-IL-6 therapy reduces leptin serum levels in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2020;38(6):1201–5.

    PubMed  Google Scholar 

  43. Nikolopoulos D, Manolakou T, Polissidis A, et al. Microglia activation in the presence of intact blood-brain barrier and disruption of hippocampal neurogenesis via IL-6 and IL-18 mediate early diffuse neuropsychiatric lupus. Ann Rheum Dis. 2023;82(5):646–57.

    Article  CAS  PubMed  Google Scholar 

  44. Cimmino G, Conte S, Morello M, et al. Vitamin D inhibits IL-6 pro-atherothrombotic effects in human endothelial cells: a potential mechanism for protection against COVID-19 infection? J Cardiovasc Dev Dis. 2022;9(1):27.

  45. Grover SP, Mackman N. Tissue factor: an essential mediator of hemostasis and trigger of thrombosis. Arterioscler Thromb Vasc Biol. 2018;38(4):709–25.

    Article  CAS  PubMed  Google Scholar 

  46. O'Barr S, Cooper NR. The C5a complement activation peptide increases IL-1beta and IL-6 release from amyloid-beta primed human monocytes: implications for Alzheimer's disease. J Neuroimmunol. 2000;109(2):87–94.

    Article  CAS  PubMed  Google Scholar 

  47. Newkirk MM, Zbar A, Baron M, Manges AR. Distinct bacterial colonization patterns of Escherichia coli subtypes associate with rheumatoid factor status in early inflammatory arthritis. Rheumatology. 2010;49(7):1311–6.

    Article  PubMed  Google Scholar 

  48. Christensen MG, Fagerberg SK, de Bruijn PI, et al. [Ca2+]i Oscillations and IL-6 release induced by alpha-hemolysin from Escherichia coli require P2 receptor activation in renal epithelia. J Biol Chem. 2015;290(23):14776–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2021;73(7):1108–23.

    Article  PubMed  Google Scholar 

  50. Nadareishvili Z, Michaud K, Hallenbeck JM, Wolfe F. Cardiovascular, rheumatologic, and pharmacologic predictors of stroke in patients with rheumatoid arthritis: a nested, case-control study. Arthritis Rheum. 2008;59(8):1090–6.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Penner LS, Gavan SP, Ashcroft DM, Peek N, Elliott RA. Does co-prescribing non-steroidal anti-inflammatory drugs and oral anticoagulants increase the risk of major bleeding, stroke and systemic embolism? Br J Clin Pharmacol. 2022;88(11):4789–4811.

  52. Luo Y, Wang X, Matsushita K, et al. Associations between estimated glomerular filtration rate and stroke outcomes in diabetic versus nondiabetic patients. Stroke. 2014;45(10):2887–93.

    Article  PubMed  Google Scholar 

  53. Ugolini A, Nuti M. Rheumatoid factor: a novel determiner in cancer history. Cancers (Basel). 2021;13(4):591.

  54. Avouac J, Gossec L, Dougados M. Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: a systematic literature review. Ann Rheum Dis. 2006;65(7):845–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kastbom A, Strandberg G, Lindroos A, Skogh T. Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project). Ann Rheum Dis. 2004;63(9):1085–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Witte T, Hartung K, Sachse C, et al. Rheumatoid factors in systemic lupus erythematosus: association with clinical and laboratory parameters. SLE study group. Rheumatol Int. 2000;19(3):107–11.

    Article  CAS  PubMed  Google Scholar 

  57. Coskun Y, Yuksel I. Serum rheumatoid factor is correlated with liver fibrosis in patients with chronic hepatitis B. Wien Klin Wochenschr. 2021;133(9-10):432–40.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the study participants and their relatives and the clinical staff at all participating hospitals for their support and contribution to this project. We thank the investigators of GISCOME study, IMPROVE study, and the European-descent GWAS of rheumatoid arthritis for making their results publicly available. Full acknowledgement and funding statements for each of these resources are available via the relevant cited reports.

Funding

This study was supported by the National Natural Science Foundation of China (grant: 82020108028 and 82103917), and the Natural Science Research Project of Jiangsu Provincial Higher Education (grant: 21KJB330006).

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  1. Yiming Jia and Kaixin Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Medical College of Soochow University, 199 Renai Road, Industrial Park District, Suzhou, 215123, Jiangsu Province, China

    Yiming Jia, Kaixin Zhang, Mengyao Shi, Daoxia Guo, Pinni Yang, Aili Wang, Tan Xu, Zhengbao Zhu & Yonghong Zhang

  2. Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA

    Mengyao Shi, Jing Chen, Jiang He & Zhengbao Zhu

  3. School of Nursing, Suzhou Medical College of Soochow University, Suzhou, China

    Daoxia Guo

  4. Department of Epidemiology, School of Public health, Chongqing Medical University, Chongqing, China

    Xiaoqing Bu

  5. Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA

    Jing Chen & Jiang He

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  1. Yiming Jia
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Contributions

The study was conceived and designed by YJ, KZ, ZZ, and YZ. YJ, KZ, ZZ, and YZ coordinated the study. YJ, KZ, MS, DG, PY, XB, JC, AW, TX, JH, ZZ, and YZ contributed to data collection. YJ and KZ performed the statistical analysis and prepared the first draft of manuscript. ZZ and YZ revised the paper and helped to write the final draft of manuscript. ZZ and YZ is guarantor.

Corresponding authors

Correspondence to Zhengbao Zhu or Yonghong Zhang.

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Ethics Declarations

The CATIS trial is registered at clinicaltrials.gov (Identifier: NCT01840072). The CATIS protocol was approved by the Institutional Review Boards at Soochow University in China and Tulane University in the United States, and all participating hospitals. Written consent was obtained from all study participants or their representatives.

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Jia, Y., Zhang, K., Shi, M. et al. Associations of Rheumatoid Factor, Rheumatoid Arthritis, and Interleukin-6 Inhibitor with the Prognosis of Ischemic Stroke: a Prospective Multicenter Cohort Study and Mendelian Randomization Analysis. Transl. Stroke Res. (2023). https://doi.org/10.1007/s12975-023-01161-5

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