Abstract
Introduction
Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by a chronic grade of inflammation. Cardiovascular events represent the major causes of morbidity and mortality in patients with inflammatory rheumatic diseases; however, the significance and prevalence of cardiovascular disease in patients with pSS remain unclear.
Objective
To determine the clinical significance of cardiovascular disease in pSS and analyze the risk of cardiovascular disease according to glandular/extraglandular involvement and positivity to anti-Ro/SSA and/or anti-La/SSB autoantibodies.
Methods
A retrospective study including patients diagnosed with pSS fulfilling the 2016 ACR/EULAR classification criteria was followed and evaluated in our outpatient clinic between 2000 and 2022. The prevalence of cardiovascular risk factors with pSS was evaluated, and a possible association with clinical and immunological characteristics, the treatments received, and the impact on cardiovascular disease were determined. Univariate and multivariate regression analyses were performed in an attempt to determine potential risk factors associated with cardiovascular involvement.
Results
A total of 102 pSS patients were included. Eighty-two percent were female, with a mean age of 65±24 years and a disease duration of 12.5 ±6 years. Thirty-six patients (36%) had at least one cardiovascular risk factor. Arterial hypertension was diagnosed in 60 (59%) patients, dyslipidemia in 28 (27%), diabetes in 15 (15%), obesity in 22 (22%), and hyperuricemia in 19 (18%). History of arrhythmia was found in 25 (25%), conduction defects in 10 (10%), arterial peripheral vascular disease in 7 (7%), venous thrombosis in 10 (10%), coronary artery disease in 24 (24%), and cerebrovascular disease in 22 (22%) of patients. Patients with extraglandular involvement had a higher prevalence of arterial hypertension (p=0.04), dyslipidemia (p=0.003), LDL mean values (p=0.038), hyperuricemia (p=0.03), and coronary artery disease (p=0.01) after adjusting for age, sex, disease duration, and the significant variables in the univariate analysis. Patients with Ro/SSA and La/SSB autoantibodies had a substantially higher risk of hyperuricemia (p=0.01), arrhythmia (p=0.01), coronary artery disease (p=0.02), cerebrovascular disease (p=0.02), and venous thrombosis (p =0.03). In the multivariate logistic regression analysis, higher odds of cardiovascular risk factors were associated with extraglandular involvement (p=0.02), treatment with corticosteroids (p=0.02), ESSDAI>13 (p=0.02), inflammatory markers including ESR levels (p 0.007), and serologic markers such as low C3 levels (p=0.03) and hypergammaglobulinemia (p=0.02).
Conclusions
Extraglandular involvement was associated with a higher prevalence of arterial hypertension, dyslipidemia, hyperuricemia, and coronary artery disease. Anti-Ro/SSA and anti-La/SSB seropositivity was associated with a higher prevalence of cardiac rhythm abnormalities, hyperuricemia, venous thrombosis, coronary artery disease, and cerebrovascular disease. Raised inflammatory markers, disease activity measured by ESSDAI, extraglandular involvement, serologic markers including hypergammaglobulinemia and low C3, and treatment with corticosteroids were associated with a higher risk for cardiovascular comorbidities.
Key Points • Patients with pSS are vulnerable to cardiovascular risk factors. There is an interconnection between extraglandular involvement, disease activity, inflammatory markers, and cardiovascular risk comorbidities. • Anti-Ro/SSA and anti-La/SSB seropositivity was associated with a higher frequency of cardiac conduction abnormalities, coronary artery disease, venous thrombosis, and stroke. • Hypergammaglobulinemia, elevated ESR, and low C3 are associated with a higher prevalence of cardiovascular comorbidities. • Valid risk stratification tools to help with prevention and consensus on the management of CVDs in pSS patients are warranted. |
Similar content being viewed by others
Data availability
All data are available in the article.
References
Mariette X, Criswell LA (2018) Primary Sjogren’s syndrome. N Engl J Med 378(10):931–939
Ramos-Casals M, Tzioufas AG, Font J (2005) Primary Sjogren’s syndrome: new clinical and therapeutic concepts. Ann Rheum Dis 64:347–354
Sherer Y, Zinger H, Shoenfeld Y (2010) Atherosclerosis in systemic lupus erythematosus. Autoimmunity 43:98–102
Font J, Ramos-Casals M, Cervera R et al (2001) Cardiovascular risk factors and the long-term outcome of lupus nephritis. QJM 94:19–26
Bello N, Meyers KJ, Workman J, Hartley L, McMahon M (2023) Cardiovascular events and risk in patients with systemic lupus erythematosus: Systematic literature review and meta-analysis. Lupus 32(3):325–341
Gonzalez-Gay MA, Gonzalez-Juanatey C, Martin J (2005) Rheumatoid arthritis: a disease associated with accelerated atherogenesis. Semin Arthritis Rheum 35:8–17
Bartoloni E, Shoenfeld Y, Gerli R (2011) Inflammatory and autoimmune mechanisms in the induction of atherosclerotic damage in systemic rheumatic diseases: two faces of the same coin. Arthritis Care Res 63:178–183
Arts EE, Popa C, Den Broeder AA et al (2015) Performance of four current risk algorithms in predicting cardiovascular events in patients with early rheumatoid arthritis. Ann Rheum Dis 74:668–674
Yong WC, Sanguankeo A (2018) Upala: Association between primary Sjögren’s syndrome, cardiovascular and cerebrovascular disease: a systematic review and meta-analysis. Clin Exp Rheumatol 36(Suppl.112):S190–S197
Vaudo G, Bocci EB, Shoenfeld Y et al (2005) Precocious intima-media thickening in patients with primary Sjogren’s syndrome. Arthritis Rheum 52:3890–3897
Ramos-Casals M, Brito-Zerón P, Sisó A, Vargas A, Ros E, Bove A, Belenguer R, Plaza J, Benavent J, Font J (2007) High prevalence of serum metabolic alterations in primary Sjögren’s syndrome: influence on clinical and immunological expression. J Rheumatol 34(4):754–761
Mofors J, Holmqvist M, Westermark L et al (2019) Concomitant Ro/ SSA and La/SSB antibodies are biomarkers for the risk of venous thromboembolism and cerebral infarction in primary Sjogren’s syndrome. J Intern Med 286:458–468
Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, Daniels TE, Fox PC, Fox RI, Kassan SS, Pillemer SR, Talal N, Weisman MH (2002 Jun) European Study Group on Classification Criteria for Sjögren’s Syndrome. Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 61(6):554–558
Seror R, Ravaud P, Bowman SJ, Baron G, Tzioufas A, Theander E, Gottenberg JE, Bootsma H, Mariette X, Vitali C, EULAR Sjögren’s Task Force (2010) EULAR Sjogren’s syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjogren’s syndrome. Ann Rheum Dis 69(6):1103–1109
Delli K, Vissink A, Spijkervet FK (2014) Salivary gland biopsy for Sjogren’s syndrome. Oral Maxillofac Surg Clin North Am 26:23–33
Manfrè V, Cafaro G, Riccucci I, Zabotti A, Perricone C, Bootsma H et al (2020) One Year in Review 2020: Comorbidities, Diagnosis and Treatment of Primary Sjögren’s Syndrome. Clin Exp Rheumatol 38(Suppl 126):10–22
Bartoloni E, Baldini C, Schillaci G, Quartuccio L, Priori R, Carubbi F et al (2015) Cardiovascular Disease Risk Burden in Primary Sjögren’s Syndrome: Results of a Population-Based Multicentre Cohort Study. J Intern Med 278(2):185–192
Beltai A, Barnetche T, Daien C, Lukas C, Gaujoux-Viala C, Combe B et al (2020) Cardiovascular Morbidity and Mortality in Primary Sjögren’s Syndrome: A Systematic Review and Meta-Analysis. Arthritis Care Res 72(1):131–139
Juarez M, Toms TE, de Pablo P, Mitchell S, Bowman S, Nightingale P et al (2014) Cardiovascular Risk Factors in Women With Primary Sjögren’s Syndrome: United Kingdom Primary Sjögren’s Syndrome Registry Results. Arthritis Care Res 66(5):757–764
Augusto KL, Bonfa E, Pereira RMR, Bueno C, Leon EP, Viana VST et al (2016) Metabolic Syndrome in Sjögren’s Syndrome Patients: A Relevant Concern for Clinical Monitoring. Clin Rheumatol 35(3):639–647
Wang Y, Hou Z, Qiu M et al (2018) Risk factors for primary Sjogren syndrome-associated interstitial lung disease. J Thorac Dis 10(4):2108–2117
Juarez M, Toms TE, De Pablo P et al (2014) Cardiovascular risk factors in women with primary Sjögren’s syndrome: United Kingdom primary Sjögren’s syndrome registry results. Arthritis Care Res 5:757–764
Pérez-De-Lis M, Akasbi M, Sisó A, Diez-Cascon P, Brito-Zerón P, Diaz-Lagares C, Ortiz J, Perez-Alvarez R, Ramos-Casals M, Coca A (2010) Cardiovascular risk factors in primary Sjögren’s syndrome: a case-control study in 624 patients. Lupus 19:941–948
Bartoloni E, Alunno A, Gerli R (2018) Hypertension as a cardiovascular risk factor in autoimmune rheumatic diseases. Nat Rev Cardiol 15:33–44
Gravani F, Papadaki I, Antypa E et al (2015) Subclinical atherosclerosis and impaired bone health in patients with primary Sjögren’s syndrome: prevalence, clinical and laboratory associations. Arthritis Res Ther 17:99
Balarini GM, Zandonade E, Tanure L et al (2016) Serum calprotectin is a biomarker of carotid atherosclerosis in patients with primary Sjögren’s syndrome. Clin Exp Rheum 34:1006–1012
Gunter S, Robinson C, Norton GR, Woodiwiss AJ, Tsang L, Dessein PH, Millen AME (2017) Cardiovascular Risk Factors and Disease Characteristics Are Consistently Associated with Arterial Function in Rheumatoid Arthritis. J Rheumatol 44(8):1125–1133
Lodde BM, Sankar V, Kok MR, Leakan RA, Tak PP, Pillemer SR (2006) Serum lipid levels in Sjögren’s syndrome. Rheumatology 45:481–484
Cruz W, Fialho S, Morato E et al (2010) Is there a link between inflammation and abnormal lipoprotein profile in Sjögren’s syndrome? Joint Bone Spine 77:229–231
Binder A, Maddison PJ, Skinner P, Kurtz A, Isenberg DA (1989) Sjögren’s syndrome: association with type-1 diabetes mellitus. Br J Rheumatol 28:518–520
Luo Q, Qin L, Zhang Y, Yang X, Wang H (2022) Relationship between serum uric acid and hypertension in patients with primary Sjögren’s syndrome: A retrospective cohort study. J Clin Hypertens (Greenwich) 24(8):1026–1034
Alunno A, Carubbi F, Mariani FM et al (2022) AB0524 Relationship between serum acid, cardiovascular risk and inflammatory status in Primary Sjogren’s syndrome. Ann Rheum Dis 81:1390
Mofors J, Holmqvist M, Westermark L, Björk A, Kvarnström M, Forsbladd’Elia H et al (2019) Concomitant Ro/SSA and La/SSB antibodies are biomarkers for the risk of venous thromboembolism and cerebral infarction in primary Sjögren’s syndrome. J Intern Med 286:458–468
Flament T, Bigot A, Chaigne B, Henique H, Diot E, Marchand-Adam S (2016) Pulmonary Manifestations of Sjögren’s Syndrome. Eur Respir Rev 25(140):110–123
Johr CR (2020) Chapter 6 - Extraglandular Abnormalities in Sjögren’s Syndrome. In: Vivino FB (ed) Sjogren’s Syndrome: A Clinical Handbook 1st Edition - October 13, 2019. Elsevier, Sjogren’s Syndrome, pp 93–115
Akuka A, Ben-Shabat N, Watad A (2022) Avishai M Tsur, Scott Ehrenberg, Dennis McGonagle, Doron Comaneshter, Roy Beinart, Arnon D Cohen, Howard Amital, Association of anti-Ro seropositivity with cardiac rhythm and conduction disturbances. Eur Heart J 43(47):4912–4919
Lazzerini PE, Laghi-Pasini F, Boutjdir M, Capecchi PL (2021) Anti-Ro/SSA Antibodies and the Autoimmune Long-QT Syndrome. Front Med (Lausanne) 6(8):730161
Ruiz-Irastorza G, Egurbide MV, Pijoan JI et al (2006) Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus 15:577–583
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
Robinson CP, Yamachika S, Alford CE et al (1997) Elevated levels of cysteine protease activity in saliva and salivary glands of the nonobese diabetic (NOD) mouse model for Sjogren syndrome. Proc Natl Acad Sci U S A 94:5767–5771
Movahedi M, Beauchamp ME, Abrahamowicz M, Ray DW, Michaud K, Pedro S et al (2016) Risk of Incident Diabetes Mellitus Associated With the Dosage and Duration of Oral Glucocorticoid Therapy in Patients With Rheumatoid Arthritis. Arthritis Rheumatol 68(5):1089–1098
Wu J, Keeley A, Mallen C, Morgan AW, Pujades-Rodriguez M (2019) Incidence of infections associated with oral glucocorticoid dose in people diagnosed with polymyalgia rheumatica or giant cell arteritis: a cohort study in England. CMAJ 191(25):E680–E688
Mebrahtu TF, Morgan AW, West RM, Stewart PM, Pujades-Rodriguez M (2020) Oral glucocorticoids and incidence of hypertension in people with chronic inflammatory diseases: a population-based cohort study. CMAJ 192(12):E295–E301
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethics
This study was approved by Complejo Asistencial Universitario de León’s Ethical Committee. Participants gave written consent to participate in the study before taking part.
Disclosures
None.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Santos, C.S., Salgueiro, R.R., Morales, C.M. et al. Risk factors for cardiovascular disease in primary Sjögren’s syndrome (pSS): a 20-year follow-up study. Clin Rheumatol 42, 3021–3031 (2023). https://doi.org/10.1007/s10067-023-06686-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10067-023-06686-6