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Association between comorbidities and extraglandular manifestations in primary Sjögren’s syndrome: a multicenter cross-sectional study

Abstract

Introduction

Primary Sjögren’s syndrome (pSS) has been related to a higher risk of comorbidities, but studies examining comorbidities among patients with and without extraglandular manifestations are limited. The objectives of this study were to assess the prevalence of comorbidities in Chinese pSS patients and to determine the relationship between comorbidities and extraglandular manifestations.

Method

This cross-sectional study was based on the multicenter pSS registry established by the Chinese Rheumatism Data Center. Patients fulfilling the 2002 American-European criteria or the 2016 classification criteria for pSS were enrolled from May 2016 to December 2018. Demographic data, disease characteristics, comorbidities (cardiovascular disease, thyroid disorder, malignancy, and fragility fracture), and extraglandular manifestations were collected. Multivariate analyses were used to assess the relationships between comorbidities and extraglandular manifestations.

Results

A total of 4087 pSS patients were included (95.7% female and mean age of 51.2 ± 13.1 years). The baseline prevalence of comorbidities was 3.8% for cardiovascular diseases, 12.1% for thyroid disorders, 1.8% for malignancies, and 1.7% for fragility fractures. The presence of extraglandular manifestations was associated with more comorbidities. Patients with more than one extraglandular manifestation had a higher prevalence of cardiovascular disease (adjusted odds ratio [aOR] 2.004, 95% confidence interval [CI] 1.221–3.288), thyroid disorder (aOR 1.380, 95% CI 1.022–1.863), and fragility fracture (aOR 2.684, 95% CI 1.505–4.786) after adjustment for age, sex, disease duration, and the significant variables in the univariate analysis.

Conclusions

The presence of extraglandular manifestations in pSS was associated with an increased comorbidity burden, especially cardiovascular disease, thyroid disorder, and fragility fracture.

Key Points
This is the first study assessing the association between extraglandular manifestations and comorbidity burden based on the largest pSS registry in China.
Patients with multiple extraglandular manifestations tend to have increased comorbid cardiovascular disease, thyroid disorder, and fragility fracture.

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Data availability

The principal investigators, Dong Xu and Yan Zhao, had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

References

  1. Mariette X, Criswell LA (2018) Primary Sjogren’s syndrome. N Engl J Med 378(10):931–939. https://doi.org/10.1056/NEJMcp1702514

    Article  PubMed  Google Scholar 

  2. Ramos-Casals M, Brito-Zeron P, Siso-Almirall A et al (2012) Primary Sjogren syndrome. BMJ 344:e3821. https://doi.org/10.1136/bmj.e3821

    CAS  Article  PubMed  Google Scholar 

  3. Singh AG, Singh S, Matteson EL (2016) Rate, risk factors and causes of mortality in patients with Sjogren’s syndrome: a systematic review and meta-analysis of cohort studies. Rheumatology (Oxford) 55(3):450–460. https://doi.org/10.1093/rheumatology/kev354

    Article  Google Scholar 

  4. Flores-Chavez A, Kostov B, Solans R et al (2018) Severe, life-threatening phenotype of primary Sjogren’s syndrome: clinical characterisation and outcomes in 1580 patients (GEAS-SS Registry). Clin Exp Rheumatol Suppl 112(3):121–129

    Google Scholar 

  5. Loza E, Jover JA, Rodriguez L et al (2009) Multimorbidity: prevalence, effect on quality of life and daily functioning, and variation of this effect when one condition is a rheumatic disease. Semin Arthritis Rheum 38(4):312–319. https://doi.org/10.1016/j.semarthrit.2008.01.004

    Article  PubMed  Google Scholar 

  6. Beltai A, Barnetche T, Daien C et al (2018) Cardiovascular morbidity and mortality in primary Sjogren syndrome: a systematic review and meta-analysis. Arthritis Care Res (Hoboken) 69. https://doi.org/10.1002/acr.23821

  7. Liang Y, Yang Z, Qin B, Zhong R (2014) Primary Sjogren’s syndrome and malignancy risk: a systematic review and meta-analysis. Ann Rheum Dis 73(6):1151–1156. https://doi.org/10.1136/annrheumdis-2013-203305

    Article  PubMed  Google Scholar 

  8. Pego-Reigosa JM, Restrepo Velez J, Baldini C et al (2019) Comorbidities (excluding lymphoma) in Sjogren’s syndrome. Rheumatology (Oxford). https://doi.org/10.1093/rheumatology/key329

  9. Radner H, Yoshida K, Frits M et al (2015) The impact of multimorbidity status on treatment response in rheumatoid arthritis patients initiating disease-modifying anti-rheumatic drugs. Rheumatology (Oxford) 54(11):2076–2084. https://doi.org/10.1093/rheumatology/kev239

    CAS  Article  Google Scholar 

  10. Ballegaard C, Hojgaard P, Dreyer L et al (2018) Impact of comorbidities on tumor necrosis factor inhibitor therapy in psoriatic arthritis: a population-based cohort study. Arthritis Care Res (Hoboken) 70(4):592–599. https://doi.org/10.1002/acr.23333

    CAS  Article  Google Scholar 

  11. Bartoloni E, Baldini C, Schillaci G, Quartuccio L, Priori R, Carubbi F, Bini V, Alunno A, Bombardieri S, de Vita S, Valesini G, Giacomelli R, Gerli R (2015) Cardiovascular disease risk burden in primary Sjogren’s syndrome: results of a population-based multicentre cohort study. J Intern Med 278(2):185–192. https://doi.org/10.1111/joim.12346

    CAS  Article  PubMed  Google Scholar 

  12. Brito-Zeron P, Kostov B, Fraile G et al (2017) Characterization and risk estimate of cancer in patients with primary Sjogren syndrome. J Hematol Oncol 10(1):90. https://doi.org/10.1186/s13045-017-0464-5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Nocturne G, Virone A, Ng WF et al (2016) Rheumatoid factor and disease activity are independent predictors of lymphoma in primary Sjogren’s syndrome. Arthritis Rheumatol 68(4):977–985. https://doi.org/10.1002/art.39518

    CAS  Article  PubMed  Google Scholar 

  14. Perez-De-Lis M, Akasbi M, Siso A et al (2010) Cardiovascular risk factors in primary Sjogren’s syndrome: a case-control study in 624 patients. Lupus 19(8):941–948. https://doi.org/10.1177/0961203310367504

    CAS  Article  PubMed  Google Scholar 

  15. Juarez M, Toms TE, de Pablo P et al (2014) Cardiovascular risk factors in women with primary Sjogren’s syndrome: United Kingdom primary Sjogren’s syndrome registry results. Arthritis Care Res (Hoboken) 66(5):757–764. https://doi.org/10.1002/ACR.22227

    CAS  Article  Google Scholar 

  16. Kang JH, Lin HC (2010) Comorbidities in patients with primary Sjogren’s syndrome: a registry-based case-control study. J Rheumatol 37(6):1188–1194. https://doi.org/10.3899/jrheum.090942

    Article  PubMed  Google Scholar 

  17. Brito-Zeron P, Acar-Denizli N, Zeher M et al (2017) Influence of geolocation and ethnicity on the phenotypic expression of primary Sjogren’s syndrome at diagnosis in 8310 patients: a cross-sectional study from the Big Data Sjogren Project Consortium. Ann Rheum Dis 76(6):1042–1050. https://doi.org/10.1136/annrheumdis-2016-209952

    Article  PubMed  Google Scholar 

  18. Zhang NZ, Shi CS, Yao QP, Pan GX, Wang LL, Wen ZX, Li XC, Dong Y (1995) Prevalence of primary Sjogren’s syndrome in China. J Rheumatol 22(4):659–661

    CAS  PubMed  Google Scholar 

  19. Li MT, Tian XP, Zhang W, Leng X, Zeng X (2015) CRDC: a Chinese rheumatology research platform. Clin Rheumatol 34(8):1347–1352. https://doi.org/10.1007/s10067-015-3003-1

    Article  PubMed  Google Scholar 

  20. 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, European Study Group on Classification Criteria for Sjögren’s Syndrome (2002) Classification criteria for Sjogren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 61(6):554–558. https://doi.org/10.1136/ard.61.6.554

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, Rasmussen A, Scofield H, Vitali C, Bowman SJ, Mariette X, International Sjögren’s Syndrome Criteria Working Group (2017) 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjogren’s syndrome: a consensus and data-driven methodology involving three international patient cohorts. Ann Rheum Dis 76(1):9–16. https://doi.org/10.1136/annrheumdis-2016-210571

    Article  PubMed  Google Scholar 

  22. 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. https://doi.org/10.1136/ard.2009.110619

    Article  PubMed  Google Scholar 

  23. Seror R, Ravaud P, Mariette X, Bootsma H, Theander E, Hansen A, Ramos-Casals M, Dörner T, Bombardieri S, Hachulla E, Brun JG, Kruize AA, Praprotnik S, Tomsic M, Gottenberg JE, Devauchelle V, Devita S, Vollenweider C, Mandl T, Tzioufas A, Carsons S, Saraux A, Sutcliffe N, Vitali C, Bowman SJ, EULAR Sjögren’s Task Force (2011) EULAR Sjogren’s Syndrome Patient Reported Index (ESSPRI): development of a consensus patient index for primary Sjogren’s syndrome. Ann Rheum Dis 70(6):968–972. https://doi.org/10.1136/ard.2010.143743

    Article  PubMed  Google Scholar 

  24. Li M, Wang Q, Zhao J, Li Z, Ye Z, Li C, Li X, Zhu P, Wang Z, Zheng Y, Li X, Zhang M, Tian Z, Liu Y, He J, Zhang F, Zhao Y, Zeng X, CSTAR co-authors (2014) Chinese SLE Treatment and Research group (CSTAR) registry: II. Prevalence and risk factors of pulmonary arterial hypertension in Chinese patients with systemic lupus erythematosus. Lupus 23(10):1085–1091. https://doi.org/10.1177/0961203314527366

    Article  PubMed  Google Scholar 

  25. Rua-Figueroa I, Fernandez Castro M, Andreu JL et al (2017) Comorbidities in patients with primary Sjogren’s syndrome and systemic lupus erythematosus: a comparative registries-based study. Arthritis Care Res (Hoboken) 69(1):38–45. https://doi.org/10.1002/acr.23015

    Article  Google Scholar 

  26. Turesson C, McClelland RL, Christianson TJ, Matteson EL (2007) Severe extra-articular disease manifestations are associated with an increased risk of first ever cardiovascular events in patients with rheumatoid arthritis. Ann Rheum Dis 66(1):70–75. https://doi.org/10.1136/ard.2006.052506

    CAS  Article  PubMed  Google Scholar 

  27. Turesson C, Jacobsson L, Bergstrom U (1999) Extra-articular rheumatoid arthritis: prevalence and mortality. Rheumatology (Oxford) 38(7):668–674. https://doi.org/10.1093/rheumatology/38.7.668

    CAS  Article  Google Scholar 

  28. Ibañez D, Gladman DD, Urowitz MB (2005) Adjusted mean Systemic Lupus Erythematosus Disease Activity Index-2K is a predictor of outcome in SLE. J Rheumatol 32(5):824–827

    PubMed  Google Scholar 

  29. Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG (2008) Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med 359(18):1897–1908. https://doi.org/10.1056/NEJMoa0707402

    CAS  Article  PubMed  Google Scholar 

  30. Ramos-Casals M, Brito-Zeron P, Solans R et al (2014) Systemic involvement in primary Sjogren’s syndrome evaluated by the EULAR-SS disease activity index: analysis of 921 Spanish patients (GEAS-SS Registry). Rheumatology (Oxford) 53(2):321–331. https://doi.org/10.1093/rheumatology/ket349

    Article  Google Scholar 

  31. 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. https://doi.org/10.21037/jtd.2018.03.120

    Article  PubMed  PubMed Central  Google Scholar 

  32. Nathan SD, Basavaraj A, Reichner C, Shlobin OA, Ahmad S, Kiernan J, Burton N, Barnett SD (2010) Prevalence and impact of coronary artery disease in idiopathic pulmonary fibrosis. Respir Med 104(7):1035–1041. https://doi.org/10.1016/j.rmed.2010.02.008

    Article  PubMed  Google Scholar 

  33. Chronic Kidney Disease Prognosis C, Matsushita K, van der Velde M et al (2010) Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 375(9731):2073–2081. https://doi.org/10.1016/S0140-6736(10)60674-5

    Article  Google Scholar 

  34. Baldini C, Ferro F, Mosca M, Fallahi P, Antonelli A (2018) The association of Sjogren syndrome and autoimmune thyroid disorders. Front Endocrinol (Lausanne) 9:121. https://doi.org/10.3389/fendo.2018.00121

    Article  Google Scholar 

  35. Caramaschi P, Biasi D, Caimmi C, Scambi C, Pieropan S, Barausse G, Adami S (2013) The co-occurrence of Hashimoto thyroiditis in primary Sjogren’s syndrome defines a subset of patients with milder clinical phenotype. Rheumatol Int 33(5):1271–1275. https://doi.org/10.1007/s00296-012-2570-6

    CAS  Article  PubMed  Google Scholar 

  36. Pasoto SG, Augusto KL, Alvarenga JC et al (2016) Cortical bone density and thickness alterations by high-resolution peripheral quantitative computed tomography: association with vertebral fractures in primary Sjogren’s syndrome. Rheumatology (Oxford) 55(12):2200–2211. https://doi.org/10.1093/rheumatology/kew332

    CAS  Article  Google Scholar 

  37. Liu JM, Ma LY, Bi YF, Xu Y, Huang Y, Xu M, Zhao HY, Sun LH, Tao B, Li XY, Wang WQ, Ning G (2012) A population-based study examining calcaneus quantitative ultrasound and its optimal cut-points to discriminate osteoporotic fractures among 9352 Chinese women and men. J Clin Endocrinol Metab 97(3):800–809. https://doi.org/10.1210/jc.2011-1654

    CAS  Article  PubMed  Google Scholar 

  38. Pimentel A, Urena-Torres P, Zillikens MC et al (2017) Fractures in patients with CKD-diagnosis, treatment, and prevention: a review by members of the European Calcified Tissue Society and the European Renal Association of Nephrology Dialysis and Transplantation. Kidney Int 92(6):1343–1355. https://doi.org/10.1016/j.kint.2017.07.021

    Article  PubMed  Google Scholar 

  39. Gravani F, Papadaki I, Antypa E, Nezos A, Masselou K, Ioakeimidis D, Koutsilieris M, Moutsopoulos HM, Mavragani CP (2015) Subclinical atherosclerosis and impaired bone health in patients with primary Sjogren’s syndrome: prevalence, clinical and laboratory associations. Arthritis Res Ther 17(1):99–13. https://doi.org/10.1186/s13075-015-0613-6

    Article  PubMed  PubMed Central  Google Scholar 

  40. Both T, Zillikens MC, Hoorn EJ, Zietse R, van Laar J, Dalm VA, van Duijn C, Versnel MA, Maria NI, van Hagen P, van Daele P (2016) Bone mineral density in Sjogren syndrome patients with and without distal renal tubular acidosis. Calcif Tissue Int 98(6):573–579. https://doi.org/10.1007/s00223-016-0112-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Fauchais AL, Ouattara B, Gondran G et al (2010) Articular manifestations in primary Sjogren’s syndrome: clinical significance and prognosis of 188 patients. Rheumatology (Oxford) 49(6):1164–1172. https://doi.org/10.1093/rheumatology/keq047

    Article  Google Scholar 

  42. Oomatia A, Fang H, Petri M et al (2014) Peripheral neuropathies in systemic lupus erythematosus: clinical features, disease associations, and immunologic characteristics evaluated over a twenty-five-year study period. Arthritis Rheumatol 66(4):1000–1009. https://doi.org/10.1002/art.38302

    CAS  Article  PubMed  Google Scholar 

  43. Yokomoto-Umakoshi M, Kanazawa I, Kondo S, Sugimoto T (2017) Association between the risk of falls and osteoporotic fractures in patients with type 2 diabetes mellitus. Endocr J 64(7):727–734. https://doi.org/10.1507/endocrj.EJ17-0011

    Article  PubMed  Google Scholar 

  44. Malladi AS, Sack KE, Shiboski SC, Shiboski CH, Baer AN, Banushree R, Dong Y, Helin P, Kirkham BW, Li M, Sugai S, Umehara H, Vivino FB, Vollenweider CF, Zhang W, Zhao Y, Greenspan JS, Daniels TE, Criswell LA (2012) Primary Sjogren’s syndrome as a systemic disease: a study of participants enrolled in an international Sjogren’s syndrome registry. Arthritis Care Res (Hoboken) 64(6):911–918. https://doi.org/10.1002/acr.21610

    Article  Google Scholar 

  45. Zhang W, Feng S, Yan S et al (2010) Incidence of malignancy in primary Sjogren’s syndrome in a Chinese cohort. Rheumatology (Oxford) 49(3):571–577. https://doi.org/10.1093/rheumatology/kep404

    Article  Google Scholar 

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Acknowledgments

We acknowledged the contributions from all medical centers in the CRDC all over China and the HealthCloud Co., Ltd. as the system provider.

Funding

This work was financially supported by the Chinese National Key Technology R&D Program, Ministry of Science and Technology (2017YFC0907601, 2017YFC0907605).

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Authors and Affiliations

Authors

Contributions

MTL, LYZ, JLZ, DX, YZ, and XFZ contributed to the conception and design of the study. LYZ, QL, JL, PTY, XDK, XWD, MJZ, XML, YFW, and JX contributed to data collection. YYZ and YHW participated in statistical analysis and interpretation. YYZ drafted the manuscript. MTL, YHW, EH, and DX revised the manuscript critically. DX, MTL, YZ, and XFZ supervised the study. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Dong Xu or Yan Zhao.

Ethics declarations

Written informed consent was obtained from all patients at enrollment. Ethics approval for the registry was obtained from the Medical Ethics Committee of Peking Union Medical College Hospital (PUMCH, JS-2038).

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None.

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Zhang, Y., Li, M., Zhang, L. et al. Association between comorbidities and extraglandular manifestations in primary Sjögren’s syndrome: a multicenter cross-sectional study. Clin Rheumatol 39, 2677–2688 (2020). https://doi.org/10.1007/s10067-020-04992-x

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  • DOI: https://doi.org/10.1007/s10067-020-04992-x

Keywords

  • Comorbidity
  • Extraglandular manifestation
  • Sjögren’s syndrome