{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T19:15:23Z","timestamp":1777403723253,"version":"3.51.4"},"reference-count":33,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Sj\u00f6gren\u2019s disease (SjD) is a chronic autoimmune rheumatic disorder primarily affecting exocrine glands, leading to dryness and systemic involvement. B-cell hyperactivity and autoantibody production drive its pathogenesis and contribute to increased lymphoma risk. Although several long-term studies exist, we present a review of a closely monitored cohort assessed over 40 years. Methods: Retrospective observational study at University College London Hospital included patients fulfilling the 2016 ACR\/EULAR criteria for SjD between 1986\u20132025. Patients with associated SjD were excluded. Associations between serological markers and clinical features were analysed using chi-square or Fisher\u2019s exact tests (p &lt; 0.05). Differences between ethnic groups were also assessed. Results: 283 patients were included, 93.3% female, with mean age at diagnosis of 50.1 \u00b1 15.2 years and mean follow-up of 12.5 \u00b1 8.6 years. Common manifestations were fatigue (61.5%), parotid swelling (30.5%), arthritis (25.8%), and Raynaud\u2019s phenomenon (27.6%). Anti-Ro and anti-La antibodies were present in 75.7% and 45.2%, respectively; rheumatoid factor in 57.3%. Lymphoma developed in 9.9% (mostly non-Hodgkin MALT) and was associated with hypergammaglobulinemia (p = 0.03; RR = 2.56) and parotid swelling (p &lt; 0.001; RR = 5.53). Serological markers correlated with systemic features including lymphadenopathy, vasculitis, and pulmonary involvement. Caucasian patients showed higher mortality (p &lt; 0.001; RR = 3.89) and peripheral nervous system involvement (p = 0.02; RR = 2.18), and less ANA positivity (p = 0.004; RR = 0.88), anti-Ro (p = &lt;0.001; RR = 0.77) and RF (p = 0.04; RR = 0.81) and hypergammaglobulinemia (p = &lt;0.001; RR = 0.63) when compared with non-Caucasian patients. Conclusions: This long-term cohort confirms the strong association between B-cell activation markers and adverse outcomes in Sj\u00f6gren\u2019s disease. Hypergammaglobulinemia and parotid swelling emerged as key predictors of lymphoma, supporting their role in risk stratification. These findings reinforce the importance of long-term monitoring and may help guide personalized clinical management and surveillance strategies.<\/jats:p>","DOI":"10.3390\/jcm15093316","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T09:55:39Z","timestamp":1777370139000},"page":"3316","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Anatomy of a Cohort: 40-Year Follow-Up of a Sj\u00f6gren\u2019s Cohort"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0732-0931","authenticated-orcid":false,"given":"Blanca","family":"Viejo-Sosa","sequence":"first","affiliation":[{"name":"Servicio de Reumatolog\u00eda, Hospital Universitario Jerez de la Frontera, 11407 C\u00e1diz, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7794-551X","authenticated-orcid":false,"given":"Ux\u00eda","family":"Couto-Lareo","sequence":"additional","affiliation":[{"name":"Servicio de Reumatolog\u00eda, Hospital Universitario A Coru\u00f1a, 15006 A Coru\u00f1a, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4007-6320","authenticated-orcid":false,"given":"M\u00f2nica","family":"Angerri-Nadal","sequence":"additional","affiliation":[{"name":"Servei Medicina Interna, Hospital Universitari Dr. Josep Trueta, 17007 Girona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9514-2455","authenticated-orcid":false,"given":"David A.","family":"Isenberg","sequence":"additional","affiliation":[{"name":"Department of Ageing, Rheumatology and Regenerative Medicine, University College London, London WC1E 6BT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,27]]},"reference":[{"key":"ref_1","first-page":"247","article-title":"The epidemiology of Sj\u00f6gren\u2019s syndrome","volume":"6","author":"Patel","year":"2014","journal-title":"Clin. Epidemiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1177\/0961203319857132","article-title":"Prognostic markers of lymphoma development in primary Sj\u00f6gren syndrome","volume":"28","author":"Retamozo","year":"2019","journal-title":"Lupus"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/art.39859","article-title":"2016 American College of Rheumatology\/European League Against Rheumatism Classification Criteria for Primary Sj\u00f6gren\u2019s Syndrome: A Consensus and Data-Driven Methodology Involving Three International Patient Cohorts","volume":"69","author":"Shiboski","year":"2017","journal-title":"Arthritis Rheumatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e3821","DOI":"10.1136\/bmj.e3821","article-title":"Primary Sjogren syndrome","volume":"344","author":"Bosch","year":"2012","journal-title":"BMJ"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5928232","DOI":"10.1155\/2021\/5928232","article-title":"Advances in Pathogenesis of Sj\u00f6gren\u2019s Syndrome","volume":"2021","author":"Tian","year":"2021","journal-title":"J. Immunol. Res."},{"key":"ref_6","first-page":"2336","article-title":"Pathogenesis of Sj\u00f6gren\u2019s disease: One year in review 2024","volume":"42","author":"Baldini","year":"2024","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/s41584-021-00605-2","article-title":"Epithelial-immune cell interplay in primary Sj\u00f6gren syndrome salivary gland pathogenesis","volume":"17","author":"Verstappen","year":"2021","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1007\/s00296-019-04285-w","article-title":"ESSDAI activity index of the SJ\u00d6GRENSER cohort: Analysis and comparison with other European cohorts","volume":"39","author":"Rosas","year":"2019","journal-title":"Rheumatol. Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1093\/rheumatology\/keq047","article-title":"Articular manifestations in primary Sj\u00f6gren\u2019s syndrome: Clinical significance and prognosis of 188 patients","volume":"49","author":"Fauchais","year":"2010","journal-title":"Rheumatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2230","DOI":"10.1093\/rheumatology\/kev200","article-title":"Characterization of systemic disease in primary Sj\u00f6gren\u2019s syndrome: EULAR-SS Task Force recommendations for articular, cutaneous, pulmonary and renal involvements","volume":"54","author":"Seror","year":"2015","journal-title":"Rheumatology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.ccm.2019.05.002","article-title":"Pulmonary Involvement in Sj\u00f6gren Syndrome","volume":"40","author":"Natalini","year":"2019","journal-title":"Clin. Chest Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1055\/s-0044-1785675","article-title":"Pulmonary Manifestations of Sj\u00f6gren\u2019s Disease","volume":"45","author":"Byrne","year":"2024","journal-title":"Semin. Respir. Crit. Care Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.rdc.2017.06.002","article-title":"Neurologic Manifestations of Primary Sj\u00f6gren Syndrome","volume":"43","author":"Margaretten","year":"2017","journal-title":"Rheum. Dis. Clin. N. Am."},{"key":"ref_14","first-page":"192","article-title":"The kaleidoscope of neurological manifestations in primary Sj\u00f6gren\u2019s syndrome","volume":"37","author":"Alunno","year":"2019","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_15","first-page":"123","article-title":"Renal involvement in primary Sj\u00f6gren\u2019s syndrome: Natural history and treatment outcome","volume":"37","author":"Goules","year":"2019","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1007\/s10067-007-0638-6","article-title":"Thyroid disease in Sj\u00f6gren\u2019s syndrome","volume":"26","author":"Jara","year":"2007","journal-title":"Clin. Rheumatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1007\/s12016-018-8709-9","article-title":"Sj\u00f6gren\u2019s Syndrome and Autoimmune Thyroid Disease: Two Sides of the Same Coin","volume":"56","author":"Anaya","year":"2019","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_18","first-page":"686","article-title":"Anti-Ro52 antibody testing influences the classification and clinical characterisation of primary Sj\u00f6gren\u2019s syndrome","volume":"30","author":"Retamozo","year":"2012","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Bodak\u00e7i, E. (2024). Clinical Characteristics of Distinct Subgroups of Patients with Primary Sj\u00f6gren\u2019s Syndrome Classified by Serological Profiles: A Comparison Study. J. Pers. Med., 14.","DOI":"10.20944\/preprints202407.1089.v1"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11","DOI":"10.46439\/rheumatology.4.023","article-title":"35 years follow-up of primary Sjogren\u2019s syndrome: A single center study","volume":"4","author":"Yildrim","year":"2024","journal-title":"Curr. Rheumatol. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"647507","DOI":"10.1155\/2014\/647507","article-title":"Clinical course, prognosis, and cause of death in primary Sj\u00f6gren\u2019s syndrome","volume":"2014","author":"Horvath","year":"2014","journal-title":"J. Immunol. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1136\/annrheumdis-2014-206418","article-title":"Systemic activity and mortality in primary Sj\u00f6gren syndrome: Predicting survival using the EULAR-SS Disease Activity Index (ESSDAI) in 1045 patients","volume":"75","author":"Kostov","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"E579","DOI":"10.1503\/cmaj.122037","article-title":"Sj\u00f6gren syndrome","volume":"186","author":"Mavragani","year":"2014","journal-title":"Can. Med. Assoc. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1097\/MD.0b013e3181b76ab5","article-title":"Hematologic manifestations and predictors of lymphoma development in primary Sj\u00f6gren syndrome: Clinical and pathophysiologic aspects","volume":"88","author":"Baimpa","year":"2009","journal-title":"Medicine"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1093\/rheumatology\/kep404","article-title":"Incidence of malignancy in primary Sjogren\u2019s syndrome in a Chinese cohort","volume":"49","author":"Zhang","year":"2010","journal-title":"Rheumatology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/s13045-017-0464-5","article-title":"Characterization and risk estimate of cancer in patients with primary Sj\u00f6gren syndrome","volume":"10","author":"Kostov","year":"2017","journal-title":"J. Hematol. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1136\/ard.2004.025676","article-title":"Primary Sj\u00f6gren\u2019s syndrome: New clinical and therapeutic concepts","volume":"64","author":"Tzioufas","year":"2005","journal-title":"Ann. Rheum. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"157","DOI":"10.7861\/clinmedicine.14-2-157","article-title":"A retrospective study of long-term outcomes in 152 patients with primary Sjogren\u2019s syndrome: 25-year experience","volume":"14","author":"Abrol","year":"2014","journal-title":"Clin. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1007\/s40744-021-00314-y","article-title":"Primary Sj\u00f6gren\u2019s Syndrome: A Retrospective Cohort Study of Burden of Illness in Sweden","volume":"8","author":"Westerlund","year":"2021","journal-title":"Rheumatol. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1759720X211020179","DOI":"10.1177\/1759720X211020179","article-title":"Ten-year survival analysis of patients with primary Sj\u00f6gren\u2019s syndrome in China: A national prospective cohort study","volume":"13","author":"Qian","year":"2021","journal-title":"Ther. Adv. Musculoskelet. Dis."},{"key":"ref_31","first-page":"102","article-title":"How immunological profile drives clinical phenotype of primary Sj\u00f6gren\u2019s syndrome at diagnosis: Analysis of 10,500 patients (Sj\u00f6gren Big Data Project)","volume":"36","author":"Ng","year":"2018","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e002955","DOI":"10.1136\/rmdopen-2022-002955","article-title":"Impact of patient ancestry on heterogeneity of Sj\u00f6gren\u2019s disease","volume":"9","author":"Beydon","year":"2023","journal-title":"RMD Open"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1136\/annrheumdis-2016-209952","article-title":"Influence of geolocation and ethnicity on the phenotypic expression of primary Sj\u00f6gren\u2019s syndrome at diagnosis in 8310 patients: A cross-sectional study from the Big Data Sj\u00f6gren Project Consortium","volume":"76","author":"Zeher","year":"2017","journal-title":"Ann. Rheum. Dis."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/9\/3316\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T10:28:18Z","timestamp":1777372098000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/9\/3316"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,27]]},"references-count":33,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["jcm15093316"],"URL":"https:\/\/doi.org\/10.3390\/jcm15093316","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,27]]}}}