{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T10:45:25Z","timestamp":1764153925687,"version":"3.46.0"},"reference-count":45,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cCarol Davila\u201d University of Medicine and Pharmacy, Bucharest, Romania"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fatigue is a common and disabling symptom in Sj\u00f6gren\u2019s disease (SjD), yet its links with hematologic parameters and salivary gland histopathology are not well established. This study aimed to investigate associations between complete blood count (CBC) indices, fatigue severity, and minor salivary gland biopsy findings in SjD using a multidimensional, disease-specific fatigue instrument. Ninety-seven patients meeting the 2012 ACR criteria for SjD underwent CBC, immunologic testing, and detailed clinical evaluation. Fatigue was assessed with the Profile of Fatigue and Discomfort\u2013Sicca Symptoms Inventory (PROFAD-SSI-SF). Histopathology data, including focus score, were available for a subset of patients. Correlation analyses, subgroup comparisons, and multivariable regressions explored associations among hematologic, immunologic, and fatigue variables. No strong correlations were found between fatigue and hematologic indices. The strongest were between total PROFAD and leukocyte (r = 0.18) or platelet counts (r = 0.16). ANA and anti-Ro52 positivity were associated with higher total SSI scores, while anti-SSB positivity correlated with lower somatic fatigue. Joint pain showed a borderline association with increased somatic fatigue. Focus score and other histopathologic features did not correlate with fatigue domains. In conclusion, fatigue in SjD is multifactorial and only weakly related to hematologic indices, emphasizing the need for longitudinal biomarker studies integrating clinical and histopathologic data.<\/jats:p>","DOI":"10.3390\/ijms262311418","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T10:04:57Z","timestamp":1764151497000},"page":"11418","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lack of Significant Associations Between Hematological Parameters, Salivary Gland Histopathology and Fatigue in Sj\u00f6gren\u2019s Disease"],"prefix":"10.3390","volume":"26","author":[{"given":"Denise-Ani","family":"Mardale","sequence":"first","affiliation":[{"name":"Faculty of Medicine, \u2018Carol Davila\u2019 University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Internal Medicine and Rheumatology, \u2018Sf. Maria\u2019 Clinical Hospital, 011192 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0172-5962","authenticated-orcid":false,"given":"Mihai Alexandru","family":"Preda","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u2018Carol Davila\u2019 University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Ear, Nose and Throat (ENT) Department, \u2018Sf. Maria\u2019 Clinical Hospital, 011192 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3883-9672","authenticated-orcid":false,"given":"Daniela","family":"Opri\u0219-Belinski","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u2018Carol Davila\u2019 University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Internal Medicine and Rheumatology, \u2018Sf. Maria\u2019 Clinical Hospital, 011192 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Violeta","family":"Bojinc\u0103","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u2018Carol Davila\u2019 University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Internal Medicine and Rheumatology, \u2018Sf. Maria\u2019 Clinical Hospital, 011192 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristian-Mihai","family":"Ilie","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u2018Carol Davila\u2019 University of Medicine and Pharmacy, 050474 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3405-9273","authenticated-orcid":false,"given":"Florian","family":"Berghea","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u2018Carol Davila\u2019 University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Internal Medicine and Rheumatology, \u2018Sf. Maria\u2019 Clinical Hospital, 011192 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4175-1199","authenticated-orcid":false,"given":"Laura Maria","family":"Gro\u0219eanu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u2018Carol Davila\u2019 University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Internal Medicine and Rheumatology, \u2018Sf. Maria\u2019 Clinical Hospital, 011192 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0688-9173","authenticated-orcid":false,"given":"Andra Rodica","family":"B\u0103l\u0103nescu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u2018Carol Davila\u2019 University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Internal Medicine and Rheumatology, \u2018Sf. Maria\u2019 Clinical Hospital, 011192 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/s41584-025-01268-z","article-title":"International Task Force on Nomenclature of Sj\u00f6gren Disease. 2023 International Rome consensus for the nomenclature of Sj\u00f6gren disease","volume":"21","author":"Baer","year":"2025","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1056\/NEJMcp1702514","article-title":"Primary Sj\u00f6gren\u2019s Syndrome. Solomon CG, editor","volume":"378","author":"Mariette","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"16047","DOI":"10.1038\/nrdp.2016.47","article-title":"Sj\u00f6gren syndrome","volume":"2","author":"Baldini","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.4081\/cp.2019.1190","article-title":"Primary Sjogren\u2019s syndrome presenting as autoimmune cytopenia","volume":"9","author":"Meena","year":"2019","journal-title":"Clin. Pract."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1016\/j.jaci.2016.01.024","article-title":"Cytometry by time-of-flight immunophenotyping identifies a blood Sj\u00f6gren\u2019s signature correlating with disease activity and glandular inflammation","volume":"137","author":"Mingueneau","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_6","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_7","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1080\/1744666X.2022.2123794","article-title":"Biomarkers of lymphoma in Sj\u00f6gren\u2019s syndrome: What\u2019s the latest?","volume":"18","author":"Stergiou","year":"2022","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"102316","DOI":"10.1016\/j.jaut.2019.102316","article-title":"Predictive markers of lymphomagenesis in Sj\u00f6gren\u2019s syndrome: From clinical data to molecular stratification","volume":"104","author":"Kapsogeorgou","year":"2019","journal-title":"J Autoimmun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1080\/00365513.2019.1591636","article-title":"A comprehensive comparison of hematological parameters among 39 common diseases","volume":"79","author":"Gao","year":"2019","journal-title":"Scand. J. Clin. Lab. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1309\/EK3C7CTDKNVPXVTN","article-title":"Automated blood cell counts: State of the art","volume":"130","author":"Buttarello","year":"2008","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1111\/apm.12722","article-title":"Comparisons of neutrophil-, monocyte-, eosinophil-, and basophil- lymphocyte ratios among various systemic autoimmune rheumatic diseases","volume":"125","author":"Yang","year":"2017","journal-title":"Apmis"},{"key":"ref_12","first-page":"e13992","article-title":"Haematologic indices and disease activity index in primary Sjogren\u2019s syndrome","volume":"75","year":"2021","journal-title":"Int. J. Clin. Pract."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Dong, F., Zheng, L., An, W., Xue, T., and Zhong, X. (2023). A meta-analysis of the clinical significance of neutrophil-to-lymphocyte ratios in interstitial lung disease. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0286956"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Mihai, A., Caruntu, A., Opris-Belinski, D., Jurcut, C., Dima, A., Caruntu, C., and Ionescu, R. (2022). The Predictive Role of Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Monocytes-to-Lymphocyte Ratio (MLR) and Gammaglobulins for the Development of Cutaneous Vasculitis Lesions in Primary Sj\u00f6gren\u2019s Syndrome. J. Clin. Med., 11.","DOI":"10.3390\/jcm11195525"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.clinbiochem.2014.08.022","article-title":"Red blood cell distribution width and neutrophil\/lymphocyte ratio are positively correlated with disease activity in primary Sj\u00f6gren\u2019s syndrome","volume":"47","author":"Hu","year":"2014","journal-title":"Clin. Biochem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"M\u00e6land, E., Miyamoto, S.T., Hammenfors, D., Valim, V., and Jonsson, M.V. (2021). Understanding Fatigue in Sj\u00f6gren\u2019s Syndrome: Outcome Measures, Biomarkers and Possible Interventions. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.703079"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Mardale, D.A., Opri\u0219-Belinski, D., Bojinc\u0103, V., Bojinc\u0103, M., Mazilu, D., P\u0103s\u0103ran, E., Ni\u021b\u0103a, C., Gro\u0219eanu, L., Berghea, F., and B\u0103l\u0103nescu, A.R. (2024). The Physical and Psychosocial Impact of Fatigue among Patients with Sjogren\u2019s Syndrome: A Systematic Review. J. Clin. Med., 13.","DOI":"10.3390\/jcm13061537"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1002\/acr.22720","article-title":"Fatigue in Primary Sj\u00f6gren\u2019s Syndrome: Clinical, Laboratory, Psychometric, and Biologic Associations","volume":"68","author":"Karageorgas","year":"2016","journal-title":"Arthritis Care Res."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Milic, V., Grujic, M., Barisic, J., Marinkovic-Eric, J., Duisin, D., Cirkovic, A., and Damjanov, N. (2019). Personality, depression and anxiety in primary Sjogren\u2019s syndrome\u2014Association with sociodemographic factors and comorbidity. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0210466"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1093\/rheumatology\/keq023","article-title":"Sleepiness or fatigue? Can we detect treatable causes of tiredness in primary Sj\u00f6gren\u2019s syndrome?","volume":"49","author":"Theander","year":"2010","journal-title":"Rheumatology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.1093\/rheumatology\/kez027","article-title":"Pain and fatigue in primary Sj\u00f6gren\u2019s syndrome","volume":"60","author":"Omdal","year":"2021","journal-title":"Rheumatology"},{"key":"ref_22","first-page":"S82","article-title":"Fatigue in Sjogren\u2019s syndrome: Relationship with fibromyalgia, clinical and biologic features","volume":"28","author":"Priori","year":"2010","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_23","first-page":"2318","article-title":"Fatigue in primary Sj\u00f6gren\u2019s syndrome is associated with an objective decline in physical performance, pain and depression","volume":"40","author":"Prak","year":"2022","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2361","DOI":"10.1007\/s10067-018-4159-2","article-title":"Serological lymphocytic activity and patient-reported outcomes in Sj\u00f6gren\u2019s syndrome","volume":"37","author":"Kanne","year":"2018","journal-title":"Clin. Rheumatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/s41584-024-01135-3","article-title":"Update on the pathophysiology and treatment of primary Sj\u00f6gren syndrome","volume":"20","author":"Baldini","year":"2024","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1016\/j.autrev.2018.05.005","article-title":"Clinical and immunological parameters of Sj\u00f6gren\u2019s syndrome","volume":"17","author":"Psianou","year":"2018","journal-title":"Autoimmun. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1093\/rheumatology\/ken426","article-title":"Patient-reported outcomes in primary Sjogren\u2019s syndrome: Comparison of the long and short versions of the Profile of Fatigue and Discomfort--Sicca Symptoms Inventory","volume":"48","author":"Bowman","year":"2009","journal-title":"Rheumatology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.jaut.2013.12.010","article-title":"Outcome measures for primary Sj\u00f6gren\u2019s syndrome: A comprehensive review","volume":"51","author":"Seror","year":"2014","journal-title":"J. Autoimmun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3528","DOI":"10.1093\/rheumatology\/kez201","article-title":"Disease activity and patient reported outcome measures in Sj\u00f6gren\u2019s\u2014What are the best tools to evaluate?","volume":"60","author":"Seror","year":"2021","journal-title":"Rheumatology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"470","DOI":"10.3899\/jrheum.210633","article-title":"PROMIS Provides a Broader Overview of Health-related Quality of Life Than the ESSPRI in Evaluation of Sj\u00f6gren Syndrome","volume":"49","author":"DiRenzo","year":"2022","journal-title":"J. Rheumatol."},{"key":"ref_31","first-page":"165","article-title":"Anxiety and depression in patients with primary Sj\u00f6gren\u2019s syndrome","volume":"27","author":"Lindqvist","year":"2000","journal-title":"J. Rheumatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e9208","DOI":"10.1097\/MD.0000000000009208","article-title":"Health-related quality of life and psychological status of women with primary Sj\u00f6gren\u2019s syndrome: A cross-sectional study of 304 Chinese patients","volume":"96","author":"Liu","year":"2017","journal-title":"Medicine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.3390\/clinpract13060137","article-title":"The Translation, Validation and Cultural Adaptation of Questionnaires Assessing the Quality of Life and Fatigue among Patients with Sjogren\u2019s Syndrome for the Romanian Context","volume":"13","author":"Mardale","year":"2023","journal-title":"Clin. Pract."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"103425","DOI":"10.1016\/j.autrev.2023.103425","article-title":"Is minor salivary gland biopsy still mandatory in Sjogren\u2019s syndrome? Does seronegative Sjogren\u2019s syndrome exist?","volume":"23","author":"Baldini","year":"2024","journal-title":"Autoimmun. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Fiorentini, E., Bernardini, P., Zeka, D., Capassoni, M., Novelli, L., Palomba, A., Tofani, L., Cometi, L., and Guiducci, S. (2025). Minor Salivary Gland Biopsy in the Differential Diagnosis of Sicca Syndrome: A Monocentric Cohort Analysis. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26136463"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"102690","DOI":"10.1016\/j.autrev.2020.102690","article-title":"Minor salivary gland biopsy: Its role in the classification and prognosis of Sj\u00f6gren\u2019s syndrome","volume":"19","author":"Vivas","year":"2020","journal-title":"Autoimmun. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1080\/1744666X.2024.2368189","article-title":"Salivary gland biopsy as a prognostic tool in Sj\u00f6gren\u2019s syndrome","volume":"20","author":"Cafaro","year":"2024","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/s12974-019-1502-8","article-title":"Interleukin-1-related activity and hypocretin-1 in cerebrospinal fluid contribute to fatigue in primary Sj\u00f6gren\u2019s syndrome","volume":"16","author":"Brede","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/s41584-021-00692-1","article-title":"Fatigue in inflammatory rheumatic diseases: Current knowledge and areas for future research","volume":"17","author":"Davies","year":"2021","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1007\/s12035-015-9090-9","article-title":"The Neuro-Immune Pathophysiology of Central and Peripheral Fatigue in Systemic Immune-Inflammatory and Neuro-Immune Diseases","volume":"53","author":"Morris","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Milic, V., Colic, J., Cirkovic, A., Stanojlovic, S., and Damjanov, N. (2019). Disease activity and damage in patients with primary Sjogren\u2019s syndrome: Prognostic value of salivary gland ultrasonography. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0226498"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"717","DOI":"10.3899\/jrheum.200482","article-title":"Clinical Phenotyping of Primary Sj\u00f6gren Syndrome Patients Using Salivary Gland Ultrasonography: Data From the RESULT Cohort","volume":"48","author":"Mossel","year":"2021","journal-title":"J. Rheumatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"263","DOI":"10.3899\/jrheum.2023-0202","article-title":"The Novel OMERACT Ultrasound Scoring System for Salivary Gland Changes in Patients With Sj\u00f6gren Syndrome Is Associated With MRI and Salivary Flow Rates","volume":"51","author":"Inanc","year":"2024","journal-title":"J. Rheumatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1002\/art.42723","article-title":"Increased Diagnostic Accuracy of the Labial Gland Biopsy in Primary Sj\u00f6gren Syndrome When Multiple Histopathological Features Are Included","volume":"76","author":"Nakshbandi","year":"2024","journal-title":"Arthritis Rheumatol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1136\/annrheumdis-2016-210448","article-title":"Standardisation of labial salivary gland histopathology in clinical trials in primary Sj\u00f6gren\u2019s syndrome","volume":"76","author":"Fisher","year":"2017","journal-title":"Ann. Rheum Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11418\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T10:09:35Z","timestamp":1764151775000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11418"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,26]]},"references-count":45,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ijms262311418"],"URL":"https:\/\/doi.org\/10.3390\/ijms262311418","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,26]]}}}