Elevated IL-8 and abnormal Lymphocytes in pediatric primary Sjögren's syndrome: A single-center study

Elevated IL-8 and abnormal Lymphocytes in pediatric primary Sjögren's syndrome: A single-center study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Elevated IL-8 and abnormal Lymphocytes in pediatric primary Sjögren's syndrome: A single-center study Xianfei Gao, Wen Tang, Xiaoyou Huang, Yifan Liua, Jiawei Zhou, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7238562/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Jan, 2026 Read the published version in European Journal of Medical Research → Version 1 posted 12 You are reading this latest preprint version Abstract Background : Cytokines and lymphocytes orchestrating the pathophysiological landscape have been well explored in adults but are rare in children with Sjögren's syndrome. We aimed to assess their potential as biomarkers in pediatric Sjögren's syndrome. Methods : We reviewed 14 pediatric patients with primary Sjögren's syndrome (pSS) who attended a specialized rheumatology clinic over 2 years. A literature review of databases using MeSH headings and keywords for "Sjögren syndrome" and "pediatric." We measured the expression of cytokines: IL-4, IL-5, TNF-α, IFN-γ, TNF-β, IL-6, IL-1β, IL-2, IL-10, IL-8, IL-22, IL-12p70, IL-17F, and IL-17A in the plasma, and the percentages and absolute counts of CD3+, CD19+, CD3-CD16 + and/or CD56+, CD3 + CD4+, CD3 + CD8 + in peripheral blood, from14pSS patients and 12 healthy children. Results : A comparison of cytokines between patients with pSS and healthy children showed higher levels of IL-8 in the patients with pSS. A comparison of lymphocyte biomarkers between pSS patients and healthy children showed higher levels of CD3 + CD8 + lymphocytes in pSS patients, while markers such as CD3+, CD3 + CD4+, CD19+, and CD3-CD16 + or CD3-CD56 + were lower. Conclusions : IL-8 acts as a biomarker in pediatric pSS and might work with the abnormality of T cells, B cells, and NK cells to induce pSS. Article Summary Through the linkage of cytokine, lymphocyte, and pediatric primary Sjögren's syndrome, this study captures biomarkers of pSS based on an evaluation of child immunology status . Introduction Pediatric primary Sjögren's syndrome (pSS) is a rare autoimmune disorder that predominantly affects exocrine glands, leading to symptoms such as xerostomia and xerophthalmia, as well as systemic manifestations. While extensively studied in adults, pSS poses unique diagnostic challenges in children due to variations in clinical presentation and disease progression 1 . Early diagnosis is paramount to managing symptoms effectively and mitigating potential complications such as systemic manifestations and lymphoma. For this reason, identifying reliable biomarkers is crucial for elucidating underlying mechanisms and developing targeted therapies. Understanding these molecular mechanisms is crucial for developing effective therapeutic strategies tailored to young patients 2 . Specifically, we focused on cytokines and lymphocytes in children with pSS, and provided insight into the management of these patients in clinical practice. Materials and Methods Patient selection We included all children with pSS who were treated at the Department of Pediatrics, Allergy, Immune, and Rheumatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, between January 1, 2022, and December 31, 2024. Clinical information was collected. The pSS were diagnosed using the 2018 Japan Pediatric Sjögren syndrome clinical practice guidelines. Measurement of cytokines and lymphocytes The concentration of IL-4, IL-5, TNF-α, IFN-γ, TNF-β, IL-6, IL-1β, IL-2, IL-10, IL-8, IL-22, IL-12p70, IL-17F, and IL-17A was measured within 12 hours using commercial immunofluorescence kits (914002; QuantoBio, Tianjing, China) according to the manufacturer's instructions. The experiment was conducted by BD FACSLyric 3-Laser 10-Color Instrument, US-IVD (Cat. 662878). The percentages and absolute counts of CD3+, CD19+, CD3–CD16 + and/or CD56+, CD3 + CD4+, and CD3 + CD8 + were measured within 12 hours using commercial immunofluorescence kits (Catalog No. 662965; R&D Systems, Minneapolis, MN) according to the manufacturer's instructions. Results 1. Clinical Management of Patients with pSS in Our Cohort. The cohort consisted predominantly of females, comprising 71% of the cases. The average age of onset was 11 years, with the youngest patient being 5 years old (Table 1 ). The mean duration of delayed diagnosis was 10 months, with a maximum delay of 75 months. Only one patient had a family history of rheumatic disease. The most frequently observed symptom was a rash, present in 71% (10 out of 14) of patients. The lung was the most affected vital organ, involved in 28% of cases. Elevated erythrocyte sedimentation rate (ESR) and immunoglobulin G (IgG) levels were present in more than half of these patients. Nearly all patients showed positive results for Anti-nuclear antibodies (ANA) (100%) and Anti-Sjögren's syndrome-related antigen A (SSA) (93%), while only 57% tested positive for Anti-Sjögren's syndrome-related antigen B (SSB). Standard treatments in our cohort included corticosteroids (86%), hydroxychloroquine (79%), and methotrexate (57%). Table 1 Clinical characteristics of our cohort Variables No./Total % Clinical characters Sex(Female) 10/14 71 Race (Chinese) 14/14 100 First symptom onset mean age (Min-Max)(Year) 11(5–17) Disease diagnosis mean age (Min-Max)(Year) 12(6–17) Delayed diagnosis mean time(Min-Max)(Month) 10(1–75) Family history of rheumatic disease (Positive) 1/14 7 History of allergies (Positive) 0/14 0 History of eczema (Positive) 0/14 0 BMI(Mean + SD) 16 ± 1 Symptom Dryness of the mouth (Positive) 6/14 43 Dryness of the eyes (Positive) 4/14 29 Ocular tests (abnormal results) 12/13 92 Oral tests (abnormal results) 1/1 100 Parotitis (Positive) 5/14 36 Lymphadenopathy (Positive) 5/14 36 Rash (Positive) 10/14 71 Fatigue (Positive) 2/14 14 Fever (Positive) 6/14 43 Renal involvement (Positive) 1/14 7 Nervous system involvement (Positive) 1/14 7 Hepatitis/transaminitis (Positive) 3/14 21 Myositis/weakness/muscle pain (Positive) 0/14 0 Lung involvement (Positive) 4/14 28 Serositis (Positive) 1/14 7 Experiment High CRP 2/14 14 High ESR 8/14 57 High IgA 4/14 29 High IgM 2/14 14 High IgE 1/14 7 High IgG 10/14 71 Thrombocytopenia 2/14 14 Anemia 3/14 21 Leukopenia 3/14 21 Anti-SSB/La (Positive) 8/14 57 Anti-SSA/Ro (Positive) 13/14 93 RF (Positive) 3/9 33 ANA (Positive) 14/14 100 Low C3 2/14 14 Low C4 1/14 7 Treatment Corticosteroids 12/14 86 Hydroxychloroquine 11/14 79 Methotrexate 8/14 57 Mycophenolate mofetil 3/14 21 Adalimumab 1/14 7 Tofacitinib 1/14 7 Cyclophosphamide 1/14 7 Cyclosporin 1/14 7 BMI: Body Mass Index. CRP: C-Reactive Protein. ESR: Erythrocyte sedimentation rate. RF: rheumatoid factor. ANA: antinuclear antibody. C3: Complement 3. C4: Complement 4. IgA: immunoglobulins A. IgM: immunoglobulins M. IgG: immunoglobulins G. IgE: immunoglobulins E. The normal range of IgA, IgM, IgG, and IgE was according to the Tietz Textbook of Laboratory Medicine. 7th ed 40,41 . 2. Evaluation of Disease activity before and after treatment. Using the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), we found that all patients experienced moderate (43%) to high (57%) disease activity at the onset. However, patient outcomes significantly improved, with no high activity levels reported at the last follow-up. Although the average score for the ESSPRI was low at the onset stage (2 ± 1.2), it fell to nearly zero by the last follow-up. There were significant differences in both ESSDAI and ESSPRI scores between the onset and follow-up stages (Table 2 ). Table 2 Disease activity of our cohort Onset Last follow-up Score of ESSDAI(means ± SD) 16 ± 9.8 4 ± 3.6*(P = 0.000) No activity (No, %) 0,0% 6,43% Low activity (No, %) 0,0% 3,21% Moderate activity (No, %) 6,43% 5,36% High activity (No, %) 8,57% 0,0% Score of ESSPRI (+ SD) 2 ± 1.2 0 ± 0.0*(P = 0.001) Dryness (+ SD) 2 ± 2.4 0 ± 0.6 Fatigue (+ SD) 0 ± 0.7 0 ± 0.6 Pain (+ SD) 2 ± 2.4 0 ± 0.4 *: Comparison between Onset and Last follow-up. Mann–Whitney test 3. Comparison of cytokine and lymphocyte surface biomarkers between pSS patients and normal children. Table 3 presents a comprehensive analysis of cytokines and lymphocyte surface biomarkers in patients with pSS compared to healthy children. The two groups showed no significant differences in sex and age. IL-8 levels were significantly higher in the pSS group (314.39 ± 730.78) compared to the healthy group (13.23 ± 12.16). The levels of other cytokines did not show significant differences (P > 0.05) between the pSS and healthy groups. The percentage of CD3 + CD8 + cells was significantly higher in the pSS group, while CD3+, CD3 + CD4+, CD19+, and either CD3–CD16 + or CD3–CD56 + cells were significantly lower in the pSS group compared to the healthy cohort. Table 3 Cytokines and lymphocytes in our cohort pSS Normal P value Sex (Female,%) 9,64% 5,42% P = 0.25# Age at examination(Mean, Min-Max)(Year) 12,6–17 13,2–10 P = 0.07** IL-4 (pg/ml) 3.01 ± 1.44 (9) 3.98 ± 2.67 (11) P = 0.77* IL-5 (pg/ml) 2.12 ± 0.79(9) 6.62 ± 10.42 (12) P = 0.42* TNF-a (pg/ml) 3.56 ± 2.30 (9) 5.45 ± 6.45 (12) P = 0.41** IFN-r (pg/ml) 3.73 ± 2.43 (9) 3.54 ± 2.86 (12) P = 0.88** TNF-β (pg/ml) 0.95 ± 0.86 (3) 5.48 ± 7.69 (8) P = 0.28* IL-6 (pg/ml) 191.05 ± 532.48.44 (9) 5.08 ± 4.25 (12) P = 0.60* IL-1β (pg/ml) 4.47 ± 5.61 (9) 4.36 ± 4.43 (12) P = 0.96** IL-2 (pg/ml) 1.73 ± 0.83 (9) 1.50 ± 0.75 (12) P = 0.51** IL-10 (pg/ml) 3.11 ± 0.90 (9) 3.31 ± 1.95 (12) P = 0.86* IL-8 (pg/ml) 314.39 ± 730.78 (9) 13.23 ± 12.16 (12) P = 0.04 * IL-22 (pg/ml) 4.68 ± 3.24 (3) 3.37 ± 3.19 (8) P = 0.58** IL-12p70 (pg/ml) 3.31 ± 2.39 (9) 2.24 ± 2.89 (12) P = 0.38** IL-17F (pg/ml) 2.20 ± 1.20 (3) 3.66 ± 4.95 (8) P = 0.64** IL-17A (pg/ml) 1.53 ± 0.60 (4) 2.12 ± 2.60 (11) P = 0.67** CD3+/Lymphocyte% 72.10 ± 8.71 (13) 69.34 ± 3.60 (11) P = 0.23* CD3+ (×106/L) 1244.19 ± 537.56 (12) 1962.29 ± 457.95 (11) P = 0.003 ** CD3 + CD4+/lymphocyte% 35.08 ± 7.47 (13) 34.87 ± 3.31 (11) P = 0.57* CD3 + CD4+(×106/L) 600.08 ± 270.57 (12) 995.44 ± 231.02 (11) P = 0.001 ** CD3 + CD8+/lymphocyte% 32.18 ± 9.65 (13) 25.66 ± 4.01 (11) P = 0.04 * CD3 + CD8+(×106/L) 573.97 ± 323.16 (12) 634.91 ± 267.88 (11) P = 0.63** CD19+/lymphocyte% 18.47 ± 6.84 (13) 18.50 ± 3.40 (11) P = 0.99** CD19+(×106/L) 336.38 ± 245.68 (12) 521.64 ± 176.23 (11) P = 0.05 ** CD3-CD16 + or CD3-CD56+/lymphocyte% 8.19 ± 5.23 (13) 11.10 ± 3.43 (11) P = 0.13** CD3-CD16 + or CD3-CD56+(×106/L) 162.16 ± 175.36 (12) 301.26 ± 104.42 (11) P = 0.03 ** CD3 + CD4+/CD3 + CD8+ 1.25 ± 0.67 (13) 1.39 ± 0.23 (11) P = 0.25* CD3 + CD4 + CD8+/lymphocyte% 3.01 ± 8.73 (13) 0.20 ± 0.08 (10) P = 0.32** CD3 + CD4 + CD8+ (×106/L) 9.10 ± 8.14 (12) 5.95 ± 3.12 (10) P = 0.50* Data are means ± SD (n); # Chi-square, * Mann–Whitney test, ** t-test Discussion PSS is a systemic autoimmune disease predominantly characterized by lymphocytic infiltration of the exocrine glands, leading to xerostomia and xerophthalmia. However, unlike in adults, involvement of the salivary and lacrimal glands is less pronounced in children 2 . Standard objective tests, such as Schirmer's test and sialometry, which are typically tailored for adults, can be challenging to perform and interpret in children with non-cooperative behavior or fluctuating results due to developmental factors. This finding is consistent with our study, which showed that only 43% of patients experienced dry mouth, and 29% reported dry eyes. The diagnosis of pSS in children is complicated by the absence of a universally accepted set of diagnostic criteria tailored explicitly to pediatric cases. This shortage significantly impedes timely and accurate diagnosis 3 . Pediatric pSS presents challenges in assessing disease activity due to developmental changes and the lack of pediatric-specific indices. Current indices, such as the ESSDAI and ESSPRI, are adapted from adult versions and require careful interpretation in children, particularly when considering the unique expressions and feelings of children 4 . In our study, patients initially exhibited moderate to high disease activity in the ESSDAI, but had a relatively low ESSPRI score. Despite showing significant differences between onset and follow-up, the accuracy and appropriateness of these indices in children remain debated, highlighting the need for a specific evaluation tool for pediatric pSS 5 . Establishing criteria that account for the unique manifestations of pSS in children, possibly incorporating novel biomarkers. The immune pathogenesis of pSS involves complex interactions between cytokines and lymphocytes, which contribute to glandular dysfunction and systemic autoimmunity 6 . Adaptive immunity, characterized by antigen-specific responses mediated by T and B lymphocytes, develops gradually. Children display a Th2-biased immune profile and generate different cytokine responses compared to adults, exhibiting a more balanced Th1/Th2 response. The roles of cytokines and lymphocytes in pediatric pSS should be studied separately from those in adults 7 . However, rare publications involving three pediatric patients have previously examined cytokine and lymphocyte levels in pSS. In our study, we observed increases in CD3+, CD3 + CD4+, CD19+, and either CD3–CD16 + or CD3–CD56 + in the pSS group, alongside a decrease in CD3 + CD8+/lymphocytes, consistent with findings in adult patients 8 . IL-8 levels in our pediatric pSS patients aligned with studies of both adults and children. Previous research has indicated that other cytokines, including IL-4, IL-10, IFN-γ, IL-2, IL-17A, and IL-17F, did not demonstrate significant biomarker potential in either adult or pediatric pSS patients 8 . However, the elevated levels of IL-8 suggest it may play a critical role in the pathology of pSS. Further exploration of the relationship between IL-8 and lymphocytes may uncover additional aspects of the disease's underlying mechanisms. Conversely, IL-6, TNF-α, IL-1β, IL-5, IL-12p70, and IL-22 showed no significant differences in our pediatric pSS cohort, while these factors were increased in adult patients in other studies 9 – 11 . These discrepancies may highlight differences in the pathological mechanisms of pediatric versus adult pSS and warrant more extensive research into these cytokines among larger pediatric cohorts. Conclusion IL-8 appears to serve as a potential biomarker for pediatric pSS and may interact with abnormalities in T cells, B cells, and NK cells to contribute to the development of the syndrome. Abbreviations H&E hematoxylin and eosin pSS primary Sjögren's syndrome CARRA Childhood Arthritis and Rheumatology Research Alliance ESSDAI EULAR Sjögren's Syndrome Disease Activity Index ESSPRI EULAR Sjögren's Syndrome Patient Reported Index BMI Body Mass Index CRP C-Reactive Protein ESR Erythrocyte sedimentation rate RF Rheumatoid factor ANA: Antinuclear antibody C3 Complement 3 C4 Complement 4 IgA Immunoglobulins A IgM Immunoglobulins M IgG Immunoglobulins G IgE Immunoglobulins E Declarations Conflict of Interest Disclosures: The authors declare that the research was conducted without commercial or financial relationships that could create a conflict of interest. Funding: This study was supported by the Clinical Doctoral Start-up Research Fund of Guangzhou Women and Children's Medical Center (award number 1600218, X.G), the GuangDong Basic and Applied Basic Research Foundation (award number 2025A1515012735, P. Z), and the Municipal and University (Hospital) Joint Funding Project of Guangzhou Municipal Science and Technology Bureau (award number 2023A03J0902, F. L). Ethics approval and consent to participate The studies involving human participants were reviewed and approved by the Guangzhou Women and Children's Medical Center's hospital ethics committee (approval number: 2025078A01). The participant's legal guardian/next of kin provided written informed consent to participate in this study. Written informed consent was obtained from the individual(s) and minor(s)' legal guardian/next of kin to publish any potentially identifiable images or data in this article. Consent for publication The children's parents must give consent to publish. All presentations of case cohorts require consent to be published. Availability of data and material Not applicable Author's contributions Xianfei Gao and Wen Tang contributed to the study's conception and design. Xiaoyou Huang and Wen Tang organized the database. Jiawei Zhou and Zhirui Nie collected the patient sample. Yifan Liu, Ying Tang, Feng Li, and Qi Ren collected patient information. Mingqi Zhao and Caihong Xu measured the cytokines and lymphocytes. Xianfei Gao wrote the first draft of the manuscript, and Ping Zeng supervised and revised it. All authors contributed to the article and approved the submitted version. Acknowledgments All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article or claimed by its manufacturer may not be guaranteed or endorsed by the publisher. References Zeng W, Thatayatikom A, Winn N, et al. The Florida Scoring System for stratifying children with suspected Sjögren's disease: a cross-sectional machine learning study. The Lancet Rheumatology . 2024;6(5):e279-e290. Roescher N, Tak PP, Illei GG. Cytokines in Sjogren's syndrome: potential therapeutic targets. Ann Rheum Dis . Jun 2010;69(6):945–8. doi: 10.1136/ard.2009.115378 Goules AV, Tzioufas AG, Moutsopoulos HM. Classification criteria of Sjögren's syndrome. J Autoimmun . Feb-Mar 2014;48–49:42 – 5. doi: 10.1016/j.jaut.2014.01.013 Marrani E, Maniscalco V, Baldini C, Simonini G. Outcome measure in childhood Sjögren's disease: where do we stand? Clin Exp Rheumatol . Dec 2024;42(12):2344–2345. doi: 10.55563/clinexprheumatol/faykmn Tarn J, Lendrem D, McMeekin P, Lendrem C, Hargreaves B, Ng WF. Primary Sjögren's syndrome: Longitudinal real-world, observational data on health-related quality of life. J Intern Med . Jun 2022;291(6):849–855. doi: 10.1111/joim.13451 Wang LH, Wang WM, Lin CY, Lin SH, Shieh CC. Bidirectional relationship between primary sjögren syndrome and non-hodgkin lymphoma: A nationwide taiwanese population-based study. Journal of Rheumatology . 2020;47(9):1374–1378. Ajjan RA, McIntosh RS, Waterman EA, et al. Analysis of the T-cell receptor Valpha repertoire and cytokine gene expression in Sjögren's syndrome. Br J Rheumatol . Feb 1998;37(2):179–85. doi: 10.1093/rheumatology/37.2.179 Szodoray P, Gal I, Barath S, et al. Immunological alterations in newly diagnosed primary Sjögren's syndrome characterized by skewed peripheral T-cell subsets and inflammatory cytokines. Scand J Rheumatol . May-Jun 2008;37(3):205–12. doi: 10.1080/03009740801910361 Azuma N, Katada Y, Harada Y, et al. [Case of primary Sjogren's syndrome with hypereosinophilia and elevation of serum IgE: measurements of serum IL-4, IL-5 and the IgG subclass]. Arerugi . Jul 2005;54(7):646–51. Olsson P, Skogstrand K, Nilsson A, et al. Smoking, disease characteristics and serum cytokine levels in patients with primary Sjogren's syndrome. Rheumatol Int . Aug 2018;38(8):1503–1510. doi: 10.1007/s00296-018-4063-8 Nilsson AM, Tufvesson E, Hesselstrand R, Olsson P, Wollmer P, Mandl T. Increased B-cell activating factor, interleukin-6, and interleukin-8 in induced sputum from primary Sjögren's syndrome patients. Scand J Rheumatol . Mar 2019;48(2):149–156. doi: 10.1080/03009742.2018.1473488 Additional Declarations No competing interests reported. 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University","correspondingAuthor":false,"prefix":"","firstName":"Huishan","middleName":"","lastName":"Chen","suffix":""},{"id":500639667,"identity":"59787f07-a65c-4cf6-92d4-4a1aa3d17b31","order_by":11,"name":"Ping Zeng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3ElEQVRIiWNgGAWjYNACAzDJ+CChwoYELTwMDMwGD86kkWARUAub5MO2Q4RVyrf3Hn5dUHDHbj97d1pFAtsBBv727gS8Whh7zqVZzzB4ltzDc3bbjQSeOwwSZ85uwKuFWSLHzJjH4HAyj0QuUIvEMwYDiVz8Wtjk3yC0FCQYHCashUeCx/gxUIsdSAtDQgIRWiR4csyYZxgcTuA5c3azRMKBNB6CfpFvP2P8ueDPYXv29t6NH3/+s5Hjb+/FrwXkHWkgkdgAcykh5SDA/BlI2BOjchSMglEwCkYoAAD2mkfHAS0oTAAAAABJRU5ErkJggg==","orcid":"","institution":"Guangzhou Medical University","correspondingAuthor":true,"prefix":"","firstName":"Ping","middleName":"","lastName":"Zeng","suffix":""}],"badges":[],"createdAt":"2025-07-29 03:38:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7238562/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7238562/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40001-025-03774-y","type":"published","date":"2026-01-05T15:57:08+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":100069042,"identity":"fc4b67d7-0390-437c-abf3-666c51f4edd9","added_by":"auto","created_at":"2026-01-12 16:06:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":701654,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7238562/v1/8294cbde-ea0e-4f58-b4c2-8d12fbfc77fc.pdf"},{"id":89471181,"identity":"f89b921b-d3ab-408e-a171-7d81f621d8cd","added_by":"auto","created_at":"2025-08-20 09:27:36","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":55212,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure.docx","url":"https://assets-eu.researchsquare.com/files/rs-7238562/v1/444d7055837fd87057de5e38.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Elevated IL-8 and abnormal Lymphocytes in pediatric primary Sjögren's syndrome: A single-center study","fulltext":[{"header":"Article Summary","content":"\u003cp\u003eThrough the linkage of cytokine, lymphocyte, and pediatric primary Sj\u0026ouml;gren\u0026apos;s syndrome, this study captures biomarkers of pSS based on an evaluation of child immunology status\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003ePediatric primary Sj\u0026ouml;gren's syndrome (pSS) is a rare autoimmune disorder that predominantly affects exocrine glands, leading to symptoms such as xerostomia and xerophthalmia, as well as systemic manifestations. While extensively studied in adults, pSS poses unique diagnostic challenges in children due to variations in clinical presentation and disease progression\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Early diagnosis is paramount to managing symptoms effectively and mitigating potential complications such as systemic manifestations and lymphoma. For this reason, identifying reliable biomarkers is crucial for elucidating underlying mechanisms and developing targeted therapies. Understanding these molecular mechanisms is crucial for developing effective therapeutic strategies tailored to young patients\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e Specifically, we focused on cytokines and lymphocytes in children with pSS, and provided insight into the management of these patients in clinical practice.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003ePatient selection\u003c/p\u003e\u003cp\u003eWe included all children with pSS who were treated at the Department of Pediatrics, Allergy, Immune, and Rheumatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, between January 1, 2022, and December 31, 2024. Clinical information was collected. The pSS were diagnosed using the 2018 Japan Pediatric Sj\u0026ouml;gren syndrome clinical practice guidelines.\u003c/p\u003e\u003cp\u003eMeasurement of cytokines and lymphocytes\u003c/p\u003e\u003cp\u003eThe concentration of IL-4, IL-5, TNF-α, IFN-γ, TNF-β, IL-6, IL-1β, IL-2, IL-10, IL-8, IL-22, IL-12p70, IL-17F, and IL-17A was measured within 12 hours using commercial immunofluorescence kits (914002; QuantoBio, Tianjing, China) according to the manufacturer's instructions. The experiment was conducted by BD FACSLyric 3-Laser 10-Color Instrument, US-IVD (Cat. 662878). The percentages and absolute counts of CD3+, CD19+, CD3\u0026ndash;CD16\u0026thinsp;+\u0026thinsp;and/or CD56+, CD3\u0026thinsp;+\u0026thinsp;CD4+, and CD3\u0026thinsp;+\u0026thinsp;CD8\u0026thinsp;+\u0026thinsp;were measured within 12 hours using commercial immunofluorescence kits (Catalog No. 662965; R\u0026amp;D Systems, Minneapolis, MN) according to the manufacturer's instructions.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e1. Clinical Management of Patients with pSS in Our Cohort.\u003c/p\u003e\u003cp\u003eThe cohort consisted predominantly of females, comprising 71% of the cases. The average age of onset was 11 years, with the youngest patient being 5 years old (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The mean duration of delayed diagnosis was 10 months, with a maximum delay of 75 months. Only one patient had a family history of rheumatic disease. The most frequently observed symptom was a rash, present in 71% (10 out of 14) of patients. The lung was the most affected vital organ, involved in 28% of cases. Elevated erythrocyte sedimentation rate (ESR) and immunoglobulin G (IgG) levels were present in more than half of these patients. Nearly all patients showed positive results for Anti-nuclear antibodies (ANA) (100%) and Anti-Sj\u0026ouml;gren's syndrome-related antigen A (SSA) (93%), while only 57% tested positive for Anti-Sj\u0026ouml;gren's syndrome-related antigen B (SSB). Standard treatments in our cohort included corticosteroids (86%), hydroxychloroquine (79%), and methotrexate (57%).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClinical characteristics of our cohort\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo./Total\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e%\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClinical characters\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSex(Female)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e71\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRace (Chinese)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFirst symptom onset mean age (Min-Max)(Year)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11(5\u0026ndash;17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDisease diagnosis mean age (Min-Max)(Year)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12(6\u0026ndash;17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDelayed diagnosis mean time(Min-Max)(Month)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10(1\u0026ndash;75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFamily history of rheumatic disease (Positive)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHistory of allergies (Positive)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHistory of eczema (Positive)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBMI(Mean\u0026thinsp;+\u0026thinsp;SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSymptom\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDryness of the mouth (Positive)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e43\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDryness of the eyes (Positive)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e29\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOcular tests (abnormal results)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12/13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e92\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOral tests (abnormal results)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1/1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eParotitis (Positive)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e36\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLymphadenopathy (Positive)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e36\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRash (Positive)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e71\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFatigue (Positive)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFever (Positive)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e43\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRenal involvement (Positive)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNervous system involvement (Positive)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHepatitis/transaminitis (Positive)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMyositis/weakness/muscle pain (Positive)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLung involvement (Positive)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSerositis (Positive)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExperiment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHigh CRP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHigh ESR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e57\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHigh IgA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e29\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHigh IgM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHigh IgE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHigh IgG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e71\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eThrombocytopenia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAnemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLeukopenia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAnti-SSB/La (Positive)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e57\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAnti-SSA/Ro (Positive)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e93\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRF (Positive)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3/9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e33\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eANA (Positive)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow C3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow C4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTreatment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCorticosteroids\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e86\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHydroxychloroquine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e79\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMethotrexate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e57\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMycophenolate mofetil\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAdalimumab\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTofacitinib\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCyclophosphamide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCyclosporin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eBMI: Body Mass Index. CRP: C-Reactive Protein. ESR: Erythrocyte sedimentation rate. RF: rheumatoid factor. ANA: antinuclear antibody. C3: Complement 3. C4: Complement 4. IgA: immunoglobulins A. IgM: immunoglobulins M. IgG: immunoglobulins G. IgE: immunoglobulins E. The normal range of IgA, IgM, IgG, and IgE was according to the Tietz Textbook of Laboratory Medicine. 7th ed\u003csup\u003e40,41\u003c/sup\u003e.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e2. Evaluation of Disease activity before and after treatment.\u003c/p\u003e\u003cp\u003eUsing the EULAR Sj\u0026ouml;gren's Syndrome Disease Activity Index (ESSDAI), we found that all patients experienced moderate (43%) to high (57%) disease activity at the onset. However, patient outcomes significantly improved, with no high activity levels reported at the last follow-up. Although the average score for the ESSPRI was low at the onset stage (2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2), it fell to nearly zero by the last follow-up. There were significant differences in both ESSDAI and ESSPRI scores between the onset and follow-up stages (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDisease activity of our cohort\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOnset\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLast follow-up\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eScore of ESSDAI(means\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16\u0026thinsp;\u0026plusmn;\u0026thinsp;9.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6*(P\u0026thinsp;=\u0026thinsp;0.000)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eNo activity (No, %)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003e0,0%\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003e6,43%\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eLow activity (No, %)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003e0,0%\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003e3,21%\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eModerate activity (No, %)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003e6,43%\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003e5,36%\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eHigh activity (No, %)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003e8,57%\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003e0,0%\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eScore of ESSPRI (+\u0026thinsp;SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0*(P\u0026thinsp;=\u0026thinsp;0.001)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eDryness (+\u0026thinsp;SD)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003e2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003e0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eFatigue (+\u0026thinsp;SD)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003e0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003e0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ePain (+\u0026thinsp;SD)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003e2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003e0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003e*: Comparison between Onset and Last follow-up. Mann\u0026ndash;Whitney test\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e3. Comparison of cytokine and lymphocyte surface biomarkers between pSS patients and normal children.\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e presents a comprehensive analysis of cytokines and lymphocyte surface biomarkers in patients with pSS compared to healthy children. The two groups showed no significant differences in sex and age. IL-8 levels were significantly higher in the pSS group (314.39\u0026thinsp;\u0026plusmn;\u0026thinsp;730.78) compared to the healthy group (13.23\u0026thinsp;\u0026plusmn;\u0026thinsp;12.16). The levels of other cytokines did not show significant differences (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) between the pSS and healthy groups. The percentage of CD3\u0026thinsp;+\u0026thinsp;CD8\u0026thinsp;+\u0026thinsp;cells was significantly higher in the pSS group, while CD3+, CD3\u0026thinsp;+\u0026thinsp;CD4+, CD19+, and either CD3\u0026ndash;CD16\u0026thinsp;+\u0026thinsp;or CD3\u0026ndash;CD56\u0026thinsp;+\u0026thinsp;cells were significantly lower in the pSS group compared to the healthy cohort.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCytokines and lymphocytes in our cohort\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003epSS\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex (Female,%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9,64%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5,42%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.25#\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge at examination(Mean, Min-Max)(Year)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12,6\u0026ndash;17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13,2\u0026ndash;10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.07**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-4 (pg/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.01\u0026thinsp;\u0026plusmn;\u0026thinsp;1.44 (9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.98\u0026thinsp;\u0026plusmn;\u0026thinsp;2.67 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.77*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-5 (pg/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.79(9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.62\u0026thinsp;\u0026plusmn;\u0026thinsp;10.42 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.42*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTNF-a (pg/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.56\u0026thinsp;\u0026plusmn;\u0026thinsp;2.30 (9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.45\u0026thinsp;\u0026plusmn;\u0026thinsp;6.45 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.41**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIFN-r (pg/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.73\u0026thinsp;\u0026plusmn;\u0026thinsp;2.43 (9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.54\u0026thinsp;\u0026plusmn;\u0026thinsp;2.86 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.88**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTNF-β (pg/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.95\u0026thinsp;\u0026plusmn;\u0026thinsp;0.86 (3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.48\u0026thinsp;\u0026plusmn;\u0026thinsp;7.69 (8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.28*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-6 (pg/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e191.05\u0026thinsp;\u0026plusmn;\u0026thinsp;532.48.44 (9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.08\u0026thinsp;\u0026plusmn;\u0026thinsp;4.25 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.60*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-1β (pg/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.47\u0026thinsp;\u0026plusmn;\u0026thinsp;5.61 (9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.36\u0026thinsp;\u0026plusmn;\u0026thinsp;4.43 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.96**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-2 (pg/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.73\u0026thinsp;\u0026plusmn;\u0026thinsp;0.83 (9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.75 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.51**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-10 (pg/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.90 (9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.31\u0026thinsp;\u0026plusmn;\u0026thinsp;1.95 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.86*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-8 (pg/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e314.39\u0026thinsp;\u0026plusmn;\u0026thinsp;730.78 (9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13.23\u0026thinsp;\u0026plusmn;\u0026thinsp;12.16 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003eP\u0026thinsp;=\u0026thinsp;0.04\u003c/b\u003e*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-22 (pg/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.68\u0026thinsp;\u0026plusmn;\u0026thinsp;3.24 (3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.37\u0026thinsp;\u0026plusmn;\u0026thinsp;3.19 (8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.58**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-12p70 (pg/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.31\u0026thinsp;\u0026plusmn;\u0026thinsp;2.39 (9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.24\u0026thinsp;\u0026plusmn;\u0026thinsp;2.89 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.38**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-17F (pg/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.20\u0026thinsp;\u0026plusmn;\u0026thinsp;1.20 (3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.66\u0026thinsp;\u0026plusmn;\u0026thinsp;4.95 (8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.64**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-17A (pg/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.53\u0026thinsp;\u0026plusmn;\u0026thinsp;0.60 (4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.12\u0026thinsp;\u0026plusmn;\u0026thinsp;2.60 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.67**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCD3+/Lymphocyte%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e72.10\u0026thinsp;\u0026plusmn;\u0026thinsp;8.71 (13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e69.34\u0026thinsp;\u0026plusmn;\u0026thinsp;3.60 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.23*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCD3+ (\u0026times;106/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1244.19\u0026thinsp;\u0026plusmn;\u0026thinsp;537.56 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1962.29\u0026thinsp;\u0026plusmn;\u0026thinsp;457.95 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003eP\u0026thinsp;=\u0026thinsp;0.003\u003c/b\u003e**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCD3\u0026thinsp;+\u0026thinsp;CD4+/lymphocyte%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e35.08\u0026thinsp;\u0026plusmn;\u0026thinsp;7.47 (13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e34.87\u0026thinsp;\u0026plusmn;\u0026thinsp;3.31 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.57*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCD3\u0026thinsp;+\u0026thinsp;CD4+(\u0026times;106/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e600.08\u0026thinsp;\u0026plusmn;\u0026thinsp;270.57 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e995.44\u0026thinsp;\u0026plusmn;\u0026thinsp;231.02 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003eP\u0026thinsp;=\u0026thinsp;0.001\u003c/b\u003e**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCD3\u0026thinsp;+\u0026thinsp;CD8+/lymphocyte%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e32.18\u0026thinsp;\u0026plusmn;\u0026thinsp;9.65 (13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25.66\u0026thinsp;\u0026plusmn;\u0026thinsp;4.01 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003eP\u0026thinsp;=\u0026thinsp;0.04\u003c/b\u003e*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCD3\u0026thinsp;+\u0026thinsp;CD8+(\u0026times;106/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e573.97\u0026thinsp;\u0026plusmn;\u0026thinsp;323.16 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e634.91\u0026thinsp;\u0026plusmn;\u0026thinsp;267.88 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.63**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCD19+/lymphocyte%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18.47\u0026thinsp;\u0026plusmn;\u0026thinsp;6.84 (13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18.50\u0026thinsp;\u0026plusmn;\u0026thinsp;3.40 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.99**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCD19+(\u0026times;106/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e336.38\u0026thinsp;\u0026plusmn;\u0026thinsp;245.68 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e521.64\u0026thinsp;\u0026plusmn;\u0026thinsp;176.23 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003eP\u0026thinsp;=\u0026thinsp;0.05\u003c/b\u003e**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCD3-CD16\u0026thinsp;+\u0026thinsp;or CD3-CD56+/lymphocyte%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.19\u0026thinsp;\u0026plusmn;\u0026thinsp;5.23 (13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11.10\u0026thinsp;\u0026plusmn;\u0026thinsp;3.43 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.13**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCD3-CD16\u0026thinsp;+\u0026thinsp;or CD3-CD56+(\u0026times;106/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e162.16\u0026thinsp;\u0026plusmn;\u0026thinsp;175.36 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e301.26\u0026thinsp;\u0026plusmn;\u0026thinsp;104.42 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003eP\u0026thinsp;=\u0026thinsp;0.03\u003c/b\u003e**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCD3\u0026thinsp;+\u0026thinsp;CD4+/CD3\u0026thinsp;+\u0026thinsp;CD8+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.67 (13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.39\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.25*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCD3\u0026thinsp;+\u0026thinsp;CD4\u0026thinsp;+\u0026thinsp;CD8+/lymphocyte%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.01\u0026thinsp;\u0026plusmn;\u0026thinsp;8.73 (13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08 (10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.32**\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCD3\u0026thinsp;+\u0026thinsp;CD4\u0026thinsp;+\u0026thinsp;CD8+ (\u0026times;106/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9.10\u0026thinsp;\u0026plusmn;\u0026thinsp;8.14 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.95\u0026thinsp;\u0026plusmn;\u0026thinsp;3.12 (10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.50*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eData are means\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (n); # Chi-square, * Mann\u0026ndash;Whitney test, ** t-test\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePSS is a systemic autoimmune disease predominantly characterized by lymphocytic infiltration of the exocrine glands, leading to xerostomia and xerophthalmia. However, unlike in adults, involvement of the salivary and lacrimal glands is less pronounced in children\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Standard objective tests, such as Schirmer's test and sialometry, which are typically tailored for adults, can be challenging to perform and interpret in children with non-cooperative behavior or fluctuating results due to developmental factors. This finding is consistent with our study, which showed that only 43% of patients experienced dry mouth, and 29% reported dry eyes. The diagnosis of pSS in children is complicated by the absence of a universally accepted set of diagnostic criteria tailored explicitly to pediatric cases. This shortage significantly impedes timely and accurate diagnosis\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003ePediatric pSS presents challenges in assessing disease activity due to developmental changes and the lack of pediatric-specific indices. Current indices, such as the ESSDAI and ESSPRI, are adapted from adult versions and require careful interpretation in children, particularly when considering the unique expressions and feelings of children\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. In our study, patients initially exhibited moderate to high disease activity in the ESSDAI, but had a relatively low ESSPRI score. Despite showing significant differences between onset and follow-up, the accuracy and appropriateness of these indices in children remain debated, highlighting the need for a specific evaluation tool for pediatric pSS\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eEstablishing criteria that account for the unique manifestations of pSS in children, possibly incorporating novel biomarkers.\u003c/p\u003e\u003cp\u003eThe immune pathogenesis of pSS involves complex interactions between cytokines and lymphocytes, which contribute to glandular dysfunction and systemic autoimmunity\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Adaptive immunity, characterized by antigen-specific responses mediated by T and B lymphocytes, develops gradually. Children display a Th2-biased immune profile and generate different cytokine responses compared to adults, exhibiting a more balanced Th1/Th2 response. The roles of cytokines and lymphocytes in pediatric pSS should be studied separately from those in adults\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. However, rare publications involving three pediatric patients have previously examined cytokine and lymphocyte levels in pSS.\u003c/p\u003e\u003cp\u003eIn our study, we observed increases in CD3+, CD3\u0026thinsp;+\u0026thinsp;CD4+, CD19+, and either CD3\u0026ndash;CD16\u0026thinsp;+\u0026thinsp;or CD3\u0026ndash;CD56\u0026thinsp;+\u0026thinsp;in the pSS group, alongside a decrease in CD3\u0026thinsp;+\u0026thinsp;CD8+/lymphocytes, consistent with findings in adult patients\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. IL-8 levels in our pediatric pSS patients aligned with studies of both adults and children. Previous research has indicated that other cytokines, including IL-4, IL-10, IFN-γ, IL-2, IL-17A, and IL-17F, did not demonstrate significant biomarker potential in either adult or pediatric pSS patients\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. However, the elevated levels of IL-8 suggest it may play a critical role in the pathology of pSS. Further exploration of the relationship between IL-8 and lymphocytes may uncover additional aspects of the disease's underlying mechanisms.\u003c/p\u003e\u003cp\u003eConversely, IL-6, TNF-α, IL-1β, IL-5, IL-12p70, and IL-22 showed no significant differences in our pediatric pSS cohort, while these factors were increased in adult patients in other studies\u003csup\u003e\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. These discrepancies may highlight differences in the pathological mechanisms of pediatric versus adult pSS and warrant more extensive research into these cytokines among larger pediatric cohorts.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIL-8 appears to serve as a potential biomarker for pediatric pSS and may interact with abnormalities in T cells, B cells, and NK cells to contribute to the development of the syndrome.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eH\u0026amp;E\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ehematoxylin and eosin\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003epSS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eprimary Sj\u0026ouml;gren's syndrome\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCARRA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eChildhood Arthritis and Rheumatology Research Alliance\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eESSDAI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eEULAR Sj\u0026ouml;gren's Syndrome Disease Activity Index\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eESSPRI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eEULAR Sj\u0026ouml;gren's Syndrome Patient Reported Index\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBMI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eBody Mass Index\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCRP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eC-Reactive Protein\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eESR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eErythrocyte sedimentation rate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRheumatoid factor\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eANA:\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAntinuclear antibody\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eC3\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eComplement 3\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eC4\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eComplement 4\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIgA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eImmunoglobulins A\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIgM\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eImmunoglobulins M\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIgG\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eImmunoglobulins G\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIgE\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eImmunoglobulins E\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest Disclosures:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted without commercial or financial relationships that could create a conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Clinical Doctoral Start-up Research Fund of Guangzhou Women and Children\u0026apos;s Medical Center (award number 1600218, X.G), \u0026nbsp; the GuangDong Basic and Applied Basic Research Foundation (award number 2025A1515012735, P. Z), and the Municipal and University (Hospital) Joint Funding Project of Guangzhou Municipal Science and Technology Bureau (award number 2023A03J0902, F. L).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe studies involving human participants were reviewed and approved by the Guangzhou Women and Children\u0026apos;s Medical Center\u0026apos;s hospital ethics committee (approval number: 2025078A01). The participant\u0026apos;s legal guardian/next of kin provided written informed consent to participate in this study. Written informed consent was obtained from the individual(s) and minor(s)\u0026apos; legal guardian/next of kin to publish any potentially identifiable images or data in this article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe children\u0026apos;s parents must give consent to publish. All presentations of case cohorts require consent to be published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026apos;s contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXianfei Gao and Wen Tang contributed to the study\u0026apos;s conception and design. Xiaoyou Huang and\u0026nbsp;Wen Tang organized the database. Jiawei Zhou and Zhirui Nie collected the patient sample. Yifan Liu, Ying Tang, Feng Li, and Qi \u0026nbsp;Ren collected patient information. Mingqi Zhao and Caihong Xu measured the cytokines and lymphocytes. Xianfei Gao wrote the first draft of the manuscript, and Ping Zeng supervised and revised it. All authors contributed to the article and approved the submitted version.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article or claimed by its manufacturer may not be guaranteed or endorsed by the publisher.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eZeng W, Thatayatikom A, Winn N, et al. The Florida Scoring System for stratifying children with suspected Sj\u0026ouml;gren's disease: a cross-sectional machine learning study. \u003cem\u003eThe Lancet Rheumatology\u003c/em\u003e. 2024;6(5):e279-e290.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRoescher N, Tak PP, Illei GG. Cytokines in Sjogren's syndrome: potential therapeutic targets. \u003cem\u003eAnn Rheum Dis\u003c/em\u003e. Jun 2010;69(6):945\u0026ndash;8. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/ard.2009.115378\u003c/span\u003e\u003cspan address=\"10.1136/ard.2009.115378\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGoules AV, Tzioufas AG, Moutsopoulos HM. Classification criteria of Sj\u0026ouml;gren's syndrome. \u003cem\u003eJ Autoimmun\u003c/em\u003e. Feb-Mar 2014;48\u0026ndash;49:42\u0026thinsp;\u0026ndash;\u0026thinsp;5. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jaut.2014.01.013\u003c/span\u003e\u003cspan address=\"10.1016/j.jaut.2014.01.013\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMarrani E, Maniscalco V, Baldini C, Simonini G. Outcome measure in childhood Sj\u0026ouml;gren's disease: where do we stand? \u003cem\u003eClin Exp Rheumatol\u003c/em\u003e. Dec 2024;42(12):2344\u0026ndash;2345. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.55563/clinexprheumatol/faykmn\u003c/span\u003e\u003cspan address=\"10.55563/clinexprheumatol/faykmn\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTarn J, Lendrem D, McMeekin P, Lendrem C, Hargreaves B, Ng WF. Primary Sj\u0026ouml;gren's syndrome: Longitudinal real-world, observational data on health-related quality of life. \u003cem\u003eJ Intern Med\u003c/em\u003e. Jun 2022;291(6):849\u0026ndash;855. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/joim.13451\u003c/span\u003e\u003cspan address=\"10.1111/joim.13451\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang LH, Wang WM, Lin CY, Lin SH, Shieh CC. Bidirectional relationship between primary sj\u0026ouml;gren syndrome and non-hodgkin lymphoma: A nationwide taiwanese population-based study. \u003cem\u003eJournal of Rheumatology\u003c/em\u003e. 2020;47(9):1374\u0026ndash;1378.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAjjan RA, McIntosh RS, Waterman EA, et al. Analysis of the T-cell receptor Valpha repertoire and cytokine gene expression in Sj\u0026ouml;gren's syndrome. \u003cem\u003eBr J Rheumatol\u003c/em\u003e. Feb 1998;37(2):179\u0026ndash;85. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/rheumatology/37.2.179\u003c/span\u003e\u003cspan address=\"10.1093/rheumatology/37.2.179\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSzodoray P, Gal I, Barath S, et al. Immunological alterations in newly diagnosed primary Sj\u0026ouml;gren's syndrome characterized by skewed peripheral T-cell subsets and inflammatory cytokines. \u003cem\u003eScand J Rheumatol\u003c/em\u003e. May-Jun 2008;37(3):205\u0026ndash;12. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/03009740801910361\u003c/span\u003e\u003cspan address=\"10.1080/03009740801910361\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAzuma N, Katada Y, Harada Y, et al. [Case of primary Sjogren's syndrome with hypereosinophilia and elevation of serum IgE: measurements of serum IL-4, IL-5 and the IgG subclass]. \u003cem\u003eArerugi\u003c/em\u003e. Jul 2005;54(7):646\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOlsson P, Skogstrand K, Nilsson A, et al. Smoking, disease characteristics and serum cytokine levels in patients with primary Sjogren's syndrome. \u003cem\u003eRheumatol Int\u003c/em\u003e. Aug 2018;38(8):1503\u0026ndash;1510. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00296-018-4063-8\u003c/span\u003e\u003cspan address=\"10.1007/s00296-018-4063-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNilsson AM, Tufvesson E, Hesselstrand R, Olsson P, Wollmer P, Mandl T. Increased B-cell activating factor, interleukin-6, and interleukin-8 in induced sputum from primary Sj\u0026ouml;gren's syndrome patients. \u003cem\u003eScand J Rheumatol\u003c/em\u003e. Mar 2019;48(2):149\u0026ndash;156. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/03009742.2018.1473488\u003c/span\u003e\u003cspan address=\"10.1080/03009742.2018.1473488\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-medical-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejmr","sideBox":"Learn more about [European Journal of Medical Research](http://eurjmedres.biomedcentral.com)","snPcode":"40001","submissionUrl":"https://submission.nature.com/new-submission/40001/3","title":"European Journal of Medical Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7238562/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7238562/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Cytokines and lymphocytes orchestrating the pathophysiological landscape have been well explored in adults but are rare in children with Sjögren's syndrome. We aimed to assess their potential as biomarkers in pediatric Sjögren's syndrome.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: We reviewed 14 pediatric patients with primary Sjögren's syndrome (pSS) who attended a specialized rheumatology clinic over 2 years. A literature review of databases using MeSH headings and keywords for \"Sjögren syndrome\" and \"pediatric.\" We measured the expression of cytokines: IL-4, IL-5, TNF-α, IFN-γ, TNF-β, IL-6, IL-1β, IL-2, IL-10, IL-8, IL-22, IL-12p70, IL-17F, and IL-17A in the plasma, and the percentages and absolute counts of CD3+, CD19+, CD3-CD16 + and/or CD56+, CD3 + CD4+, CD3 + CD8 + in peripheral blood, from14pSS patients and 12 healthy children.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: A comparison of cytokines between patients with pSS and healthy children showed higher levels of IL-8 in the patients with pSS. A comparison of lymphocyte biomarkers between pSS patients and healthy children showed higher levels of CD3 + CD8 + lymphocytes in pSS patients, while markers such as CD3+, CD3 + CD4+, CD19+, and CD3-CD16 + or CD3-CD56 + were lower.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: IL-8 acts as a biomarker in pediatric pSS and might work with the abnormality of T cells, B cells, and NK cells to induce pSS.\u003c/p\u003e","manuscriptTitle":"Elevated IL-8 and abnormal Lymphocytes in pediatric primary Sjögren's syndrome: A single-center study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-20 09:27:31","doi":"10.21203/rs.3.rs-7238562/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-20T10:31:37+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-03T13:03:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-01T15:11:56+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-28T17:49:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"141242594308117809069252230031433079835","date":"2025-09-28T16:58:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"39780417366208970712639248441829227992","date":"2025-09-26T10:04:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"336896541303858586514231382829143826223","date":"2025-09-18T15:48:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"195285931338451591189908484787379533905","date":"2025-09-14T15:15:33+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-12T14:00:21+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-31T06:43:45+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-29T10:45:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Medical Research","date":"2025-07-29T03:32:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-medical-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejmr","sideBox":"Learn more about [European Journal of Medical Research](http://eurjmedres.biomedcentral.com)","snPcode":"40001","submissionUrl":"https://submission.nature.com/new-submission/40001/3","title":"European Journal of Medical Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8c014d54-709b-44d3-8ab8-ca7c83bc8af9","owner":[],"postedDate":"August 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-12T16:00:05+00:00","versionOfRecord":{"articleIdentity":"rs-7238562","link":"https://doi.org/10.1186/s40001-025-03774-y","journal":{"identity":"european-journal-of-medical-research","isVorOnly":false,"title":"European Journal of Medical Research"},"publishedOn":"2026-01-05 15:57:08","publishedOnDateReadable":"January 5th, 2026"},"versionCreatedAt":"2025-08-20 09:27:31","video":"","vorDoi":"10.1186/s40001-025-03774-y","vorDoiUrl":"https://doi.org/10.1186/s40001-025-03774-y","workflowStages":[]},"version":"v1","identity":"rs-7238562","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7238562","identity":"rs-7238562","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}