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Sjogren's Disease: Multidimensional Perspectives on Pathogenesis, Clinical Manifestations, and Therapeutic Advancements

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 November 2025 | Viewed by 3217

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Special Issue Editor

Dr. Xiang Lin

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Guest Editor

School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong
Interests: autoimmune disease

Special Issue Information

Dear Colleagues,

Sjögren’s disease (SjD) is a common autoimmune disease, typically characterized by lymphocytic infiltration and tissue destruction of the salivary and lachrymal glands, leading to dry mouth and dry eye symptoms. SjD can be further complicated by systemic inflammations, including interstitial lung diseases, kidney injuries, malignancies, etc., which are among the most high-risk systemic autoimmune diseases.

With the support of the European League Against Rheumatism (EULAR), a multinational initiative has developed the ESSDAI (European SS Disease Activity Index) to measure systemic inflammation and organ involvement. Notably, ESSDAI includes 12 domains (constitutional, glandular, cutaneous, respiratory, renal, articular, muscular, peripheral and central nervous systems, hematological, lymphoid, and biological) to holistically assess disease activity. In this Special Issue, we invite submissions that elucidate the molecular mechanisms underlying the pathogenesis, clinical manifestations, and therapeutic advancements of SjD. We seek original research articles that delve into genetic deposition and the molecular dynamics of disease initiation and progression, focusing on lymphocyte activation and function, glandular epithelial and endothelial cells, environmental factors (e.g., oxidative stress, cytokines, chemokines, etc.), and the functional characterization of autoantigens and autoantibody production. Studies on the clinical and translational impact are also of particular interest. Additionally, we welcome comprehensive review articles in these domains, as well as innovative research on therapeutic targets, treatment strategies, novel diagnostic methodologies, and potential biomarkers.

Dr. Xiang Lin
Guest Editor

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Keywords

Sjögren's disease
diagnosis
therapeutics
bioinformatics
pre-clinical
cytokine
lymphocytes
autoantibodies
exocrine glands

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Published Papers (7 papers)

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20 pages, 1214 KiB

Open AccessArticle

Minor Salivary Gland Biopsy in the Differential Diagnosis of Sicca Syndrome: A Monocentric Cohort Analysis

by Elisa Fiorentini, Pamela Bernardini, Dorilda Zeka, Marco Capassoni, Luca Novelli, Annarita Palomba, Lorenzo Tofani, Laura Cometi and Serena Guiducci

Int. J. Mol. Sci. 2025, 26(13), 6463; https://doi.org/10.3390/ijms26136463 - 4 Jul 2025

Viewed by 255

Abstract

Sicca syndrome is a common condition that draws the attention of rheumatologists, and is frequently related to Sjögren’s disease (SjD). This study analyzed 164 patients with sicca syndrome (clinically suspected for SjD) who underwent minor salivary gland biopsy (mSGB). Patients completed the Xerostomia Inventory (XI) and Standard Patient Evaluation of Eye Dryness (SPEED) questionnaires to assess Patient-Reported Outcome Measures (PROMs), and biopsies were graded using the Chisholm and Mason system. Patients were classified as seropositive (SSA, SSB, Ro52, Ro60 positive) or seronegative, and also divided into three groups by age. Positive biopsies (60.37%) were more common in older patients (61–80) and associated with confirmed SjD, more severe xerostomia, and stronger lymphocytic infiltrates. Among these, 37.37% were seropositive, showing higher disease activity, hypergammaglobulinemia, and elevated IgG. Seronegative patients had a heavier symptom burden, confirmed by the PROMs, and more fibrosis and fatty replacement in biopsies. Age-stratified analysis showed younger patients (18–40) were more affected by ocular dryness, while older patients had worse xerostomia and more severe histological and ultrasound changes. Younger individuals had higher IgG/IgA, more anemia, and reduced C3. Hydroxychloroquine was used more in younger and seropositive groups; older patients used more topical therapies. These results highlight mSGB’s diagnostic value, especially in seronegative cases, and stress the importance of combining clinical, histological, imaging, and patient-reported outcomes for optimal care. Full article

(This article belongs to the Special Issue Sjogren's Disease: Multidimensional Perspectives on Pathogenesis, Clinical Manifestations, and Therapeutic Advancements)

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14 pages, 2140 KiB

Open AccessArticle

Comprehensive Clinical, Serological, and Molecular Biomarker Profiling of Primary Sjögren’s Syndrome: A Single-Center Cohort Study in Northeastern Romania

by Alexandru Lodba, Codrina Ancuta, Diana Tatarciuc, Magda Ecaterina Antohe, Ana Maria Fatu, Luciana-Oana Lodba and Cristina Iordache

Int. J. Mol. Sci. 2025, 26(13), 6327; https://doi.org/10.3390/ijms26136327 - 30 Jun 2025

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Abstract

Primary Sjögren’s syndrome (pSS) exhibits considerable clinical and immunological heterogeneity, complicating personalized management. We aimed to delineate the demographic, functional, serological, histopathological, and therapeutic features of a Romanian pSS cohort and to identify biomarker–treatment correlations that could inform patient-oriented strategies. Thirty-two patients meeting the 2016 ACR/EULAR classification criteria for pSS were retrospectively analyzed. Data collected included demographics, autoantibody profiles (Anti-Ro/SSA, Anti-La/SSB, ANA, RF, Anti-CCP), immunoglobulin levels, complement consumption (C3/C4), minor salivary gland biopsy (focus score), salivary flow tests, and systemic inflammation markers (CRP). Pearson correlation matrices were constructed to explore the associations between serological markers and prescribed therapies. The cohort was predominantly female (87.5%) with a mean age of 52.8 ± 9.9 years. Seropositivity rates were 50% for Anti-Ro/SSA, 77% for Anti-La/SSB, and 40% for ANA. Clinically significant glandular dysfunction was evident in 65% of patients (unstimulated flow ≤ 0.1 mL/min), and all biopsies demonstrated focus scores > 1. Methotrexate use correlated strongly with Anti-Ro/SSA and Anti-La/SSB positivity (p ≤ 0.05), indicating its targeted application in seropositive sub-phenotypes. Conclusion: These findings underscore the immunologic and clinical diversity of pSS and support a biomarker-driven, multidisciplinary framework for personalized treatment. Larger prospective and multicenter studies are warranted to validate these correlations and to refine precision medicine approaches in pSS. Full article

(This article belongs to the Special Issue Sjogren's Disease: Multidimensional Perspectives on Pathogenesis, Clinical Manifestations, and Therapeutic Advancements)

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16 pages, 3450 KiB

Open AccessArticle

Elucidating Regulatory Mechanisms of Genes Involved in Pathobiology of Sjögren’s Disease: Immunostimulation Using a Cell Culture Model

by Daniel D. Kepple, Thomas E. Thornburg, Micaela F. Beckman, Farah Bahrani Mougeot and Jean-Luc C. Mougeot

Int. J. Mol. Sci. 2025, 26(12), 5881; https://doi.org/10.3390/ijms26125881 - 19 Jun 2025

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Abstract

Sjögren’s disease (SjD) is an autoimmune disease of exocrine tissues. Prior research has shown that ETS proto-oncogene 1 (ETS1), STAT1, and IL33 may contribute to the disease’s pathology. However, the regulatory mechanisms of these genes remain poorly characterized. Our objective was to explore the mechanisms of SjD pathology and to identify dysfunctional regulators of these genes by immunostimulation of SjD and sicca relevant cell lines. We used immortalized salivary gland epithelial cell lines (iSGECs) from Sjögren’s disease (pSS1) and sicca (nSS2) patients, previously developed in our lab, and control cell line A253 to dose with immunostimulants IFN-γ or poly(I:C) (0 to 1000 ng/mL and 0 to 1000 µg/mL, respectively) over a 72 h time course. Gene expression was determined using qRT-PCR delta-delta-CT method based on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) for mRNA and U6 small nuclear RNA 1 (U6) for miRNA, using normalized relative fold changes 48 h post-immunostimulation. Protein expression was quantified 72 h post-stimulation by Western blotting. Reference-based RNA-seq of immunostimulated pSS1 and nSS2 cells was performed to characterize the reactome of genes conserved across all used doses. The expression of ETS1 and STAT1 protein was upregulated (p < 0.05) in IFN-γ-treated pSS1 and nSS2, as compared to A253 cells. IFN-γ-treated nSS2 cell showed significant IL33 upregulation. Also, IL33 had a correlated (p < 0.01) U-shaped response for low-mid-range doses for IFN-γ- and poly(I:C)-treated pSS1 cells. RNA-seq showed 175 conserved differentially expressed (DE) genes between nSS2 and pSS1 immunostimulated cells. Of these, 44 were shown to interact and 39 were more abundant (p < 0.05) in pSS1 cells. Western blotting demonstrated nSS2 cells expressing ETS1 uniformly across treatments compared to pSS1 cells, despite similar mRNA abundance. miR-145b and miR-193b were significantly under-expressed in IFN-γ-treated nSS2 cells compared to pSS1 cells (p < 0.01). ETS1 and IL33 showed disproportionate mRNA and protein abundances between immunostimulated Sjögren’s disease-derived (pSS1), and sicca-derived (nSS2) cell lines. Such differences could be explained by higher levels of miR-145b and miR-193b present in pSS1 cells. Also, RNA-seq results suggested an increased sensitivity of pSS1 cells to immunostimulation. These results reflect current pathobiology aspects, confirming the relevance of immortalized salivary gland epithelial cell lines. Full article

(This article belongs to the Special Issue Sjogren's Disease: Multidimensional Perspectives on Pathogenesis, Clinical Manifestations, and Therapeutic Advancements)

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16 pages, 269 KiB

Open AccessArticle

The Role of Anti-SSB/La Antibodies as Predictors of Decreased Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) in Primary Sjögren Disease

by Simona Caraiola, Laura Voicu, Daniela Opriș-Belinski, Claudia Oana Cobilinschi, Magda Ileana Pârvu, Ion Andrei Ion, Daniela Ștefana Gologanu and Răzvan Adrian Ionescu

Int. J. Mol. Sci. 2025, 26(12), 5867; https://doi.org/10.3390/ijms26125867 - 19 Jun 2025

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Abstract

Lung involvement is the most common extraglandular manifestation of primary Sjögren’s Disease (pSjD). There is an increasing interest in finding the clinical/serological risk predictors of this feature. A cross-sectional study evaluating anti-SSA/Ro antibodies, anti-SSB/La antibodies, rheumatoid factor, antinuclear antibodies, and the diffusing capacity of the lungs for carbon monoxide (DLCO) in 26 pSjD patients who presented interstitial changes on the chest CT scan was performed. The titres and positivity rates for anti-SSA/Ro (p = 0.02, p = 0.02) and anti-SSB/La antibodies (p = 0.01, p = 0.001) proved to be significantly increased in patients with abnormal DLCO. Anti-SSB/La antibodies’ titres seemed to be the best predictor for decreased DLCO–AUC 0.791 (0.587–0.994), p = 0.016. A close-to-significance decrease was found in the titres (p = 0.07) and positivity rates—p = 0.09 and OR of 0.15 (0.01–1.63)—of anti-SSB/La antibodies in patients with usual interstitial pneumonia (UIP), indicating their possible protective role against UIP. The lymphocytic interstitial pneumonitis (LIP) pattern on lung CT scan was significantly associated with the simultaneous positivity of the four examined serological markers (p = 0.03). The increase in anti-SSB/La antibody positivity rate in patients with LIP patterns was situated close to the significance level (p = 0.09). Quadruple positivity, as well as isolated anti-SSB/La positivity, could be risk factors for developing LIP in pSjD patients. Thus, anti-SSB/La antibodies might represent a marker of lung involvement in pSjD patients. Full article

(This article belongs to the Special Issue Sjogren's Disease: Multidimensional Perspectives on Pathogenesis, Clinical Manifestations, and Therapeutic Advancements)

10 pages, 220 KiB

Open AccessArticle

Clinical Characterization of Autoimmune Hepatic Involvement in Sjogren’s Disease: A Retrospective Cohort Study in Korea

by Youngjae Park, Jennifer Jooha Lee, Ji Hyeon Ju, Wan-Uk Kim, Sung-Hwan Park and Seung-Ki Kwok

Int. J. Mol. Sci. 2025, 26(12), 5734; https://doi.org/10.3390/ijms26125734 - 15 Jun 2025

Viewed by 436

Abstract

Sjogren’s disease (SjD) is a systemic autoimmune disease primarily affecting the exocrine glands. Systemic manifestations, including hepatic involvement, are increasingly recognized. This study aimed to delineate the clinical features and associated factors of autoimmune hepatic involvement in SjD. A retrospective analysis was conducted on patients diagnosed with SjD at Seoul St. Mary’s Hospital over the past 10 years. Autoimmune hepatic involvement was defined by fulfilling diagnostic criteria for autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC). Clinical, serological, and demographic data were obtained from medical records. Among 1119 patients with SjD, 51 (4.6%) had autoimmune hepatic involvement. AIH (64.7%) was the most common type, followed by PBC (27.5%) and overlapping disease (7.8%). Compared to those without hepatic involvement, affected patients were older at diagnosis (p = 0.003) and showed higher frequencies of thrombocytopenia, splenomegaly, anti-centromere antibody (ACA), and elevated antinuclear antibody titers as measured by indirect immunofluorescence (IFI-HEp-2) (all p < 0.001). Multivariable analysis identified splenomegaly, elevated IFI-HEp-2 titer, and ACA positivity as independent factors associated with hepatic involvement. Most patients responded well to immunosuppressive therapy, with only a small proportion (15.7%) progressing to liver fibrosis. Autoimmune hepatic involvement is relatively uncommon but clinically meaningful in patients with SjD. Full article

(This article belongs to the Special Issue Sjogren's Disease: Multidimensional Perspectives on Pathogenesis, Clinical Manifestations, and Therapeutic Advancements)

13 pages, 3751 KiB

Open AccessArticle

Additive Value of Rheumatoid Factor Isotypes in Sjögren’s Syndrome Patients with Joint Complaints of Different Etiologies—Can Rheumatoid Factor IgA Serve as an Early, Poor Prognostic Biomarker Candidate?

by Zsófia Aradi, Bernadett Bói, Gábor Nagy, Péter Antal-Szalmás, Kincső Mezei, Ildikó Fanny Horváth and Antónia Szántó

Int. J. Mol. Sci. 2025, 26(10), 4797; https://doi.org/10.3390/ijms26104797 - 16 May 2025

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Abstract

The aim of the paper was to characterize rheumatoid factor IgA, IgG, and IgM isotypes in patients with Sjögren’s syndrome (SS) subsets, based on the absence or presence of joint complaints of different etiologies. In total, 164 SS patients were grouped based on whether they had polyarthritis as an extraglandular manifestation (n = 73, SS+pa), rheumatoid arthritis as an associated autoimmune disorder (n = 46, SS+RA), or Sjögren’s syndrome without inflammatory joint pain (n = 45, SS). The highest IgA rheumatoid factor isotype levels were detected in SS patients, whereas the lowest levels were found in the SS+RA group, without a significant difference. Neither IgG nor IgM RF differed significantly between the patient subclasses. In addition to other disease-specific markers, seropositive patients who were seropositive for any RF isotype were significantly more frequently anti-Ro/SS-A and anti-La/SS-B positive and had higher ESSDAI levels. In SS and SS+pa patients, a strong negative correlation was observed between IgA RF and age, whereas a strong positive correlation was found between IgA RF and ESSDAI, RF, IgA, IgG, anti-Ro/SS-A, and anti-La/SS-B levels. High total IgG levels together with high IgA RF levels occurred most frequently in SS patients (p = 0.05), whereas the combination of normal IgG and high IgM RF was significantly more frequent in the SS+RA group. The co-occurrence of high total IgG and normal IgM RF did not differ significantly between the patient subsets; however, this was the combination with the highest sensitivity (94.5%) for SS+pa patients. Based on our findings, rheumatoid factor isotypes have an additive value in the differentiation of non-erosive polyarthritis and erosive rheumatoid arthritis during the disease course of patients with Sjögren’s syndrome. All rheumatoid factor isotypes predict a more severe disease course, but IgA RF may serve as a candidate for being an early, poor prognostic factor for SS patients. Full article

(This article belongs to the Special Issue Sjogren's Disease: Multidimensional Perspectives on Pathogenesis, Clinical Manifestations, and Therapeutic Advancements)

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9 pages, 514 KiB

Open AccessCase Report

Cellular Metabolic Disorders in a Cohort of Patients with Sjogren’s Disease

by Julian L. Ambrus, Alexander Jacob and Abhay A. Shukla

Int. J. Mol. Sci. 2025, 26(10), 4668; https://doi.org/10.3390/ijms26104668 - 13 May 2025

Viewed by 659

Abstract

Metabolism disorders have been seen in multiple autoimmune diseases, including SLE and Sjogren’s disease. The current studies were designed to evaluate mutations in genes involved in metabolism in a cohort of patients with Sjogren’s disease, diagnosed from clinical criteria and the presence of antibodies to salivary gland antigens. Patients were from an Immunology clinic that follows a large population of patients with autoimmune and metabolic disorders. The patients included in these studies were patients who met the criteria for Sjogren’s disease and for whom we were able to obtain genetic studies, sequencing of the mitochondrial DNA, and whole exome sequencing. There were 194 of these patients, and 192 had mutations in one or more gene involved in metabolism: 188 patients had mutations in mitochondrial respiratory chain genes, 17 patients had mutations in mitochondrial tRNA genes, 10 patients had mutations in mitochondrial DLOOP regions, 6 patients had mutations involved in carnitine transport, 6 patients had mutations in genes causing mitochondrial depletion, and 7 patients had glycogen storage diseases. In all cases, the treatment of the metabolic disorder led to symptomatic improvement in energy, exercise tolerance, gastrointestinal dysmotility, and the management of infections. In conclusion, metabolic disorders are common in patients with Sjogren’s disease and may be one of the factors leading to the initiation of the disease. The treatment of patients with Sjogren’s disease should include the treatment of the underlying/associated metabolic disorder. Full article

(This article belongs to the Special Issue Sjogren's Disease: Multidimensional Perspectives on Pathogenesis, Clinical Manifestations, and Therapeutic Advancements)

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