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Sjogren’s Syndrome: Clinical Advances and Insights
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Sjogren’s Syndrome: Clinical Advances and Insights

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Immunology & Rheumatology".

Deadline for manuscript submissions: 7 June 2026 | Viewed by 5095

Special Issue Editor

Prof. Dr. David A. Isenberg

E-Mail Website
Guest Editor
Centre for Rheumatology, Division of Medicine, University College London, London WC1E 6JF, UK
Interests: lupus; autoimmune rheumatic diseases; sjogren’s syndrome
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Sjogren's disease remains a major cause of morbidity and, for some of its victims, mortality.

The condition is named after Henrik Sjogren, a Swedish ophthalmologist who described 19 cases of severe dryness of the eyes and mouth as part of his doctoral thesis submitted in 1933 (which, ironically, was rejected). He also linked these symptoms to arthritis.

This Special Issue seeks to update our current knowledge of the clinical features, causes, activity, damage assessment tools, and therapy. Several international experts and their colleagues have kindly provided detailed accounts of these aspects of this now 'classic' autoimmune rheumatic disease. I hope you will enjoy reading these reviews and linked original articles.

Prof. Dr. David A. Isenberg
Guest Editor

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Keywords

  • xerostomia
  • xerophthalmia
  • non-Hodgkins lymphoma
  • autoimmune rheumatic diseases
  • Sjogren’s syndrome

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Published Papers (7 papers)

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Research

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15 pages, 1520 KB  
Article
Association of Vitamin D Deficiency with Mortality and Cardiorenal Events in Sjögren’s Syndrome and Osteoporosis
by Ying-Kai Chen, Chien-Lin Lu, Kuo-Cheng Lu, Yu-Chen Cheng and Wui-Chiu Mui
J. Clin. Med. 2026, 15(4), 1430; https://doi.org/10.3390/jcm15041430 - 12 Feb 2026
Viewed by 424
Abstract
Background: Sjögren’s syndrome (SjS) is a chronic systemic autoimmune disease associated with substantial extraglandular morbidity, including osteoporosis, cardiovascular disease, and renal involvement. Vitamin D deficiency (VDD) is highly prevalent in patients with SjS and has been linked to immune dysregulation, systemic inflammation, and [...] Read more.
Background: Sjögren’s syndrome (SjS) is a chronic systemic autoimmune disease associated with substantial extraglandular morbidity, including osteoporosis, cardiovascular disease, and renal involvement. Vitamin D deficiency (VDD) is highly prevalent in patients with SjS and has been linked to immune dysregulation, systemic inflammation, and adverse cardiorenal outcomes in other clinical settings. However, the prognostic significance of VDD in patients with SjS and osteoporosis remains incompletely characterized. Methods: We conducted a retrospective cohort study using de-identified electronic health records from the TriNetX research network between 2010 and 2024. Adult patients with SjS and osteoporosis who had at least one serum 25-hydroxyvitamin D measurement within six months before or after cohort entry were included. VDD was defined as a serum 25-hydroxyvitamin D concentration below 20 ng/mL, and vitamin D adequacy (VDA) as a concentration of 30 ng/mL or higher. Propensity score matching was performed at a 1: 1 ratio using 95 baseline covariates. The primary outcome was all-cause mortality. Secondary outcomes included major adverse cardiovascular events (MACEs), major adverse kidney events (MAKEs), and fractures. Results: Among 19,177 eligible patients, 1218 with VDD and 7659 with VDA met the inclusion criteria. After propensity score matching, 1067 well-balanced pairs were analyzed. Over five years of follow-up, VDD was associated with higher risks of all-cause mortality, MACEs, and MAKEs compared with VDA. In contrast, fracture risk did not differ significantly between groups. Sensitivity analyses demonstrated consistent associations across analytic approaches. Conclusions: In patients with SjS and osteoporosis, VDD was associated with increased risks of mortality, MACEs, and MAKEs, but not fractures. These findings suggest that VDD may serve as a marker of a high-risk clinical phenotype and may be useful for long-term risk stratification in this vulnerable population. Full article
(This article belongs to the Special Issue Sjogren’s Syndrome: Clinical Advances and Insights)
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16 pages, 4321 KB  
Article
Correlated Expression of Notch2 and ADAM17 in Primary Sjögren’s Syndrome Salivary Glands
by Margherita Sisto, Sabrina Lisi, Roberto Tamma, Michelina De Giorgis, Giuseppe Ingravallo, Mario Della Mura, Joana Sorino, Eliano Cascardi and Domenico Ribatti
J. Clin. Med. 2026, 15(1), 182; https://doi.org/10.3390/jcm15010182 - 26 Dec 2025
Viewed by 504
Abstract
Background/Objectives: The Notch–ADAM17 pathway is a fundamental signaling mechanism where ADAM17, a disintegrin and metalloprotease, cleaves the Notch receptor after the Notch receptor binds to a ligand. Crosstalk between Notch and ADAM17 is often altered in pathological situations. Alterations in Notch2 expression, [...] Read more.
Background/Objectives: The Notch–ADAM17 pathway is a fundamental signaling mechanism where ADAM17, a disintegrin and metalloprotease, cleaves the Notch receptor after the Notch receptor binds to a ligand. Crosstalk between Notch and ADAM17 is often altered in pathological situations. Alterations in Notch2 expression, in particular, appears to be correlated with the onset of various autoimmune diseases. In primary Sjögren’s disease (pSjD), an autoimmune disorder characterized by chronic inflammation, the role of ADAM17 has been extensively explored, but a correlation with Notch2 has not yet been evaluated. Methods: To analyze the gene and protein expression of Notch2 in pSjD and a possible correlation with ADAM17 expression and with the patient’s inflammatory grade, we employed an integrated co-detection protocol to analyze salivary gland tissue sections by combining in situ hybridization (ISH) with immunohistochemistry (IHC). Results: combined ISH/IHC allows us to demonstrate an increased expression of Notch2 mRNA and protein in pSjD salivary glands (SGs) biopsies, which appears correlated with an increased expression of ADAM17, both in acinar and duct cells and in infiltrating lymphocytes. Notch2/ADAM17 expression is higher in biopsies of pSjD SGs characterized by a high degree of inflammation. Conclusions: this work demonstrates the correlated expression in pSjD SGs of ADAM17, which plays multiple roles in the pathogenesis of SjD, and Notch2, widely considered a key player in various inflammatory mechanisms, offering a starting point for future therapeutic interventions to investigate. Full article
(This article belongs to the Special Issue Sjogren’s Syndrome: Clinical Advances and Insights)
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Review

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14 pages, 907 KB  
Review
Update on the Aetiopathogenesis of Sjögren Disease: From Interferon Signaling to Epithelial Dysfunction
by Loïc Meudec, Gaetane Nocturne and Xavier Mariette
J. Clin. Med. 2026, 15(5), 1945; https://doi.org/10.3390/jcm15051945 - 4 Mar 2026
Viewed by 449
Abstract
Sjögren disease (SjD) is a prototypical autoimmune disease whose management has long suffered from a limited understanding of its underlying pathophysiological mechanisms. However, major advances have been made over the past decade. The innate immune system is now recognized as playing a key [...] Read more.
Sjögren disease (SjD) is a prototypical autoimmune disease whose management has long suffered from a limited understanding of its underlying pathophysiological mechanisms. However, major advances have been made over the past decade. The innate immune system is now recognized as playing a key role in the early stages of the disease, particularly through activation of interferon (IFN) pathways, driven in part by epithelial cells, which actively attract autoreactive lymphocytes. Furthermore, the mechanisms of B-cell activation in SjD are now better understood, notably with the recognition of BAFF (B-cell activating factor), a Tumor necrosis factor (TNF) family cytokine, whose production is highly dependent on type I and II IFN signaling. The involvement of other cell types, such as fibroblasts and T cells, has also been underlined. Significant progress has been achieved in elucidating lymphomagenesis, the most severe complication of SjD. Together, these advances provide a clearer picture of SjD pathogenesis and open avenues for the development of new targeted therapeutic strategies. Full article
(This article belongs to the Special Issue Sjogren’s Syndrome: Clinical Advances and Insights)
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16 pages, 292 KB  
Review
Activity and Damage Indices for Sjögren’s Disease
by Elodie Portier, Maxime Beydon, Simon J. Bowman and Raphaèle Seror
J. Clin. Med. 2026, 15(4), 1478; https://doi.org/10.3390/jcm15041478 - 13 Feb 2026
Viewed by 871
Abstract
Primary Sjögren’s disease (SjD) is a systemic autoimmune disease with heterogeneous clinical manifestations, ranging from isolated glandular dysfunction to multisystem involvement and severe complications. This variability complicates disease management, particularly the assessment of disease activity and long-term outcomes. Disease activity in SjD encompasses [...] Read more.
Primary Sjögren’s disease (SjD) is a systemic autoimmune disease with heterogeneous clinical manifestations, ranging from isolated glandular dysfunction to multisystem involvement and severe complications. This variability complicates disease management, particularly the assessment of disease activity and long-term outcomes. Disease activity in SjD encompasses both systemic manifestations and patient-reported outcomes (PROs). The EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) remains the standard for systemic activity, while the ESSPRI complements these scores by capturing subjective symptom burden. These tools have limitations because they do not evaluate the same manifestations of SjD and may therefore respond differently to treatment. Thus, composite outcomes such as the Sjögren’s Tool for Assessing Response (STAR) and the Composite of Relevant Endpoints for Sjögren Syndrome (CRESS) have been developed. They integrate improvements in ClinESSDAI, PROs, biological parameters and objective dryness, providing a more comprehensive measure of disease activity. Assessment of damage, defined as irreversible sequelae, remains an unmet need in SjD. Damage is a reflection of the natural evolution of the disease, and is also relevant to measuring the impact and health economic effects of therapeutic interventions. Existing measures, including cumulative ESSDAI, track longitudinal activity and reflect the severity of the disease, but do not specifically capture damage. In summary; SjD assessment requires complementary tools for systemic activity and PROs, with composite scores a recent innovation. An important remaining gap is a validated method to evaluate damage, essential to fully evaluate disease progression. Full article
(This article belongs to the Special Issue Sjogren’s Syndrome: Clinical Advances and Insights)
13 pages, 286 KB  
Review
Sjogren’s Disease—Aspects of Clinical Disease Beyond Dry Eyes/Mouth
by Simon J. Bowman
J. Clin. Med. 2026, 15(3), 1189; https://doi.org/10.3390/jcm15031189 - 3 Feb 2026
Viewed by 894
Abstract
Primary Sjogren’s Disease (SjD) is characterized by features of dryness arising from inflammation in the secretary glands, particularly the salivary and lachrymal glands. Generalized symptoms of fatigue and limb pain are very common but, in addition, about 40% of patients have one or [...] Read more.
Primary Sjogren’s Disease (SjD) is characterized by features of dryness arising from inflammation in the secretary glands, particularly the salivary and lachrymal glands. Generalized symptoms of fatigue and limb pain are very common but, in addition, about 40% of patients have one or more features of organ-specific systemic disease. This review goes through the background of SjD including diagnosis and classification, epidemiology, impact and investigations such as ultrasound and lip biopsy. It then focuses in detail on each of the systemic organ-specific features, principally using the European League against Rheumatism (EULAR) Sjogren’s Syndrome Disease Activity Index (ESSDAI) along with some non-ESSDAI domains, before concluding with comments on disease heterogeneity, treatment, vaccination, pregnancy and surgery along with observations on patient perspectives. The aim is to provide a general overview of these aspects of the disease to complement other chapters in this monograph. Full article
(This article belongs to the Special Issue Sjogren’s Syndrome: Clinical Advances and Insights)
12 pages, 272 KB  
Review
Practical Guide to the Local Treatment of Sjogren’s Disease
by Elizabeth J. Price, Shirleen Hallang and Guy Smith
J. Clin. Med. 2026, 15(3), 1078; https://doi.org/10.3390/jcm15031078 - 29 Jan 2026
Viewed by 808
Abstract
Dryness (sicca) of mucosal surfaces is the hallmark of adult-onset Sjogren’s disease (SjD). In our experience, clinicians frequently lack confidence in managing the sicca symptoms effectively. Successful management requires an understanding of the condition and personalisation of care. We have reviewed the available [...] Read more.
Dryness (sicca) of mucosal surfaces is the hallmark of adult-onset Sjogren’s disease (SjD). In our experience, clinicians frequently lack confidence in managing the sicca symptoms effectively. Successful management requires an understanding of the condition and personalisation of care. We have reviewed the available evidence and, when necessary, used personal and expert experience to provide comprehensive advice on the management of ocular, oral, and systemic sicca, enabling the treating physician to support their patients and manage their symptoms effectively and prevent long-term damage. Our objective is to ensure that the non-specialist feels confident in managing the myriad manifestations of sicca in SjD. Full article
(This article belongs to the Special Issue Sjogren’s Syndrome: Clinical Advances and Insights)

Other

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14 pages, 1682 KB  
Systematic Review
Comparative Analysis of Clinical Trials of Biologic Drugs for Patients with Primary Sjögren’s Syndrome
by Carlota Navarro-Joven, Silvia Piunno, Maryia Nikitsina, Carmen San José Méndez and David A. Isenberg
J. Clin. Med. 2026, 15(3), 950; https://doi.org/10.3390/jcm15030950 - 24 Jan 2026
Viewed by 715
Abstract
Background/Objectives: To evaluate and compare the characteristics of clinical trials (CTs) involving patients with primary Sjögren’s syndrome (pSS), using biologics, and focusing on the features of the patients recruited. Methods: This systematic review assessed pSS CTs evaluating biologic drugs published from 2010 [...] Read more.
Background/Objectives: To evaluate and compare the characteristics of clinical trials (CTs) involving patients with primary Sjögren’s syndrome (pSS), using biologics, and focusing on the features of the patients recruited. Methods: This systematic review assessed pSS CTs evaluating biologic drugs published from 2010 to 2024 according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The literature search of the electronic databases was performed individually by the authors. The extracted variables regarding the baseline characteristics of participants and trial-related information were defined a priori, collected, and compared. Results: A total of 16 CTs were included in this review in line with the inclusion criteria. The trials were predominantly multicenter (75%) randomized controlled trials with a placebo arm (93.8%), with only five trials recruiting participants across multiple (≥3) continents. The search included a total of 1607 patients (mean age 51 years, 94% female) with a mean disease duration of 6.47 years. Race and ethnicity were underrepresented variables, found in 37.5% and 12.5% of the trials, respectively, with White patients comprising the majority (77.8%). The EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) was reported in 93.8% of the CTs. However, only recent studies have emphasized it as the primary outcome. Conclusions: Recent trials on biologics in pSS patients show better methodological quality, with a more standardized assessment of disease activity using ESSDAI, and an increased focus on patient-reported outcomes. Global participation is increasing, but limited racial and ethnic diversity, endpoint variability, and inconsistent biomarker reporting remain critical issues. Full article
(This article belongs to the Special Issue Sjogren’s Syndrome: Clinical Advances and Insights)
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