Sjogren's Syndrome

Sjögren's disease (SjD) is an autoimmune disease that causes salivary gland dysfunction due to immune-mediated destruction. While autoantibodies such as anti-SSA and anti-centromere (CENT) are associated with distinct clinical manifestations, the molecular features remain to be elucidated. In this study, we apply multi-modal single-cell technologies: single-cell RNA sequencing, T cell and B cell receptor sequencing and spatial transcriptomics to salivary gland lesions, aiming to elucidate common and unique cellular and transcriptional signatures linked to different autoantibody profiles. Our analysis demonstrates that GZMB+GNLY+ CD8+ T cells are the main expanded subset across different autoantibody statuses, highlighting their central role in SjD pathogenesis, while the enrichment of memory B cells is more prominent in anti-CENT-positive patients. Cytokine signaling also differs by autoantibody profile, with an activated interferon signature in anti-SSA-positive patients, whereas TGFβ signaling is enhanced in anti-CENT-positive patients. Furthermore, spatial profiling reveals THY1+ fibroblasts, expressing complement genes and chemokines, as key hubs orchestrating inflammation within the salivary glands. These findings deepen our understanding of the pathogenesis of SjD, and may inform the development of targeted and personalized therapeutic strategies.

BackgroundIdiopathic inflammatory myopathies (IIM) and Sjögren's disease (SjD) may coexist, but data on their combined presentation and treatment response remain limited.MethodsWe retrospectively analyzed 23 patients with biopsy-confirmed IIM and coexisting SjD, compared to 24 age- and sex-matched IIM controls without SjD. Clinical, electrophysiological, and immunological data, as well as treatments and outcomes, were assessed. Outcome assessment included EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) and the ACR/EULAR Myositis Response Criteria for adult polymyositis and dermatomyositis.ResultsAmong IIM-SjD patients, 39% had inclusion body myositis (IBM), 61% had poly- or dermatomyositis. Compared to controls, asymmetric muscle weakness (78%, p=0.0012), non-muscular manifestations (52%, p=0.0035), and more immunosuppressive therapies (median 3; p=0.0253), including more frequent anti-CD20 use (30%, p=0.0039) were found in IIM-SjD. After a median follow-up of 80 months, patients showed better outcomes (lower ESSDAI and higher ACR/EULAR response scores; p=0.0031 and p=0.0083). IBM was a strong predictor of higher ESSDAI scores at follow-up (p=0.014).ConclusionsThe study suggests that IIM-SjD is characterized by more asymmetric muscle weakness and extramuscular involvement. Enhanced immunosuppression led to better outcomes in patients with poly- or dermatomyositis, while IBM was linked to higher disease activity. Further research is needed to clarify underlying mechanisms.

Keratoconjunctivitis sicca (KCS), also commonly known as dry eye disease (DED), is one of the most prevalent and crippling features of Sjögren disease (SD), a chronic systemic autoimmune disorder featuring lymphocytic infiltration and progressive impairment of exocrine glands. KCS affects up to 95% of patients with SD and is often the earliest and most persistent manifestation, significantly compromising visual function, ocular comfort, and overall quality of life. Beyond the ocular surface, KCS mirrors a wider spectrum of immune dysregulation and epithelial damage characteristic of the disease, making it a valuable window into the underlying systemic pathology. The pathophysiology of KCS in SD is complex and multifactorial, involving an interplay between autoimmune-mediated lacrimal gland dysfunction, neuroimmune interactions, ocular surface inflammation, and epithelial instability. Tear film instability and epithelial injury result from the aberrant activation of innate and adaptive immunity, involving T and B lymphocytes, pro-inflammatory cytokines, and type I interferon pathways. Despite the clinical significance of KCS, its diagnosis remains challenging, with frequent discrepancies between subjective symptoms and objective findings. Traditional diagnostic tools often lack sensitivity and specificity, prompting the development of novel imaging techniques, tear film biomarkers, and standardized scoring systems. Concurrently, therapeutic strategies have evolved from palliative approaches to immunomodulatory and regenerative treatments, aiming to restore immune homeostasis and epithelial integrity. This review provides a comprehensive update on the pathogenesis, diagnostic landscape, and emerging treatments of KCS in the context of SD.

ObjectivesTo examine whether the JAK inhibitor tofacitinib alleviates secretory dysfunction and modulates Th17/Treg balance in a Sjögren's disease (SjD) murine model.MethodsIntegrated analysis of SjD transcriptome sequencing (GSE159574, GSE247662) identified key signalling pathways, potential therapeutic agents, and immune cell infiltration. NOD/ShiLtj mice were administered with or without tofacitinib. Secretory function and inflammation were assessed via fluorescein ocular surface staining, tear flow rate, histopathology (HE, Masson, Sirius Red), saliva flow rate, immunohistochemistry, immunofluorescence, flow cytometry, and cytokine measurement. Pearson's linear regression evaluated the correlation between Th17/Treg balance and secretory function.ResultsBioinformatics analysis showed the JAK-STAT pathway and CD4+ T cells contribute to SjD pathogenesis. Tofacitinib reduced corneal fluorescein staining, increased tear break-up time and secretion, diminished salivary gland lymphocytic inflammation, improved saliva flow rate, and altered phospho-JAK3-STAT1 expression. It also reduced Th17 cell proportion, increased Treg cell proportion in salivary glands and spleens, decreased IL-17, and increased IL-10 and TGF-β in blood. A strong negative correlation existed between secretory function and Th17/Treg balance.ConclusionsTofacitinib potently attenuated secretory dysfunction and inflammation in SjD mice, possibly by modulating Th17/Treg balance, suggesting it may be a therapeutic agent for SjD.