Search Results (512)

Background: Immune checkpoint inhibitors (ICIs) can induce a sicca-like syndrome that differs from primary Sjögren’s disease in both immunopathogenesis and clinical phenotype. Despite growing recognition of this entity, data describing real-world management and outcomes, particularly in the context of ICI discontinuation and rechallenge, remain limited. Methods: Patients with new onset of sicca syndrome or exacerbation of previous symptoms following ICI therapy were retrospectively identified and assessed. Results: Fifty-nine patients with diverse malignancies (including melanoma, gastrointestinal, genitourinary, etc.) and sicca syndrome following treatment with ICIs (most often pembrolizumab or nivolumab +/− ipilimumab) were evaluated. Acute-onset dry mouth, primarily CTCAE v6.0 grades 1 (n = 24, 40.7%) and 2 (n = 34, 57.6%), occurred at a median of 104 days after ICI initiation, sometimes with associated dry eye (n = 8, 13.6%). Most were managed conservatively with behavioral modification and over-the-counter therapies alone (n = 37, 62.7%) while others received sialagogues (n = 9, 15.3%), dexamethasone oral rinse (n = 11, 18.6%), and/or systemic corticosteroids (n = 16, 27.1%). Additional management strategies included de-escalation to ICI monotherapy (n = 5, 8.5%) or discontinued ICI (n = 6, 10.2%). Half of patients treated with corticosteroids demonstrated subjective improvement in symptoms while 75% improved following ICI discontinuation. Four patients underwent rechallenge after a median interruption of 564 days; all (n = 4) demonstrated sicca recurrence. Conclusions: In this largest cohort to date of ICI-associated sicca syndrome, we confirm frequent improvement with steroids and/or supportive care and suggest a greater than previously appreciated risk of recurrence with rechallenge. Full article

Background and Objectives: Sjögren’s disease (SjD) is a chronic autoimmune disorder in which the immune system attacks the glands that produce tears and saliva, leading to symptoms such as dry eyes and dry mouth. If left untreated, SjD can also cause inflammation and damage to other parts of the body, including the skin, lungs, kidneys, and nervous system, and increase the risk of developing lymphoma. The human leukocyte antigen (HLA) class II molecule HLA-DR3 is strongly associated with SjD. Materials and Methods: To investigate how post-translational modifications (PTMs) influence the presentation of SjD-associated autoantigens by HLA-DR3, we employed a computational framework to determine the binding of PTM-mimic peptides to HLA-DR3. We further supported the in-silico results with in-vitro experiments. Results: Our analysis revealed that PTM-mimic substitutions at canonical anchor positions rarely improved predicted binding affinity using the Stabilized Matrix Method, with most modifications resulting in reduced affinity. However, a comprehensive analysis of full-length SjD-associated autoantigen sequences (Ro60, Ro52, La) identified discrete regions with high densities of PTM-eligible anchor sites, specifically, the Ro60 HEAT solenoid, Ro52 RING/B-box/PRY-SPRY modules, and the La motif-RRM1 region, suggesting that PTMs may alter epitope presentation in a sequence-dependent manner. Experimental validation of selected PTM-mimic peptides showed enhanced T cell responses, which were associated with increased binding affinity to HLA-DR3. Structural modeling of a representative complex revealed that PTM-mimic peptides adopt a slightly shifted backbone orientation and altered side-chain positioning, leading to a larger peptide–DR3 interaction interface. Conclusions: These findings provide new insights into the role of PTMs in shaping the immunogenicity of SjD-associated autoantigens and highlight the potential for PTM-mimic peptides to modulate T cell responses in SjD. Full article

Background: Sjögren’s disease (SjD) is a chronic systemic autoimmune disorder primarily characterized by lymphocytic infiltration of exocrine glands, leading to xerostomia and xerophthalmia. Beyond glandular involvement, the disease frequently presents with a broad spectrum of systemic and neuropsychiatric manifestations that significantly affect patients’ quality of life. Methods: A review of the literature was conducted to identify studies addressing neuropsychological symptoms in patients with SjD. Relevant publications describing cognitive dysfunction, mood disorders, sleep disturbances, fatigue, and sexual dysfunction, as well as potential underlying mechanisms and therapeutic approaches, were included and analyzed. Results: Available evidence indicates that neuropsychological symptoms are common among patients with SjD. Cognitive impairment, often described as “brain fog”, may involve deficits in memory, attention, and executive functioning. Depression and anxiety appear to occur more frequently than in the general population and may interact with chronic fatigue and sleep disturbances, contributing to functional impairment. While somatic causes of sexual dysfunctions such as vaginal dryness are well recognized, psychological and psychosexual aspects, including reduced sexual desire, have received comparatively little attention. The pathogenesis of these manifestations is likely multifactorial and may involve immune-mediated processes, cytokine dysregulation, neuroendocrine alterations, microvascular changes, and psychosocial factors. Conclusions: Neuropsychological manifestations represent a significant component of the overall disease burden in SjD. Increased awareness and multidisciplinary management strategies may help improve symptom recognition, patient care, and quality of life. Full article

Background/Objectives: Primary Sjögren’s disease is a systemic autoimmune disease characterized by chronic inflammation of exocrine glands and heterogeneous clinical manifestations. There remains a need for objective, non-invasive biomarkers that reflect local glandular involvement and disease-related immune activity. Methods: This observational cross-sectional case–control study included 34 patients fulfilling the 2016 ACR/EULAR classification criteria for primary Sjögren’s disease and 34 healthy controls between December 2024 and February 2025. Unstimulated whole-saliva samples were collected in the morning using the passive drool method, and salivary galectin-9 concentrations were measured via the enzyme-linked immunosorbent assay. Disease activity and symptom burden were assessed using validated indices, and receiver operating characteristic analysis was performed to evaluate discriminatory performance. Results: Salivary galectin-9 levels were significantly higher in patients with primary Sjögren’s disease compared with healthy controls. However, no significant associations were observed between salivary galectin-9 levels and disease activity scores after correction for multiple comparisons, nor with patient-reported symptoms, autoantibody profiles, Schirmer test results, or minor salivary gland biopsy findings. Salivary galectin-9 demonstrated limited discriminative ability between patients and controls. Conclusions: Salivary galectin-9 levels were elevated in primary Sjögren’s disease and may be associated with local glandular immune processes. Further prospective studies are needed to determine their clinical relevance. Full article

Background/Objectives: Idiopathic inflammatory myopathies (IIMs) are chronic immune-mediated disorders, causing striated muscle weakness and extramuscular symptoms. Real-world, single-centre data are needed to interpret phenotype patterns and evolving therapies. Methods: A single-centre, retrospective cohort study was conducted at the Rheumatology Clinic of the National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland from 1 January 2022 to 31 December 2025. Data included demographics, IIM subtypes, extramuscular involvement, co-existing Sjögren disease (SD), biopsy results, autoantibodies, and treatment. Due to sample size, descriptive analysis was used. Results: The study included 35 patients (31.4% men). Mean age was 50.7 years; mean body mass index (BMI) was 26.0 kg/m². The cohort consisted of 10 dermatomyositis (DM), one polymyositis (PM), two immune-mediated necrotising myopathy (IMNM), one inclusion body myositis (IBM), 16 anti-synthetase syndrome (ASyS), four juvenile dermatomyositis (JDM), and one clinically amyopathic dermatomyositis (CADM). SD co-occurred in eight cases, including six cases of ASyS. Anti-Jo1 was observed in 13 ASyS cases and one DM. Glucocorticoids (GCSs) were administered in all patients for induction in addition to cyclophosphamide (28.6%), mycophenolate mofetil (MMF) (51.4%), and methotrexate (MTX) (17.1%). Maintenance therapy included MTX (20%), MMF (31.4%), rituximab (34.3%), azathioprine (AZA) (42.9%), and others. Two DM, two JDM, and one ASyS patient received JAK inhibitors, one DM and one JDM anifrolumab, one IBM sirolimus, and four patients with interstitial lung disease (ILD) nintedanib. Conclusions: This Polish single-centre cohort shows effective use of novel therapies for IIM. Sirolimus, JAK inhibitors, and nintedanib were effective. Co-occurrence of SD in ASyS patients requires further research. Full article

The gut microbiome regulates host metabolism, barrier integrity, and immune homeostasis through microbe–host signaling and bioactive metabolites. Growing evidence suggests that dysbiosis may also influence ocular immune privilege and blood–retinal barrier stability, supporting the emerging concept of the gut–eye axis. This narrative review aimed to integrate retinal, uveal, and ocular surface disorders within a shared functional framework, with emphasis on recurring mechanistic pathways and their translational relevance rather than on single diseases or isolated taxonomic findings. The review was based on a literature search of PubMed and Scopus and primarily included English-language studies published between 2015 and 2025, with earlier seminal papers included when needed. The search was last updated in March 2026, and 101 sources were included in the final narrative synthesis. Across age-related macular degeneration, diabetic retinopathy, glaucoma, uveitis, dry eye disease, and Sjögren’s syndrome, the most consistent microbiome-related signals were functional rather than taxonomic. Recurrent mechanistic themes included Th17/Treg immune programming, barrier dysfunction with microbial product translocation, and systemic metabolite signaling, particularly involving short-chain fatty acids, bile acid receptor pathways, and tryptophan-derived metabolites. Age-related macular degeneration and diabetic retinopathy showed the strongest multi-layered support, whereas uveitis provided a compelling immune-centered biological model that remains limited by treatment-related confounding in human studies. In glaucoma and ocular surface disease, evidence supports biological plausibility, especially in relation to neuroinflammation, mucosal immune dysregulation, and metabolite-dependent anti-inflammatory pathways, although much of the available human literature remains associative. Overall, current evidence supports dysbiosis as a disease modifier that may influence ocular inflammation, angiogenesis, neurodegeneration, and barrier stability. However, clinical translation remains limited by cohort heterogeneity, methodological variability, and incomplete control of confounding factors. Further progress will depend on longitudinal multi-omics cohorts and controlled intervention trials focused on actionable microbial functions. Full article

Sjögren’s Disease is an autoimmune epithelitis targeting the exocrine glands, predominantly the salivary and lacrimal glands, resulting in the major symptoms of dry mouth and dry eyes. The aim of this study is to review the pertinent literature on studies linking the oral manifestations of SjD patients, with the underlying molecular events driving SjD pathogenesis. These include mechanisms inducing innate sensing in salivary gland epithelial cells, activation of interferon signaling pathway, amplification of cytokines and chemokines, and orchestration of the inflammatory milieu in salivary glands, as well as mechanisms inducing salivary epithelial tissue destruction and secretory dysfunction, such as programmed cell death pathways, mitochondrial dysfunction, structural disorganization, loss of junctional integrity, and quantitative and qualitative aberrations in salivary secretory process. Full article

Intermittent fasting confers protection in diverse diseases through various mechanisms, including the clearance of senescent and pathogenic cells, modulation of tissue inflammation and enhancement of stem/progenitor cell niche and functionality. Our previous study demonstrated the beneficial impact of alternate-day fasting (ADF) on xerostomia and sialadenitis, along with an improvement in salivary gland ductal compartments, where salivary gland progenitor cells reside, in non-obese diabetic mice, a spontaneous model of Sjögren’s syndrome (SS). In the present study, we induced SS-associated hyposalivation in KRT5^CreERT2; R26^tdTomato lineage tracing mice by immunizing them with submandibular gland proteins from wild-type C57BL/6 mice. ADF alleviated salivary gland hypofunction, which was accompanied by decreased expression of the senescent cell marker p16^INK4a, reduced protein levels of anti-apoptotic proteins BCL-2, BCL-XL, and MCL-1, and attenuated NLRP3 inflammasome activity in the submandibular glands, particularly within the ductal compartments, of this inducible model. Furthermore, immunofluorescence staining of submandibular gland sections revealed the expression of the acinar cell marker aquaporin 5 in a small subset of Keratin 5⁺ cells in 2 of 9 mice that were subjected to ADF, whereas no such cells were detected in the control mice. Taken together, these findings indicate that ADF favorably modulates the salivary gland progenitor cell niche, potentially by promoting apoptosis-mediated senescent cell clearance, suppressing NLRP3 inflammasome signaling, and promoting Keratin 5⁺ progenitor cell-derived acinar cell replenishment, thereby contributing to the structural and functional restoration of damaged salivary glands in autoimmune exocrinopathy. Full article

Background: Sjögren’s disease (SjD) is a chronic autoimmune rheumatic disorder primarily affecting exocrine glands, leading to dryness and systemic involvement. B-cell hyperactivity and autoantibody production drive its pathogenesis and contribute to increased lymphoma risk. Although several long-term studies exist, we present a review of a closely monitored cohort assessed over 40 years. Methods: Retrospective observational study at University College London Hospital included patients fulfilling the 2016 ACR/EULAR criteria for SjD between 1986–2025. Patients with associated SjD were excluded. Associations between serological markers and clinical features were analysed using chi-square or Fisher’s exact tests (p < 0.05). Differences between ethnic groups were also assessed. Results: 283 patients were included, 93.3% female, with mean age at diagnosis of 50.1 ± 15.2 years and mean follow-up of 12.5 ± 8.6 years. Common manifestations were fatigue (61.5%), parotid swelling (30.5%), arthritis (25.8%), and Raynaud’s phenomenon (27.6%). Anti-Ro and anti-La antibodies were present in 75.7% and 45.2%, respectively; rheumatoid factor in 57.3%. Lymphoma developed in 9.9% (mostly non-Hodgkin MALT) and was associated with hypergammaglobulinemia (p = 0.03; RR = 2.56) and parotid swelling (p < 0.001; RR = 5.53). Serological markers correlated with systemic features including lymphadenopathy, vasculitis, and pulmonary involvement. Caucasian patients showed higher mortality (p < 0.001; RR = 3.89) and peripheral nervous system involvement (p = 0.02; RR = 2.18), and less ANA positivity (p = 0.004; RR = 0.88), anti-Ro (p = <0.001; RR = 0.77) and RF (p = 0.04; RR = 0.81) and hypergammaglobulinemia (p = <0.001; RR = 0.63) when compared with non-Caucasian patients. Conclusions: This long-term cohort confirms the strong association between B-cell activation markers and adverse outcomes in Sjögren’s disease. Hypergammaglobulinemia and parotid swelling emerged as key predictors of lymphoma, supporting their role in risk stratification. These findings reinforce the importance of long-term monitoring and may help guide personalized clinical management and surveillance strategies. Full article

Oxidative stress is a key contributor to the pathogenesis of immune-mediated diseases through its effects on cellular metabolism, mitochondrial function, immune signaling pathways, and inflammatory tissue injury. Disruption of redox homeostasis promotes metabolic reprogramming and persistent activation of innate and adaptive immune responses, contributing to disease progression across multiple inflammatory and autoimmune disorders. Recent advances in high throughput molecular technologies have generated large scale multi-omics datasets that enable comprehensive investigation of redox-associated mechanisms at a systems level. Integration of these datasets with computational analytical approaches has facilitated the identification of multidimensional molecular signatures associated with disease development and progression. This systematic review evaluates studies applying computational frameworks to analyze redox-related molecular data in immune-mediated diseases including multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, Sjögren’s syndrome, and inflammatory bowel disease. Across the reviewed studies, oxidative stress associated with molecular signatures were consistently linked to immune activation, mitochondrial metabolism, and inflammatory signaling pathways. Computational analyses also identified regulatory genes involved in antioxidant defense and metabolic regulation, as well as pathways associated with regulated cell death. These findings highlight the translational potential of computational redox analysis for biomarker discovery, disease stratification, and development of targeted therapeutic strategies aimed at restoring redox balance and improving clinical management of immune-mediated diseases. Full article

Hyperuricemia influences several aspects of the immune system. It enhances cytokine production by monocytes and activates neutrophils and natural killer cells. Within the adaptive immune system, hyperuricemia enhances antigen presentation, skews T helper cell differentiation toward the Th17 lineage and may also activate B cells. Beyond its established role in the pathogenesis of gout, hyperuricemia may therefore contribute to other rheumatic diseases. In this review, we summarize current evidence on the role of hyperuricemia in osteoarthritis, psoriatic arthritis, axial spondylarthritis, rheumatoid arthritis, systemic sclerosis, primary Sjögren’s disease and systemic lupus erythematosus. Available data do not support a causal role for hyperuricemia in the disease onset of osteoarthritis or rheumatoid arthritis. In contrast, hyperuricemia is associated with the development of psoriatic arthritis and may be linked to a more severe disease course. Small, predominantly cross-sectional studies further suggest a potentially adverse role of hyperuricemia in systemic sclerosis, Sjögren’s disease, and systemic lupus erythematosus. Across several rheumatic diseases, hyperuricemia is associated with cardiovascular disease, renal dysfunction and interstitial lung disease. However, both mechanistic and causal evidence remain limited, underscoring the need for more studies. Full article

Sjögren’s disease (SjD) is a chronic autoimmune disorder characterized by progressive dysfunction of the exocrine glands, driven primarily by aberrant T- and B-cell activation. Current therapeutic strategies remain largely symptomatic and are frequently limited by off-target effects and long-term toxicity, underscoring an urgent need for safer, mechanism-based adjunctive approaches. In recent years, nutritional interventions and medicinal herbs have emerged as promising complementary strategies, owing to their capacity to modulate immune–metabolic pathways and restore immune homeostasis. Nutrients such as n-3 polyunsaturated fatty acids (PUFAs) and short-chain fatty acids (SCFAs) exert well-documented anti-inflammatory effects and influence immune cell differentiation via immunometabolic reprogramming. Concurrently, bioactive constituents derived from medicinal herbs offer multi-target regulation of inflammatory signaling and lymphocyte function. This review synthesizes current advances in the immunomodulatory roles of dietary components and edible herbs in the context of SjD, focusing on their mechanistic convergence on T-cell subsets, B-cell responses, and the gut–immune axis. By integrating traditional knowledge with contemporary immunological insights, this article aims to provide a conceptual framework for the rational integration of nutritional and herbal strategies into the clinical management of SjD. Full article

Migraine is a highly prevalent and disabling neurovascular disorder that represents a major global health burden due to its significant impact on quality of life and socioeconomic costs. Increasing evidence suggests that migraine pathophysiology involves complex interactions between neuronal hyperexcitability, vascular dysregulation, oxidative stress, and neuroinflammatory processes. Oxidative and nitrosative stress are increasingly recognized as key contributors to migraine mechanisms, influencing mitochondrial dysfunction, cortical spreading depression, and trigeminovascular activation. Nitric oxide plays a central role in these processes by regulating vascular tone, nociceptive signaling, and neurogenic inflammation through downstream pathways such as the soluble guanylate cyclase–cyclic guanosine monophosphate (NO–sGC–cGMP) signaling cascade. Dysregulation of nitric oxide signaling and increased oxidative stress may contribute to endothelial dysfunction and impaired cerebrovascular regulation observed in migraine patients. In addition, accumulating evidence highlights the role of neuroinflammatory mechanisms, including microglial activation and cytokine-mediated signaling, which may amplify nociceptive transmission within trigeminal pathways. Migraine is increasingly recognized as a systemic disorder associated with several comorbid conditions, including Parkinson’s disease, fibromyalgia, and autoimmune diseases such as Sjögren’s syndrome. This review summarizes recent advances regarding the interactions between oxidative stress, nitric oxide signaling, endothelial dysfunction, and neuroinflammation in migraine and discusses their potential therapeutic implications. Full article

Background/Objectives: Corneal epithelial thickness (CET) alterations reflect distinct mechanisms in aqueous-deficient and evaporative dry eye disease (DED) subtypes. In this study, we compare the CET profiles between patients with Sjögren’s syndrome (SS) and those with meibomian gland dysfunction (MGD) to elucidate the underlying mechanisms. Methods: We retrospectively analyzed 30 patients with SS and 30 age- and sex-matched with MGD. Assessments included corneal staining, Ocular Surface Disease Index (OSDI), tear meniscus height (TMH), non-invasive breakup time, lipid layer thickness (LLT), and anterior segment optical coherence tomography (AS-OCT) CET mapping. Regional CET and superior–inferior asymmetry were compared. Results: The SS group exhibited higher corneal staining scores (2.18 ± 1.23 vs. 1.03 ± 1.18, p = 0.001) and lower TMHs (0.14 ± 0.06 vs. 0.18 ± 0.07 mm, p = 0.013), while the MGD group reported greater OSDI scores (40.39 ± 22.49 vs. 31.25 ± 22.81, p = 0.029). A significantly thinner central epithelium (p = 0.043) and localized inferior paracentral thinning (2–5 mm zone, p = 0.008) were noted in SS. Corneal staining was identified as the primary independent predictor of central and inferior CET reduction in both groups. In the MGD group, LLT was associated with the preserved inferior CET (p = 0.045) and superior–inferior thickness difference (p = 0.015). Conclusions: Distinct structural signatures are observed between DED subtypes. SS features central/inferior thinning from aqueous deficiency-mediated friction, whereas MGD shows a relatively preserved epithelial thickness influenced by LLT. Regional CET analysis may provide mechanistic insights into DED subtyping. Full article

Background/Objectives: Superficial oral mucosal (SOM) lesions are prevalent among patients with Sjögren’s disease (SjD) due to mucosal dryness. Given the limited evidence on screening and referral for SOMs, and the presence of relevant information only in dental clinical notes, a natural language processing (NLP) pipeline was developed to screen for SOMs among SjD patients. This retrospective study analyzed dental clinical notes from 180 linked electronic dental and health records, including both with and without a diagnosis of SjD. Materials and Methods: An annotation schema with four classes (SOMs, signs and symptoms of dry mouth, treatment for xerostomia, referral to specialists) was inductively created using the Extensible Human Oracle Suite of Tools (eHOST) to manually annotate clinical notes. Relevant keyterms were retrieved using a rule-based approach with Python’s Natural Language Toolkit (NLTK). SjD and control groups were compared using Fisher’s Exact tests. Four annotators reviewed ninety-three records. Results: SjD patients (mean age 54.8 ± 11.7 years) had fewer total visits across 15 years but had more dental visits per year (10.2 ± 13.3) than controls. SjD patients were more likely to have oral candidiasis (p = 0.041), exhibit signs and symptoms of dry mouth (p = 0.004), receive treatments for xerostomia (p < 0.001), be treated with cholinergic agonists (p = 0.005), and be referred to a specialist (p = 0.046), but findings were not significant for all SOMs. Additionally, SjD patients had a higher proportion of sialadenitis (p = 0.045), rheumatoid arthritis (p = 0.001), systemic lupus erythematosus (p < 0.001), myalgia/myositis/fibromyalgia (p = 0.010), and anxiety/nervousness (p = 0.004). Conclusions: These findings encourage the feasibility of using text mining from dental clinical notes for screening and management of oral conditions. Full article