Search Results (298)

Aortopathies in autoimmune rheumatic diseases (ARD) include a spectrum of aortic pathologies—including aortitis, aneurysms, dissections, and insufficiency—primarily caused by systemic inflammation. This comprehensive review investigates the clinical manifestations, pathophysiology, diagnostic modalities, and management strategies across various rheumatic diseases associated with aortopathies such as large vessel vasculitis (e.g., Takayasu arteritis, giant cell arteritis), connective tissue diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, systemic sclerosis) and less common conditions (e.g., relapsing polychondritis, Cogan’s syndrome, Behçet’s disease, IgG4-related disease). Disease-specific pathophysiologic mechanisms of aortic wall inflammation and remodeling, including granulomatous and lymphoplasmacytic patterns and mixed inflammatory infiltrates, are described. Diagnostic imaging modalities—such as CTA, MRI, and PET/CT—are evaluated for their roles in detecting active inflammation, assessing structural complications, and guiding clinical decision-making. Histopathological findings provide insight into disease-specific vascular changes. Management strategies focus on the use of glucocorticoids, disease-modifying antirheumatic drugs (DMARDs), and biologics, including IL-6 and TNF-α inhibitors, with an emphasis on patient-centered approaches, multidisciplinary care, and timely surgical intervention for complications. Evidence gaps include optimal screening intervals and the role of novel biomarkers in risk stratification and in monitoring disease progression, highlighting the need for early recognition, frequent monitoring, and aggressive management of aortic involvement in rheumatic diseases to prevent life-threatening complications. Full article

Biotherapeutics are medicinal agents derived from or related to naturally occurring molecules in the body and are designed to modulate specific immune targets. This review examines clinically established biologics and targeted small molecules that affect cytokine-driven transcriptional programs, principally JAK/STAT and canonical and non-canonical NF-κB signaling, across autoimmune, neoplastic, hematological, dermatological, and rheumatic diseases. Periodontitis is used as a translational model because dysbiotic mucosal inflammation, cytokine signaling, and osteoclastogenesis may also intersect with systemic autoimmunity. In particular, Porphyromonas gingivalis-associated protein citrullination provides a plausible link to anti-citrullinated protein antibody-positive rheumatoid arthritis in genetically susceptible individuals, although causality remains unproven. The review also evaluates plant-derived modulators of JAK/STAT and related transcriptional pathways. Curcumin and resveratrol have entered small rheumatoid arthritis studies, whereas evidence for catechins, celastrol, and artemisinin derivatives in autoimmune disease remains predominantly preclinical. These compounds may inform adjunctive or locally delivered strategies, but clinical translation requires better target selectivity, bioavailability, dose standardization, and safety data. Full article

Autoimmune rheumatic diseases are still treated predominantly through broad or targeted suppression of inflammatory pathways, yet durable restoration of self-tolerance remains a central unmet therapeutic goal. This narrative review examines restoration of immune tolerance as an emerging translational framework in rheumatology, integrating checkpoint agonism, antigen-specific immunotherapy, regulatory cell-based strategies, and immune-reset approaches within a unified therapeutic perspective. Rather than treating these strategies as isolated innovations, the review evaluates how each attempts to restore, reinforce, or reconfigure immune restraint at distinct biological levels, spanning inhibitory receptor signaling, antigen-selective non-responsiveness, dominant regulatory control, and deeper reconfiguration of pathogenic immune architecture. Their relevance is considered across rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s disease, and systemic sclerosis, with emphasis on mechanistic rationale, translational maturity, disease-specific therapeutic fit, biomarkers, therapeutic timing, and major barriers to clinical implementation. Collectively, these approaches suggest a shift in rheumatology from repeated control of inflammatory consequences toward more selective and potentially durable recalibration of autoreactive immunity. Although the field remains biologically and clinically immature, restoration of immune tolerance is emerging as an important organizing principle for the development of more precise and potentially disease-modifying therapies in autoimmune rheumatic disease. Full article

Background: Sensorineural hearing loss (SNHL) has increasingly been recognized as an extra-articular manifestation of systemic autoimmune rheumatic disease (SARDs), but its burden and clinical characteristics remain inconsistent. This systematic review and meta-analysis evaluated the prevalence, risk, audiometric characteristics, diagnostic methods and prognostic factors of SNHL in patients with major SARDs. Methods: A systematic search of the PubMed, Scopus and Cochrane Library databases was conducted between 25 June and 3 July 2026 in accordance with PRISMA 2020 guidelines. Observational studies evaluating SNHL in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjögren syndrome (pSS) and systemic sclerosis (SSc) were included. Meta-analyses using a random-effects model were performed to estimate pooled prevalence and odds ratios (OR). Subgroup analyses, meta-regression, sensitivity analysis, publication bias assessment and certainty of evidence evaluation were performed. Results: Twenty-two studies met the eligibility criteria and were included. The pooled prevalence of SNHL was 50% (95% CI: 13–87%, p < 0.001) in patients with RA, 61% (95% CI: 22–95%, p < 0.001) in SLE, 31% (95% CI: 5–67%, p < 0.001) in pSS and 28% (95% CI: 14–44%, p < 0.001) in SS. Patients with RA (OR 1.92; 95% CI: 1.29–2.87) and SLE (OR 21.68; 95% CI: 4.65–100.99) had significantly increased odds of SNHL compared to healthy controls. Hearing loss was predominantly mild, bilateral, and cochlear in origin, and affected high or extended high frequencies. Longer disease duration and greater disease activity were associated with worse hearing thresholds. In exploratory analyses of RA studies, sample size, study setting, and study design were significant study-level moderators of heterogeneity. Conclusions: SNHL is reported with appreciable prevalence across several major systemic autoimmune rheumatic diseases, although prevalence estimates are highly heterogeneous and should be interpreted cautiously. Comparative evidence supports increased odds of SNHL in RA, whereas the magnitude of the association in SLE remains uncertain because of the limited and imprecise evidence. Evidence establishing increased comparative risk in pSS and SSc remains insufficient. Audiological assessment may be particularly relevant in patients with longstanding or active disease. Full article

Background: Pharmacovigilance systems have flagged possible associations between mRNA COVID-19 vaccination and systemic autoimmune inflammatory rheumatic diseases (AIRDs), generating uncertainty for rheumatologists counselling patients. As the first population-scale deployment of an mRNA vaccine platform, COVID-19 vaccination provides a unique setting to examine whether autoimmune safety signals detected in spontaneous reporting systems correspond to measurable disease risk. We synthesised pharmacovigilance and population-based evidence on incident EULAR-defined systemic AIRDs after mRNA COVID-19 vaccination and assessed whether disproportionality signals were corroborated by analytical studies. Methods: We conducted a PRISMA 2020-compliant systematic review searching MEDLINE, Web of Science, Scopus, Embase, and the Cochrane Library from 2019 to April 2026, supplemented by medRxiv and trial registries. Eligible studies included pharmacovigilance disproportionality analyses and analytical studies, including cohorts and randomised controlled trials, evaluating BNT162b2 or mRNA-1273 in adults without known pre-existing autoimmune disease. Risk of bias was assessed using READUS-PV, ROBINS-I, and RoB 2. Meta-analysis was not performed because of substantial heterogeneity. Results: Fourteen studies were included: seven pharmacovigilance studies and seven analytical studies. Disproportionality analyses suggested increased reporting of selected AIRDs, most consistently polymyalgia rheumatica and giant cell arteritis, mainly when all other adverse-event reports served as comparators. These signals were largely neutral when influenza vaccines were the reference. Across analytical studies, associations were inconsistent; modest increases in systemic lupus erythematosus appeared only in selected analyses. Long-term evidence was scarce: only four studies, from three countries (South Korea, Israel, and Norway), followed participants for up to approximately one year, and three of these reported at least one positive association—systemic lupus erythematosus, post-booster rheumatoid arthritis, and polymyalgia rheumatica in older adults—whereas studies restricted to risk windows of three months or less reported no increase. Conclusions: The available evidence does not indicate a consistent increase in incident systemic AIRDs after mRNA COVID-19 vaccination. Although pharmacovigilance studies identified comparator-dependent signals for selected diseases, particularly polymyalgia rheumatica and giant cell arteritis, these findings were generally not confirmed in comparative population-based studies and should be considered hypothesis-generating. Delayed-onset disease remains poorly characterised, and studies with at least one year of follow-up are needed. Full article

Background/Objectives: Antinuclear antibody testing by indirect immunofluorescence on HEp-2 cells (ANA-IIF) remains the reference test for systemic autoimmune rheumatic diseases (SARD). However, complete serological characterization requires integration with extractable nuclear antigen (ENA) screening, antigen-specific solid-phase assays (SPA), and confirmatory indirect immunofluorescence (IIF) tests. This study aimed to: (1) quantify real-world serological pathway incompleteness in ANA testing performed outside a structured reflex strategy; (2) compare simulated stepwise and upfront parallel reflex approaches in terms of serological yield, laboratory workload, and costs. Methods: We retrospectively analyzed 2207 consecutive patients referred for ANA-IIF testing between July 2025 and April 2026. Serological incompleteness was defined as non-completion of the predefined Regione Lombardia reflex framework. A fully characterized subgroup of 514 patients, defined by complete reflex-serological assessment, was used to compare a stepwise strategy, in which ANA-IIF positivity triggered downstream testing, with an upfront parallel strategy, in which ANA-IIF, ENA screening, and anti-double-stranded DNA (anti-dsDNA) testing were performed upfront. Results: ANA-IIF was positive in 913/2207 patients (41.4%). Overall, 508 patients (23.0%) had at least one missing follow-up assay expected under the reflex framework. In the fully characterized subgroup, the upfront parallel strategy increased the number of patients with at least one fully characterized autoantibody finding from 15 to 22 (+1.4%), but required 657 additional tests and an estimated incremental cost of approximately €2592. Conclusions: ANA-IIF testing outside a structured reflex pathway frequently resulted in incomplete serological assessment. Although the upfront parallel strategy increased serological yield, it required substantially greater laboratory workload and costs than the stepwise approach. Further studies are needed to define the optimal balance between serological yield, clinical relevance, and cost-effectiveness. Full article

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease defined by persistent synovial inflammation, progressive cartilage and bone erosion, and extra-articular manifestations. Current treatments, such as disease-modifying anti-rheumatic drugs (DMARDs), glucocorticoids, and non-steroidal anti-inflammatory drugs (NSAIDs), control disease activity but are limited by toxicity, reduced response over time, and are expensive, demonstrating the need for safer and more effective adjuncts. The marine environment is a rich, largely untapped source of structurally diverse bioactive molecules that could be used to develop new therapeutics. This review compiles current evidence on anti-inflammatory and immunomodulatory compounds from marine organisms relevant to RA, including macroalgae, true marine microalgae, marine microorganisms (bacteria and fungi, including deep-sea taxa), sea cucumbers, sponges, mussels, corals, and jellyfish. Recurring mechanisms of action include inhibition of the NF-κB, MAPK, and JAK/STAT signalling cascades; suppression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2); reduced production of tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6; and activation of the Nrf2 antioxidant response. Particular attention is given to functional lipids (eicosapentaenoic and docosahexaenoic acids, prostaglandin-like oxylipins) and pigments (astaxanthin, fucoxanthin, β-carotene) from marine microalgae and heterotrophic protists, which recent literature identifies as the most clinically advanced marine leads. To clarify translational status, compounds are grouped by their development stage (marketed nutraceutical, clinical trial, or preclinical) and summarised in a dedicated table. Some compounds, such as green-lipped mussel extract, microalgal omega-3 oils, and astaxanthin, have reached the stage of randomised controlled trials for arthritis. However, most other potential treatments are still in the early, preclinical phase. It is worth noting that ocean-derived compounds appear generally safe, but more thorough studies, especially in living organisms and in clinical settings, are needed to confirm their effectiveness for rheumatoid arthritis before any claims can be made about their therapeutic benefits. Full article

Patients with autoimmune rheumatic diseases, particularly rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), experience excess cardiovascular risk that is not fully captured by conventional lipid measurements. In active RA, lower cholesterol may coexist with higher vascular risk, a pattern known as the lipid paradox. We propose that systemic inflammation can uncouple lipid concentration from lipoprotein function and organize the evidence along five mechanistic axes. Inflammatory cytokines, mainly interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), IL-1β, IL-17/IL-23 and type I interferons, remodel lipoprotein metabolism. High-density lipoproteins (HDL) lose protective functions and may become pro-inflammatory. Apolipoprotein-B particles are oxidized or otherwise modified, linking lipid metabolism to autoimmunity. Macrophage cholesterol imbalance and cholesterol crystals activate inflammasome pathways in experimental atherosclerosis, while immune-cell metabolic rewiring may amplify cytokine output; these mechanisms are treated as extrapolated when direct rheumatic-disease evidence is limited. The pathways converge on endothelial dysfunction and thrombo-inflammation. RA and SLE are the mechanistic anchors, whereas psoriatic disease, axial spondyloarthritis, systemic sclerosis, vasculitides and antiphospholipid syndrome are weighted by evidence category. Standard lipid panels may therefore underestimate risk in selected contexts, especially during active inflammatory disease. Full article

Background/Objectives: Sjögren’s disease (SjD) is a chronic autoimmune disorder characterized by a wide range of clinical manifestations, often leading to delayed diagnosis. This study aimed to evaluate and compare the clinical and laboratory characteristics of patients with primary and secondary SjD and those with sicca symptoms without SjD. Methods: This comparative cross-sectional study included 84 participants enrolled between 2019 and 2024: 27 patients with primary Sjögren’s disease (pSjD), 4 with secondary Sjögren’s disease (sSjD), and 53 with sicca symptoms without SjD (non-SjD/NSjD). Primary SjD was diagnosed according to the 2016 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria. Results: Compared with NSjD patients, those with pSjD and sSjD had significantly lower unstimulated whole saliva (UWS) and stimulated whole saliva (SWS) flow rates (p < 0.001), a higher prevalence of antinuclear antibodies (ANA) (twice as frequent) (p = 0.005), and higher frequencies of anti-SSA/Ro60, anti-SSA/Ro52, anti-SSB/La, and rheumatoid factor (RF) positivity (p = 0.002, p = 0.003, p = 0.005, and p = 0.019, respectively). In addition, SjD patients had higher EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) scores (p = 0.026) and more frequently demonstrated a focus score (FS) ≥ 1 on minor labial salivary gland (MLSG) biopsy (p < 0.001). Serum vitamin D levels were lower in pSjD patients than in NSjD patients; however, the difference was not statistically significant (57.8 ± 20.4 vs. 70.6 ± 18.3; p = 0.259). Conclusions: Patients with pSjD exhibited distinct clinical and laboratory characteristics compared with those with sicca symptoms without SjD. Sialometry, anti-SSA antibodies, and MLSG biopsy were identified as the most important diagnostic tools for differentiating SjD from NSjD. Full article

Background: Autoimmune diseases (AIDs) are associated with increased cardiovascular risk. However, specific protein mediators linking AIDs to major adverse cardiovascular events (MACE) and cardiovascular death (CV death) remain unexplored. This study identifies proteomic mediators linking AIDs to MACE via high-dimensional mediation analysis in the UK Biobank. Methods: We used UK Biobank data with proteomic profiling by Olink platform. Participants with prevalent myocardial infarction (MI), stroke, and heart failure at baseline were excluded. AIDs were categorized into musculoskeletal (MSK), vasculitis, gastrointestinal (GI), neurologic, and rheumatic fever subsets. Fine–Gray models assessed associations between AIDs and MACE and CV death. Proteome-wide association studies identified proteins associated with both AIDs and cardiovascular outcomes. High-dimensional mediation analysis (HIMA) explored protein-mediated pathways. All models adjusted for age, sex, lipids, BMI, smoking, hypertension, diabetes, chronic kidney disease, atrial fibrillation, and coronary artery disease. Results: Among 400,633 participants (median follow-up 14.5 years, 44.8% male), AIDs were present in 28,754 (7.2%). All AID categories were associated with increased MACE (sHR: MSK 1.34, vasculitis 1.67, GI 1.20, neurologic 1.33, rheumatic fever 1.38; all p < 0.001). For CV death, MSK, vasculitis, and rheumatic fever showed increased risk (sHR 1.34, 1.78, 1.51; all p ≤ 0.004), but not GI or neurologic AIDs. In 43,599 participants with proteomic data, HIMA identified 66 and 32 unique potential mediators linking AIDs to MACE and CV death, respectively. Four proteins (Growth Differentiation Factor 15, Interleukin-15, urokinase plasminogen activator receptor, and Tenascin C) mediated the AID-MACE relationship across multiple AID categories. Growth Differentiation Factor 15 and Interleukin-15 were shared mediators for CV death. Conclusions: This proteomic analysis identifies specific proteins that may mediate the association between AIDs and adverse cardiovascular outcomes, offering mechanistic insights into immune-related cardiovascular risk. These findings are hypothesis-generating and require replication and validation before the identified proteins can be considered causal mediators or adopted for clinical risk stratification. Full article

Background: Adult parvovirus B19 (B19V) infection occurs with cyclic outbreaks and can be associated with inflammatory manifestations mimicking or heralding the onset of systemic autoimmune diseases. Little is known about clinical traits distinguishing patients with transient vs. persisting manifestations. Methods: Leveraging data from the 2024 B19V infection outbreak, we set up a retrospective, multicentre, observational study investigating the epidemiology and clinical phenotypes of patients with B19V infection presenting to tertiary care for immune-mediated manifestations, including patients with pre-existing autoimmunity. Results: A total of 39 B19V infections were identified, yielding an annual incidence of 1.78 cases/1000 patients. Autoimmune rheumatic diseases were pre-existing in 7/39 and newly diagnosed in 5/39. One patient was hospitalised. Arthritis was more frequent in new-onset (89%) than in pre-existing (14%; p = 0.010) or no autoimmunity (19%; p < 0.001). Anaemia was not found in patients with pre-existing autoimmunity in contrast to those with new autoimmune disease diagnoses (40%; p = 0.039) or transient manifestations (52%; p = 0.013). Skin manifestations were numerically less frequent in this latter group (56%) than in patients with pre-existing (100%) or newly onset autoimmunity (80%). Autoantibodies were detected in 44% of cases and were more frequent in patients with constitutional symptoms but were not confirmed in the long term in most cases. Glucocorticoids were more frequently employed in patients with new-onset rather than pre-existing autoimmune diseases (p = 0.006) or without chronic autoimmunity (p = 0.027). Conclusion: B19V-associated new-onset autoimmunity may occur in one in six cases observed in tertiary immunology care, show distinct clinical features, and require significant immunosuppression. Full article

Tick-borne encephalitis (TBE) is a neuroinvasive flavivirus infection with a wide spectrum of clinical manifestations whose molecular mechanisms remain insufficiently characterized. MiRNAs regulate pro-inflammatory cytokine production; therefore, changes in their profiles across different forms of TBE may determine the nature of the cytokine response. The aim of this work was to identify the specific features of the circulating miRNA and cytokine profiles in different clinical forms of TBE, as well as to analyze the correlations between them. The study included patients with febrile, meningeal, and encephalitic forms of TBE, patients with inflammatory rheumatic diseases (IRD), and healthy donors. Plasma concentrations of eight miRNAs (miR-25-3p, miR-29a-3p, miR-92a-3p, miR-146a-5p, miR-146b-5p, miR-181a-5p, miR-486-3p, and miR-766-3p) were measured by stem-loop real-time RT-PCR. Cytokine concentrations (IL-1β, IL-2, IL-8, IL-18, TNF-α) were measured by ELISA. Kendall’s rank correlation test was used for the correlation analysis. In all forms of TBE, a distinct circulating miRNA signature emerges (↑ miR-25-3p, miR-146b-5p, ↑ miR-766-3p, and ↓ miR-29a-3p), which is associated with an acute antiviral response and is not specific to chronic autoimmune inflammation. Several miRNAs (miR-29a-3p, miR-92a-3p, miR-146b-5p, and miR-486-3p) showed opposite changes in TBE and IRD, pointing to fundamentally different mechanisms of immune regulation in acute neuroinfection and systemic autoimmune pathology. Several statistical associations between circulating miRNA and pro-inflammatory cytokine levels were identified. TNF-α levels positively correlated with miR-146b-5p and negatively with miR-25-3p, while IL-2 positively correlated with miR-25-3p. In the encephalitic form of TBE, IL-1β positively correlated with miR-146b-5p and miR-92a-3p. The present study is of a pilot nature. The miRNA and cytokine patterns identified here were based on a small sample size and should therefore be regarded as preliminary. Once confirmed, these signatures may provide a basis for the differential diagnosis of TBE and the development of prognostic biomarkers of disease severity. Full article

Systemic sclerosis (SSc) is a severe autoimmune rheumatic disease with high mortality. Epigenetic factors, particularly micro-RNAs (miRNAs), may contribute to its pathogenesis by regulating gene expression. In this cross-sectional study, we assessed altered miRNA–mRNA regulatory networks in SSc and associated them with disease-related biological processes. We analyzed the miRNA profiles and differentially expressed genes (DEGs) of peripheral blood mononuclear cells (PBMCs) from 52 SSc patients (42 women and 10 men; mean age: 59.1 years) and 24 age- and gender-matched healthy controls. Total RNA was isolated and subjected to high-throughput next-generation sequencing for both miRNA and mRNA profiling. We identified 58 differentially expressed miRNAs (DEMs), 33 upregulated and 25 downregulated in SSc. In parallel, 6610 DEGs were detected (Mann–Whitney U-test, p < 0.05); 31 remained upregulated and nine downregulated after false discovery rate (FDR) correction. Integration of miRNA and mRNA data revealed 180 validated inverse miRNA–mRNA interactions. Notably, 22 of 31 upregulated DEGs corresponded to targets of downregulated miRNAs, indicating coordinated derepression. Functional enrichment analyses highlighted pathways related to extracellular matrix (ECM) remodeling, immune responses, fibrosis, and transcriptional regulation. Our findings suggest that altered miRNA expression contributes to widespread transcriptional dysregulation in SSc, promoting pro-fibrotic and immune-activated molecular pathways through coordinated miRNA–mRNA interactions. Full article

Background/Objectives: Systemic sclerosis (SSc) is a heterogeneous systemic autoimmune rheumatic disease characterized by immune dysregulation, vasculopathy, and fibrosis involving the skin and internal organs. Interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), and cardiac involvement remain major causes of morbidity and mortality, yet prediction of disease progression and therapeutic responsiveness remains difficult. Methods: This narrative review summarizes studies of circulating blood biomarkers in SSc, with emphasis on literature published since 2020 and on Japanese multicenter longitudinal cohort studies. Disease-specific autoantibodies were intentionally excluded from the main scope, and the review focuses on soluble biomarkers measurable in peripheral blood that reflect inflammation, endothelial injury, and fibrotic remodeling. Results: Multiple cytokines, chemokines, adhesion molecules, endothelial markers, extracellular vesicle-associated molecules, and extracellular matrix (ECM)-related molecules have been associated with disease activity, organ involvement, prognosis, and therapeutic response in SSc. Clinically established biomarkers such as KL-6 and surfactant protein-D (SP-D) for SSc-associated interstitial lung disease (ILD), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) for pulmonary arterial hypertension (PAH), are already used as adjunctive tools in routine clinical assessment, whereas many other candidate biomarkers, including interleukin (IL)-6, CCL2, CXCL8, CXCL4, intercellular adhesion molecule-1 (ICAM-1), CCL18, periostin, endostatin, endothelin-1, extracellular vesicle signatures, and ECM turnover markers remain at varying stages of clinical validation. In particular, Japanese multicenter longitudinal studies have demonstrated the prognostic significance of circulating chemokines and adhesion molecules in early SSc and, more recently, identified biomarker-based clusters associated with distinct pulmonary trajectories. Recent multidimensional proteomic and transcriptomic approaches further support biologically based patient stratification in SSc. Conclusions: Blood biomarkers may contribute to risk stratification, prediction of organ progression, and future precision medicine in SSc. Integrated biomarker signatures may better capture the biological heterogeneity of SSc than single biomarkers alone. However, most candidate biomarkers still require external validation, assay standardization, and demonstration of incremental value over conventional clinical variables before routine clinical implementation. Full article

Background/Objectives: Primary Sjögren’s syndrome (pSS) is a chronic autoimmune rheumatic disease that clinically presents with symptoms of xerostomia and xerophthalmia, as well as a wide range of other symptoms that may affect patients’ daily functioning and life satisfaction. The main purpose of this study was to assess their health-related quality of life (HRQoL) using both general and disease-specific questionnaires. Methods: This cross-sectional observational research with prospective data collection was conducted at the Rheumatology Clinic of the University Clinical Centre of Kragujevac. Participants were divided into two groups: patients with oral manifestations (oral manifestations group) and those presenting with xerostomia only, without other oral lesions or symptoms (xerostomia-only group). A complete clinical examination of the patient’s oral cavity was performed by one doctor of dental medicine. HRQoL was evaluated using various generic and disease-specific instruments. Results: A total of 80 participants were included in the study, of whom 40 were in the oral manifestations group and 40 in the xerostomia-only group. Patients with oral manifestations had significantly higher scores across all PSS-QoL domains compared with the xerostomia-only group (p < 0.001). A statistically significant difference in the total EQ-5D result was detected between groups (0.7 (0.3) vs. 0.8 (0.1), p < 0.001). In multivariable regression analysis (R² = 0.921), the ESSPRI score (β = 0.418, p < 0.001) and the presence of oral manifestations (β = −1.155, p < 0.001) were significant independent predictors of impaired HRQoL, while disease activity showed no significant association (p = 0.895). Conclusions: Patients with primary Sjögren’s syndrome presenting with oral manifestations have poorer HRQoL compared with participants with xerostomia only. Symptom burden, including dryness, pain, fatigue, and oral manifestations, may be associated with decreased HRQoL, in contrast to disease activity. Full article