Background Interstitial lung disease (ILD) and small airways disease (SAD) are prominent pulmonary manifestations of Sjögren disease (SjD) but their association and real prevalence are still elusive. Our purpose was to explore the clinical landscape and potential associations of pulmonary disease in SjD. Methods Eighty three consecutive SjD patients with respiratory symptoms and/or abnormal pulmonary function tests (PFTs) were prospectively recruited. Participants underwent high resolution computed tomography (HRCT) of the lungs, evaluation for small airways function with: i. forced expiratory flow after an expiration of 25% to 75% of forced vital capacity (FEF25-75) measured by spirometry, and ii) resistance difference between 5Hz and 20Hz (R5-R20) measured by oscillometry, and responded to specific questionnaires for dyspnea and cough. Clinical, laboratory and histopathologic data were also collected and analyzed. Results Twenty six (31.3%) patients had ILD findings on HRCT. SjD-ILD patients had more severe respiratory symptoms assessed by specific questionnaires and higher disease activity measured by ESSDAI (12 vs. 2, p < 0.0001), and presented more frequently lymphoma history (33% vs. 10%, p = 0.020), and higher focus score (4.25 vs. 1.50, p = 0.005) compared to non-ILD-SjD patients. The prevalence of SAD based on FEF25-75, and R5-R20 was 34% and 65% respectively. SjD-ILD patients had lower FEF25-75 (mean: 64.0 vs 90.8%, p = 0.002), higher R5-R20 (median: 0.149 vs. 0.085 kPa/L/s, p = 0.0006) and presented more frequently SAD defined by R5-R20 (92% vs. 53%, p = 0.0004) compared to non-ILD SjD patients. Conclusion ILD and SAD occur frequently among SjD patients and are clinically associated, implying a potential pathophysiologic link between them.

Minor salivary gland biopsy occupies a distinctive position in the evaluation of Sjögren disease (SjD), offering diagnostic and prognostic insights that are rarely achievable in other systemic autoimmune conditions. It contributes essential diagnostic information, particularly for patients lacking anti-Ro/SSA antibodies or pediatric patients, and supports identification of key histopathologic features. Beyond its established diagnostic role, the biopsy carries prognostic information related to systemic involvement, B-cell activity, and lymphoma risk, supported by features such as ectopic germinal centers, lymphoepithelial lesions, and molecular monoclonality. Its clinical value extends to incident lymphoma detection and exclusion of diseases that mimic SjD. Emerging technologies - including standardized sampling approaches, digital pathology, and early applications of artificial intelligence - may further enhance diagnostic accuracy and prognostic utility. Although the procedure is generally safe, careful consideration is required to balance clinical benefit with patient burden. Overall, salivary gland biopsy remains a cornerstone for advancing SjD understanding and management.

We aim to present recent advancements in predictive markers for lymphomagenesis in SjD, concisely organize existing knowledge, and identify corresponding unmet needs and future perspectives. First, we briefly describe the mechanisms of lymphomagenesis in SjD. Followingly, the reasons justifying the importance of early lymphoma diagnosis in SjD are presented. Subsequently, recent advancements regarding lymphoma risk factors in SjD, both in translational and clinical research, are discussed, and how they fit in the preexisting knowledge landscape. Following, the effects of predicting a high risk of lymphoma development on clinical practice, clinical trials, monitoring strategies, as well as the currently known value of preventive treatment are presented. Lastly, we suggest future perspectives and unmet needs. The paradigm is shifting towards time-sensitive reevaluation of traditional risk factors and analysis of novel markers. Characterization of the exact site of occurrence of pathobiological events is increasingly punctual. Isolated biological B cell hyperactivity seems to be a temporally distant harbinger of lymphomagenesis, while clinical manifestations of B cell hyperactivity potentially signal imminent transition to clinically overt lymphoma. Data regarding protective factors and lymphoma prevention strategies are scarce. Deep learning for lymphoma prediction or automated identification of lymphoma risk factors is completely unexplored. Consensus guidelines regarding lymphoma prediction, monitoring, and prevention are lacking. Further advancements are anticipated in the field of predicting, monitoring, treating, and potentially preventing lymphoma in SjD. That is through refinement of study design, employment of deep learning, and, eventually, development of consensus guidelines to guide both research and clinical practice.

BACKGROUND:Sjögren's Disease (SjD) is histopathologically characterized by focal sialadenitis in minor labial salivary gland biopsies (mLSGB), which is evaluated by utilizing the focus score (FS). Focus score ≥1 identification is a critical step of the diagnostic approach and SjD classification. Nonetheless, during mLSGB analysis, FS reporting is neglected in a staggering 17 %, and a degree of inter-observer variability is introduced, even among specialized university centers. As the unmet need for reliable FS reporting is displayed, leveraging artificial intelligence in mLSGB evaluation shows encouraging potential and mandates to be investigated. METHODS:Minor LSGBs stained only with hematoxylin and eosin (H&E) during evaluation of individuals with a clinical suspicion of SjD, were randomly chosen from our archive. All mLSGBs were scanned digitally as whole slide images (WSI) and the final dataset was partitioned into a training (70 %) and a test set (30 %). An attention-based deep learning binary classification model was employed for evaluation of mLSGBs positivity (FS ≥ 1 or FS < 1). RESULTS:The final dataset consisted of 271 mLSGBs, with 153 (56 %) having FS < 1 and 118 (44 %) FS ≥ 1. In the FS ≥ 1 subset, 74 (63 %) were in the FS = 1-2 range, and the remaining biopsies had FS > 2, following the expected FS distribution among the typical SjD population. Our model resulted in: AUC = 0.932 (0.881-0.984), sensitivity 87 % (0.733-0.944), specificity 84 % (0.71-0.915) and accuracy 85.2 % (0.763-0.912), achieving better performance from previous works. CONCLUSION:Artificial intelligence models may overcome the intra-observer biases and inter-observer variability in FS evaluation, reinforcing the diagnosis and biomarker discovery in SjD.

Graves’ orbitopathy (GO) is an autoimmune disease affecting the orbit and the retro-ocular tissues. GO pathogenesis involves multiple complex mechanisms, including the contribution of many inflammatory cytokines, such as interleukin-6 (IL-6). GO severity ranges from mild to severe and sight-threatening cases, with the latter affecting only a small percentage of patients. A considerable number of these patients do not respond to first-line immunosuppressive therapy with weekly intravenous pulses of corticosteroids and therefore, there is an unmet need for a second-line treatment, based on immunosuppressive drugs. In recent years tocilizumab (TCZ), an IL-6 inhibitor, has emerged as an effective and safe alternative option for the treatment of active, moderate-to-severe, refractory to steroids cases of GO. This review focuses on the up-to-date concepts regarding TCZ administration for the management of these patients.

Sjögren's disease represents a complex systemic autoimmune disorder mainly driven by T and B lymphocytic infiltration of exocrine gland, activation of different signalling pathways and systemic cytokine production. These interacting pathogenic mechanisms may differently contribute to characterise highly variable phenotypic expression of the disease, ranging from an asymptomatic, indolent course with only glandular involvement to several extra-glandular systemic manifestations. Moreover, approximately 5-10% of patients develop lymphoproliferative disease, with an overall risk reported to be up to 48 times higher in comparison to healthy population. Due to the substantial clinical heterogeneity of the disease, in recent years, research focused to investigate biomarkers able to identify distinct subtypes of Sjögren's disease, facilitate earlier patient recognition and homogenise patient subgroups in clinical trials aiming to develop tailored therapies. Surely, a more detailed understanding of pathogenetic mechanisms and recognition of different disease phenotypes may facilitate earlier diagnosis, enable recognition of patient clusters and suggest novel therapeutic modalities to address the unmet needs of the disease in the upcoming years. In this review, following the others of this series, we will update the most recent literature on Sjögren's disease focusing in particular on new insights into clinical stratification, imaging techniques and targeted therapeutic advances.

Nomenclature for the disease widely known as Sjögren syndrome has proven unsatisfactory. Patients have perceived ‘syndrome’ as indicative of a vague collection of symptoms, prompting the Sjögren’s Foundation to abandon the term. Furthermore, the traditional distinction between ‘primary’ and ‘secondary’ forms fails to account for the complex interplay between overlapping autoimmune diseases. Following a bibliometric analysis, systematic literature review and a Delphi consensus process with equal involvement of professional and patient representatives, five recommendations are now issued. First, the term ‘Sjögren disease’ should replace ‘Sjögren syndrome’. Second, the acronym ‘SjD’ should be used as an abbreviation for ‘Sjögren disease’. Third, the descriptor ‘associated’ should be used in lieu of ‘secondary’ for Sjögren disease occurring in association with a second systemic autoimmune disease for which classification criteria are fulfilled. Fourth, Sjögren disease is the preferred terminology in common parlance and in clinical diagnosis, without differentiation as to primary and associated forms. Fifth, the differentiation between primary and associated Sjögren is recommended for scientific studies to define a homogeneous population. In conclusion, the consensus endorses ‘Sjögren disease’ as the official nomenclature to acknowledge the distinct pathogenesis of this disorder and to improve clarity in both clinical practice and research. In this Consensus Statement, an international group of experts and patient representatives validates and endorses the transition from the term ‘Sjögren syndrome’ to ‘Sjögren disease’, and issue several additional recommendations regarding the nomenclature of this disorder.

The wide spectrum of Sjögren's disease (SjD) clinical manifestations coupled with its multifaceted pathogenesis has complicated drug target development, optimal clinical trial design, identification of suitable SjD subgroups, selection of appropriate outcome measures, and interpretation of treatment efficacy. Despite recent advancements in biologic treatments for autoimmune diseases, the targeted therapy(ies) for SjD remain an unmet need, with no regulatory approvals, so far. Recent large, randomized studies have suggested some patient benefits; however, reproducibility is needed, and assessment of treatment efficacy requires refinement. In this review, we explore the potential for curing SjD taking into consideration the main pathogenetic mechanisms, clinical phenotypes, and underlying endotypes. We provide an overview of current recommendations and targeted treatments, identify potential reasons for treatment failures, and propose strategies (in and out of the box) for future directions. By addressing these areas, we offer a comprehensive perspective that may inform future research and therapeutic strategies for SjD.

PURPOSE:To organize the existing literature regarding applications of artificial intelligence (AI) in biopsies and imaging modalities of patients with systemic autoimmune rheumatic diseases (SARDs) and to familiarize readers with the most commonly occurring concepts. RESULTS:Firstly, we present a workflow that summarizes techniques implemented in AI for biopsies and imaging modalities in SARDs. Next, we describe challenges specific to image analysis for medicine. Subsequently, we describe the goals for an AI study in this field, and the prerequisites to meet them in SARDs. Finally, after reviewing the existing literature, we present the applications of AI for image analysis in each SARD. Accordingly, we analyze 1-2 studies from each SARD and mention key messages and lessons derived from them. Lastly, we create a recommendation landscape identifying unmet needs for AI applications in each SARD. The vast majority of studies employ supervised learning for image classification or segmentation, and rarely for regression. The median dataset size was 116 patients for imaging studies and 271 patients for biopsies studies, while the number of images per study varied greatly. Reporting of multiple performance metrics was frequently neglected. CONCLUSIONS:Employing AI for SARD image analysis ultimately demands large datasets with multimodal and adequately diverse data to effectively capture the heterogeneity of SARDs. In the field of rheumatology, plagued by subjectivity and interobserver variability, issues regarding data quality, regulatory authorities and the specificity and clinical impact of questions posed will define the time needed for clinical adoption of AI-assisted medical care.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease, with key features being synovial hyperplasia, autoantibody production, and ultimately cartilage and bone destruction. The pathogenesis of rheumatoid arthritis (RA) is not fully understood, but it is estimated that genetic factors account for 50–60% of the risk, with the remainder attributed to environmental factors, including infectious agents, smoking, gut microbiota, and diet. Given that most current clinical trials on RA and nutrition are limited in sample size and duration, there is an unmet need for higher-quality studies in the future, a need that EULAR has already recognized. Objective: This article aims to investigate the impact of diet and nutritional factors on the development, progression, and potential prevention of RA. Specifically, it provides a comprehensive review of certain foods, such as alcohol, gluten, red meat, and saturated and trans fats, and their contribution to the onset and progression of rheumatoid arthritis (RA). In addition, it examines the effect of key anti-inflammatory nutrients in reducing the risk of RA, including olive oil, fatty fish, juices, and certain fruits. Finally, it discusses the potential protective effects of certain dietary patterns, such as the Mediterranean diet (MD) and diets rich in omega-3 polyunsaturated fatty acids (PUFAs). Methods: A comprehensive literature search was conducted in the PubMed/Medline, Science Direct, and Scopus databases (1990–2025). English-language observational studies, clinical trials, and systematic reviews addressing the relationship between diet and dietary patterns and RA were included. Results: High consumption of red and processed meat, saturated and trans fats, sugary drinks, and gluten (in vulnerable individuals) is associated with increased RA risk and greater disease activity, partly through pro-inflammatory pathways and gut dysbiosis. In contrast, regular intake of olive oil, fatty fish rich in omega-3 polyunsaturated fatty acids, fruit juices, cocoa, certain fruits, and vitamin D appears protective and may reduce disease activity and symptom severity. Adherence to anti-inflammatory dietary patterns, particularly the Mediterranean diet and diets rich in omega-3 fatty acids, is consistently associated with a lower incidence of RA, reduced inflammatory markers, and improved clinical outcomes. However, most available studies are limited by small sample sizes, short duration, heterogeneous methodologies, and potential confounding by other lifestyle factors (e.g., smoking, obesity). Conclusions: Although an appropriate diet and dietary habits cannot replace pharmacological therapy, current knowledge supports the inclusion of an anti-inflammatory diet as an adjunct strategy in the prevention and management of RA. The relatively limited studies that have been conducted suggest that high-quality, large-scale, prospective studies are needed to prevent and treat RA. These studies should incorporate genetic, microbiome, and long-term clinical endpoints, so as to establish definitive dietary recommendations and allow for personalized nutritional interventions for patients with RA.

Introduction:Giant Cell Arteritis (GCA) and Polymyalgia Rheumatica (PMR) are autoimmune/autoinflammatory disorders presenting as acute inflammatory responses and are highly responsive to steroids. In this report, we aim to decipher the immune landscape including immune cell subpopulations, plasma cytokines, and small lipid mediators (LMs) at the very early stages of steroid treatment initiation in 4 distinct time points at: 0h (T1), 48h (T2), 96h (T3), and 24 weeks (T4). Patients and methods:Serum, plasma and peripheral blood mononuclear cells (PBMCs) were collected prospectively from 8 GCA and 6 PMR newly diagnosed patients. Sixteen healthy individuals served as controls (HC). Deep immunophenotyping by CyTOF was performed in PBMCs at T1-T3. A multiplex Luminex assay measured serum levels of 21 cytokines at T1 and T3. Levels of lipid mediators (LMs) were evaluated at T1, T3 and T4 with the LC-MS/MS method. Results:Total CD8+ T cells and DCs were decreased within 48-96 hours, following steroid treatment, while B-cells were increased at 48 hours. Further analysis of immune subpopulations containing the major cell types revealed different frequencies of distinct CD8+, CD4+, DCs, and B cell subtypes. Out of 21 cytokines/chemokines evaluated, only ITAC levels were decreased at T3. The ratio of pro/anti-inflammatory LMs was high at T1 in patients with either PMR or GCA. However, 6 months after steroid treatment it returned to normal in PMR patients, but remained high in GCA patients, providing the only discriminatory element between the two diseases. Conclusion:The rapid clinical improvement of GCA and PMR patients, following steroid treatment, is associated with immune cell type alterations, but it is poorly associated with plasma cytokine levels. Small lipid mediators can differentiate GCA and PMR patients. The persistently elevated levels of pro-inflammatory LMs might be related to the underlying residual tissue inflammation described in GCA. These preliminary results suggest that further studies in a larger patient cohort are required to validate these findings.

OBJECTIVES:To investigate the effect of treatment in a series of patients with Sjögren's disease (SjD) associated interstitial lung disease (ILD). METHODS:Twenty-four primary SjD-ILD patients, followed-up from October 2022 to June 2025 were included in the study. Based on clinical judgement, 12 received treatment for ILD, while 12 did not, following a "watch-and-wait" policy. Participants were evaluated in 2 time points with an interval of 24±6 months. ILD was diagnosed by HRCT according to Fleischner Society definitions, performed at baseline due to respiratory symptoms and/or abnormal pulmonary function tests. Spirometry and diffusing capacity for carbon monoxide (DLCO) were performed at both visits. Progression of ILD was defined as absolute decline of predicted forced vital capacity (FVC) ≥5%. RESULTS:The treatment regimens of 12 SjD-ILD patients who received treatment included rituximab, mycophenolate mofetil, azathioprine and tocilizumab. The treated group displayed higher extent of ILD on HRCT at baseline visit (median: 20% vs. 10%, p=0.006), more frequently findings of small airways disease on HRCT (58% vs. 8%, p=0.027) and tended to present lower FVC (mean: 81.3% vs. 96.7%, p=0.086) compared to the untreated. FVC and DLCO remained stable between baseline and follow-up visit in both groups. However, the change in DLCO between the two visits was worse in the treated than untreated patients (mean: -11.2% vs. 4.8%, p=0.003). The number of SjD-ILD patients presenting progression of ILD did not differ between the two groups (25% vs. 33%, p=0.999). CONCLUSIONS:SjD-ILD clinical course is variable, with the most aggressive form to be controlled by immunosuppressive treatment.

Sjögren’s is a chronic autoimmune disease affecting exocrine glands and is subclassified into SSA-positive (SSA+) and SSA-negative (SSA-) subtypes, with a complex diagnostic journey and an average diagnostic delay of almost 4 years. While SSA+ cases can be detected via serological testing, current assays lack specificity. For SSA-patients, no non-invasive diagnostic tools exist, and diagnosis often requires invasive lip biopsy. A saliva-based liquid biopsy capable of diagnosing both subtypes is therefore of high clinical interest. However, saliva poses challenges due to its abundant oral microbiome, which complicates unbiased biomarker discovery. In this study, we present a novel RNA sequencing workflow that efficiently depletes microbial content, enabling deep profiling of long RNAs within salivary extracellular vesicles (EVs). This approach identified both known and novel RNA biomarkers capable of diagnosing SSA+ and SSA-subtypes with high sensitivity and specificity. Moreover, we uncovered distinct RNA signatures that allow molecular stratification of Sjögren’s subtypes. Pathway analysis in SSA+ cases revealed enrichment of immune and glandular pathways consistent with prior tissue-based studies, supporting the utility of salivary EVs as a non-invasive surrogate for tissue biopsy. Importantly, our data provides new molecular insights into the under-characterized SSA-subtype, laying the foundation for future mechanistic studies and facilitating their broader inclusion in clinical trials. ### Competing Interest Statement The authors have declared no competing interest.

Background: Sjögren's disease (SjD) is a complex systemic autoimmune disease with substantial morbidity and 21 known genetic associations. The International Sjögren's Genetics Network (SGENE) is a growing international collaboration focused on understanding how genetic variants influence SjD pathology. As sample sizes increase, we are focusing our efforts on the analyses of clinical subsets, which few studies have done. Objectives: Our genome-wide association study (GWAS) aimed to identify additional risk loci of genome-wide significance (GWS, p<5E-08; suggestive, p<5x10E-5) in European-derived subsets of SjD. Methods: This study was conducted with IRB/EC approvals. All SjD patients met the 2002 AECG criteria for SjD. A total of 5058 cases and 25943 controls were genotyped on GWAS arrays. After QC, 4855 cases and 25408 controls were included in the analyses. Logistic regression was calculated, adjusting for ancestry using the first 4 principal components to identify SjD-associated SNPs. Cases were split into Ro/SSA+ (n=2898) and Ro/SSA- (n=1313), and analyzed vs. each other, controls, and all-SjD. Results: We observed many differences in the genomic architecture of Ro/SSA- compared to Ro/SSA+ and all SjD (Figure 1a,b), most notably, a complete loss of the significance of the association with MHC on chromosome 6 in the Ro/SSA- cases(Figure 1b). The Ro/SSA+ subjects had a much stronger HLA association with OR ≈ 4 (Figure 1a), while the overall SjD showed OR ≈ 3. While none of the associations observed in the Ro/SSA- population reached GWS, 8 regions (near PLXNA2, PCDH7, IRF5-TNPO3, DLD, LOC100134229, JAK3, LOC643529, and TMTC1) show suggestive associations (Figure. 1a). Of these, only two, IRF5-TNPO3 and LOC643529, are also suggestive in the Ro/SSA+ subset. However, while the Ro/SSA+ have both the IRF5 promoter effect and the extended haplotype through TNPO3, the Ro/SSA- lack the IRF5 promoter effect. Interestingly, previous studies have shown that lupus and systemic sclerosis have both haplotypes while primary biliary cholangitis only has the haplotype extending into TNPO3, similar to Ro/SSA- SjD [1]. When comparing Ro/SSA- to the all-SjD dataset, PLXNA2 and LOC100134229 showed no association; PCDH7, DLD, and TMTC1 showed some association but did not reach suggestive levels; and LOC643529, IRF5-TNPO3, and JAK3 surpassed the suggestive threshold, the latter two nearing or surpassing GWS. Two of the novel suggestive associations in Ro/SSA- are particularly intriguing. PLXNA2 is a member of a semaphorin co-receptor family that mediates repulsive effects on axon pathfinding during nervous system development; interestingly, Ro/SSA- SjD has a higher frequency of neurological involvement. JAK3 is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction; it is predominantly expressed in immune cells. Mutations in this gene are associated with autosomal severe combined immunodeficiency disease. Novel drugs target the JAK-STAT pathways, making this finding markedly relevant. Conclusion: Our findings highlight the relevance of expanding genetic studies to specific subphenotypes of the disease. While we continue to increase our GWAS sample size and explore other subphenotypes, more work is needed to increase the power of these studies to determine if the suggestive regions will surpass the GWS threshold. REFERENCES: [1] Kottyan LC, et al. Hum Mol Genet. 2015 Jan 15;24(2):582-96. Acknowledgements: NIH/NIAMS R01 AR073855, P50 AR060804; NIH/NIDCR U01DE028891; Sjögren's Foundation; Jerome L. Greene Foundation. Disclosure of Interests: Astrid Rasmussen: None declared, Marcin Radziszewski: None declared, Bhuwan Khatri: None declared, Kandice L Tessneer: None declared, Elena Pontarini: None declared, Michele Bombardieri: None declared, Maureen Rischmueller: None declared, Marie Wahren-Herlenius: None declared, Marika Kvarnström: None declared, Torsten Witte: None declared, Hendrika Bootsma: None declared, Gwenny M. Verstappen: None declared, Frans G.M. Kroese: None declared, Arjan Vissink: None declared, Sarah Pringle: None declared, Athanasios Tzioufas: None declared, Clio Mavragani: None declared, Alan Baer Received consulting fees from Bristol Myers Squibb (BMS) and iCell Gene Therapeutics., Marta Alarcon-Riquelme: None declared, Javier Martin: None declared, Xavier Mariette: None declared, Gaetane Nocturne: None declared, Jacques-Olivier Pers: None declared, Jacques-Eric Gottenberg: None declared, Wan-Fai Ng I have consulted for Novartis, BMS, Janssen, Sanofi, Abbvie, IQVIA, Argenx, Resolve Therapeutics., Caroline Shiboski: None declared, Kimberly E Taylor: None declared, Lindsey Criswell: None declared, Blake M Warner: None declared, A Darise Farris Grant/research support from Johnson and Johnson Innovative Medicine (formerly Janssen; ended 12/31/2023)., Judith A. James: None declared, R Hal Scofield Received consulting fees from Johnson and Johnson Innovative Medicine (formerly Janssen) and Merk Pharmaceuticals., Joel M Guthridge: None declared, Daniel J Wallace: None declared, Swamy Venuturupali: None declared, Michael T Brennan: None declared, Juliana Imgenberg-Kreuz: None declared, Lars Ronnblom: None declared, Eva Baecklund: None declared, Maija-leena Eloranta: None declared, Lara A Aqrawi: None declared, Øyvind Palm: None declared, Johan G Brun: None declared, Daniel Hammenfors: None declared, Malin V Jonsson: None declared, Silke Appel: None declared, Sara Magnusson Bucher: None declared, Helena Forsblad-d'Elia: None declared, Thomas Mandl Employee of UCB., Per Eriksson: None declared, Gunnel Nordmark: None declared, Christopher J Lessard Grant/research support from Johnson and Johnson Innovative Medicine (formerly Janssen; ended 12/31/2023).

Background: The diagnosis of Sjogren’s disease (SjD) relies on clinical, serological, and functional tests combined with the evaluation of Focus Score (FS). The FS serves as the histopathological hallmark of the disease, characterized by the presence of one or more dense aggregates with 50 or more lymphocytes (focus), typically located in the periductal space. A minor salivary gland biopsy (MSG) can also provide valuable clinical information regarding prognosis of the disease and the potential presence of lymphoma. However, whether performing a second biopsy under specific clinical indications provides any useful clinical information remains still unknown. Objectives: The aim of this study is to assess whether the inflammatory infiltrate of the MSG and the clinical associated features change over time. This analysis may enhance our understating of the circumstances under which a second biopsy may be necessary. Methods: We retrospectively evaluated all patients who fulfilled the 2016 ACR/EULAR and underwent at least two minor salivary gland biopsies over time. Patients diagnosed with lymphoma at any timepoint during their disease course were excluded from the present study. The decision to perform a second biopsy was made according to physicians’ clinical judgement including new onset of clinical manifestations, exclusion of lymphoma, or abrupt reduction in saliva production. All first and second biopsies were re-evaluated by the same expert on MSG biopsy of SjD. Our analysis focused on assessing changes in the Focus Scores from the first to the second biopsy. Patients were divided into three categories based on the increase (>1), decrease (<1) or stability of FS. For the overall focus score comparison, the Wilcoxon matched-pairs signed ranked test was used while for the 3-group comparison the Kruskal-Wallis test. Results: In our histologic database of 1117 SjD patients, 132 individuals underwent 2 or more MSG biopsies. We excluded 51 patients with lymphoma diagnosis, resulting in 81 subjects eligible for the current analysis. The median biopsy time interval was 5,28 years (range 1-25 years). In 28 patients the focus score increased by at least 1 absolute point (group 1). In 14 patients decreased by at least 1 point (Group 2) and in 34 patients the FS remained relatively unchanged (Group 3). Overall, there was a statistically significant difference between the first and second biopsy in terms of the Focus Score (mean FS Value 1.61 vs. 2.4 respectively, p=0.0285) (Image). A statistically significant difference was also noted in FS at the first diagnostic biopsy between the three groups (Mean FS value Group 1:1,115, Group 2: 2.655 and Group 3: 1.02, P<0.0001). Exploring clinical and serologic parameters, the group exhibiting an elevated FS demonstrated a higher prevalence of Raynaud’s phenomenon (48.1% vs. 20.5%, p=0.04), while the group with decreased FS showed higher frequency of cryoglobulinemia (33,3% vs 0%, p=0,03), lower C4 hypocomplementemia (58,3% vs 18,1%, p=0,03) and less arthralgias (21,4% vs 55,8% p=0,05) compared to patients with a second stable FS. Conclusion: Sequential biopsy data suggest that the focus score may change across time implying a potential correlation with key clinical characteristics of the disease. Initial analyses suggest that patients with a lower focus score in the second biopsy began with a higher starting point and exhibited more cryoglobulinemia along with lower C4 levels. These observations raise considerations about the potential influence of treatment selection on the reduction of the focus score. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: None declared.Figure 1