"An update on the approach to treatment of Sjogren's Disease in pregnancy".

BACKGROUND: Women with Sjögren's Disease are more likely to experience pregnancy complications compared to their counterparts without the disease. Attention to detail and familiarity with the most recent research and guidelines in this field are required to achieve optimal maternal and fetal outcomes. Such complications include pregnancy induced hypertension, fetal growth restriction, thromboembolic events, and preterm delivery. Among the most life-threatening sequela of maternal Sjogren's Disease is fetal autoimmune congenital heart block (ACHB), which has high potential to cause intrauterine fetal death, neonatal mortality, developmental delay, and other long-term pediatric complications. Currently, surveillance with weekly echocardiograms and obstetric sonograms in the second trimester are recommended to screen for ACHB with the goal of early detection and intervention before progression from first- or second- of heart block to complete heart block. OBJECTIVE: We describe a case of maternal Sjogren's Disease, which prompted us to raise questions regarding the optimal frequency of obtaining fetal echocardiograms, and the ideal management in case a prolonged PR interval was to be found. We use this case to provide a springboard for discussion on updated antenatal management strategies for ACHB prevention. METHODS: To conduct this analysis, we searched PubMed for articles published over the last 10 years, with attention focused on articles written since 2016. Additionally, updated guidelines by other specialties such as Rheumatology, Cardiology and Pediatrics on this issue were reviewed. RESULTS: Thorough search of the literature yielded several meta-analyses concurring that the mothers with Sjogren's Disease had increased rates of premature birth, pregnancy induced hypertension, increased risks of delivering infants with intrauterine growth restriction (IUGR), with the most life-threatening risk being that of congenital heart block. Literature supporting prophylactic hydroxychloroquine and the use of steroids to reverse or halt the progression of congenital heart block at the time of diagnoses appeared at the forefront of search results. CONCLUSION: Pregnant women with SS have an increased risk for complications such as intrauterine growth restriction, thromboembolic events, pregnancy-induced hypertension, preterm delivery, and cesarean delivery and should prioritize obtaining pre- or peri-conceptional counseling. In women with anti SSA/SSB antibodies, a medication regimen should be considered with the object of decreasing the concentration of these antibodies, and hence decrease the risks of ACHB. Current literature supports the inclusion of hydroxychloroquine for this purpose, even prior to conception. Although the most recent studies recommend against prophylactic use of steroids, their potential to prevent progression to complete block should be weighed against their potential negative effects. Short and long-term treatment with corticosteroids has been associated with increased maternal risk of infection, weight gain, osteonecrosis, hypertension and bone mineral density disorders. Intrauterine growth restriction, oligohydramnios, and adrenal suppression have been among the fetal risks associated with steroids while improved infant survival or decreased need for pacing have not been demonstrated. Management of these pregnancies is complex and should include a multidisciplinary approach involving a maternal-fetal medicine sub-specialist, a rheumatologist, a pediatrician, a neonatologist, and the patient herself with her family in a model of shared decision-making.

Association between interleukin-12 p40 subunit and risk of primary Sjögren's syndrome: a Mendelian randomization study.

OBJECTIVES: Interleukin-12 (IL-12) signalling was proposed in the immunopathogenesis of primary Sjögren's disease. The efficacy of therapies targeting this pathway is currently unclear. Herein, we investigated the associations between circulating proteins involved in the IL-12 and IL-23 signalling pathways on primary Sjögren's disease using mendelian randomization. METHODS: We selected SNPs from protein quantitative trait loci of IL12A, IL12B, IL12Rß1, IL12Rß2, and IL23R to examine the association between alterations in their levels and risk of primary Sjögren's disease. Genetic association data for proteins were taken from studies ranging from 3,301-54 306 in sample size, and from 3,232 cases of primary Sjögren's disease and 17 481 controls. The Wald ratio or inverse variance weighted methods estimated causal effects. We applied colocalization and pleiotropy-robust methods as sensitivity analyses for confounding. RESULTS: There was a negative association between genetically predicted IL-12p40 (encoded by IL12B) and primary Sjögren's disease. In the two independent exposure datasets odds ratio (OR) 0.79 (95% confidence interval [CI] 0.68-0.93; P-value = 0.004) and OR 0.86 (95% CI 0.78-0.95; P-value = 0.003) per standard deviation decrease in genetically predicted IL-12p40. Neither IL-12Rß2 and IL-23R met the threshold P-value after MR analyses (P-value < 0.01) for colocalization assessment. No variants for the IL12A gene met prerequisite thresholds for weak instrument bias. CONCLUSION: This study provides genetic evidence that IL-12p40 has a causal role in primary Sjögren's disease pathogenesis. Our data suggest that decreasing levels of IL-12p40 may be deleterious. We would not suggest selecting this drug target as a therapeutic option.

Outcomes from a Multidisciplinary Otolaryngology and Rheumatology Clinic for the Management of Chronic Sialadenitis.

OBJECTIVE: Determine the outcomes in children with recurrent sialadenitis after establishment of a multidisciplinary pediatric otolaryngology and rheumatology clinic. STUDY DESIGN: Retrospective review. SETTING: Single-center tertiary medical center. METHODS: We reviewed all children presenting to a multidisciplinary pediatric otolaryngology/rheumatology clinic with recurrent parotitis between December 2019 and April 2023. RESULTS: Thirty-three children presented with recurrent parotitis to a multidisciplinary clinic. Seventy-seven percent of those with childhood Sjögren's disease (cSjD) had xerophthalmia, and 67% had xerostomia. The cSjD group was more likely to have both abnormal parotid and submandibular findings when compared to the non-cSjD group (P < .001). Sixteen percent of the cSjD group had a positive SSA/SSB autoantibody and 47% were antinuclear antibody positive. Fifty percent of the cSjD cohort had a focus score of ≥1 from a minor salivary gland biopsy. There were no significant differences from sialendoscopy outcome between the 2 groups. Seventy percent with juvenile recurrent parotitis showed partial response (PR) or complete response (CR) to sialendoscopy. In the cSjD cohort 3 (27%) reported a CR and 5 (45%) reported a PR. In the non csSjD cohort 5 (42%) reported a CR and 3 (25%) reported a PR. Ten of the 12 cSjD patients on hydroxychloroquine have shown symptom improvement. CONCLUSION: The establishment of a multidisciplinary otolaryngology and rheumatology clinic can provide a more comprehensive evaluation and treatment of the child with recurrent or persistent parotitis than from a regular ENT clinic.

Screening for autoimmune diseases in apparently healthy antinuclear antibody positive individuals.

Background: Anti-nuclear antibodies (ANA) assessed by immunofluorescence (IF) microscopy are associated with systemic autoimmune rheumatic diseases (SARD) and can be detected years before onset of clinical symptoms. Recent data indicate dysregulation of the immune system with increased levels of proinflammatory cytokines, including type I interferons (IFN), in ANA-positive versus ANA-negative individuals. Herein, the aims were to investigate IF-ANA, ANA fine specificities, and IFN-α protein levels in relation to self-reported symptoms, as well as clinical signs, of SARD in a large group of healthy blood donors (HBD). Methods: Sera from 825 HBD (48.8% females) were included. IF-ANA was assessed, using HEp-2 cells, according to the routine at the accredited laboratory of Clinical Immunology, Linköping University Hospital. All samples were analyzed for IgG-ANA fine specificities using addressable laser bead assay (ALBIA) at the same laboratory. IFN-α was determined using ELISA. Antibody-positive individuals, and their sex- and age-matched antibody-negative controls, were asked to fill a questionnaire regarding symptoms associated with SARD. Results: In total, 130 HBD (15.8%) were positive with IF-ANA and/or ALBIA. Anti-U1RNP was significantly more common among women. Generally, self-reported symptoms correlated poorly with IF-ANA and/or ALBIA results. Two females with high levels of Ro60/SSA, Ro52/SSA and IFN-α reported mild sicca symptoms and were diagnosed with Sjögren's disease after clinical evaluation. Conclusion: A considerable proportion of apparently HBD are autoantibody positive, but without clear association to self-reported symptoms. Nevertheless, the combination of autoantibodies, relevant symptoms and high IFN-α levels identified the small proportion of individuals with SARD in the study population.

Clinical outcomes of NBF gel application in managing mucositis associated with xerostomia.

BACKGROUND: Xerostomia, or dry mouth, can be a temporary or persistent symptom resulting from various factors, such as medication use, therapeutic radiation, chemotherapy, autoimmune conditions (e.g., Sjögren's syndrome), and hormonal imbalances. Xerostomia often leads to associated mucositis, which significantly impacts patients' quality of life. The nano-bio-fusion (NBF) gingival gel, a gel-type functional toothpaste containing vitamins C, E, propolis, and herbal extracts in a nano-emulsion state, has shown potential in accelerating the healing of oral mucosal lesions. METHODS: A total of 127 patients (102 females, 25 males) with persistent xerostomia were treated from 2018 to 2023. Of these, 32 patients were treated exclusively with NBF Gel, while 95 patients received NBF Gel in combination with other medications, such as pilocarpine. The underlying causes of xerostomia included irradiation and chemotherapy (12 patients), medication (40 patients), hormonal imbalance (28 patients), and Sjögren's syndrome (47 patients). NBF Gel was applied 2-3 times daily to the tongue and oral mucosa. Treatment effectiveness was evaluated through physical examinations and a patient-reported scale ranging from 1 (no improvement) to 10 (complete improvement), focusing on the healing of mucosal lesions rather than saliva production. RESULTS: Both treatment groups showed significant improvements in the healing of xerostomia-associated mucositis, particularly in severe cases with visible lesions. Patients treated with NBF Gel reported improved symptoms related to mucosal health, while those who received combination therapy also experienced reduced side effects of pilocarpine due to dose reduction. The most substantial improvements were observed in patients with drug-induced and hormonally-caused xerostomia-related mucositis. No adverse side effects from NBF Gel were reported during the study. CONCLUSION: NBF gingival gel proved to be beneficial in accelerating the healing of mucositis associated with xerostomia, regardless of the underlying cause, including medication use, radiotherapy, chemotherapy, hormonal imbalances, and Sjögren's syndrome. It presents a promising adjunctive treatment to improve mucosal health and quality of life for patients suffering from xerostomia-associated mucositis.

Syndecan-1 Plays a Role in the Pathogenesis of Sjögren's Disease by Inducing B-Cell Chemotaxis through CXCL13-Heparan Sulfate Interaction.

In Sjögren's disease (SjD), the salivary glandular epithelial cells can induce the chemotaxis of B cells by secreting B-cell chemokines such as C-X-C motif chemokine ligand 13 (CXCL13). Syndecan-1 (SDC-1) is a major transmembrane heparan sulfate proteoglycan (HSPG) predominantly expressed on epithelial cells that binds to and regulates heparan sulfate (HS)-binding molecules, including chemokines. We aimed to determine whether SDC-1 plays a role in the pathogenesis of SjD by acting on the binding of HS to B-cell chemokines. To assess changes in glandular inflammation and SDC-1 concentrations in the submandibular gland (SMG) and blood, female NOD/ShiLtJ and sex- and age-matched C57BL/10 mice were used. In the SMG of NOD/ShiLtJ mice, inflammatory responses were identified at 8 weeks of age, but increased SDC-1 concentrations in the SMG and blood were observed at 6 weeks of age, when inflammation had not yet started. As the inflammation of the SMG worsened, the SDC-1 concentrations in the SMG and blood increased. The expression of the CXCL13 and its receptor C-X-C chemokine receptor type 5 (CXCR5) began to increase in the SMG at 6 weeks of age and continued until 12 weeks of age. Immunofluorescence staining in SMG tissue and normal murine mammary gland cells confirmed the co-localization of SDC-1 and CXCL13, and SDC-1 formed a complex with CXCL13 in an immunoprecipitation assay. Furthermore, NOD/ShiLtJ mice were treated with 5 mg/kg HS intraperitoneally thrice per week for 6-10 weeks of age, and the therapeutic effects in the SMG were assessed at the end of 10 weeks of age. NOD/ShiLtJ mice treated with HS showed attenuated salivary gland inflammation with reduced B-cell infiltration, germinal center formation and CXCR5 expression. These findings suggest that SDC-1 plays a pivotal role in the pathogenesis of SjD by binding to CXCL13 through the HS chain.

Type I Interferons in Systemic Autoimmune Rheumatic Diseases: Pathogenesis, Clinical Features and Treatment Options.

Type I interferon (IFN) pathway dysregulation plays a crucial role in the pathogenesis of several systemic autoimmune rheumatic diseases (SARDs), including systemic lupus erythematosus (SLE), Sjögren's disease (SjD), systemic sclerosis (SSc), dermatomyositis (DM) and rheumatoid arthritis (RA). Genetic and epigenetic alterations have been involved in dysregulated type I IFN responses in systemic autoimmune disorders. Aberrant type I IFN production and secretion have been associated with distinct clinical phenotypes, disease activity, and severity as well as differentiated treatment responses among SARDs. In this review, we provide an overview of the role of type I IFNs in systemic autoimmune diseases including SLE, RA, SjD, SSc, and DM focusing on pathophysiological, clinical, and therapeutical aspects.

Bronchiolar adenoma/ciliated muconodular papillary tumor complicated by lymphoid interstitial pneumonia in a patient with Sjögren's disease: A case report and systematic review.

Bronchiolar adenoma (BA)/ciliated muconodular papillary tumor (CMPT) is a rare pulmonary neoplasm, with less than 150 cases documented in the literature. We report a unique case of BA/CMPT complicated by lymphoid interstitial pneumonia (LIP) in a 55-year-old male with Sjögren's disease. This is the first documented instance of such a comorbidity. Through a systematic review of PubMed, we also summarize the demographic, clinical, radiological, histopathological, and treatment characteristics of CMPT.

Corneal Epithelial Thickness in Sjogren's Disease: A Pilot Study.

Purpose: This study was to assess corneal epithelial thickness (CET) in patients with Sjogren's disease (SjD). Methods: A retrospective chart review was conducted of SjD patients from September 2021 to January 2022. Patient demographics, unanesthetized Schirmer's test, serologic markers, and symptoms as measured by the Ocular Surface Disease Index (OSDI) were reviewed. Epithelial thickness from both eyes was measured using anterior segment OCT at the central 3mm and concentric 5mm, 7mm, and 9mm zones for the superior, temporal, inferior, and nasal corneal quadrants. Associations between corneal epithelial thickness with patient demographics, clinical characteristics, and symptoms were evaluated using regression models. Results: Fifteen SjD patients (100% female) were included with a mean age of 58.4 years. Patients with Sjogren's disease had a significantly thinner superior corneal epithelium compared to the inferior epithelium (mean 47.7mm vs 53.1mm, p = 0.001). The epithelial thickness mean standard deviation (MSD) was significantly inversely correlated with the unanesthetized Schirmer test (r=-0.39, p = 0.005), suggesting that an overall variability of CET correlates with decreased aqueous tear production. SS-A, SS-B, ANA, and RF positivity were not associated with any measures of CET. Conclusion: This pilot study suggests that there is significant superior versus inferior thinning of corneal epithelium in Sjogren's patients. There was a significant correlation between variability of corneal epithelial thickness and decreased tear production in Sjogren's patients. Further larger studies are needed to understand the relationship of CET with objective and subjective measurements of ocular surface disease.

Altered characteristics of regulatory T cells in target tissues of Sjögren's syndrome in murine models.

SjÓ§gren's syndrome (SS), also known as Sjögren's disease, is a chronic autoimmune condition predominantly affecting the salivary and lacrimal glands. The disease is driven by autoimmune responses involving the activation and actions of major innate- and adaptive immune cell subsets. However, the specific characteristics and roles of regulatory T cells (Tregs) in SS remain elusive. This study seeks to clarify the main phenotypic and functional attributes of Tregs in the salivary glands and their draining lymph nodes in murine models of SS. Our flow cytometric analysis revealed that Tregs in the salivary gland-draining lymph nodes of female non-obese diabetic (NOD) mice, a spontaneous model of SS, exhibited a greater proportion of activated Tregs and fewer resting Tregs compared to Balb/c mice. Furthermore, Tregs from the salivary gland-draining lymph nodes of female C57BL/6.NOD-Aec1Aec2 (B6.NOD-Aec) mice, a model for primary SS, demonstrated significantly lower IL-10 production but markedly higher IFNγ- and IL-17 production than their C57BL/6 counterparts. Additionally, treatment of C57BL/6 Tregs with IL-7, a cytokine critical for SS pathogenesis, resulted in diminished IL-10 production and enhanced IFNγ and IL-17 production in these cells. Notably, the alterations in B6.NOD-Aec Tregs also included an increased expression of the immune-inhibitory molecule CTLA-4 compared to the C57BL/6 Tregs. Intriguingly, in vitro co-cultures of Tregs with conventional CD4 T cells and other key immune populations from lymph nodes indicated that Tregs from salivary gland-draining lymph nodes of both B6.NOD-Aec and C57BL/6 strains exhibited comparable and limited immunosuppressive effects on the proliferation and function of conventional CD4 T cells. The ability of B6.NOD-Aec Tregs to directly inflict damages to salivary gland epithelial tissues and contribute to SS pathologies through IFNγ and IL-17 that they produce warrants further investigations. In addition, enhancing the relatively weak immunosuppressive capacities of these Tregs may also serve as a viable strategy to alleviate the SS phenotype in the mouse models and potentially in patients.

Diffuse Cystic Lung Disease: A Clinical Guide to Recognition and Management.

TOPIC IMPORTANCE: Diffuse cystic lung diseases (DCLDs) represent a group of pathophysiologically heterogeneous entities that share a common radiologic phenotype of multiple thin-walled pulmonary cysts. DCLDs differ from the typical fibroinflammatory interstitial lung diseases in their epidemiology, clinical presentation, molecular pathogenesis, and therapeutic approaches, making them worthy of a distinct classification. The importance of timely and accurate identification of DCLDs is heightened by the impact on patient management including recent discoveries of targeted therapeutic approaches for some disorders. REVIEW FINDINGS: This article offers a practical framework for evaluating patients with DCLD, indicating the most appropriate and current diagnostic and management approaches. We focus on the DCLDs that are most likely to be encountered by practicing pulmonologists: lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, Birt-Hogg-Dubé syndrome, and lymphoid interstitial pneumonia. Chest CT scan is the most informative noninvasive diagnostic modality to identify DCLDs. Thereafter, instituting a structured approach to high-yield associated factors (eg, medical, social, and family history; renal and dermatologic findings) increases the likelihood of identifying DCLDs and achieving a diagnosis. SUMMARY: Although the individual diseases that comprise the DCLD family are rare, taken together, DCLDs can be encountered more frequently in clinical practice than commonly perceived. An increased eagerness among general pulmonary physicians to recognize these entities, coupled with a practical and systematic clinical approach to examinations and investigations, is required to improve case findings, allow earlier intervention, and reduce morbidity and mortality.

Connecting salivary gland inflammation to specific symptoms in Sjögren's disease.

INTRODUCTION: The complex nature of Sjögren's Disease (SjD) necessitates a comprehensive and patient-centered approach in both diagnosis and management. This narrative review emphasizes the need for a holistic understanding of the connection between salivary gland inflammation and oral symptoms in SjD. AREAS COVERED: The intricate relationship between salivary gland inflammation and dry mouth is explored, highlighting the variability in associations reported in studies. The association of the severity of xerostomia and degree of inflammation is also discussed. The frequent presence of recurrent sialadenitis in SjD further accentuates the connection of compromised salivary gland function and inflammation. The review additionally discusses local inflammatory factors assessed through salivary gland biopsies, which could potentially serve as predictors for lymphoma development in SjD. Insights into compromised quality of life and hypercoagulable state and their association with salivary gland inflammations are provided. Advancements in noninvasive imaging techniques, particularly salivary gland ultrasonography and color Doppler ultrasound, offer promising avenues for noninvasive assessment of inflammation. EXPERT OPINION: There is a need for longitudinal studies to unravel the connections between salivary gland inflammation and oral symptoms. This will enhance management strategies and optimize treatment outcomes for SjD patients.

Tailoring the treatment of inflammatory rheumatic diseases by a better stratification and characterization of the clinical patient heterogeneity. Findings from a systematic literature review and experts' consensus.

Inflammatory rheumatic diseases are different pathologic conditions associated with a deregulated immune response, codified along a spectrum of disorders, with autoinflammatory and autoimmune diseases as two-end phenotypes of this continuum. Despite pathogenic differences, inflammatory rheumatic diseases are commonly managed with a limited number of immunosuppressive drugs, sometimes with partial evidence or transferring physicians' knowledge in different patients. In addition, several randomized clinical trials, enrolling these patients, did not meet the primary pre-established outcomes and these findings could be linked to the underlying molecular diversities along the spectrum of inflammatory rheumatic disorders. In fact, the resulting patient heterogeneity may be driven by differences in underlying molecular pathology also resulting in variable responses to immunosuppressive drugs. Thus, the identification of different clinical subsets may possibly overcome the major obstacles that limit the development more effective therapeutic strategies for these patients with inflammatory rheumatic diseases. This clinical heterogeneity could require a diverse therapeutic management to improve patient outcomes and increase the frequency of clinical remission. Therefore, the importance of better patient stratification and characterization is increasingly pointed out according to the precision medicine principles, also suggesting a new approach for disease treatment. In fact, based on a better proposed patient profiling, clinicians could more appropriately balance the therapeutic management. On these bases, we synthetized and discussed the available literature about the patient profiling in regard to therapy in the context of inflammatory rheumatic diseases, mainly focusing on randomized clinical trials. We provided an overview of the importance of a better stratification and characterization of the clinical heterogeneity of patients with inflammatory rheumatic diseases identifying this point as crucial in improving the management of these patients.

[Sjögren's disease: From pathophysiology to treatment]. / Maladie de Sjögren : de la physiopathologie aux avancées thérapeutiques.

Sjögren's disease (SjD) is a systemic autoimmune disorder characterized by a triad of key symptoms affecting almost all patients (salivary and lacrimal dryness, pain and fatigue) and extra-glandular systemic involvement affecting one to two-thirds of patients. Over the past decade, knowledge of the epidemiology, classification criteria, assessment of systemic activity and symptoms presented by patients has grown. In addition, advances in understanding the pathophysiology of SjD have enabled a more targeted therapeutic approach. Current management of SjD is based on EULAR treatment guidelines. But since these recommendations, new drugs targeting specific pathophysiological pathways of the disease, and essentially B lymphocyte activation, have shown efficacy in phase 2 trials. In this review, we will summarize the available evidence on systemic therapies, including: 1. advances in outcome assessment, 2. current evidence on targeted disease-modifying therapies and biologic drugs targeting primarily B lymphocytes, 3. an overview of promising drugs being tested in ongoing trials.

Title: Maladie de Sjögren : de la physiopathologie aux avancées thérapeutiques. Abstract: La maladie de Sjögren (SjD) est une maladie auto-immune systémique caractérisée par une triade de symptômes clés affectant presque tous les patients (sécheresse salivaire et lacrymale, douleur et fatigue) et une atteinte systémique extra-glandulaire pouvant toucher un à deux tiers des patients. Au cours de la dernière décennie, les connaissances sur l'épidémiologie, les critères de classification, l'évaluation de l'activité systémique et des symptômes présentés par les patients se sont développés. En outre, les progrès réalisés dans la compréhension de la physiopathologie du SjD ont permis d'adopter une approche thérapeutique plus ciblée. La prise en charge actuelle du SjD s'appuie sur les recommandations thérapeutiques de l'EULAR. Mais depuis ces recommandations, de nouveaux médicaments ciblant des voies physiopathologiques spécifiques de la maladie, et essentiellement l'activation du lymphocyte B, ont montré une efficacité dans des essais de phase 2. Dans cette revue, nous résumerons les données factuelles disponibles sur les traitements systémiques, y compris : 1. les progrès dans l'évaluation des résultats, 2. les preuves actuelles concernant les traitements de fond ciblés et les biomédicaments ciblant essentiellement les lymphocytes B, 3. une vue d'ensemble des médicaments prometteurs testés dans les études en cours.

Ro60-Roles in RNA Processing, Inflammation, and Rheumatic Autoimmune Diseases.

The Ro60/SSA2 autoantigen is an RNA-binding protein and a core component of nucleocytoplasmic ribonucleoprotein (RNP) complexes. Ro60 is essential in RNA metabolism, cell stress response pathways, and cellular homeostasis. It stabilises and mediates the quality control and cellular distribution of small RNAs, including YRNAs (for the 'y' in 'cytoplasmic'), retroelement transcripts, and misfolded RNAs. Ro60 transcriptional dysregulation or loss of function can result in the generation and release of RNA fragments from YRNAs and other small RNAs. Small RNA fragments can instigate an inflammatory cascade through endosomal toll-like receptors (TLRs) and cytoplasmic RNA sensors, which typically sense pathogen-associated molecular patterns, and mount the first line of defence against invading pathogens. However, the recognition of host-originating RNA moieties from Ro60 RNP complexes can activate inflammatory response pathways and compromise self-tolerance. Autoreactive B cells may produce antibodies targeting extracellular Ro60 RNP complexes. Ro60 autoantibodies serve as diagnostic markers for various autoimmune diseases, including Sjögren's disease (SjD) and systemic lupus erythematosus (SLE), and they may also act as predictive markers for anti-drug antibody responses among rheumatic patients. Understanding Ro60's structure, function, and role in self-tolerance can enhance our understanding of the underlying molecular mechanisms of autoimmune conditions.

Sicca syndrome/Sjögren's disease associated with cancer immunotherapy: a narrative review on clinical presentation, biomarkers, and management.

INTRODUCTION: Almost one-quarter of immune checkpoint inhibitor (ICI) recipients experience sicca syndrome, while Sjögren's disease (SjD) is estimated at 0.3-2.5%, possibly underreported. AREAS COVERED: This narrative review (Medline/Embase until January/31/2024) addresses the pathophysiology, incidence, demographic/clinical features, biomarkers, labial salivary gland biopsy (LSGB), fulfillment of the idiopathic SjD (iSjD) classificatory criteria, differential diagnosis, and management of sicca syndrome/SjD associated with ICIs. EXPERT OPINION: SjD associated with ICIs is underdiagnosed, since studies that performed the mandatory SjD investigation identified that 40-60% of patients with sicca syndrome associated with ICIs meet the iSjD classificatory criteria. LSGB played a fundamental role in recognizing these cases, as most of them had negative anti-Ro/SS-A antibody. Despite the finding of focal lymphocytic sialoadenitis in LSGB samples mimicking iSjD, immunohistochemical analysis provided novel evidence of a distinct pattern for sicca syndrome/SjD associated with ICIs compared to iSjD. The former has scarcity of B lymphocytes, which are a hallmark of iSjD. Additionally, patients with sicca syndrome/SjD associated with ICIs have demographical/clinical/serological and treatment response dissimilarities compared to iSjD. Dryness symptoms are more acute in the former than in iSjD, with predominance of xerostomia over xerophthalmia, and partial/complete response to glucocorticoids. Dryness symptoms in ICI-treated patients warrant prompt SjD investigation.

Hypocitraturia as a biomarker of renal tubular acidosis in patients with Sjögren's disease.

INTRODUCTION: Sjögren's disease (SD) is an immune-mediated chronic inflammatory disease that affects epithelial tissues, mainly salivary and lacrimal glands. It also presents extraglandular manifestations. The main renal manifestation is tubulointerstitial nephritis (TIN), which can manifest as renal tubular acidosis (RTA). Urinary citrate may be a biomarker of RTA in these patients. The objective of this study was to evaluate whether hypocitraturia is a predictive biomarker of RTA in a sample of patients with SD in a tertiary hospital in southern Brazil. METHODS: All patients with SD who met the inclusion criteria and who participated in the rheumatology outpatient clinic of the Irmandade Santa Casa de Misericórdia de Porto Alegre were included. Demographic, SD, serological and urinary data were obtained. RTA was considered in those patients who persistently presented urinary pH above 5.5 and serum pH below 7.35. Patients who persistently had urinary pH above 5.5 underwent a urinary acidification test with furosemide and fludrocortisone. These patients received 1 mg of fludrocortisone and 40 mg of furosemide and had their urine samples tested 2, 4 and 6 h after taking the medications. The test was stopped at any urine sample with pH 5.5 or less. The variables were expressed as mean and standard deviation or interquartile range. The association between hypocitraturia and RTA was assessed using the chi-square. RESULTS: Forty-two patients were included, 95.2% female with a median age of 61.73 years. The prevalence of complete distal RTA was 4.88%. Twenty-eight patients underwent urine acidification testing. Five patients had hypocitraturia, and two of them had complete distal RTA. The association between hypocitraturia and RTA was statistically significant (p < 0.012), with a sensitivity of 100%, specificity of 91.2% and accuracy of 91.7%. The negative predictive value was 100%. The global renal assessment of the population demonstrated two patients with RTA, one patient with decreased renal function and six patients with proteinuria greater than 0.5 g/24 h. CONCLUSION: The prevalence of RTA in the studied population was 4.88%. Hypocitraturia had high sensitivity and accuracy for the diagnosis of RTA.

Deleting Mitochondrial Superoxide Dismutase 2 in Salivary Gland Ductal Epithelial Cells Recapitulates Non-Sjögren's Sicca Syndrome.

Elevated oxidative stress can play a pivotal role in autoimmune diseases by exacerbating inflammatory responses and tissue damage. In Sjögren's disease (SjD), the contribution of oxidative stress in the disease pathogenesis remains unclear. To address this question, we created mice with a tamoxifen-inducible conditional knockout (KO) of a critical antioxidant enzyme, superoxide dismutase 2 (Sod2), in the salivary glands (i-sg-Sod2 KO mice). Following tamoxifen treatment, Sod2 deletion occurred primarily in the ductal epithelium, and the salivary glands showed a significant downregulation of Sod2 expression. At twelve weeks post-treatment, salivary glands from the i-sg-Sod2 KO mice exhibited increased 3-Nitrotyrosine staining. Bulk RNA-seq revealed alterations in gene expression pathways related to ribosome biogenesis, mitochondrial function, and oxidative phosphorylation. Significant changes were noted in genes characteristic of salivary gland ionocytes. The i-sg-Sod2 KO mice developed reversible glandular hypofunction. However, this functional loss was not accompanied by glandular lymphocytic foci or circulating anti-nuclear antibodies. These data demonstrate that although localized oxidative stress in salivary gland ductal cells was insufficient for SjD development, it induced glandular dysfunction. The i-sg-Sod2 KO mouse resembles patients classified as non-Sjögren's sicca and will be a valuable model for deciphering oxidative-stress-mediated glandular dysfunction and recovery mechanisms.

SLIRP promotes autoimmune diseases by amplifying antiviral signaling via positive feedback regulation.

The abnormal innate immune response is a prominent feature underlying autoimmune diseases. One emerging factor that can trigger dysregulated immune activation is cytosolic mitochondrial double-stranded RNAs (mt-dsRNAs). However, the mechanism by which mt-dsRNAs stimulate immune responses remains poorly understood. Here, we discover SRA stem-loop interacting RNA binding protein (SLIRP) as a key amplifier of mt-dsRNA-triggered antiviral signals. In autoimmune diseases, SLIRP is commonly upregulated, and targeted knockdown of SLIRP dampens the interferon response. We find that the activation of melanoma differentiation-associated gene 5 (MDA5) by exogenous dsRNAs upregulates SLIRP, which then stabilizes mt-dsRNAs and promotes their cytosolic release to activate MDA5 further, augmenting the interferon response. Furthermore, the downregulation of SLIRP partially rescues the abnormal interferon-stimulated gene expression in autoimmune patients' primary cells and makes cells vulnerable to certain viral infections. Our study unveils SLIRP as a pivotal mediator of interferon response through positive feedback amplification of antiviral signaling.

IL-27 promotes pathogenic T cells in a mouse model of Sjögren's disease.

Sjögren's disease (SjD) is a chronic autoimmune disease characterized by focal lymphocytic inflammation in lacrimal and salivary glands. We recently identified IL-27 as a requisite signal for the spontaneous SjD-like manifestations in nonobese diabetic (NOD) mice. Here, we define T cell-intrinsic effects of IL-27 in lacrimal gland disease in NOD mice. IL-27 receptor was required by both CD4 T effector (Te) cells and CD8 T cells to mediate focal inflammation. Intrinsic IL-27 signaling was associated with PD-1 and ICOS expressing T follicular helper (Tfh)-like CD4 Te cells within lacrimal glands, including subsets defined by CD73 or CD39 expression. CD8 T cells capable of IL-27 signaling also expressed PD-1 with subsets expressing ICOS and CD73 demonstrating a T follicular cytotoxic (Tfc)-like cell phenotype and others expressing a CD39hi exhausted-like phenotype. These findings suggest IL-27 is a key early signal driving a follicular-type response in lacrimal gland inflammation in NOD mice.