Clinical Profile of Patients with Primary Sjögren's Syndrome with Non-Identified Antinuclear Autoantibodies.

Objectives-The aim of the present study was to characterize the clinical phenotype of patients with primary Sjögren's syndrome (pSS) with non-identified antinuclear antibodies (ANA) in comparison with that of patients with pSS with negative ANA, positive typical ANA (anti-Ro/SSA and/or La/SSB) and positive atypical ANA. Methods-We conducted an observational, retrospective monocentric study at the Erasme University Hospital (Brussels, Belgium). Two hundred and thirty-three patients fulfilling the 2002 American-European Consensus Group criteria for pSS were included in this study. The patients were subdivided according to their ANA profile and demographics. The clinical and biological data of each subgroup were compared. Moreover, the relationships between these data and the ANA profiles were determined by multiple correspondence analysis. Results-In our cohort, 42 patients (18%) presented a non-identified ANA-positive profile. No statistically significant difference could be observed between non-identified ANA patients and ANA-negative patients in terms of age and/or ESSDAI score at diagnosis. There were significantly more frequent articular manifestations, positive rheumatoid factor (RF), and the use of corticosteroids in anti-Ro/SSA-positive patients compared to ANA-negative (p ≤ 0.0001) and non-identified ANA-positive patients (p ≤ 0.01). However, a significantly higher proportion of RF positivity and corticosteroid treatment was observed in non-identified ANA-positive patients compared to ANA-negative patients (p < 0.05). Conclusions-For the first time to our knowledge, our study has characterized the clinical phenotype of patients with pSS with non-identified ANA at diagnosis. The non-identified ANA-positive patients featured mostly a clinical phenotype similar to that of the ANA-negative patients. On the other hand, the non-identified ANA-positive patients were mainly distinguished from the ANA-negative patients by a greater proportion of RF positivity and the need for corticosteroid use due to articular involvement.

Involvement of CCL2 in Salivary Gland Response to Hyperosmolar Stress Related to Sjögren's Syndrome.

In primary Sjögren's syndrome (pSS) patients, salivary gland (SG) epithelial cells (SGECs) could be exposed to chronic hyperosmotic stress (HOS), consecutive to their destruction and deregulation, that exacerbates an inflammatory response. The aims of this study were to assess the mechanism accounting for C-C motif chemokine ligand 2 (CCL2) expression in an immortalized human salivary gland epithelial acinar cell line (NS-SV-AC) subjected to HOS, as well as the involvement of CCL2 in pSS. CCL2 mRNA and protein levels were determined via RT-qPCR and ELISA. Reporter plasmids and a promoter pull-down assay were used to identify transcription factors associated with CCL2 mRNA increase. Our data showed that HOS-induced CCL2 mRNA increase was independent of the nuclear factor of activated T-cells 5 (NFAT5) and nuclear factor-kappa B (NFkB) but involved Kruppel-like factor 5 (KLF5). CCL2 protein levels, quantified by enzyme-linked immunosorbent assay (ELISA) in sera samples from pSS patients, correlated with the European Alliance of Associations for Rheumatology's Sjogren's syndrome disease activity index (ESSDAI) score for systemic activity. In addition, CCL2 protein levels were higher in patients with biological activity, cutaneous manifestations, and ESSDAI score superior or equal to five. Our data suggest that chronic HOS could exacerbate pSS disease by contributing to the inflammatory process induced by the expression and secretion of CCL2.

Neuromyelitis Optica: Pathogenesis Overlap with Other Autoimmune Diseases.

PURPOSE OF REVIEW: Neuromyelitis optica (NMO) is an auto-immune disease essentially depicted by optic neuritis and transverse myelitis. Per se, NMO was initially believed to be a sub-type of multiple sclerosis with typical demyelinating cerebral lesions and optic nerve inflammation. More recently, corroborating lignes of evidence have strengthened the concept of the spectrum of diseases associated with NMO and more specifically with the role of anti-aquaporin-4 antibodies in the pathogenesis of disease. RECENT FINDINGS: In this article, we review the recent pathogenic findings in NMO and more interestingly the newly discovered role of anti-aquaporin-4 antibodies as key players in triggering cerebral lesions. The concept of spectrum of diseases associated with NMO is also discussed. These recent findings have paved in the further understanding of the pathogenesis underlying NMO and new treatments are currently being developed targeting anti-aquaporin-4 antibodies.

Involvement of Epithelial-Mesenchymal Transition (EMT) in Autoimmune Diseases.

Epithelial-mesenchymal transition (EMT) is a complex reversible biological process characterized by the loss of epithelial features and the acquisition of mesenchymal features. EMT was initially described in developmental processes and was further associated with pathological conditions including metastatic cascade arising in neoplastic progression and organ fibrosis. Fibrosis is delineated by an excessive number of myofibroblasts, resulting in exuberant production of extracellular matrix (ECM) proteins, thereby compromising organ function and ultimately leading to its failure. It is now well acknowledged that a significant number of myofibroblasts result from the conversion of epithelial cells via EMT. Over the past two decades, evidence has accrued linking fibrosis to many chronic autoimmune and inflammatory diseases, including systemic sclerosis (SSc), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), and inflammatory bowel diseases (IBD). In addition, chronic inflammatory states observed in most autoimmune and inflammatory diseases can act as a potent trigger of EMT, leading to the development of a pathological fibrotic state. In the present review, we aim to describe the current state of knowledge regarding the contribution of EMT to the pathophysiological processes of various rheumatic conditions.

Adult-Onset Still's Disease (AOSD) Associated With Collagenous Colitis (CC) and Basedow's Disease: A Case Report.

Adult-onset Still's disease (AOSD) is a rare auto-inflammatory syndrome of unknown etiology. Basedow's disease is a common cause of auto-immune hyperthyroidism. Collagenous colitis (CC) is a form of microscopic colitis (MC) affecting predominantly young women. While the etiology of the disease remains unclear, some studies suggest the role of auto-immunity. The association between AOSD and Basedow's disease has been reported in previous cases, suggesting auto-inflammation as a potential trigger of relapsing thyroid dysfunction. Although the co-existence of AOSD with inflammatory gastrointestinal disorders such as Crohn's disease and ulcerative colitis has also been described, we did not find any correlation with MC in the literature. We here describe the case of a woman having AOSD associated with Basedow's disease and CC.

Intense Pulsed Light Therapy in the Treatment of Dry Eye Diseases: A Systematic Review and Meta-Analysis.

BACKGROUND: Intense pulsed light therapy (IPL) is a recently developed way of treating dry eye disease (DED). During the last decade, there was a multiplication of trials studying IPL efficacy. The goal of this review is to summarize the most important and significant results of these trials estimating effect sizes. METHODS: The PubMed and sciencedirect databases were searched using a PICO model-based approach. Randomized controlled trials including at least 20 patients with DED and no other eye condition, with a control group and break-up time or symptom scores data available for extraction were included in this review. Statistical analysis evaluated the tear break-up time (TBUT), non-invasive break-up time (NIBUT), ocular surface disease index (OSDI), and standard patient evaluation of eye dryness (SPEED). Three comparisons were carried on for each outcome: longest follow-up values vs. baseline in the treatment group, longest follow-up values in the treatment group vs. control group, and changes from baseline in the treatment group vs. control group. A subgroup analysis was carried on. RESULTS: Eleven randomized controlled trials, published between 2015 and 2021 were included in this systematic review with 759 patients in total. The longest follow-up values vs. baseline in the treatment group analyses were significantly in favor of IPL for all the parameters studied for instance: NIBUT (effect size (ES), 2.02; 95% confidence interval (CI), (1.43; 2.62)), TBUT (ES, 1.83; 95% CI, (0.96; 2.69)), OSDI (ES, -1.38; 95% CI, (-2.12; -0.64)) and SPEED (ES, -1.15; 95% CI, (-1.72; -0.57)). The longest follow-up values in the treatment group vs. control group analyses, and, the change from baseline in the treatment group vs. control group analyses, were both significantly in favor of IPL for NIBUT, TBUT, and SPEED but not for OSDI. CONCLUSIONS: IPL seems to have a positive effect on tear stability evaluated by the break-up times. However, the effect on DED symptoms is less clear. Some confounding factors such as the age and the IPL device used influence the results indicating that the ideal settings still need to be found and personalized for the patient.

Aquaporin-5 Dynamic Regulation.

Aquaporin-5 (AQP5), belonging to the aquaporins (AQPs) family of transmembrane water channels, facilitates osmotically driven water flux across biological membranes and the movement of hydrogen peroxide and CO2. Various mechanisms have been shown to dynamically regulate AQP5 expression, trafficking, and function. Besides fulfilling its primary water permeability function, AQP5 has been shown to regulate downstream effectors playing roles in various cellular processes. This review provides a comprehensive overview of the current knowledge of the upstream and downstream effectors of AQP5 to gain an in-depth understanding of the physiological and pathophysiological processes involving AQP5.

Involvement of aquaporin 5 in Sjögren's syndrome.

Sjögren's syndrome (SS) is a chronic autoimmune disease with the pathological hallmark of lymphoplasmacytic infiltration of exocrine glands - more specifically salivary and lacrimal glands - resulting in a diminished production of tears and saliva (sicca syndrome). The pathophysiology underscoring the mechanisms of the sicca symptoms in SS has still yet to be unraveled but recent advances have identified a cardinal role of aquaporin-5 (AQP5) as a key player in saliva secretion as well as salivary gland epithelial cell dysregulation. AQP5 expression and localization are significantly altered in salivary glands from patients and mice models of the disease, shedding light on a putative mechanism accounting for diminished salivary flow. Furthermore, aberrant expression and localization of AQP5 protein partners, such as prolactin-inducible protein and ezrin, may account for altered AQP5 localization in salivary glands from patients suffering from SS and are considered as new players in SS development. This review provides an overview of the role of AQP5 in SS salivary gland epithelial cell dysregulation, focusing on its trafficking and protein-protein interactions.

Waning humoral immunity of SARS-CoV-2 vaccination in a rheumatoid arthritis cohort and the benefits of a vaccine booster dose.

OBJECTIVES: We aimed to assess SARS-CoV-2 spike-specific antibody kinetics postvaccination and the benefit of a mRNA vaccine booster dose in rheumatoid arthritis (RA) patients treated with immunosuppressive drugs. METHODS: Consecutive RA patients on immunosuppressive therapies, with no known history of SARS-CoV-2 infection or high-risk contact, vaccinated with 2 doses SARS-CoV-2 mRNA, BNT162b2 or mRNA-1273, or viral vectored ChAdOx1 nCoV-19 vaccine were recruited during their routine rheumatology consultation. Anti-SARS-CoV-2 IgG spike-specific antibodies were quantified at 1, 3 and 6 months respectively following the second vaccine dose. The incidence of SARS-CoV-2 infection post-vaccination during this 6-month longitudinal study was also assessed. RESULTS: Of the 104 RA patients included, 79 patients completed the 6-month trial follow-up. A significant decrease in anti-SARS-CoV-2 spike-specific IgG titres was observed between 1-month and 3-month postvaccination (p<0.01). Among the 46 patients (46/79) receiving a booster dose, all developed detectable anti-SARS-CoV-2 spike-specific IgG antibodies at the 6-month follow-up with significantly higher titres compared to 1-month (p<0.001) and 3-month (p<0.0001) post-vaccination. Conversely, the antibody titres among the 33 patients (33/79) not receiving a booster dose decreased significantly at the 6-month follow-up compared to 1-month (p<0.0001) and 3-month (p<0.01) post-vaccination. The incidence of COVID-19 disease postvaccination was 8.9% without severe forms. CONCLUSIONS: To our knowledge, this is the first study to report on anti-SARS-CoV-2 spike-specific antibody kinetics postvaccination and the effect of a booster dose in a cohort of RA patients. The latter is essential given the waning humoral immunity observed in vaccinated RA patients and the increased incidence of COVID-19 diseases postvaccination in this 6-month longitudinal study.

Granulomatosis with Polyangiitis Overlapping with IgG4-Related Disease.

IgG4-related disease and granulomatosis with polyangiitis share several features as well as the presence of ANCA antibodies and serum IgG4 immunoglobulins. It is often difficult to distinguish between two entities. We hereby report the case of a patient portraying the clinical conundrum with clinical and biological features of the two diseases.

Aquaporins: Unexpected actors in autoimmune diseases.

Aquaporins (AQPs), transmembrane proteins allowing the passage of water and sometimes other small solutes and molecules, are involved in autoimmune diseases including neuromyelitis optica, Sjögren's syndrome and rheumatoid arthritis. Both autoantibodies against AQPs and altered expression and/or trafficking of AQPs in various tissue cell types as well as inflammatory cells are playing key roles in pathogenesis of autoimmune diseases. Detection of autoantibodies against AQP4 in the central nervous system has paved the way for a deeper understanding in disease pathophysiology as well as enabling diagnosis. This review provides a comprehensive summary of the roles of AQPs in autoimmune diseases.

The Involvement of Alarmins in the Pathogenesis of Sjögren's Syndrome.

Sjögren's syndrome (SS) is a chronic autoimmune disease that affects exocrine glands, primarily the salivary and lachrymal glands. It is characterized by lymphoplasmacytic infiltration of the glandular tissues, ultimately leading to their dysfunction and destruction. Besides classic dry eyes and dry mouth defined as sicca syndrome, patients affected by the disease also typically display symptoms such as fatigue, pain and in more than 50% of cases, systemic manifestations such as arthritis, interstitial lung involvement, neurological involvement and an increased risk of lymphoma. The pathophysiological mechanisms underlying SS still remain elusive. The crucial role of innate immunity has been advocated in recent years regarding the pathogenesis of pSS, especially in the initiation and progression toward autoimmunity. Alarmins are endogenous molecules that belong to the large family of damage associated molecular pattern (DAMP). Alarmins are rapidly released, ensuing cell injury and interacting with pattern recognition receptors (PRR) such as toll-like receptors (TLR) to recruit and activate cells of the innate immune system and to promote adaptive immunity responses. This review highlights the current knowledge of various alarmins and their role in the pathogenesis of pSS.

Involvement of IL-33 in the Pathophysiology of Systemic Lupus Erythematosus: Review.

IL-33 is a newly discovered cytokine displaying pleiotropic localizations and functions. More specifically, it also functions as an alarmin, following its release from cells undergoing cell death or necrosis, to alert the innate immune system. The role of IL-33 has been underlined in several inflammatory and autoimmune diseases including systemic lupus erythematosus (SLE). The expressions of IL-33 as well as its receptor, ST2, are significantly upregulated in SLE patients and in patients with lupus nephritis. This review discusses the involvement of IL-33 in the pathology of SLE.

Addressing the clinical unmet needs in primary Sjögren's Syndrome through the sharing, harmonization and federated analysis of 21 European cohorts.

For many decades, the clinical unmet needs of primary Sjögren's Syndrome (pSS) have been left unresolved due to the rareness of the disease and the complexity of the underlying pathogenic mechanisms, including the pSS-associated lymphomagenesis process. Here, we present the HarmonicSS cloud-computing exemplar which offers beyond the state-of-the-art data analytics services to address the pSS clinical unmet needs, including the development of lymphoma classification models and the identification of biomarkers for lymphomagenesis. The users of the platform have been able to successfully interlink, curate, and harmonize 21 regional, national, and international European cohorts of 7,551 pSS patients with respect to the ethical and legal issues for data sharing. Federated AI algorithms were trained across the harmonized databases, with reduced execution time complexity, yielding robust lymphoma classification models with 85% accuracy, 81.25% sensitivity, 85.4% specificity along with 5 biomarkers for lymphoma development. To our knowledge, this is the first GDPR compliant platform that provides federated AI services to address the pSS clinical unmet needs.

Histopathological Characteristics and Therapeutic Outcomes of Endoscopic Submucosal Dissection for Gastric High-Grade Intraepithelial Neoplasia.

Background: The endoscopic resection of suspected gastric high-grade intraepithelial neoplasia (HGIN) may incidentally cause the patient to suffer from early gastric cancer (EGC), complicating the subsequent clinical management. Identifying the risk factors for such misstaging may help guide the clinical management. Methods: The information obtained from 123,460 patients, who underwent conventional upper gastrointestinal endoscopy at the First Affiliated Hospital of Nanjing Medical University from January 2010 to December 2015, were retrospectively reviewed. Patients with an initial diagnosis of HGIN underwent endoscopic submucosal dissection (ESD), and received a final diagnosis of EGC. The risk factors for the upgraded pathology and noncurative resection were analyzed. Results: Among the 134 patients initially diagnosed with HGIN, 35 (26.12%) patients were finally diagnosed with EGC after ESD. A lesion size of ≥2 cm (odds ratio [OR] = 5.16, 95% confidence interval [CI] = 2.04-13.05; P < .01), ≤4 biopsies taken (OR = 2.73, 95% CI = 1.15-6.48; P < .05), and the presence of upper gastrointestinal bleeding (UGIB; OR = 15.64, 95% CI = 1.29-189.75; P < .05) were the independent risk factors for upgraded pathology. In addition, patients >65 years old (OR = 0.022, 95% CI = 0.901-6.549; P < .05) or with a lesion size of ≥2 cm (OR = 4.237, 95% CI = 1.650-10.878; P < .01) were more likely to endure the noncurative resection. Conclusion: For suspected gastric HGIN patients, age, lesion size, the number of biopsies, and UGIB should be taken into account before deciding on the ESD.

Assessment of sarcopenia in patients with fibromyalgia.

Fibromyalgia is a chronic disorder characterized by persistent widespread musculoskeletal pain. Patients with fibromyalgia have reduced physical activity and increased sedentary rate. The age-associated reduction of skeletal muscle mass and function is called sarcopenia. The European Working Group on Sarcopenia in Older People developed a practical clinical definition and consensus diagnostic criteria for sarcopenia. Loss of muscle function is common in fibromyalgia and in the elderly. The goal of this study is to determine whether the reduction of muscle function in fibromyalgia is related to sarcopenia according to the European Working Group on Sarcopenia in Older People criteria. Forty-five patients with fibromyalgia and thirty-nine healthy control female subjects were included. All the participants were assessed by Fibromyalgia Impact Questionnaire and SARC-F questionnaire. Muscle mass was evaluated by bioimpedance analysis, muscle strength by handgrip strength test and physical performance with the Short Physical Performance Battery. Fibromyalgia Impact Questionnaire and SARC-F scores were statistically significantly higher in the fibromyalgia group than in the control group, showing severe disease and a higher risk of sarcopenia in the fibromyalgia group (p < 0.001). Muscle strength and physical performance were statistically significantly lower in the group with fibromyalgia than in the control group (p < 0.001). There was no statistical difference between fibromyalgia and control groups regarding skeletal muscle mass (p = 0.263). Our study demonstrated a significant reduction in muscle function in fibromyalgia patients without any loss of muscle mass. Loss of muscle function without decrease in muscle mass is called dynapenia.

Soluble ST2 is increased in systemic lupus erythematous and is a potential marker of lupus nephritis.

OBJECTIVES: To investigate the role of the interleukin IL-33/ST2 axis in systemic lupus erythematosus (SLE). METHODS: Serum concentrations of IL-33 and sST2 were measured by sandwich ELISA in SLE patients (n=111) compared to sex- and age-matched healthy controls (n=36). The serum concentrations of IL-33 and sST2 were correlated with various clinical and biological parameters. The expressions of IL-33 and ST2L were investigated in kidney sections by immunohistochemistry in lupus nephritis patients (n=23) and controls (n=10). RESULTS: Serum levels of IL-33 were significantly higher in SLE patients (11.64±3.141 pg/mL) than in controls (1.043±0.8526 pg/mL) (p<0.0001). Similarly, the serum concentrations of sST2 were significantly higher in SLE patients (34.013±2.043 pg/mL) than in controls (25.278±2.258 pg/mL) (p=0.046). sST2, but not IL-33, correlated significantly with disease activity index (SLEDAI). In addition, serum levels of sST2 were significantly higher in patients with lupus nephritis (45.438±5.661 pg/mL) that in SLE patients without renal involvement (30.691±1.941 pg/mL) (p=0.016). The immunoreactivity of IL-33 in renal biopsies of patients with lupus nephritis was not increased compared to controls, while the glomerular expression of ST2L was significantly higher in nephritis patients compared to controls. CONCLUSIONS: Although IL-33 and sST2 levels are both increased in SLE, sST2 represents a surrogate marker of disease activity and complications of nephritis.

Ezrin Is a Novel Protein Partner of Aquaporin-5 in Human Salivary Glands and Shows Altered Expression and Cellular Localization in Sjögren's Syndrome.

Sjögren's syndrome (SS) is an exocrinopathy characterized by the hypofunction of salivary glands (SGs). Aquaporin-5 (AQP5); a water channel involved in saliva formation; is aberrantly distributed in SS SG acini and contributes to glandular dysfunction. We aimed to investigate the role of ezrin in AQP5 mislocalization in SS SGs. The AQP5-ezrin interaction was assessed by immunoprecipitation and proteome analysis and by proximity ligation assay in immortalized human SG cells. We demonstrated, for the first time, an interaction between ezrin and AQP5. A model of the complex was derived by computer modeling and in silico docking; suggesting that AQP5 interacts with the ezrin FERM-domain via its C-terminus. The interaction was also investigated in human minor salivary gland (hMSG) acini from SS patients (SICCA-SS); showing that AQP5-ezrin complexes were absent or mislocalized to the basolateral side of SG acini rather than the apical region compared to controls (SICCA-NS). Furthermore, in SICCA-SS hMSG acinar cells, ezrin immunoreactivity was decreased at the acinar apical region and higher at basal or lateral regions, accounting for altered AQP5-ezrin co-localization. Our data reveal that AQP5-ezrin interactions in human SGs could be involved in the regulation of AQP5 trafficking and may contribute to AQP5-altered localization in SS patients.