In vitro effects of curcumin on proinflammatory cytokines and expression of their genes in minor salivary gland tissue of patients with Sjogren's syndrome.

Curcumin reduces disease severity and ameliorates lupus-like/Sjögren's Syndrome-like disease in mice model. The immunological basis of these effects is largely unknown. This study examined the effects of curcumin on pro-inflammatory cytokines secreted by minor salivary glands in patients with primary Sjögren's syndrome (pSS). Minor salivary gland (MSG) tissue samples were collected from patients undergoing biopsy for suspected pSS. The tissues were treated with phytohemagglutinin (PHA) alone as well as PHA with curcumin (30 µM) and cultured in RPMI 1640 medium for 48 h at 37 °C in CO2 incubator. After the incubation period, culture supernatant and tissues were stored in the freezer (-80 °C). IL-6 levels were measured in supernatant by ELISA kit. Gene expressions of pro-inflammatory cytokines, namely IL-6, IL-8, TNF-α, IL-1ß, IL-4, IL-10, IL-17, IL-21, and IFN-γ, were measured by qPCR. IL-6 secretion levels and gene expressions were compared statistically between groups by Student's t test. Forty-seven patients were screened. Eight patients satisfied ACR/EULAR criteria for pSS. Seven patients with absent glandular inflammation and negative serology constituted sicca controls. These 15 subjects were included in final analysis. In pSS group, but not in controls, median IL-6 levels in supernatant were less in curcumin-treated as compared to PHA-alone subset [5.5 (0.7-13.34) vs 18.3 (12-32) ng/ml; p = 0.0156]. mRNA expression levels of IL-6 were also lower in curcumin-treated samples as compared to PHA alone, when cases and controls were analyzed together as well as in cases alone (p = 0.0009 and p = 0.0078, respectively); however, mRNA expression of IL-1ß was lower in curcumin-treated samples as compared to PHA alone, only when cases and controls were analyzed together (p = 0.0215). There was no difference in other cytokine gene expression levels between the subsets under the in-vitro experimental conditions. In conclusion, curcumin reduced mRNA expression as well as secretion of IL-6 levels by salivary gland tissue of patients with pSS. Curcumin also suppressed PHA-induced mRNA expression levels of IL-6 and IL-1ß in MSG tissue of patients with pSS and controls when analyzed together as a combined group.

Childhood-onset of primary Sjögren's syndrome: phenotypic characterization at diagnosis of 158 children.

OBJECTIVES: To characterize the phenotypic presentation at diagnosis of childhood-onset primary SS. METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry using worldwide data-sharing cooperative merging of pre-existing clinical SS databases from the five continents. For this study, we selected those patients in whom the disease was diagnosed below the age of 19 years according to the fulfilment of the 2002/2016 classification criteria. RESULTS: Among the 12 083 patients included in the Sjögren Big Data Registry, 158 (1.3%) patients had a childhood-onset diagnosis (136 girls, mean age of 14.2 years): 126 (80%) reported dry mouth, 111 (70%) dry eyes, 52 (33%) parotid enlargement, 118/122 (97%) positive minor salivary gland biopsy and 60/64 (94%) abnormal salivary US study, 140/155 (90%) positive ANA, 138/156 (89%) anti-Ro/La antibodies and 86/142 (68%) positive RF. The systemic EULAR Sjögren's syndrome disease activity index (ESSDAI) domains containing the highest frequencies of active patients included the glandular (47%), articular (26%) and lymphadenopathy (25%) domains. Patients with childhood-onset primary SS showed the highest mean ESSDAI score and the highest frequencies of systemic disease in 5 (constitutional, lymphadenopathy, glandular, cutaneous and haematological) of the 12 ESSDAI domains, and the lowest frequencies in 4 (articular, pulmonary, peripheral nerve and CNS) in comparison with patients with adult-onset disease. CONCLUSIONS: Childhood-onset primary SS involves around 1% of patients with primary SS, with a clinical phenotype dominated by sicca features, parotid enlargement and systemic disease. Age at diagnosis plays a key role in modulating the phenotypic expression of the disease.

Influence of the age at diagnosis in the disease expression of primary Sjögren syndrome. Analysis of 12,753 patients from the Sjögren Big Data Consortium.

OBJECTIVES: To analyse how the main components of the disease phenotype (sicca symptoms, diagnostic tests, immunological markers and systemic disease) can be driven by the age at diagnosis of primary Sjögren's syndrome (pSS). METHODS: By January 2021, the participant centres had included 12,753 patients from 25 countries that fulfilled the 2002/2016 classification criteria for pSS. The age at diagnosis was defined as the time when the attending physician confirmed fulfilment of the criteria. Patients were clustered according to age at diagnosis. 50 clusters with more than 100 observations (from 27 to 76 years) were used to study the influence of the age at diagnosis in the disease expression. RESULTS: There was a consistent increase in the frequency of oral dryness according to the age at diagnosis, with a frequency of <90% in patients diagnosed at the youngest ages and >95% in those diagnosed at the oldest ages. The smooth curves that best fitted a linear model were the frequency of dry mouth (adjusted R2 0.87) and the frequency of abnormal oral tests (adjusted R2 0.72). Therefore, for each 1-year increase in the age at diagnosis, the frequency of dry mouth increased by 0.13%, and the frequency of abnormal oral diagnostic tests by 0.11%. There was a consistent year-by-year decrease in the frequency of all autoantibodies and immunological markers except for cryoglobulins. According to the linear models, for each 1-year increase in the age at diagnosis, the frequency of a positive result decreased by 0.57% (for anti-Ro antibodies), 0.47% (for RF) and 0.42% (for anti-La antibodies). The ESSDAI domains which showed a more consistent decrease were glandular and lymph node involvement (for each 1-year increase in the age at diagnosis, the frequency of activity decreased by 0.18%), and constitutional, cutaneous, and haematological involvements (the frequency decreased by 0.09% for each 1-year increase). In contrast, other domains showed an ascending pattern, especially pulmonary involvement (for each 1-year increase in the age at diagnosis, the frequency of activity increased by 0.22%), and peripheral nerve involvement (the frequency increased by 0.09% for each 1-year increase). CONCLUSIONS: The influence of the age at diagnosis on the key phenotypic features of pSS is strong, and should be considered critical not only for designing a personalised diagnostic approach, but also to be carefully considered when analysing the results of diagnostic tests and immunological parameters, and when internal organ involvement is suspected at diagnosis.

Anti-Sjögren's-syndrome-related antigen A autoantibodies (Anti-SSA antibody) and meningoencephalitis: Sjögren's syndrome waiting to be unveiled? A case series and review of literature.

Aseptic meningoencephalitis (AME) constitutes a variable proportion of meningoencephalitis. Patients with AME are not routinely evaluated for autoimmune disorders. Primary Sjögren's syndrome (pSS) is a prevalent, but under suspected systemic autoimmune disease characterised by exocrinopathy, though sicca symptoms may not be the dominant or presenting feature. This study was undertaken to enumerate the clinical, radiological and laboratory features of meningoencephalitis related to pSS among the total cohort of meningoencephalitis admitted in our hospital. Retrospective patient records were screened for diagnosis of meningoencephalitis from April 2016 to March 2020. Those patients with anti-SSA positivity and clinical diagnosis of pSS were included. We have reviewed all cases of Sjögren's syndrome with meningoencephalitis available in literature. Four patients with meningoencephalitis with pSS were identified. Their clinical presentations, investigations, and good response to steroids have been described with special emphasis on evolving clinical features. In all patients, sicca features were absent. Anti-SSA was positive in all. The diagnosis of pSS was considered after ruling out all infectious and other autoimmune aetiologies. Two had extra-neurological organ manifestations and required addition of second line immunosuppressive agents for optimum disease control. Consistent with this case series, absent sicca symptoms have been described in pSS patients presenting with meningoencephalitis in literature. This case series is of special interest as it describes the initial presentation of pSS as meningoencephalitis with sicca features in absentia, thereby highlighting the need for a high index of suspicion and the need for workup for pSS in AME.

Epidemiological profile and north-south gradient driving baseline systemic involvement of primary Sjögren's syndrome.

OBJECTIVE: To characterize the systemic phenotype of primary Sjögren's syndrome at diagnosis by analysing the EULAR-SS disease activity index (ESSDAI) scores. METHODS: The Sjögren Big Data Consortium is an international, multicentre registry based on worldwide data-sharing cooperative merging of pre-existing databases from leading centres in clinical research in Sjögren's syndrome from the five continents. RESULTS: The cohort included 10 007 patients (9352 female, mean 53 years) with recorded ESSDAI scores available. At diagnosis, the mean total ESSDAI score was 6.1; 81.8% of patients had systemic activity (ESSDAI score ≥1). Males had a higher mean ESSDAI (8.1 vs 6.0, P < 0.001) compared with females, as did patients diagnosed at <35 years (6.7 vs 5.6 in patients diagnosed at >65 years, P < 0.001). The highest global ESSDAI score was reported in Black/African Americans, followed by White, Asian and Hispanic patients (6.7, 6.5, 5.4 and 4.8, respectively; P < 0.001). The frequency of involvement of each systemic organ also differed between ethnic groups, with Black/African American patients showing the highest frequencies in the lymphadenopathy, articular, peripheral nervous system, CNS and biological domains, White patients in the glandular, cutaneous and muscular domains, Asian patients in the pulmonary, renal and haematological domains and Hispanic patients in the constitutional domain. Systemic activity measured by the ESSDAI, clinical ESSDAI (clinESSDAI) and disease activity states was higher in patients from southern countries (P < 0.001). CONCLUSION: The systemic phenotype of primary Sjögren's syndrome is strongly influenced by personal determinants such as age, gender, ethnicity and place of residence, which are key geoepidemiological players in driving the expression of systemic disease at diagnosis.

Systemic phenotype related to primary Sjögren's syndrome in 279 patients carrying isolated anti-La/SSB antibodies.

OBJECTIVES: To evaluate the systemic phenotype associated with the presence of isolated anti-La/SSB antibodies in a large international registry of patients with primary Sjögren's syndrome (pSS) fulfilling the 2002 classification criteria. METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry created in 2014. Baseline clinical information from leading centres on clinical research in SS of the 5 continents was collected. Combination patterns of anti-Ro/SSA-La/SSB antibodies at the time of diagnosis defined the following four immunological phenotypes: double positive (combined Ro/SSA and La/SSB,) isolated anti-Ro/SSA, isolated anti-La/SSB, and immunonegative. RESULTS: The cohort included 12,084 patients (11,293 females, mean 52.4 years) with recorded ESSDAI scores available. Among them, 279 (2.3%) had isolated anti-La/SSB antibodies. The mean total ESSDAI score at diagnosis of patients with pSS carrying isolated anti-La/SSB was 6.0, and 80.4% of patients had systemic activity (global ESSDAI score ≥1) at diagnosis. The domains with the highest frequency of active patients were the biological (42.8%), glandular (36.8%) and articular (31.2%) domains. Patients with isolated anti-La/SSB showed a higher frequency of active patients in all ESSDAI domains but two (articular and peripheral nerve) in comparison with immune-negative patients, and even a higher absolute frequency in six clinical ESSDAI domains in comparison with patients with isolated anti-Ro/SSA. In addition, patients with isolated anti-La/SSB showed a higher frequency of active patients in two ESSDAI domains (pulmonary and glandular) with respect to the most active immunological subset (double-positive antibodies). Meanwhile, systemic activity detected in patients with isolated anti-La/SSB was overwhelmingly low. Even in ESSDAI domains where patients with isolated anti-La/SSB had the highest frequencies of systemic activity (lymphadenopathy and muscular), the percentage of patients with moderate or high activity was lower in comparison with the combined Ro/SSA and La/SSB group. CONCLUSIONS: Patients carrying isolated La/SSB antibodies represent a very small subset of patients with a systemic SS phenotype characterised by a significant frequency of active patients in most clinical ESSDAI domains but with a relative low frequency of the highest severe organ-specific involvements. Primary SS still remains the best clinical diagnosis for this subset of patients.

Saliva microbiome in primary Sjögren's syndrome reveals distinct set of disease-associated microbes.

OBJECTIVE: This study systematically aims to evaluate the salivary microbiome in patients with primary Sjögren's syndrome (pSS) using 16S rRNA sequencing approach. METHODS: DNA isolation and 16S rRNA sequencing was performed on saliva of 37 pSS and 35 control (CC) samples on HiSeq 2500 platform. 16S rRNA sequence analysis was performed independently using two popular computational pipelines, QIIME and less operational taxonomic units scripts (LoTuS). RESULTS: There were no significant changes in the alpha diversity between saliva of patients and controls. However, four genera including Bifidobacterium, Lactobacillus, Dialister and Leptotrichia were found to be differential between the two sets, and common between both QIIME and LoTuS analysis pipelines (Fold change of 2 and p < .05). Bifidobacterium, Dialister and Lactobacillus were found to be enriched, while Leptotrichia was significantly depleted in pSS compared to the controls. Exploration of microbial diversity measures (Chao1, observed species and Shannon index) revealed a significant increase in the diversity in patients with renal tubular acidosis. An opposite trend was noted, with depletion of diversity in patients with steroids. CONCLUSION: Our analysis suggests that while no significant changes in the diversity of the salivary microbiome could be observed in Sjögren's syndrome compared to the controls, a set of four genera were significantly and consistently differential in the saliva of patients with pSS. Additionally, a difference in alpha diversity in patients with renal tubular acidosis and those on steroids was observed.

Systemic manifestations of primary Sjögren's syndrome out of the ESSDAI classification: prevalence and clinical relevance in a large international, multi-ethnic cohort of patients.

OBJECTIVES: To analyse the frequency and characterise the systemic presentation of primary Sjögren's syndrome (SS) out of the ESSDAI classification in a large international, multi-ethnic cohort of patients. METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry based on world-wide data-sharing and cooperative merging of pre-existing clinical SS databases from leading centres in clinical research in SS from the five continents. A list of 26 organ-by-organ systemic features not currently included in the ESSDAI classification was defined according to previous studies; these features were retrospectively recorded. RESULTS: Information about non-ESSDAI features was available in 6331 patients [5,917 female, mean age at diagnosis 52 years, mainly White (86.3%)]. A total of 1641 (26%) patients had at least one of the ESSDAI systemic features. Cardiovascular manifestations were the most frequent organ-specific group of non-ESSDAI features reported in our patients (17% of the total cohort), with Raynaud's phenomenon being reported in 15%. Patients with systemic disease due to non-ESSDAI features had a lower frequency of dry mouth (90.7% vs. 94.1%, p<0.001) and positive minor salivary gland biopsy (86.7% vs. 89%, p=0.033), a higher frequency of anti-Ro/SSA (74.7% vs. 68.7%, p<0.001), anti-La/SSB antibodies (44.5% vs. 40.4%, p=0.004), ANA (82.7% vs. 79.5%, p=0.006), low C3 levels (17.4% vs. 9.7%, p<0.001), low C4 levels (14.4% vs. 9.6%, p<0.001), and positive serum cryoglobulins (8.6% vs. 5.5%, p=0.001). Systemic activity measured by the ESSDAI, clinESSDAI and DAS was higher in patients with systemic disease out of the ESSDAI in comparison with those without these features (p<0.001 for all comparisons). CONCLUSIONS: More than a quarter of patients with primary SS may have systemic manifestations not currently included in the ESSDAI classification, with a wide variety of cardiovascular, digestive, pulmonary, neurological, ocular, ENT (ear, nose, and throat), cutaneous and urological features that increase the scope of the systemic phenotype of the disease. However, the individual frequency of each of these non-ESSDAI features was very low, except for Raynaud's phenomenon.

CXCL13 levels in serum but not in saliva are elevated in Asian Indian patients with primary Sjögren's syndrome.

Human and animal model studies suggest CXCL13 is a potential biomarker in primary Sjögren's syndrome (pSS). CXCL13 has not been studied in Indian patients with pSS. pSS cases classified by American European Consensus Group (AECG) or American college of Rheumatology(ACR) 2012 criteria, attending rheumatology clinic between July 2014 and July 2015 were included. Hospital staff and healthy, non-blood related family members of patients constituted the control group. pSS cases underwent clinical evaluation, laboratory investigations, ESSDAI and ESSPRI scoring. Unstimulated saliva was collected by the spitting method. Salivary and serum CXCL13 were quantified by indirect ELISA. CXCL13 positivity was determined using Receiver Operator Characteristic (ROC) curve. STATA13.1 (StataCorpLP,Texas,USA) software was used for statistical analysis. In this study, 45 pSS cases and 42 healthy controls were recruited. In pSS, median levels of serum CXCL13, but not salivary CXCL13 was significantly higher as compared to the corresponding levels in healthy controls (p < 0.001). Using cutoff of 43.03 pg/ml obtained by ROC, serum CXCL13 positivity was seen in 31/43(72.1%) cases and 10/34 (29.4%) controls, respectively. Serum CXCL13 levels among pSS patients on treatment, treatment naïve patients and healthy controls were statistically different. Serum CXCL13 positivity was associated with oral symptoms (p = 0.02), ocular signs (p = 0.03) and hyperglobulinemia (p = 0.01). There was no association of salivary CXCL13 level with any of the clinical variables. While serum CXCL13 was elevated in pSS, salivary CXCL13 was not. In conclusion, serum CXCL13 positivity was found to be associated with oral symptoms, ocular signs and hyperglobulinemia in pSS.

Influence of geolocation and ethnicity on the phenotypic expression of primary Sjögren's syndrome at diagnosis in 8310 patients: a cross-sectional study from the Big Data Sjögren Project Consortium.

OBJECTIVES: To analyse the influence of geolocation and ethnicity on the clinical presentation of primary Sjögren's syndrome (SjS) at diagnosis. METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry designed in 2014. By January 2016, 20 centres from five continents were participating. Multivariable logistic regression analyses were performed. RESULTS: We included 7748 women (93%) and 562 men (7%), with a mean age at diagnosis of primary SjS of 53 years. Ethnicity data were available for 7884 patients (95%): 6174 patients (78%) were white, 1066 patients (14%) were Asian, 393 patients (5%) were Hispanic, 104 patients (1%) were black/African-American and 147 patients (2%) were of other ethnicities. SjS was diagnosed a mean of 7 years earlier in black/African-American compared with white patients; the female-to-male ratio was highest in Asian patients (27:1) and lowest in black/African-American patients (7:1); the prevalence of sicca symptoms was lowest in Asian patients; a higher frequency of positive salivary biopsy was found in Hispanic and white patients. A north-south gradient was found with respect to a lower frequency of ocular involvement in northern countries for dry eyes and abnormal ocular tests in Europe (OR 0.46 and 0.44, respectively) and Asia (OR 0.18 and 0.49, respectively) compared with southern countries. Higher frequencies of antinuclear antibodies (ANAs) were reported in northern countries in America (OR=1.48) and Asia (OR=3.80) while, in Europe, northern countries had lowest frequencies of ANAs (OR=0.67) and Ro/La (OR=0.69). CONCLUSIONS: This study provides the first evidence of a strong influence of geolocation and ethnicity on the phenotype of primary SjS at diagnosis.

Gut inflammation and microbiome in spondyloarthritis.

Spondyloarthritis (SpA) is chronic inflammatory disease involving joints and the spine. Bowel inflammation is common in SpA, which may be classified as acute or chronic. Chronic gut inflammation is most common in SpA patients with axial involvement as compared to those presenting with peripheral involvement alone. The pathogenesis of gut inflammation in SpA could be explained by two factors-over-activation of immunological cells and altered gut microbiome. This is exemplified by SpA animal models, namely HLA-B27-expressing transgenic animals and SKG mice models. Immunological mechanisms include homing of activated T cells from gut into synovium, excess pro-inflammatory cytokines secretion by immune cells such as IL-23 and genetic variations in immunological genes. The evidence for role of gut microbiome in SpA is gradually emerging. Recently, metagenomic study of gut microbiome by sequencing of microbial nucleic acids has enabled identification of new microbial taxa and their functions in gut of patients with SpA. In SpA, the gut microbiome could emerge as diagnostic and prognostic marker of disease. Modulation of gut microbiome is slated to have therapeutic potential as well.

Are Indian patients with juvenile-onset ankylosing spondylitis taller than reference population ?

BACKGROUND & OBJECTIVES: Paucity of growth retardation has been observed by us in patients with juvenile-onset ankylosing spondylitis (JAS) in a tertiary care health centre in south India. We, therefore, undertook this pilot study to assess and compare anthropometry of patients with JAS who were 15 yr and older with that of adult onset ankylosing spondylitis (AAS) and matching Indian reference population. METHODS: Consecutive male patients (December 2009- October 2012) with JAS and AAS fulfilling Modified New York Criteria were selected after applying inclusion and exclusion criteria. Demography and anthropometry were noted. Height of both patient groups as well as their parents and siblings were compared with that of the reference population. Mid-parental height and delta height were derived. Those with delta height of >8.5 cm were compared with the remaining. Multivariate logistic regression was done for variables that were found to be significant by chi-square in bivariate analysis. Similar analysis was done for BMI also. RESULTS: There was no significant difference in anthropometric variables between JAS and AAS groups. Twenty eight of the 30 (93.33%) JAS patients were taller as compared to the reference population. Twenty six (86.67%) AAS patients were taller than the reference population. The mean heights of JAS (170.67 ± 6.94 cm) and AAS (168.2 ± 5.94 cm) patients were significantly higher than the reference value of 163.11 cm; both p0 <0.001. Logistic regression revealed that tallness in JAS was associated positively with hypermobility (OR=23.46,95%CI 1.2-447.2, p0 =0.036). No significant association was detected for height in AAS and for BMI in both JAS and AAS groups. INTERPRETATION & CONCLUSIONS: No growth retardation was seen in patients with JAS in our study. Majority of patients with JAS and AAS were taller than reference population. The difference between mean height of JAS and AAS was not significant. Larger studies involving different populations are required to confirm these findings.

DNA methylation profiling of labial salivary gland tissues revealed hypomethylation of B-cell-related genes in primary Sjögren's syndrome.

The objective of this epigenetic study was to investigate the cellular proportions based on DNA methylation signatures and pathways of differentially methylated genes in labial salivary gland (LSG) tissues of individuals with Sjögren's syndrome (SS). Two methylation array datasets from the Gene Expression Omnibus repository (GSE166373 and GSE110007) were utilized, consisting of 159 LSG tissues from 77 SS cases and 82 non-SS controls. The raw data underwent analysis using the Chip Analysis Methylation Pipeline (ChAMP) in R statistical tool, which identified differential methylation probes and regions. The EpiDISH and minfi packages in R were employed to identify proportions of epithelial cells, fibroblasts, and immune cells, as well as immune cell subsets. The results showed that proportions of immune cells were increased, while proportions of epithelial cells and fibroblasts were significantly decreased in the LSG of individuals with SS compared to non-SS controls. Specifically, proportions of B-cells and CD8 T-cells were increased, while CD4 T-cells, Treg, monocytes, and neutrophils were decreased in the LSG of individuals with SS. Pathway analysis indicated that genes involved in immune responses to Epstein-Barr virus infection were significantly hypomethylated in SS, and gene set enrichment analysis highlighted the hypomethylation of genes involved in the somatic recombination of immune receptors in SS. Additionally, Disease Ontology analysis showed enriched pathways related to multiple myeloma, arthritis, and the human immunodeficiency virus. The study also revealed significant hypomethylation of the WAS gene on chromosome X in LSG tissues of individuals with SS. Overall, the findings suggest an increased proportion of B-cells and genes related to B-cell function, as well as hypomethylation of genes involved in immune responses and immune receptor recombination, in LSG tissues of individuals with SS compared to non-SS controls.

Comprehensive analysis of clinical and laboratory features of 440 published cases of Sjögren's syndrome and renal tubular acidosis.

AIM: To describe the clinical and laboratory features of Sjögren's syndrome (SS) with renal tubular acidosis (RTA) from published literature. METHODS: A systematic search of indexed publications in all languages till December 2021 identified cases of SS with RTA (SS-RTA) and were included if either antibody (anti-SSA/anti-SSB) or salivary gland histopathology were positive. RESULTS: There were 440 cases of SS-RTA (63.9% from Asia, 95.5% women). The median (range) age was 37 (6-78) years. Only 7.7% had a previous diagnosis of SS. Oral or ocular sicca symptoms were present in 63.7%. Positive ocular tests, oral tests, anti-SSA, anti-SSB and salivary gland histopathology were reported in 256/331 (77.3%), 123/128 (96%), 382/407 (93.9%), 298/379 (78.6%), and 246/268 (91.8%), respectively. Hypokalemic paralysis (HP) was the presenting feature in 63.6%; 25% had multiple episodes of HP and 8.4% had respiratory paralysis. Type 1, type 2, combined type 1 & 2, and type 4 RTA was seen in 388, 8, 38, and 3 patients, respectively. Proximal dysfunction and RTA complications were infrequently evaluated. Fanconi syndrome, nephrogenic diabetes insipidus, proteinuria, and low estimated glomerular filtration rate were found in 45, 21, 178, and 157, respectively. Nephrocalcinosis, renal stones, and osteomalacia were reported in 92, 79, and 72, respectively. Tubulointerstitial nephritis was found in 142 out of 152 renal biopsies. CONCLUSION: SS-RTA is an early manifestation of SS characterized by younger age and subclinical sicca symptoms. Although evaluated less frequently, oral sicca signs and salivary gland biopsy have a high positive yield. HP is the most common presentation. RTA is mostly distal; proximal dysfunction and complications were infrequently assessed.

A novel association of osmotic demyelination in Sjögren's syndrome prompts revisiting role of aquaporins in CNS demyelinating diseases: A literature review.

BACKGROUND: Primary Sjögren's syndrome (SS) is a chronic systemic autoimmune disease with varied neurological manifestations. SS is associated with anti-aquaporin-4 antibody (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD), a demyelinating autoimmune disorder of the central nervous system (CNS). Intriguingly, there are reports of osmotic demyelinating syndrome (ODS), a supposedly non-inflammatory disorder, in the context of SS and renal tubular acidosis (RTA), both of which are not yet established risk factors for ODS. METHODS: A literature search was undertaken to identify case reports of ODS in patients with SS. Details of the clinical and laboratory features of these patients were compiled. Additionally, we searched for NMOSD in patients with SS. We looked for co-existing RTA in patients with SS-ODS as well as SS-NMOSD. We also screened for reports of ODS in RTA without underlying SS. RESULTS & DISCUSSION: We identified 15 patients (all women, median age 40 years) with ODS in SS, and all of these patients had comorbid RTA. There were only three reported cases of ODS in RTA without underlying SS. We identified a total of 67 patients with SS-NMOSD, of whom only 3 (4.5%) had RTA. Hence, unlike NMOSD, the development of ODS in SS requires a prolonged osmotic or electrolyte abnormality caused by the comorbid RTA. The 15 patients with ODS and SS -RTA, showed heterogeneous clinical manifestations and outcomes. The most common symptom was quadriparesis, seen in 14 of the 15 patients. Eleven of the 15 patients had one of the following features, either alone or in combination: worsening of the sensorium, extensor plantar response, dysphagia/dysarthria, and facial palsy. The latter four manifestations were present at the onset in 7 patients and later in the course of the illness in the remaining 4 patients. Ocular palsy was seen in only four of the 15 patients and was a late manifestation. One patient who had extensive long-segment myelitis and subsequent ODS died, but most patients recovered without significant sequelae. None had hyponatremia, while all patients had hypokalemia and/or hypernatremia. Hypokalemia causing nephrogenic diabetes insipidus (NDI) followed by rapid rise in sodium and the resultant osmotic stress could potentially explain the occurrence of ODS in SS-RTA. Aquaporin (AQP) in astrocytes is implicated in ODS, and renal AQP is downregulated in NDI. Antibodies against AQPs are present in some patients with SS. Defective AQP is therefore a common link underlying all the connected diseases, namely SS, NDI, and ODS, raising the possibility of immune-mediated AQP dysfunction in the pathogenesis. CONCLUSION: The hitherto unreported association between SS-RTA and ODS may implicate SS and/or RTA in the development of ODS. In the setting of SS-RTA, ODS must be suspected when a patient with flaccid quadriparesis does not respond to the correction of potassium or develops additional neurological features along with a rise in sodium. Defective functions of AQPs may be a possible mechanism linking demyelinating CNS lesions, SS, and RTA. Studies evaluating AQP functions and serum antibodies against AQPs in these conditions are warranted.

Associations between neuromyelitis optica spectrum disorder, Sjögren's syndrome, and conditions with electrolyte disturbances.

OBJECTIVE: Electrolyte disorders are among the important conditions negatively affecting the disease course of neuromyelitis optica spectrum disorder (NMOSD). Possible mechanisms may include renal tubular acidosis (RTA) accompanying Sjögren's syndrome (SS), syndrome of inappropriate antidiuretic hormone secretion (SIADH), and central diabetes insipidus (DI). Currently, the overlap profiles between these conditions remain uncertain. METHODS: This cross-sectional study collected data from the nationwide administrative Diagnosis Procedure Combination (DPC) database and evaluated the overlap profiles. RESULTS: Among the 28,285,908 individuals from 1203 DPC-covered hospitals, 8477 had NMOSD, 174108 had SS, 4977 had RTA, 7640 had SIADH, and 24,789 had central DI. Of those with NMOSD, 986 (12%) had SS. The odds ratio (OR) for a diagnosis of NMOSD in those with SS compared with those without was 21 [95% confidence interval (CI), 20-23]. Overlap between NMOSD and SS was seen both in males (OR, 28 [95% CI, 23-33]) and females (OR, 16 [15-17]) and was more prominent in the younger population. Among patients with SS, the prevalence of RTA was lower in patients with NMOSD compared with those without NMOSD. Patients with NMOSD showed a higher prevalence of SIADH (OR, 11 [7.5-17]; p < 0.0001) and DI (OR, 3.7 [2.4-5.3]; p < 0.0001). Comorbid SS in NMOSD was associated with a higher prevalence of DI. CONCLUSIONS: Patients with NMOSD are likely to have SS, SIADH, and central DI. RTA in SS does not facilitate the overlap between NMOSD and SS. SS in NMOSD may predispose patients to DI.

Eosinophilic esophagitis and pharyngitis presenting as mass lesion in a patient with inactive rheumatoid arthritis.

We describe here a case of longstanding rheumatoid arthritis (RA) presenting with recurrent episodes of epigastric pain, melena, nonprogressive dysphagia, and hoarseness associated with persistent peripheral blood eosinophilia. Her RA was clinically inactive, but she had significant lymphadenopathy and hepatosplenomegaly. Computed tomographic scan of the thorax revealed circumferential wall thickening extending from the oropharynx to the gastroesophageal junction with a large polypoidal mass projecting into the lumen of the stomach. Histology revealed infiltration of the esophageal mucosa by eosinophils with a density of 40 to 80 per high-power field. The stratified squamous epithelium of the pharyngeal mucosa was also infiltrated by eosinophils with a density of more than 100 per high-power field. Eosinophilic esophagitis and pharyngitis were diagnosed, and the patient was administered corticosteroids and hydroxyurea, following which her symptoms resolved. On repeat imaging, there was significant reduction in esophageal wall thickening and luminal dilatation. There are few reports of tissue eosinophilia in association with RA, but the pathogenesis and any definite association with RA are not clear.

Salivary free light chains and salivary immunoglobulins as potential non-invasive biomarkers in primary Sjögren's syndrome.

BACKGROUND: B cells contribute significantly to the pathogenesis of primary Sjögren's syndrome (pSS). Free light chains (FLCs) are generated during the production of immunoglobulins (Igs) and are surrogates of B cell activity. We hypothesized that salivary FLCs and salivary Igs could represent salivary gland inflammation and therefore, serve as biomarkers in pSS. METHODS: Patients >18 years old fulfilling the American College of Rheumatology / European League Against Rheumatism (EULAR) 2016 criteria for pSS and age-matched healthy and disease controls (sicca non-pSS, rheumatoid arthritis, systemic lupus erythematosus) were recruited for this cross-sectional study. FLCs in saliva and serum were measured by immunoturbidimetry. Serum and salivary Igs were measured by nephelometry and enzyme-linked immunosorbent assay, respectively. Area under the receiver operator characteristic curve was determined. The factors influencing the serum and salivary FLCs in pSS were determined using backward linear regression. RESULTS: A total of 78 patients with pSS, 76 healthy controls and 62 disease controls were recruited. Median EULAR SS disease activity index (interquartile range) was 1 (3.75). Serum FLCκ and FLCλ, salivary FLCλ, serum and salivary IgG, salivary IgM was significantly higher in the pSS group compared to the controls. Areas under the curve for salivary FLCλ, serum FLCκ, serum and salivary IgG were 0.75, 0.72, 0.78 and 0.77, respectively. Regression analysis showed that salivary FLCκ, salivary FLCλ and salivary IgG were associated with positive salivary gland histopathology. Use of immunosuppressants and glucocorticoids was associated with lower values of salivary parameters. CONCLUSION: Salivary FLCλ and salivary IgG were significantly different between pSS and control groups and could be potential non-invasive biomarkers in pSS. These findings should be confirmed in larger longitudinal studies.