Extraglandular Manifestations Research Articles

TLR7 expression increases with disease progression and mediates expansion of distinct B cell subsets in primary Sjögren’s Disease

Abstract Primary Sjögren’s Disease (pSD) is a systemic autoimmune disorder in which the exocrine tissue exhibits chronic inflammation. Additionally, patients often experience diminished tear and saliva production along with many extra-glandular disease manifestations. The causes of pSD are poorly understood and no curative treatments are available. Previous studies in our lab conducted in a pSD mouse model demonstrated that TLR7 agonism accelerates pSD pathogenesis and drives expansion of age-associated B cells (ABCs). To extend our prior work, we hypothesized that pSD splenocytes show heightened TLR7 expression and activation, and expansion of B cell subsets linked to autoimmunity relies on TLR7 in pSD mice. We harvested the spleens of pSD females at three different disease time points (pre-disease, clinical disease and advanced stage disease) and performed flow cytometry. Parallel experiments were performed using age and sex-matched healthy controls. Splenocytes were also cultured with the TLR7 agonist Imiquimod (Imq) and IL-6 secretion assessed by ELISA. In addition, spleens were isolated from TLR7-deficient pSD females at the clinical disease stage and flow cytometry was performed. We found splenocytes derived from pSD animals at the clinical disease stage secreted higher levels of IL-6 in response to Imq stimulation as compared to those derived from healthy control animals. TLR7 +B cells and ABCs (B220 +, CD23 −, CD21 −, T-bet +) increased with disease progression in pSD mice. In pSD mice lacking TLR7, ABCs and germinal center B cells were decreased compared to the TLR7-sufficient pSD parental strain. Thus, splenocytes from pSD mice show enhanced sensitivity to TLR7 and TLR7 signaling mediates expansion of ABC subset in pSD. NIH/NIDCR T32 DE023056 NIH/NIDCR R01 DE029472

OA11 Juvenile Sjögren’s syndrome is characterised by dysregulated of B and T memory cell frequencies: a pilot immunophenotyping analysis of this rare disease phenotype

Abstract Background/Aims Sjögren’s syndrome (SS) is an autoimmune rheumatic disease characterised by dryness resulting from chronic lymphocytic infiltration of the exocrine glands and extra glandular manifestations such as arthritis, anemia, and fatigue. The disease is more frequent in women aged 30-50. However, in rare cases, the disease starts in childhood, known as juvenile SS (jSS). Children have different clinical manifestations compared to adults, with dryness being less common, making the diagnosis very challenging. Our aim is to investigate in depth the immune cell profile of patients with jSS and their cytokine profile for better understanding of disease pathogenesis. Methods Peripheral blood was collected from a cohort of patients with jSS (n = 10) and age and sex-matched healthy controls (HC) (n = 10). None of the patients had received B-cell depletion therapy. Peripheral blood immune-phenotyping of 29 immune-cell subsets, including B and T cells, was performed using flow cytometry as we have reported previously for patients with adult-onset SS. Data were analyzed using multiple t-tests and compared with the adult SS immune phenotype. A panel of 15 serum cytokines associated with SS pathology were measured by Luminex, multiple t-tests were performed to detect statistically significant differences between jSS and HCs. Results Patients with jSS had an average age of 18 years (range 16-21) with an average age of disease onset at 14 years (range 12-18). 60% of patients had anti-Ro autoantibodies and 50% had anti-La autoantibodies. Patients with jSS had an altered immune profile compared to age-matched healthy controls (HCs) (mean age = 18 years, range 15-25). In the B cell compartment, jSS patients had higher frequencies of total CD19+ B cells (p = 0.0044), naïve B cells (CD19+IgD+CD27-) (p = 0.0183) and bm2 (CD19+IgD+CD38+) (p = 0.0490) whereas memory B cell subsets such as early bm5 (CD19+IgD-CD38+) and late bm5 (CD19+IgD-CD38-) were significantly reduced (p = 0.0249 and p = 0.0117, respectively). Interestingly, in the CD4+ T cell compartment, central memory T cells (CD4+CD27+CD45RA-) were significantly reduced (p = <0.0001) but effector memory (CD4+CD27-CD45-) and effector memory-re-expressing-CD45RA (EMRA, CD4+CD27-CD45RA+) T-cell subsets were significantly elevated (p = 0.0171 and p = 0.0002 respectively). There was also a significant increase in CD8+CD25-CD127+ responders T cells (p = 0.0392) in jSS patients versus HCs. Serum cytokines levels of APRIL and CCL8 were significantly elevated in jSS. Conclusion This is the first pilot study investigating the immune profile of patients with jSS. In line with our previous studies in adults we detected elevated naïve and reduced frequencies of memory B cells, suggesting an immunological rationale for the use of similar therapies across age. However, we also found a specific dysregulation of the responder CD8+ T cell subpopulation in jSS versus HCs, which requires further investigation. Our cytokine data could indicate an ongoing dysregulation of the homeostasis of mature B-cells and activation of different immune cells. Disclosure L. Martin-Gutierrez: None. H. Peckham: None. A. Radziszewska: None. J. Peng: None. O. Nettey: None. E. Jury: None. C. Ciurtin: None.

An unusual clue in the diagnosis of primary Sjogren’s syndrome

Sjogren’s syndrome (SSj) is a chronic autoimmune disease mainly targeting the exocrine glands, but sometimes associating extra-glandular manifestations. Xerosis, purpura, Raynaud’s phenomenon, cutaneous vasculitis, annular erythema are the main forms of skin involvement. A 26-year-old female patient was admitted for diffuse erythematous rash and angioedema, xerophthalmia and symmetrical arthralgia of hand joints. Anti-nuclear antibodies, anti-SSA and anti-Ro52 antibodies were identified, Schirmer’s test was positive, thus the diagnoses of primary SSj and associated urticarial vasculitis were established. Treatment with oral methylprednisolone, azathioprine and hydroxychloroquine was initiated, with favorable response over the next week. Patients with primary SSj that develop cutaneous vasculitis, lymphadenopathies or lymphopenia may be at risk for additional extra-glandular manifestations, including non-Hodgkin lymphoma.

Interstitial Lung Disease and Pulmonary Damage in Primary Sjögren's Syndrome: A Systematic Review and Meta-Analysis.

Pulmonary lung involvement is the most common extra-glandular manifestation in patients with primary Sjögren's syndrome (pSS), leading to a worsening of the patient's prognosis. To date, different studies have assessed the prevalence of pulmonary involvement and interstitial lung disease (ILD) in pSS patients with different results. We performed a systematic literature review and meta-analysis on ILD pooled prevalence in pSS according to the PRISMA and MOOSE guidelines. Furthermore, we explored the pooled prevalence of the two main presentations of pSS-ILD, nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP). We analysed the pSS-ILD prevalence in 30 studies including 8255 pSS patients. The pSS-ILD pooled prevalence was 23% (95% CI: 16-30). For NSIP, we found a pooled prevalence of 52% (CI 41-64), and for UIP we found a pooled prevalence of 44% (CI: 32-55). Regarding the meta-regression analysis, male gender, DLco value, country, and HRCT seem to contribute to the ILD presence. At least 20% of pSS patients have a comorbid ILD, usually NSIP. Male gender and alteration in DLco value may be considered the most important independent factors supporting an active search of lung complications during the clinical history of pSS patients.

A Non-Hodgkin’s Lymphoma Case in a Patient with Sjogren Syndrome and Covid-19

Background: Sjogren syndrome (SS) is a chronic autoimmune disorder of the exocrine glands, accompanied by lymphocyte infiltration of these glands, that manifests clinically with dryness of the eyes (lacrimal glands involvement) and of the mouth (salivary glands involvement). SS can develop extraglandular manifestations and complications such as hematologic malignant transformation. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible coronavirus discovered in 2019, causing a world pandemic by developing an acute respiratory disease ‘coronavirus disease 2019’ (COVID-19). We are presenting a case with pSS, complicated with Non Hodgkin Lymphoma (NHL), after infection with SARS-CoV-2. Case presentation: The patient is a 52 year old female, who presented in the clinic complaining of dryness of the eyes and mouth, swollen nodule in the neck region. According to European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) criteria, the patient is diagnosed with SS and starts treatment with Plaquenil 200mg/day, Medrol 4mg/day, Calcium, D3 vitamin, Proton-pump inhibitor (PPI). After infection with SARS-CoV-2, the patients has aggravation of her symptoms related to SS and in a time frame of 8 months she manifests weakness, tiredness and weight loss and generalized lymphadenopathy. Biopsy is performed confirming the diagnosis of Non Hodgkin Lymphoma. Conclusions: This clinical case presentation tries to explain a possible relation between COVID-19 and hematologic malignant transformation in predisposed patients, like patients with pSS.

Genetics and epigenetics of primary Sjögren syndrome: implications for future therapies.

In primary Sjögren syndrome (pSS), chronic inflammation of exocrine glands results in tissue destruction and sicca symptoms, primarily of the mouth and eyes. Fatigue, arthralgia and myalgia are also common symptoms, whereas extraglandular manifestations that involve the respiratory, nervous and vascular systems occur in a subset of patients. The disease predominantly affects women, with an estimated female to male ratio of 14 to 1. The aetiology of pSS, however, remains incompletely understood, and effective treatment is lacking. Large-scale genetic and epigenetic investigations have revealed associations between pSS and genes in both innate and adaptive immune pathways. The genetic variants mediate context-dependent effects, and both sex and environmental factors can influence the outcome. As such, genetic and epigenetic studies can provide insight into the dysregulated molecular mechanisms, which in turn might reveal new therapeutic possibilities. This Review discusses the genetic and epigenetic features that have been robustly connected with pSS, putting them into the context of cellular function, carrier sex and environmental challenges. In all, the observations point to several novel opportunities for early detection, treatment development and the pathway towards personalized medicine.

CNS demyelinating events in primary Sjögren's syndrome: A single-center case series on the clinical phenotype.

The study aimed to assess the prevalence, clinical characteristics, and therapeutic outcomes of the central nervous system (CNS) demyelinating disease in a large cohort of primary Sjögren's syndrome (pSS). This is an explorative cross-sectional study of patients with pSS seen in the departments of rheumatology, otorhinolaryngology, or neurology of a tertiary university center between January 2015 and September 2021. In a cohort of 194 pSS patients, 22 patients had a CNS manifestation. In this CNS group, 19 patients had a lesion pattern suggestive of demyelination. While there were no obvious differences in the patients' epidemiological disposition or rate of other extraglandular manifestations, the CNS group differed from the remaining patients with pSS by having less glandular manifestations but a higher seroprevalence for anti-SSA/Ro antibodies. Notably, patients with CNS manifestations were often diagnosed with multiple sclerosis (MS) and treated as such, although age and disease course were atypical of MS. Many first-line MS agents were ineffective in these "MS look-alikes"; however, the disease course was benign with B-cell-depleting agents. Neurological symptoms of pSS are common and clinically manifest mainly as myelitis or optic neuritis. Notably, in the CNS, the pSS phenotype can overlap with MS. The prevailing disease is crucial since it has a major impact on the long-term clinical outcome and the choice of disease-modifying agents. Although our observations neither confirm pSS as a more appropriate diagnosis nor rule out simple comorbidity, physicians should consider pSS in the extended diagnostic workup of CNS autoimmune diseases.

Childhood-onset primary Sjögren’s syndrome in a tertiary center in China: clinical features and outcome

ObjectivesTo characterize the clinical features and outcomes of childhood-onset primary Sjögren’s syndrome (pSS).MethodsPatients less than 18 years old who were diagnosed with pSS by paediatric rheumatologists were included, and all patients were applied the 2002 American-European Consensus Group (ACEG) criteria, the 2016 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria for pSS, or the 1999 proposed juvenile pSS criteria. The electronic medical records of patients with pSS from 2013 to 2020 were collected and analysed.ResultsThirty-nine patients were included. Of them, 27 (69.2%), 38 (97.4%) and 35 (89.7%) patients fulfilled the AECG criteria, ACR/EULAR criteria and proposed juvenile pSS criteria, respectively. The female:male ratio was 3.9:1. The median ages at first signs or symptoms and at diagnosis were 9.2 (4.7, 14.5) years and 10.9 (6.3, 15.0) years, respectively. The main clinical manifestations were rash or purpura (20, 51.3%), followed by fever (12, 30.8%), glandular enlargement/recurrent parotitis (10, 25.6%), and dry mouth and/or dry eyes (9, 23.1%). Twenty-eight (56.4%) patients had systemic damage, the most common of which was haematological involvement (14, 35.9%), followed by hepatic (13, 33.3%) and renal involvement (8, 20.5%). Thirty-eight (97.4%) patients underwent labial minor salivary gland biopsy, and all exhibited focal lymphocytic sialadenitis. All patients had a global ESSDAI score ≥ 1 at diagnosis, and the median total score at diagnosis was 8 (2, 31). Thirty-six (92.3%) patients were followed up for a median time of 23.6 (7.9, 79.5) months, and three patients developed systemic lupus erythematosus (SLE) at follow-up times of 13.3, 38.8 and 63.8 months.ConclusionsThe presentation of childhood-onset pSS is atypical, and extraglandular manifestations and systemic involvement are more common than in adult-onset pSS. Labial salivary gland biopsy is vital for patients with probable pSS. Some patients may develop SLE over time.

Phases and Natural History of Sjögren's Disease: A New Model for an Old Disease?

Sjögren's disease (SjD) is an archetypal and heterogenous autoimmune disorder that is characterized by exocrine glandular dysfunction. A proportion of patients develop severe extraglandular manifestations, such as cryoglobulinemia, and have an increased risk of lymphoma, both of which can adversely affect quality of life and occasionally mortality. As with most autoimmune disorders, the pathogenesis is poorly understood and difficult to predict, and, frustratingly, there is a lack of targeted therapies to cure this disease. We review the disease manifestations of SjD and propose a staged model for understanding the evolution of pathology. In longitudinal studies, most patients remain relatively stable in terms of their laboratory and clinical parameters. However, in the setting of various risk factors, a proportion of patients develop severe symptoms and/or lymphoma. We discuss potential underlying mechanisms for disease progression and the strengths and limitations of using a staged model to correlate the pathogenesis and spectrum of manifestations in SjD. Ultimately, understanding how and why some patients remain relatively stable, whereas others progress and develop florid systemic disease and a fraction develop lymphoma, is key to developing preventative and therapeutic treatments.

Sjogren’s syndrome presenting as hypokalemic periodic paralysis, a rare manifestation: A case series

Sjogren’s syndrome is a chronic and slowly progressing autoimmune disease characterized by lyphocytic infiltration of exocrine glands resulting in Sicca syndrome (xerostomia and keratocunjuntivitis sicca). The disease can present alone or along with other autoimmune diseases leading to significant organ specific and systemic disease. Middle aged women (Female: Male: 9:1) are primarily affected. Extraglandular (systemic) manifestations are seen in one third of patients with Sjogren’s syndrome. Among the extraglandular manifestations, renal involvement is commonly seen. Renal involvement in the form of tubulointerstitial nephritis (TIN) is more common compared to glomerular involvement. Distal renal tubular acidosis (RTA) is more common manifestation of TIN presenting as mild hypokalemia, metabolic acidosis, and rarely with hypokalemic periodic paralysis. We report three cases of hypokalemic periodic paralysis with metabolic acidosis, two in respiratory paralysis, diagnosed as distal RTA. On further evaluation of distal RTA, the patient diagnosed to have Sjogren’s syndrome and managed accordingly. Our report shows that Sjogren’s syndrome is a rare but important cause of hypokaemic periodic paralysis due to RTA.

Central Nervous System Involvement in Primary Sjögren’s Syndrome: Narrative Review of MRI Findings

Central nervous system (CNS) involvement is one of the numerous extraglandular manifestations of primary Sjögren's syndrome (pSS). Moreover, neurological complaints precede the sicca symptoms in 25-60% of the cases. We review the magnetic resonance imaging (MRI) lesions typical for pSS, involving the conventional examination, volumetric and morphometric studies, diffusion tensor imaging (DTI) and resting-state fMRI. The most common radiological lesions in pSS are white matter hyperintensities (WMH), scattered alterations hyperlucent on T2 and FLAIR sequences, typically located periventricularly and subcortically. Cortical atrophy and ventricular dilatation can also occur in pSS. Whilst these conditions are thought to be more common in pSS than healthy controls, DTI and resting-state fMRI alterations demonstrate evident microstructural changes in pSS. As pSS is often accompanied by cognitive symptoms, these MRI alterations are expectedly related to them. This relationship is not clearly delineated in conventional MRI studies, but DTI and resting-state fMRI examinations show more convincing correlations. In conclusion, the CNS manifestations of pSS do not follow a certain pattern. As the link between the MRI lesions and clinical manifestations is not well established, more studies involving larger populations should be performed to elucidate the correlations.

TLR7 agonism accelerates disease in a mouse model of primary Sjögren's syndrome and drives expansion of T-bet+ B cells.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterized by chronic inflammation of exocrine tissue, resulting in loss of tears and saliva. Patients also experience many extra-glandular disease manifestations. Treatment for pSS is palliative, and there are currently no treatments available that target disease etiology. Previous studies in our lab demonstrated that MyD88 is crucial for pSS pathogenesis in the NOD.B10Sn-H2b (NOD.B10) pSS mouse model, although the way in which MyD88-dependent pathways become activated in disease remains unknown. Based on its importance in other autoimmune diseases, we hypothesized that TLR7 activation accelerates pSS pathogenesis. We administered the TLR7 agonist Imiquimod (Imq) or sham treatment to pre-disease NOD.B10 females for 6 weeks. Parallel experiments were performed in age and sex-matched C57BL/10 controls. Imq-treated pSS animals exhibited cervical lymphadenopathy, splenomegaly, and expansion of TLR7-expressing B cells. Robust lymphocytic infiltration of exocrine tissues, kidney and lung was observed in pSS mice following treatment with Imq. TLR7 agonism also induced salivary hypofunction in pSS mice, which is a hallmark of disease. Anti-nuclear autoantibodies, including Ro (SSA) and La (SSB) were increased in pSS mice following Imq administration. Cervical lymph nodes from Imq-treated NOD.B10 animals demonstrated an increase in the percentage of activated/memory CD4+ T cells. Finally, T-bet+ B cells were expanded in the spleens of Imq-treated pSS mice. Thus, activation of TLR7 accelerates local and systemic disease and promotes expansion of T-bet-expressing B cells in pSS.

Association Between Vitamin D and Minor Salivary Gland Inflammation.

Objective There has been increasing research regarding the effects of vitamin D on autoimmune disorders. There is some evidence of a correlation between vitamin D levels and sicca symptoms. We attempted to evaluate the correlation between vitamin D levels and inflammation of the minor salivary gland (MSG). Methods Data for 214 patients who had undergone MSG biopsy were reviewed. Eighteen patients with other autoimmune/neoplastic processes were excluded. Seventy-seven of 196 patients had serum Vitamin D levels available and were selected for this retrospective study. Demographic, clinical, and immunological features, extra-glandular manifestations, autoantibodies, and clinical laboratory tests were collected and compared between patient groups with a focus score (FS) of 0 and 1 or more. Results Out of 77, 29 patients had an FS of 0 while 48 had an FS of 1 or more. Mean vitamin D levels were noted to be lower in patients with an FS of 1 when compared to patients with an FS of 1 or more. Conclusion In this study, patients with an FS of 1 were noted to have low vitamin D levels but this association was not seen at a higher FS.

Anticentromere antibody positive patients with primary Sjögren's syndrome have distinctive clinical and immunological characteristics.

To investigate the clinical manifestations, immunological characteristics, circulating lymphocyte subsets and risk factors of anticentromere antibody (ACA) positive patients with primary Sjögren's syndrome (pSS). Data of 333 patients with newly diagnosed pSS were collected and analysed retrospectively. The demographic features, glandular dysfunction, extraglandular manifestations, laboratory data, peripheral blood lymphocyte profiles and serum cytokines were compared between ACA-positive and ACA-negative pSS patients. Logistic regression analysis was used to evaluate the association between ACA and pSS characteristics. The prevalence of ACA among pSS patients was 13.5%. ACA-positive pSS patients were older at diagnosis and had longer disease duration. Xerostomia, xerophthalmia, parotid enlargement, Raynaud's phenomenon (RP), lung and digestive system involvement were more common in ACA-positive group, whereas haematological involvement such as leukopenia was more common in the ACA-negative group. Less frequency of rheumatoid factor, hypergammaglobulinaemia, anti-SSA and anti-SSB positivity, as well as higher positivity rate of ANA were observed in ACA-positive pSS patients, who exhibited a lower ESSDAI. In addition, decreased B cells and elevated NK cells were found in ACA-positive patients. Multivariate analysis identified that disease duration longer than 5 years, parotid enlargement, normal immunoglobulin and the absence of anti-SSA antibody were risk factors of ACA-positive pSS. ACA positive pSS patients have distinctive clinical manifestations and less severe immunological features, present a lower disease activity and lower activation of the humoral immune system. Physicians should pay attention to RP, lung and liver involvement in this subset of pSS.

Primary Gougerot-Sjogren Syndrome at the Moulay Ismail Military Hospital in Meknes: Epidemiological, Clinical and Immunological Aspects

Introduction: Gougerot Sjögren's syndrome (GSS) is a connective tissue disease characterized by lymphocytic infiltration of the exocrine glands, and systemic manifestations of an immuno-inflammatory nature. This infiltration is predominant in the salivary and lacrimal glands, responsible for dry mouth and eyes. Clinically, the dry syndrome characteristic of SS may be mild or even absent, and extra glandular systemic manifestations may be the main circumstance in which this connective tissue is discovered. The diagnosis is based on a bundle of arguments, clinical, histological and immunological. SS is characterized by the fairly frequent presence of autoantibodies whose diagnostic value is indisputable, and some of which testify to the activity of the disease. In addition, these autoantibodies may have a correlation with certain organ damage as well as certain progressive forms. The objective of this work is to determine, through a retrospective and comparative study, the epidemiological, clinical and immunological characteristics of patients with primary Gougerot Sjögren's syndrome (SGSp) followed in the internal medicine department of the Military Hospital. Moulay Ismail from Meknes (HMIM), Morocco. Patients and Methods: We report a retrospective study of patients with primary Gougerot-Sjörgen syndrome followed in the internal medicine department of the Moulay Ismail military hospital (Meknes), over a period of 08 years (January 2010 - December 2018). All patients meeting AECG diagnostic criteria were included. Results: 13 cases of S.G.Sp are collected. There was a clear predominance of the female sex, with 12 women (92.3%) and 01 man (7.69%), sex ratio (F/M=12/1). The average age at diagnosis was 48 years with extremes ranging from 20 to 60 years? The clinical picture was dominated by dry syndrome in 100% of cases associated with inflammatory polyarthralgia found in 76.9% of cases. The immunological profile was variable with positive ANA in 61.5% of cases, .......

A rare case report of primary Sjögren’s syndrome with clinical characteristics similar to those of CLIPPERS

BackgroundPrimary Sjögren’s syndrome (pSS) is an autoimmune inflammatory disease characterized by dryness of the eyes, mouth and other mucous membranes. Patients with pSS can also present with extraglandular manifestations, such as pulmonary, kidney and nervous system involvement. Central nervous system (CNS) manifestations have rarely been described in pSS.Case presentationA 33-year-old man was admitted with a one-month history of dizziness, speech disturbance, and walking instability. His brain enhanced magnetic resonance imaging (MRI) showed symmetrical, enhanced “salt-and-pepper-like” speckled lesions in the brainstem, basal ganglia, and subcortical regions, and his diagnosis was considered possible chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Further examination revealed that anti-SSA antibody was positive, and the Schirmer test and labial salivary gland histopathology were abnormal, which supported the diagnosis of pSS.ConclusionpSS is a chronic systemic autoimmune disease that involves neurological complications. This case suggests that CNS lesions of pSS can present with clinical and MRI findings similar to those of CLIPPERS.

Recommendations for evaluation and diagnosis of extra-glandular manifestations of primary Sjögren syndrome: results of an epidemiologic systematic review/meta-analysis and a consensus guideline from the Brazilian society of rheumatology (hepatic, gastrointestinal and pancreatic)

Sjogren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration of the exocrine glands and other organs, associated with sicca syndrome but also with systemic involvement with varying degrees of severity. Despite their importance, some systemic manifestations, mainly liver, gastrointestinal, and pancreatic are not routinely evaluated. To address these manifestations, the Sjögren's Syndrome Committee of the Brazilian Society of Rheumatology conducted a broad systematic review of the literature on studies investigating prevalence and diagnosis of these symptoms in Sjogren´s patients and made recommendations based on the findings. Agreement between the experts was achieved using the Delphi method. This is the second part of this guideline, providing 6 recommendations for liver, gastrointestinal, and pancreatic care of SS patients.

Saliva Free Light Chains in Patients with Neuro-Sjögren.

Background: Sjögren’s syndrome (SS) is an autoimmune disease characterized by sicca symptoms and various extra-glandular manifestations. The diagnosis of SS requires sicca symptoms, anti-SSA(Ro)-antibody positivity, and/or pathological focus scores on a minor salivary gland biopsy. Previous studies have investigated different biomarkers in order to avoid invasive diagnostic procedures. It was found that kappa and lambda free light chains (KFLC and LFLC) in saliva are specific for SS. Methods: FLC concentrations in saliva and serum were determined in 130 patients—50 with SS and neurological involvement (Neuro-Sjögren) and 80 neurological controls. The EULAR SS disease activity index and patient reported index (ESSPRI) were determined in patients with SS. Results: Patients with SS revealed increased pain and decreased saliva production according to the ESSPRI and Saxon test, respectively, with increasing FLC concentrations in the saliva. No significant differences in serum and salivary protein concentrations were observed between patients with SS and controls. Conclusion: KFLC and LFLC concentrations in saliva are not suitable to distinguish patients with Neuro-Sjögren and neurological control subjects, thus a diagnostic biopsy is still required. The association of salivary KFLC and LFLC concentrations with saliva production and ESSPRI pain score suggests a complex relationship between dryness and pain in patients with SS.

The Predictive Role of Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Monocytes-to-Lymphocyte Ratio (MLR) and Gammaglobulins for the Development of Cutaneous Vasculitis Lesions in Primary Sjögren's Syndrome.

Background: In primary Sjögren’s Syndrome (pSS), cutaneous vasculitis lesions (CVL) are extraglandular manifestations with an important clinical and prognostic impact and their early detection might contribute to the improvement of disease control and even patients’ survival. The aim of this study was to evaluate the predictive potential of hematological elements in the development of CVL in pSS patients. Methods: In this single center, retrospective study, a total of 245 participants were included (124 pSS patients and 121 healthy controls). Complete blood count, inflammatory and immunological parameters were determined at the initial visit. pSS patients underwent a periodical follow-up program, when disease progression and response to therapy was monitored, including the emergence of CVL. Results: In pSS, leucocytes, lymphocyte, neutrophil, monocyte, erythrocyte and platelet counts are significantly decreased compared to healthy subjects (p < 0.001), whereas cellular ratios: NLR, PLR, MLR, and immunological and inflammatory parameters are significantly increased (p < 0.001). A total of 34 patients with pSS (27.41%) developed CVL during the follow-up period. The occurrence of CVL was positively correlated with neutrophil and platelet counts (p < 0.001), while for lymphocytes the correlation was negative (p < 0.001). Cellular ratios: NLR, PLR and MLR, and gammaglobulins also revealed significant positive correlations with the emergence of CVL in pSS (p < 0.001). The multivariate analysis confirmed the independent predictive character for CVL emergence in pSS for NLR (CI95% 0.053–0.2, p < 0.002), PLR (CI95% 0.001–0.003, p < 0.003), MLR (CI95% 0.086–0.935, p < 0.019), and gammaglobulins (CI95% 0.423–0.688, p < 0.001). Conclusions: Standard hematological parameters, widely used in the assessment of pSS patients, such as NLR, PLR, MLR and gammaglobulins could become valid elements that might be used for the early detection of patients at risk for the development of CVL.

Increased Threat of Thyroid Diseases in Patients With Sjogren's Syndrome: A Systematic Review.

Sjogren's syndrome is an autoimmune disorder of the body's exocrine glands; however, it is known to have numerous extra-glandular and endocrine manifestations in the body. Moreover, other autoimmune have also been reported with high prevalence in patients with Sjogren's syndrome, including thyroid diseases. Therefore in this study, we aimed to ascertain the increased risk of developing thyroid disorders in patients with pre-existing Sjogren's syndrome. The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Online searches on PubMed, PubMed Central (PMC), Google Scholar, and Cochrane were done till 5th June 2022 to filter out studies published in the last twenty years. Based on the inclusion-exclusion criteria, 167 studies were initially selected. They were screened and assessed by quality assessment tools that yielded seven studies, including one meta-analysis, three non-randomized control trials, and three systematic reviews. The study proved that patients with Sjogren's syndrome are at significant risk of developing thyroid disorders, especially autoimmune thyroiditis. This also highlights the need for advanced research and better diagnostic and screening protocols for these patients to reduce the seriousness of the disease.