Different perception of dry eye symptoms between patients with and without primary Sjogren's syndrome.

Here, we investigated the different perception of dry eye symptoms between in patients with and without primary Sjogren's syndrome (pSS). In this study, 221 patients with dry eye disease (DED) without pSS (non-SS DED group) and 55 patients with DED with pSS (SS DED group) were included. The ocular discomfort was evaluated using ocular surface disease index (OSDI) questionnaire and patients were further divided into 3 severity subgroups according to OSDI scores. The OSDI score was higher in the non-SS DED group even after matching corneal erosion scores despite the ocular surface erosions and tear deficiency was worse in the SS DED group. The corneal sensitivity was nearly normal in both groups without inter-group difference (Non-SS DED group: 5.82 ± 0.54 cm, SS DED group: 5.90 ± 0.29 cm, p = 0.217). Moreover, all clinical parameters were not significantly correlated with OSDI scores in both non-SS DED group and SS DED group. In the mild and severe OSDI subgroups, the ocular surface erosions and tear deficiency were worse in the SS DED group whereas the OSDI scores were not different between groups. In conclusion, clinicians should be aware that pSS patients may complain less of their discomfort unlike their actual severe status of DED.

The impact of SjÓ§gren's syndrome on the quality of sexual life of female patients in the UK: a controlled analysis.

Mucosal dryness and dyspareunia are symptoms that may significantly affect women with primary SjÓ§gren syndrome (pSS). We investigated whether vaginal dryness is correlated with sexual function, and the impact may have on the quality of life (QoL) and mental health well-being in pSS patients. Ethically approved comparative cross-sectional study was designed to assess sexual function using the Female Sexual Function Index (FSFI) in 65 pSS female patients vs 62 sex-matched controls. The effect of vaginal dryness and fatigue on sexual function was investigated. Vaginal dryness was correlated with oral dryness estimated by salivary flow rate and the Clinical Oral Dryness Score to investigate whether genital dryness is indicative of general mucosal dryness in pSS. Validated questionnaires were used to investigate the effect of sexual function on QoL and mental health well-being. The number of sexually active pSS participants was significantly less than in the control group (28/65 vs 42/62, p < 0.05). The sexual function was significantly impaired in the pSS group (mean FSFI = 19 vs 28.3, p < 0.05). There was no significant association between self-reported vaginal dryness and oral dryness or sexual function. The open-ended questions showed that the most troublesome symptom reported by pSS patients was oral dryness (43%, n = 28/65) followed by fatigue (31%, n = 20/65). Sexual dysfunction had a negative impact on QoL and the mental health well-being of pSS patients in all aspects, especially on the quality of social life (ß = 0.7, p = 0.02). Addressing sexual dysfunction can potentially improve the QoL of pSS patients significantly, especially their social well-being.

Cardiac involvement in primary SjÓ§gren's syndrome.

Primary SjÓ§gren's syndrome (pSS) is an autoimmune-mediated, inflammatory, and systemic connective tissue disease (CTD), especially in middle-aged women, which often involves multiple systems and organs of the body. In fact, the heart is an important target organ in patients with pSS. In recent years, it has been confirmed that the morbidity of cardiac involvement has increased in patients with pSS, and cardiovascular disease (CVD) is one of the main causes of death. The increased risk of CVD in pSS patients is associated with a great variety of risk factors, such as age, gender, hypertension, diabetes mellitus, dyslipidemia, disease duration, extra-glandular manifestations, therapeutic drugs of pSS, and so on. Early recognition and effective treatment of CVD may play a crucial role in improving adverse cardiovascular prognosis. Whereas cardiac involvement is closely related to patient prognosis and survival, the cardiac involvement of patients with pSS remains poorly studied. Therefore, this article reviews the cardiovascular risk factors, clinical manifestations of cardiac involvement, cardiovascular biomarkers, and therapeutic strategies of pSS patients.

Trajectory mapping of primary Sjögren's syndrome via transcriptome learning demonstrates limitations of peripheral blood sequencing.

Primary Sjögren's syndrome (pSS) is a complex autoimmune disease characterized by aberrant immune cell action against secretory glands throughout the body. A number of studies have previously identified unique characteristics in the circulating expression profile of white blood cells of pSS patients. However, the molecular progression pattern of pSS is unclear. Through a systematic analysis of pSS transcriptome information, we found that pSS transcriptomes display broad heterogeneity, but cannot be distinguished from the broad range of possible profiles of healthy controls. Instead, only sample learning using a subset of pre-identified signature genes could achieve partial separation through a trajectory governed by interferon activity. Interestingly, this trajectory is correlated with a decrease in dendritic cell counts. Our study thus highlights a major limitation to the utility of broad blood transcriptome analysis in the context of pSS, while also identifying several factors that influence the divergence between patient samples.

Asymptomatic myocardial dysfunction was revealed by feature tracking cardiac magnetic resonance imaging in patients with primary Sjögren's syndrome.

AIM: To evaluate subclinical left ventricular (LV) regional dysfunction in patients with primary Sjögren's syndrome (pSS) using feature tracking cardiac magnetic resonance (FT-CMR) imaging and to identify pSS characteristics independently associated with LV regional dysfunction. METHOD: Fifty patients with pSS and 20 controls without cardiovascular disease underwent non-contrast CMR imaging. Labial gland biopsy was performed in 42 patients (84%). Disease activity was assessed using the European League Against Rheumatism Sjögren's syndrome disease activity index (ESSDAI). LV global longitudinal strain (GLS), global circumferential strain (GCS), and global radial strain (GRS) were measured using FT-CMR. RESULTS: No significant differences in cardiovascular risk factors were found between the pSS group and controls. The pSS group had significantly lower GLS (P = .015) and GCS (P = .008) than the control group. Multiple linear regression analysis indicated that GCS was significantly associated with Raynaud's phenomenon (P = .015), focus score ≥2 (P = .032), and total ESSDAI score ≥8 (P = .029). CONCLUSION: FT-CMR can reveal subclinical LV regional dysfunction in patients with pSS without cardiovascular disease. Furthermore, patients with pSS and Raynaud's phenomenon, a focus score ≥2, or an ESSDAI score ≥8 were considered to be at high risk for myocardial dysfunction.

Characterization of Lipids in Saliva, Tears and Minor Salivary Glands of Sjögren's Syndrome Patients Using an HPLC/MS-Based Approach.

The diagnostic work-up of primary Sjögren's syndrome (pSS) includes quantifying saliva and tear production, evaluation of autoantibodies in serum and histopathological analysis of minor salivary glands. Thus, the potential for further utilizing these fluids and tissues in the quest to find better diagnostic and therapeutic tools should be fully explored. Ten samples of saliva and tears from female patients diagnosed with pSS and ten samples of saliva and tears from healthy females were included for lipidomic analysis of tears and whole saliva using high-performance liquid chromatography coupled to time-of-flight mass spectrometry. In addition, lipidomic analysis was performed on minor salivary gland biopsies from three pSS and three non-SS females. We found significant differences in the lipidomic profiles of saliva and tears in pSS patients compared to healthy controls. Moreover, there were differences in individual lipid species in stimulated saliva that were comparable to those of glandular biopsies, representing an intriguing avenue for further research. We believe a comprehensive elucidation of the changes in lipid composition in saliva, tears and minor salivary glands in pSS patients may be the key to detecting pSS-related dry mouth and dry eyes at an early stage. The identified differences may illuminate the path towards future innovative diagnostic methodologies and treatment modalities for alleviating pSS-related sicca symptoms.

Rhinological manifestations of Sjögren's syndrome: a cohort-matched, prospective, cross-sectional, observational study.

OBJECTIVE: To assess the prevalence of abnormal rhinological findings in a Sjögren's syndrome population. METHODS: A cohort-matched, prospective, cross-sectional, observational study was conducted. Sixty-seven subjects (30 patients and 37 controls) were enrolled. Rhinological assessment including smell threshold was evaluated using a standardised, validated clinical test as part of a larger study. RESULTS: Smell thresholds were -4.4 and -5.4 in the Sjögren's syndrome and control groups, respectively (p = 0.001). Hyposmia (threshold values of less than -4.5) was demonstrated in the Sjögren's syndrome group (47 per cent). Smell was negatively correlated with age (p = 0.040). Nasal septal perforation was noted in 3 Sjögren's syndrome patients (10 per cent) and nasal mucosal dryness in 10 patients (33 per cent), but none of the control group were affected. CONCLUSION: Hyposmia in Sjögren's syndrome was demonstrated using the Smell Threshold Test. Nasal septal perforation and nasal mucosa dryness were also noted in patients with Sjögren's syndrome. A diagnosis of Sjögren's syndrome should be considered and investigated in smell deprivation and/or nasal septal perforation patients.

Metformin as a Treatment Strategy for Sjögren's Syndrome.

Sjögren's syndrome (SS), a chronic inflammatory disease involving the salivary and lacrimal glands, presents symptoms of sicca as well as systemic manifestations such as fatigue and musculoskeletal pain. Only a few treatments have been successful in management of SS; thus treatment of the disease is challenging. Metformin is the first-line agent for type 2 diabetes and has anti-inflammatory potential. Its immunomodulatory capacity is exerted via activation of 5' adenosine monophosphate-activated protein kinase (AMPK). Metformin inhibits mitochondrial respiratory chain complex I which leads to change in adenosine mono-phosphate (AMP) to adenosine tri-phosphate (ATP) ratio. This results in AMPK activation and causes inhibition of mammalian target of rapamycin (mTOR). mTOR plays an important role in T cell differentiation and mTOR deficient T cells differentiate into regulatory T cells. In this manner, metformin enhances immunoregulatory response in an individual. mTOR is responsible for B cell proliferation and germinal center (GC) differentiation. Thus, reduction of B cell differentiation into antibody-producing plasma cells occurs via downregulation of mTOR. Due to the lack of suggested treatment for SS, metformin has been considered as a treatment strategy and is expected to ameliorate salivary gland function.

Intrathecal drug delivery to treat intractable neuropathic pain following Sjögren's syndrome-induced transverse myelitis: A case report.

RATIONALE: Transverse myelitis (TM) is a spinal cord inflammatory myelopathy that causes motor/sensory loss and urinary retention below the level of the affected spinal cord. Although a few case reports have described the control of neuropathic pain in patients with TM via spinal cord stimulation, no documented case regarding the control of severe allodynia following TM via intrathecal pump has been described. PATIENT CONCERNS: A 37-year-old woman was referred to a pain clinic for severe intractable pain below the T5 level followed by Sjögren's syndrome-induced TM. DIAGNOSES: A neurological examination revealed paresthesia and allodynia below the T5 level. The sensory evaluation was limited by extreme pain and jerking movements. The muscle strength of both lower limbs was grade 3. INTERVENTIONS: Intrathecal pump was inserted into the left lower abdomen. Catheter tip was placed at the midline of the T8 level. OUTCOMES: The numeric rating scale (NRS) for pain score decreased from 10 to 5. Functional Independence Measure score increased from 67 before implantation to 92 at the time of discharge, while the patient's Barthel score increased from 31 to 46. LESSONS: Neuropathic pain due to Sjögren's syndrome-related TM could be controlled effectively using the intrathecal morphine pump.

A new molecular classification to drive precision treatment strategies in primary Sjögren's syndrome.

There is currently no approved treatment for primary Sjögren's syndrome, a disease that primarily affects adult women. The difficulty in developing effective therapies is -in part- because of the heterogeneity in the clinical manifestation and pathophysiology of the disease. Finding common molecular signatures among patient subgroups could improve our understanding of disease etiology, and facilitate the development of targeted therapeutics. Here, we report, in a cross-sectional cohort, a molecular classification scheme for Sjögren's syndrome patients based on the multi-omic profiling of whole blood samples from a European cohort of over 300 patients, and a similar number of age and gender-matched healthy volunteers. Using transcriptomic, genomic, epigenetic, cytokine expression and flow cytometry data, combined with clinical parameters, we identify four groups of patients with distinct patterns of immune dysregulation. The biomarkers we identify can be used by machine learning classifiers to sort future patients into subgroups, allowing the re-evaluation of response to treatments in clinical trials.

A 63-Year-Old Woman With an Acute Exacerbation of Interstitial Pneumonia.

CASE PRESENTATION: A 63-year-old, non-smoking Asian woman presented to our hospital due to abnormal findings on chest radiography. She had no history of dust exposure. Chest radiography and CT imaging showed patchy ground-glass attenuation (GGA) in the bilateral lower lung lobes, a ground-glass nodule in the right lower lung lobe (diameter, 9.8 mm), and some thin-walled cysts in both lungs (Fig 1). Thickening of the interlobular septa, mediastinal lymphadenopathy, and pleural effusion were not evident. Video-assisted thoracic surgery was performed for the examination of the nodule and the background lung disease, and the nodule was histologically diagnosed as lung adenocarcinoma. Simultaneously, the lung background showed diffuse lymphocytic infiltration in the alveolar septum and peribronchovascular interstitium (Fig 2). There were no symptoms suggestive of autoimmune diseases such as dryness, arthralgia, skin rash, or fever. The patient was followed up without treatment for the interstitial lung disease.

Identification of the key genes and pathways involved in B cells in primary Sjögren' s syndrome.

Primary Sjögren' s syndrome (pSS) is a relatively common autoimmune disease, which mainly involves the exocrine glands, causing dry eye, dryness of mouth, fatigue and pain in the joints, thus severely affecting the normal lives of patients. B cell populations are considered to play an important role in their pathogenesis and pSS patients are generally characterized by exhibiting biological signs of B cell activation. Moreover, another important characterized change in the peripheral blood of pSS patients is found to be the decreased number of circulating memory B cells. However, the mechanisms underlying the B cell activation and the decreased level of circulating memory B cells in pSS patients are still unclear. Therefore, we identified key genes and pathways involved in B cells in pSS through a combination of several bioinformatic approaches including Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) and weighted gene co-expression network analysis (WGCNA) using gene expression data of pSS patients and controls from an open database Gene Expression Omnibus (GEO). The results may provide some novel insights into the pathogenesis of pSS. Moreover, we constructed and validated a diagnostic model for pSS by using the expression patterns of these key genes, which may assist clinicians in diagnosing pSS.

Ocular Pathophysiology of Sjögren's Syndrome.

The purpose of this review is to delve into the clinical and research understanding of the pathophysiology and presentation of Sjögren's-related keratoconjunctivitis sicca in order address the diagnostic and management challenge that it represents, as well as to provide a basis for appreciating the pharmacotherapies designed to treat the ophthalmic symptoms of Sjögren's disease.

The Role of Interferons in the Pathogenesis of Sjögren's Syndrome and Future Therapeutic Perspectives.

There is a great deal of evidence pointing to interferons (IFNs) as being key cytokines in the pathogenesis of different systemic autoimmune diseases, including primary Sjögren's syndrome (pSS). In this disease, a large number of studies have shown that an overexpression of type I IFN, the 'so-called' type I IFN signature, is present in peripheral blood mononuclear cells, and that this finding is associated with the development of systemic extra-glandular manifestations, and a substantial production of autoantibodies and inflammatory cytokines. In contrast, the absence or a milder expression of type I IFN signature and low level of inflammatory cytokines characterizes patients with a different clinical phenotype, where the disease is limited to glandular involvement and often marked by the presence of widespread pain and depression. The role of type II (IFNγ) in this subset of pSS patients, together with the potentially related activation of completely different immunological and metabolic pathways, are emerging issues. Expression of both types of IFNs has also been shown in target tissues, namely in minor salivary glands where a predominance of type II IFN signature appeared to have a certain association with the development of lymphoma. In view of the role played by IFN overexpression in the development and progression of pSS, inhibition or modulation of IFN signaling has been regarded as a potential target for the therapeutic approach. A number of therapeutic compounds with variable mechanisms of action have been tested or are under consideration for the treatment of patients with pSS.

Unstimulated whole salivary flow in Sjögren's Syndrome: systematic literature review and meta-analysis.

BACKGROUND: Sjögren's Syndrome compromises the exocrine function, producing xerostomia and xerophthalmia. It can appear as an isolated condition or associated with other autoimmune diseases (polyautoimmunity). The Unstimulated Salivary Flow rate (UWSF) is used to quantify saliva production. There is no objective evidence to differentiate the values in patients with Sjögren's versus healthy people or patients with non-Sjögren's sicca. The objective of the present review was to evaluate the UWSF in patients with Sjögren's syndrome in comparison to controls (healthy and non-Sjögren's sicca patients). METHODS: A systematic literature review was carried out (PRISMA guidelines). Analytical observational studies of cases and controls, cross-sectional studies, cohort studies and randomized clinical trials (including healthy controls) were considered. The Medline/OVID, Lilacs, Embase, and Cochrane/OVID databases were consulted. MeSH, DeCS, keywords, and Boolean operators were used. The meta-analysis (RevMan 5.2) was done through the random-effects model [mean difference (MD)]. Level and quality of evidence were evaluated by the Oxford Center Levels of Evidence and Joanna Brigs list respectively. RESULTS: Thirty-two articles were included (20 were case-control studies, 6 were cross-sectional, 2 prospective cohort, 2 retrospective cohort, and 2 studies were abstracts) and 28 were meta-analyzed. The unstimulated whole salivary flow rate in the Sjögren's group was lower than in controls (healthy and patients with non-Sjögren Sicca syndrome) (MD-0.18 ml/min; 95% CI, - 0.24 to - 0.13; chi2-P-value < 0.00001). Heterogeneity was 97% and there was publication bias (funnel plot). The level of evidence was mostly 3 or 4. The quality of evidence was met (97% of items valued). CONCLUSION: For the first time, the unstimulated whole salivary flow rate is found to be lower in patients with Sjögren's syndrome compared to controls (healthy and non-SS sicca) through a meta-analysis. TRIAL REGISTRATION: PROSPERO CRD42020211325 .

New frontiers in precision medicine for Sjogren's syndrome.

Introduction: Sjögren's syndrome is a unique systemic autoimmune disease, placed in the center of systemic autoimmunity and at the crossroads of autoimmunity and lymphoproliferation. The diverse clinical picture of the disease, the inefficacy of current biologic treatments, and the co-existence with lymphoma conferring to the patients' morbidity and mortality force the scientific community to review disease pathogenesis and reveal the major implicated cellular and molecular elements.Areas covered: Biomarkers for early diagnosis, prediction, stratification, monitoring, and targeted treatments can serve as a tool to interlink and switch from the clinical phenotyping of the disease into a more sophisticated classification based on the underlying critical molecular pathways and endotypes. Such a transition may define the establishment of the so-called precision medicine era in which patients' management will be based on grouping according to pathogenetically related biomarkers. In the current work, literature on Sjogren's syndrome covering several research fields including clinical, translational, and basic research has been reviewed.Expert opinion: The perspectives of clinical and translational research are anticipated to define phenotypic clustering of high-risk pSS patients and link the clinical picture of the disease with fundamental molecular mechanisms and molecules implicated in pathogenesis.

Clinical features and outcomes from the Singapore Sjögren's syndrome study.

OBJECTIVE: To study the clinical features, treatment and outcomes of primary Sjögren's Syndrome (pSS) in a Singapore cohort from an outpatient rheumatology clinic. METHODS: Computerised Physician Order entry records of patients who fulfilled the 2016 ACR-EULAR classification criteria for pSS between 1993 and 2013 were retrospectively analysed. RESULTS: There were 102 patients, of which 96 (94.1%) were females, and 91 (89.2%) Chinese. Mean age at diagnosis was 49.3 ± 11.8 years, mean disease duration was 9.0 ± 4.6 years. The most common manifestations were keratoconjunctivitis sicca (99.0%), xerostomia (96.1%), arthralgia/arthritis (56.9%). Exocrine glandular enlargement comprised parotidomegaly (28, 27.5%), with concurrent submandibular and lacrimal gland enlargement in one. The nervous system (15.7%) was the most commonly affected internal organ, with peripheral nervous system (peripheral neuropathy, mononeuritis multiplex) involvement more common than central. Hydroxychloroquine was most frequently used (88.2%), followed by methotrexate (7.8%) and azathioprine (6.9%). Pulsed intravenous (IV) methylprednisolone 500 mg/day for 3 days was used in 5 patients followed by oral (4) or IV cyclophosphamide (1) for cardiomyopathy and interstitial lung disease (1), and neurological involvement (4). These comprised neuromyelitis optica, transverse myelopathy, cranial neuropathy, mononeuritis multiplex and/or peripheral neuropathy alone or in combination. Intravenous immunoglobulins (2.0%) was used for sensory neuropathy and mononeuritis multiplex; rituximab (1.0%) in 1 patient for treatment of non-Hodgkin's B-cell lymphoma. There were no deaths. CONCLUSION: Musculoskeletal manifestations were common, with the nervous system (peripheral more than central) the most common internal organ involved. Lymphoma was uncommon despite up to one-third of the cohort developing glandular enlargement.

A New Screening Questionnaire to Identify Patients With Dry Eye With a High Likelihood of Having Sjögren Syndrome.

PURPOSE: To develop a screening questionnaire to identify patients with dry eye with a high likelihood of having underlying Sjögren syndrome (SS). METHODS: This was a cross-sectional study of participants with dry eye complaints who were self-referred or referred by an ophthalmologist to the Sjögren's International Collaborative Clinical Alliance study. Symptoms and ocular surface examination findings were candidate predictors. Univariable and multivariable logistic regression analyses were performed to estimate odds ratios (ORs) and 95% confidence intervals (95% CI) for the association of a symptom and/or ocular sign with SS. Area under the receiver operating characteristic curve (AUC) was used to summarize the predictive ability of different regression models and the derived likelihood score. RESULTS: Four questions were statistically significant in the final multivariable model: 1) Is your mouth dry when eating a meal? [Yes = OR 1.63 (1.18-2.26)]; 2) Can you eat a cracker without drinking a fluid or liquid? [No = OR 1.46 (1.06-2.01)]; 3) How often do you have excessive tearing? [None of the time = OR 4.06 (1.81-9.10)]; and 4) Are you able to produce tears? [No = OR 2.24 (1.62-3.09)]. The SS likelihood score had an AUC of 0.70 (95% CI, 0.66-0.73), and when including tear break-up time and conjunctival staining, it yielded an AUC of 0.79 (95% CI, 0.77-0.82). CONCLUSIONS: This questionnaire can be used to identify patients with dry eye with a high likelihood of having SS. With future refinement and validation, this screening tool could be used alone or in combination with examination findings to identify patients with SS earlier, thereby facilitating better clinical outcomes.