EULAR Sjögren's Syndrome Disease Activity Index Research Articles

Improved Fatigue Management in Primary Sjögren's Syndrome: A Retrospective Analysis of the Efficacy of Methotrexate in Chinese Patients.

To assess the efficacy of methotrexate (MTX) and hydroxychloroquine (HCQ) in improving fatigue symptoms in patients with primary Sjögren's syndrome (pSS). A single-center retrospective study was conducted on pSS patients experiencing fatigue symptoms. All patients received either MTX, HCQ, or a combination of MTX + HCQ for a period of six months. Clinical efficacy was measured using the European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI), EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), fatigue severity scale (FSS), and visual analog scale (VAS) score. These measures were assessed at baseline and at 1, 2, 3, and 6 months. A total of 86 pSS patients with fatigue symptoms were enrolled (27 received MTX, 29 received HCQ, and 30 received MTX + HCQ). Patients receiving MTX and MTX + HCQ showed significant improvements at 6th month in ESSDAI, ESSPRI, FSS, FACIT-F, and VAS scores (all P < 0.01) compared with baseline. Repeated-measures analysis of variance revealed that patients treated with MTX and MTX + HCQ experienced significant improvements in ESSDAI, FSS, FACIT-F, and VAS scores (all P < 0.01) from baseline to the 6th month. The HCQ group did not show significant improvement in FSS, FACIT-F, and VAS scores (all P > 0.05), although their ESSDAI and ESSPRI scores did improve significantly (all P < 0.01). Patients in the MTX group showed the most improvement in mean changes of ESSDAI score, FSS score, FACIT-F score, and VAS score from baseline to the 6th month. And patients received MTX treatment significantly had more fatigue remission numbers (all P < 0.05). In clinical practice, methotrexate is more effective than hydroxychloroquine in improving fatigue symptoms, as measured by patient-reported fatigue scales (FSS, FACIT-F, and VAS scores) in patients with pSS.

A biopsychosocial questionnaire for patients with primer Sjögren's syndrome: The BETY-Biopsychosocial Questionnaire.

The BETY-Biopsychosocial Questionnaire (BETY-BQ) is a scale developed to assess the biopsychosocial domains of patients with rheumatic diseases under a single roof. The study aimed to determine the validity and reliability of the BETY-BQ in patients with primary Sjögren's Syndrome (pSS). At enrollment and one week, 91 patients with pSS completed the BETY-BQ. Construct validity was measured by correlating the BETY-BQ total score responses with the Health Assessment Questionnaire (HAQ), Hospital Anxiety and Depression Scale (HADS), 36-Item Short-Form Health Survey (SF-36), EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), Primary Sjögren's Syndrome Quality of Life questionnaire (PSS-QoL), and Euro-QoL 5D (EQ-5D). The BETY-BQ correlated high to moderate with HAQ, bodily pain subscale of SF-36, Euro Qol-5D, PSS-QoL, HADS, and ESSPRI (0.776 to 0.557, p <0.05). Spearman's correlation coefficients between BETY-BQ total scores at baseline and average one week were very high (rho = 0.98, <0.001) and indicated substantial agreement between test-retest scores (ICC = 0.99, <0.001). Internal consistency reliability at baseline was 0.91 for the BETY-BQ. BETY-BQ is valid and reliable for assessing biopsychosocial status in patients with pSS and can be used to measure outcomes in pSS.

Long-term survival analysis of patients with primary Sjögren's syndrome in China: A multicenter retrospective cohort study.

This study aimed to evaluate the long-term survival, causes of death, and prognostic factors in Chinese patients with primary Sjögren syndrome (pSS). We included patients with pSS registered in the Chinese Rheumatism Data Centre between May 2016 and December 2021, and collected baseline clinical, laboratory, and treatment data. Survival and standard mortality rates were calculated using general population mortality data. Factors related to mortality were identified using Cox proportional hazards regression. Among the 8588 patients included, 274 died during a median follow-up of 4.0 years. The overall standardized mortality ratio was 1.61 (95% CI: 1.43-1.81). Overall survival rates were 98.2% at 5 years and 93.8% at 10 years. The predominant causes of death were comorbidities, including cardiovascular diseases, tumors, and infections, while the most frequent pSS-related causes of death were interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). Male sex, older age, ILD, PAH, and high EULAR Sjögren's syndromedisease activity index (ESSDAI), thrombocytopenia, anemia, high immunoglobulin A (IgA) level, and glucocorticoid treatment independently increased the mortality risk, while using hydroxychloroquine was a protective factor. Mortality rates have significantly increased in Chinese patients with pSS. Comorbidities, rather than pSS-related organ damage, were the main causes of death. All-cause mortality was associated with male sex, older age, ILD, PAH, high ESSDAI, thrombocytopenia, anemia, high IgA level, and glucocorticoid treatment, whereas hydroxychloroquine use might improve the long-term survival.

Subjective Symptoms and Disease Activity Related to Serum Zinc Concentration in Primary Sjögren's Syndrome.

Background/Objectives: We examined the frequency of zinc deficiency in patients with Sjögren's syndrome (SS) and the relationship between zinc deficiency and each of the subjective symptoms and disease activity. Methods: We enrolled 164 patients aged ≥ 20 years with primary SS (pSS) based on the revised diagnostic criteria of the Ministry of Health, Labor and Welfare (1999) and 144 patients with RA diagnosed according to the ACR/EULAR classification criteria for RA (2010) as a comparison group. Subjective symptoms were confirmed using an original questionnaire, and disease activity was determined using the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI). The serum zinc concentrations were measured in both SS and RA patients. Results: The rate of zinc deficiency in the SS group was 26.1%, significantly higher than that in the RA group (7.6%). The rate of zinc deficiency was significantly higher in the pSS group compared with Japanese health checkup recipients reported in the literature. The mean serum zinc concentration in primary SS was 60.6 ± 7.3 µmol/L in the high disease activity group with an ESSDAI of ≥5 points, which was significantly lower than the concentration of 69.7 ± 10.2 µmol/L in patients with an ESSDAI of ≤4 points. Conclusions: The frequency of zinc deficiency was higher in patients with pSS than in patients with RA. Disease activity was also higher in patients with zinc deficiency, suggesting an association between zinc concentration and organ involvement in pSS.

ANA-associated arthritis: clinical and biomarker characterization of a population for basket trials.

ANA-associated rheumatic and musculoskeletal (MSK) diseases (RMDs) [SLE, primary SS (pSS), scleroderma, inflammatory myositis, MCTD and UCTD] make up a disease spectrum with overlapping clinical and immunological features. MSK inflammation is common and impactful across ANA-associated RMDs. The objectives of this study were to evaluate MSK inflammation (ANA-associated arthritis) prevalence in a multidisease ANA-associated RMD study, assess its clinical impact across ANA-associated RMD diagnoses, propose new basket groupings of patients, and evaluate immunological profiles in legacy and new basket contexts. An observational study enrolled patients with ANA-associated RMDs. Demographic variables, comorbidities, therapies, disease activity instruments [BILAG, SLEDAI, the EULAR SS disease activity index (ESSDAI), physician visual analogue scale (VAS)], patient-reported outcomes [SF36, FACIT-Fatigue, EQ5D, ICECAP-A, Work Productivity and Activity impairment (WPAI), patient VAS] and the biomarker profile (six-gene expression scores, flow cytometry, autoantibody profile) were analysed. Reclustering utilized Gaussian mixture modelling (GMM). The clinical and immune features of new and legacy clusters were compared. Inflammatory MSK symptoms were prevalent across ANA-associated RMDs, in 213/294 patients. In ANA-associated arthritis patients, most variables did not differ between diagnoses, with the exception of the EQ5D-5L index and mobility domains (lower in MCTD/pSS, both P < 0.05). FM and OA prevalence were similar across diagnoses. Therapy use differed significantly, the use of biologics being greatest in SLE (P < 0.05). GMM yielded two multidisease clusters: High MSK disease activity (n = 89) and low MSK disease activity (n = 124). The high MSK disease activity cluster included all patients with active joint swelling, and they had significantly higher prednisolone usage, physician global assessment (PGA), Sm/RNP/SmRNP/chromatin positivity, Tetherin mean fluorescence intensity (MFI), and IFN Score-A activity, along with numerically lower FM and OA prevalence. We defined ANA-associated arthritis, a more clinically and immunologically homogeneous population than existing RMD populations for trials, and a more prevalent population for therapies in the clinic.

Safety and efficacy of subcutaneous iscalimab (CFZ533) in two distinct populations of patients with Sjögren's disease (TWINSS): week 24 results of a randomised, double-blind, placebo-controlled, phase 2b dose-ranging study

Sjögren's disease is a chronic autoimmune disease with an unmet need for targeted therapies. The aim of the TWINSS study is to evaluate the safety and efficacy of iscalimab, a monoclonal antibody against CD40, in patients with active Sjögren's disease. This randomised, double-blind, placebo-controlled, phase 2b study, conducted at 71 sites in 23 countries, enrolled patients aged 18 years or older fulfilling the American College of Rheumatology/European Alliance of Associations for Rheumatology (EULAR) 2016 criteria. In the dose-ranging cohort 1, patients with a EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score of 5 or higher and a EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of 5 or higher were randomly assigned (1:1:1:1) to subcutaneous iscalimab 150 mg, 300 mg, 600 mg, or placebo. In the proof-of-concept cohort 2, patients with an ESSDAI score of less than 5, ESSPRI (dryness or fatigue) score of 5 or higher, and Impact of Dry Eye on Everyday Life score of 30 or higher were randomly assigned (1:1) to iscalimab 600 mg or placebo. The sponsor, investigator, site personnel, and patients were masked to the treatment assignment. The primary objectives were to demonstrate a dose-response relationship of iscalimab based on the change in ESSDAI from baseline to week 24 in cohort 1 by Multiple Comparison Procedure-Modelling (MCP-Mod), and to assess the effect of iscalimab 600 mg on ESSPRI at week 24 in cohort 2. All the efficacy analyses included all patients who were randomly assigned, and safety analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03905525), and is complete. Between Oct 1, 2019, and Feb 28, 2022, 460 patients were screened; 173 patients were assigned to cohort 1 (44 to iscalimab 150 mg, 43 to 300 mg, 43 to 600 mg, and 43 to placebo) and 100 to cohort 2 (50 to each group). In cohort 1, the MCP step showed a significant dose-response relationship for placebo-adjusted ESSDAI change from baseline in one of four models (Linlog model, one-sided p=0·0041). ESSDAI decreased from baseline to week 24 with all three doses of iscalimab; 150 mg and 600 mg doses showed statistically significant improvement (placebo-adjusted least squares [LS] mean difference -3·0 [95% CI -4·9 to -1·1]; p=0·0025 for 150 mg and -2·9 [-4·9 to -1·0]; p=0·0037 for 600 mg). In cohort 2, ESSPRI showed a trend towards improvement with iscalimab 600 mg (placebo-adjusted LS mean change from baseline -0·57 points [95% CI -1·30 to 0·15]; p=0·12). Serious adverse events were reported in nine patients in cohort 1 (one [2%] of 43 in the placebo group, one [2%] of 44 in the iscalimab 150 mg group, three [7%] of 42 in the 300 mg group, four [9%] of 44 in the 600 mg group) and four patients in cohort 2 (two [4%] of 50 in each group). No deaths occurred over the 24-week period. The study met the primary objective of demonstrating a significant dose-response relationship with iscalimab in terms of disease activity at week 24. Iscalimab was well tolerated and showed initial clinical benefit over placebo in two distinct populations of patients with Sjögren's disease, to be confirmed in larger trials. Novartis Pharma.

Do Disease Parameters Related to Primary Sjögren's Syndrome have an Impact on the Severity of Co-Existing Fibromyalgia Syndrome or Vice Versa?

Abstract Objectives We aimed to examine whether primary Sjögren's syndrome (pSS)-related parameters may affect the severity of co-existing fibromyalgia syndrome (FMS) in pSS patients or vice versa; co-existing FMS might have an influence on the severity of sicca symptoms and disease activity measurements in pSS. Method Our study included a total of 49 pSS patients (24 with concomitant FMS; 25 without FMS) and 30 patients with primary FMS (pFMS). The EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) and the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) were used to evaluate pSS symptoms and disease activity. Sicca symptom severity (SSS) scores were recorded on a visual analogue scale for pSS patients. A minor salivary gland biopsy was performed in 34 pSS patients. The Revised Fibromyalgia Impact Questionnaire (FIQR) was used to evaluate the total spectrum of fibromyalgia-related problems. Results There was no statistically significant difference between disease activity measurements (ESSDAS, ESSPRI) in pSS patients with FMS and pSS patients (p=0.913, p=0.952, respectively). However, SSS scores were significantly higher in pSS patients with FMS than in pSS patients (p=0.045). There was no statistically significant difference between pFMS and pSS patients with FMS in terms of FIQR scores (p=0.149). Conclusions It was demonstrated that the severity of fibromyalgia assessed by FIQR is comparable between both groups.

Recommendations on cutaneous and hematological manifestations of Sjögren’s disease by the Brazilian Society of Rheumatology

Sjogren’s disease (SjD) is an autoimmune disease that is characterized not only by the sicca symptoms it causes but also by its systemic nature, which is capable of several and not yet fully understood extraglandular manifestations. To gain a clearer understanding of these manifestations as well as a better practical approach, a panel of experts from the Brazilian Society of Rheumatology conducted a systematic review and meta-analysis on the identification of epidemiologic and clinical features of the extraglandular manifestations present in ESSDAI (EULAR Sjogren´s syndrome disease activity index), followed by a voting panel with recommendations for clinical practice. This publication is complementary to others already published and covers cutaneous and hematological manifestations, with prevalence data generated by a meta-analysis of 13 clinical or laboratory manifestations and 6 clinical management recommendations.

Elevated unphosphorylated STAT1 and IRF9 in T and B cells of primary sjögren's syndrome: Novel biomarkers for disease activity and subsets

ObjectivesAutoreactive B cells and interferon (IFN) signature are hallmarks of primary sjögren's syndrome (pSS), but how IFN signaling pathways influence autoantibody production and clinical manifestations remain unclear. More detailed studies hold promise for improved diagnostic methodologies and personalized treatment. MethodsWe analyzed peripheral blood T and B cell subsets from 34 pSS patients and 38 healthy donors (HDs) at baseline and upon stimulation regarding their expression levels of type I and II IFN signaling molecules (STAT1/2, IRF1, IRF9). Additionally, we investigated how the levels of these molecules correlated with serological and clinical characteristics and performed ROC analysis. ResultsPatients showed elevated IFN pathway molecules, including STAT1, STAT2 and IRF9 among most T and B cell subsets. We found a reduced ratio of phosphorylated STAT1 and STAT2 in patients in comparison to HDs, although B cells from patients were highly responsive by increased phosphorylation upon IFN stimulation. Correlation matrices showed further interrelations between STAT1, IRF1 and IRF9 in pSS. Levels of STAT1 and IRF9 in T and B cells correlated with the IFN type I marker Siglec-1 (CD169) on monocytes.High levels of STAT1 and IRF9 within pSS B cells were significantly associated with hypergammaglobulinemia as well as anti-SSA/anti-SSB autoantibodies. Elevated STAT1 levels were found in patients with extraglandular disease and could serve as a biomarker for this subgroup (p < 0.01). Notably, IRF9 levels in T and B cells correlated with EULAR Sjögren's syndrome disease activity index (ESSDAI). ConclusionHere, we provide evidence that in active pSS patients, enhanced IFN signaling incl. unphosphorylated STAT1 and STAT2 with IRFs entertain chronic T and B cell activation. Furthermore, increased STAT1 levels candidate as biomarker of extraglandular disease, while IRF9 levels can serve as biomarker for disease activity.

Comprehensive analysis of the clinical manifestations and hematological parameters associated with secondary immune thrombocytopenia in patients with primary Sjögren syndrome: An observational study.

Primary Sjögren Syndrome (pSS) is a chronic autoimmune disease that primarily affects exocrine glands and can lead to various extraglandular manifestations, including secondary immune thrombocytopenia (ITP). Understanding the clinical and hematological differences in pSS patients with and without secondary ITP is crucial for improved patient management and treatment strategies. This retrospective study, conducted from January 2020 to December 2023, involved a cohort of pSS patients, dividing them into 2 groups: those with secondary ITP and those without. Patients were evaluated using the European League Against Rheumatism Sjögren Syndrome Disease Activity Index (ESSDAI), EULAR Sjögren Syndrome Patient-Reported Index (ESSPRI), Health Assessment Questionnaire, and other hematological parameters. Inclusion criteria were based on the American-European Consensus Group or ACR/EULAR classification criteria for pSS. Exclusion criteria included other autoimmune or hematological disorders, prior splenectomy, recent blood transfusions, and lack of informed consent. Statistical analysis was performed using SPSS software, with various tests applied to analyze the data, including logistic regression to identify risk factors for secondary ITP. Significant differences were noted in fatigue, lymphadenopathy, arthritis, mean age, and ESSDAI scores between the secondary ITP and non-secondary ITP groups. Patients with secondary ITP exhibited higher platelet counts, more prevalent lymphopenia, higher immunoglobulin G (IgG) levels, lower complement 3 levels, and reduced white blood cell and hemoglobin levels. Logistic regression analysis identified lymphadenopathy as a risk factor and arthritis as a protective factor for the development of secondary ITP. The study reveals distinct clinical and hematological characteristics in pSS patients with secondary ITP, suggesting a higher disease activity in this subset. These findings underscore the need for further exploration of these associations to develop more precise treatment approaches for pSS, focusing on preventing secondary ITP and improving patient outcomes.

Central sensitization significantly deteriorates functionality and the interpretation of self-reported disease activity in primary Sjögren's syndrome.

Central sensitization has a major role in health-related parameters in musculoskeletal conditions. There is still a lack of understanding regarding the impact of central sensitization on the interpretation of disease activity and functional disability in primary Sjögren's syndrome (pSS). The Central Sensitization Inventory (CSI) was used to screen for central sensitization. Disease-related parameters, including objective tests, medication use, the EULAR SS Patient Reported Index (ESSPRI), and the EULAR SS Disease Activity Index (ESSDAI), were assessed. Functionality, quality of life, sleep, and mental health were evaluated by the Health Assessment Questionnaire-Disability Index (HAQ-DI), Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), Jenkins Sleep Evaluation Scale (JSS), and Hospital Anxiety and Depression Scale (HADS), respectively. The effect of central sensitization on functionality and disease activity measures was assessed by regression analyses. The frequency of central sensitization was 65% in patients with pSS (n = 60). Patients with central sensitization had higher HAQ-DI, ESSPRI, HADS, and JSS and lower SF-36 subdomain scores (p < 0.05 for all). A significant positive correlation was observed between the CSI scoreand theESSPRI, JSS, HAQ-DI, and HADS scores (Spearman's rho ranging from 0.342 to 0.739). The multiple regression analysis indicated that CSI was independently associated with HAQ-DI (adjusted R2 = 0.19, B = 0.01) and ESSPRI (adjusted R2 = 0.45, B = 0.08) (p < 0.001 for all). This study confirms that central sensitization has a major impact on functionality and the interpretation of self-reported disease activity in pSS. When devising strategies for the management of patients with pSS, it is crucial to consider these close relationships. Key Points • The frequency of central sensitization accompanying primary Sjögren's syndrome is considerable. • Central sensitization was independently associated with functionality and self-reported disease activity assessment. • This close association leads to challenges in functionality, evaluating treatment response, and planning or switching between therapies in primary Sjögren's syndrome.

P153 Exploring the relationships between objective and subjective clinical measures in Sjogren's Syndrome

Abstract Background/Aims Patient Reported Outcome Measures (PROMs) are standardised, validated questionnaires designed to measure the patient’s perception of their disease. Discordance between the patient’s perspective and objective clinical measures (clinical scores, laboratory data) has led to increased interest in PROMs in Sjogren’s syndrome (SS). Initial concern about the subjectivity of PROMs has given way to methodological rigour and clear guidance for the development of PROMs. Several studies have now used PROMs for symptom-based stratification, and recently researchers have developed composite disease assessment tools incorporating PROMs and objective clinical measures to create more clinically meaningful endpoints for SS trials. With the advent of PROM-based stratification tools and composite endpoints, it is vital to better understand the relationship between clinical measures in SS. In this project we performed network analysis with data from a large cohort of well-characterised SS patient to improve our understanding of the relationship between objectively measured parameters and PROMs. Methods The UK Primary Sjogren’s Syndrome Registry (UKPSSR) is a nationwide observational cohort of primary SS patients who fulfil the 2002 American European Consensus Group classification criteria. The UKPSSR holds detailed clinical and laboratory data that is collected prospectively, including patient-reported outcomes collected using standardized questionnaires. To assess concordance between clinical measures we used the ARACNE algorithm, which calculates mutual information between the variables of a multidimensional dataset to construct a network of shared information. Statistical analysis was performed in R-v4.1.3 and JMP Pro-v15 and network visualisation in Cytoscape-v3.8.2. Results The ARACNE network highlights key areas of concordance and discordance between PROMs, clinician-based and laboratory-based measurements. Providing assurance to this approach, multi-domain PROMs and ESSDAI (EULAR Sjögren's syndrome disease activity index) subdomains are strongly associated with their component scores and different PROMs measuring the same symptoms were also correlated. In contrast, there is a clear separation between PROMs, clinician-based and laboratory-based measurements each forming their own sub-networks. Furthermore, most laboratory measurements do not have strong relationship with clinician-based disease activity score or PROMs. EQ-5D utility and HADS (Hospital Anxiety and Depression Scale) values provide the primary link between ESSPRI (EULAR Sjogren's Syndrome Patient Reported Index) and ESSDAI subdomain scores and both ESSDAI and ESSPRI are important contributors to quality-of-life. Conclusion The dissociation between PROMs and objective clinical measures is important for clinical management and trial design. Whilst it complicates clinical management of SS including any treat-to-target strategy; it highlights the importance of PROMs in supporting clinician assessment and laboratory measurements to better capture all aspects of SS and give a more individualised, meaningful assessment. Finally, it supports the dual-target strategy of systemically pursuing two targets in the design of clinical trials: one focused on the disease activity and another focused on the symptoms and impact. Disclosure J.S. Berry: None. J. Tarn: None. D. Lendrem: None. J. Casement: None. W. Ng: Consultancies; Expert advice in the area of Sjogren’s syndrome to GlaxoSmithKline, MedImmune, UCB, Abbvie, Roche, Eli Lilly, Takeda, Resolves Therapeutics, Sanofi, Novartis and BMS.

Beyond sicca: high prevalence and predictors of baseline and worsening systemic involvement in patients with Sjögren's disease.

Systemic extraglandular involvement in SS has been reported in one-third of patients but may be more frequent. We aimed to evaluate systemic disease prevalence at baseline and throughout follow-up and find its predictors. We conducted a retrospective cohort study including SS patients followed in a tertiary centre. The cumulative EULAR SS disease activity index (ESSDAI) was calculated by adding each domain's maximum score throughout follow-up. We identified independent predictors of systemic involvement (ESSDAI ≥1 at baseline and/or follow-up) through logistic regression modelling. A survival analysis was conducted to identify predictors of new/worsening ESSDAI domains. A total of 216 patients were included, most of whom had systemic involvement (86%), frequently at diagnosis (76%). Biological (53%) and articular ESSDAI domains (44%) were most commonly involved, but all were affected at least once. Around half of the patients with baseline systemic disease developed an additional/worsening domain throughout follow-up. Although most patients had low disease activity at baseline, 60% eventually reached moderately active disease. Younger age at diagnosis [odds ratio (OR) 0.95 (95% CI 0.91, 0.99)], a positive minor salivary gland biopsy [OR 4.08 (95% CI 1.40, 11.86)] and RF [OR 4.67 (95% CI 1.52, 14.33)] were independent predictors of systemic involvement. Patients with baseline constitutional involvement [hazard ratio (HR) 2.23 (95% CI 1.13, 4.40)] and RF [HR 1.89 (95% CI 1.20, 3.00)] were more likely to develop new/worsening systemic disease activity. Systemic involvement is seen in most SS patients. Younger and RF and salivary gland biopsy-positive patients are at higher risk of systemic disease. Around half of patients with systemic involvement experienced aggravated disease over time, especially those with constitutional involvement or RF.

Sjögren's disease activity associates with cardiovascular disease and monoclonal gammopathy: a university cohort study of disease activity and comorbidities.

We used the University of Wisconsin cohort to determine the extent to which the EULAR Sjögren's syndrome disease activity index (ESSDAI) was associated with comorbidities that contribute to mortality. Our University of Wisconsin, Madison cohort had 111 patients with Sjögren's Disease (SjD) by 2016 ACR/EULAR criteria and 194 control patients with sicca. Our study was performed from March 1st, 2020 through April 1st, 2023. We collected data using a standardized collection tool, including components of the Charlson Comorbidity Index (CCI). Stratifying our SjD patients by ESSDAI < 5 and ESSDAI ≥ 5, we assessed differences in comorbidities associated with mortality. At time of SjD diagnosis, the ESSDAI ≥ 5 group had increased odds of peripheral vascular disease compared to controls (OR 10.17; 95% CI 1.18-87.87). Patients with a current ESSDAI ≥ 5 were more likely to have a myocardial infarction compared to controls (OR 9.87; 95% CI 1.17-83.49). SjD patients had increased prevalence of monoclonal gammopathy compared to controls (9.3% vs 0.5%, p < 0.001). SjD patients with high ESSDAI at diagnosis had greater prevalence of monoclonal gammopathy compared to the SjD patients with a low ESSDAI (16% vs 5%, p = .04). As reported elsewhere, the ESSDAI ≥ 5 group had increased odds of chronic pulmonary disease (OR 4.37; 95% CI 1.59-11.97). We found high ESSDAI scores were associated with worse cardiovascular outcomes, specifically peripheral vascular disease and myocardial infarction. Furthermore, monoclonal gammopathy was more frequent in SjD patients compared to sicca controls, supporting screening for monoclonal gammopathy in the appropriate clinical scenario. Key Points • High ESSDAI scores are associated with worse cardiovascular outcomes, specifically peripheral vascular disease and myocardial infarction. • Monoclonal gammopathy is more frequent in SjD patients than sicca controls, supporting screening for monoclonal gammopathy in the appropriate clinical scenario.

CXCL9 may serve as a potential biomarker for primary Sjögren’s syndrome with extra-glandular manifestations

BackgroundPrimary Sjögren's syndrome (pSS) is an autoimmune condition that causes harm to exocrine glands and also has extra-glandular manifestations (EGM). pSS patients with EGM have a worse prognosis than those with only sicca symptoms. Previous studies have shown that the minor salivary glands (MSG) of pSS patients exhibit a unique profile of cytokines and chemokines compared to healthy controls. However, there is a lack of research comparing pSS with EGM (pSS-EGM) and pSS without EGM (pSS-non-EGM). This study aims to explore potential biomarkers associated with pSS, particularly pSS with EGM.MethodsBy utilizing RNA sequencing, we conducted an analysis on the gene expression profiles of MSG in 63 patients diagnosed with pSS, as well as 12 non-pSS individuals. Furthermore, we also investigated the MSG of pSS patients, both with and without EGM. Through bioinformatics analysis, we identified genes with differential expression (DEGs) and determined the core hub genes using PPI network. We then analyzed the top 20 DEGs and their correlation with the patients' clinical characteristics, and validated our findings using peripheral blood plasma.ResultsA total of 725 differentially expressed genes (DEGs) were identified in the comparison between pSS and non-pSS groups, and 727 DEGs were observed between pSS-EGM and pSS-non-EGM. It is noteworthy that the expression levels of CXCL9 were higher in both pSS patients and pSS-EGM when compared to the control group. Taking into consideration the significance of the top 20 DEGs in relation to clinical parameters and the central hub genes, we ultimately chose CXCL9. In comparison to the non-pSS group, pSS patients exhibited notably greater expression of the CXCL9 gene in the MSG, as well as higher levels of CXCL9 protein in their plasma (p < 0.001). Furthermore, the expression of the CXCL9 gene and levels of CXCL9 protein were notably higher in pSS patients accompanied by EGM and those with SSA antibodies. Additionally, a correlation was found between the expression of the CXCL9 gene and the EULAR Sjogren’s Syndrome Disease Activity Index (ESSDAI), as well as with immunoglobulin G (IgG) levels and erythrocyte sedimentation rate (ESR). Meanwhile, the protein levels of CXCL9 were found to be correlated with IgG levels and ESSDAI.ConclusionCXCL9 proves to be a valuable biomarker in pSS, specifically due to its strong ability to differentiate between pSS patients with EGM and those without EGM. There is a significant correlation between CXCL9 and various clinical parameters both at the gene and protein level. Therefore, CXCL9 could be a potential target for future treatment of pSS.

Serum transthyretin levels and disease activity in patients with primary Sjögren's syndrome.

A strong association has been demonstrated between serum transthyretin (TTR) levels and autoimmune diseases. However, there is limited information regarding the role of serum TTR in patients with primary Sjögren's syndrome (pSS). This study was designed to explore the association between serum TTR and disease activity in patients with pSS. This study was a retrospective observational study. This study included 84 patients with pSS and 135 age- and sex-matched healthy controls retrospectively, and collected data were analyzed. The European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) and Clinical ESSDAI (ClinESSDAI) scores were used to assess the disease activity in patients with pSS. Serum TTR levels were significantly lower in patients with pSS than those in healthy controls (181.9 ± 69.2 vs 241.8 ± 48.9 mg/L, p < 0.001). Serum TTR levels were significantly and negatively correlated with ESSDAI (r = -0.385, p < 0.001) and ClinESSDAI (r = -0.340, p = 0.002) scores in patients with pSS, respectively. Multivariable linear regression analysis showed that serum TTR was significantly associated with ESSDAI (Beta = -0.248, p = 0.017) and ClinESSDAI (Beta = -0.215, p = 0.036) scores in patients with pSS, respectively. Serum TTR is a potential marker for assessing disease activity in patients with pSS, which may contribute to the clinical management of pSS.

Tofacitinib in the treatment of primary Sjögren’s syndrome-associated interstitial lung disease: study protocol for a prospective, randomized, controlled and open-label trial

IntroductionTofacitinib, a selective inhibitor of JAK1 and/or JAK3, is considered to alleviate the pulmonary condition of primary Sjögren’s syndrome (pSS)-associated interstitial lung disease (ILD) through its anti-inflammatory and antifibrotic effects.Methods and analysisThis is a single-center, prospective, randomized, open-label trial. The trial will compare a 52-week course of oral tofacitinib with traditional therapy cyclophosphamide (CYC) combined with azathioprine (AZA) in the treatment of pSS-ILD. A total of 120 patients will be randomly assigned into two treatment groups with a 1:1 ratio and followed for 52 weeks from the first dose. The primary endpoint of the study is the increase of forced vital capacity (FVC) at 52 weeks. Secondary endpoints include high-resolution computed tomography (HRCT), diffusion capacity for carbon monoxide of the lung (DLCO), the Mahler dyspnea index, the health-related quality of life (HARQoL) score, the cough symptom score, EULAR Sjögren's syndrome disease activity index (ESSDAI), and safety.DiscussionThis study will be the first randomized controlled trial to investigate tofacitinib compared to the traditional regimen of CYC in combination with AZA in the treatment of pSS-ILD, which will provide data on efficacy and safety and further elucidate the role of the JAK-STAT signaling pathway in the development of pSS-ILD.Ethics and disseminationBefore starting the experiment, the research proposal, informed consent (ICF) and relevant documents in accordance with the ethical principles of the Helsinki Declaration and the relevant requirements of the local GCP rules for ethical approval shall be submitted to the ethics committee of the hospital. The ethical approval of this study is reviewed by the Ethics Committee of Tongji Hospital and the ethical approval number is 2021-LCYJ-007. When the experiment is completed, the results will also be disseminated to patients and the public through publishing papers in international medical journals.Trial registrationThe study was registered on the Chinese Clinical Trial Registry, www.chictr.org.cn; ID ChiCTR2000031389.

14-3-3η Proteins as a Diagnostic Marker, Disease Activation Indicator, and Lymphoma Predictor in Patients with Primary Sjögren Syndrome.

Primary Sjögren syndrome (PSS) is a chronic, autoimmune, and lymphoproliferative disease of the connective tissue. In patients with PSS, the risk of developing B-cell non-Hodgkin lymphoma (NHL) increases dramatically, with a prevalence of approximately 5%. The 14-3-3 protein isoforms are phospho-serin/phospho-threonine binding proteins associated with many malignant diseases. This study aimed to evaluate the relationship between disease activity parameters and markers predicting lymphoma development in patients with PSS and 14-3-3η proteins. This study was designed as an analytical case-control study. A total of 57 PSS patients and 54 healthy volunteers were included in the study. The European League Against Rheumatism (EULAR) Sjögren syndrome disease activity index (ESSDAI) was used to assess systemic disease activity in PSS. Receiver operating characteristic (ROC) analysis was used to test the diagnostic accuracy measures of the analytical results. Multivariable linear regression analysis was used to evaluate the effects of independent variables on the 14-3-3η protein. The 14-3-3η protein serum levels were found to be significantly higher in PSS (2.72 [2.04-4.07]) than healthy controls (1.73 [1.41-2.43]) (P<0.0001). A significant relationship was found between 14-3-3η protein levels and ESSDAI group (β=0.385, 95%CI=0.318-1.651, P=0.005), hypocomplementemia (C3 or C4) (β=0.223, 95% CI=0.09-1.983, P=0.048) and purpura (β=0.252, 95% CI=0.335-4.903, P=0.022), which are accepted as lymphoma predictors. A significant correlation was found between PSS disease activity score ESSDAI and 14-33η protein (β=0.496, 95% CI=0.079-0.244, P=0.0002). 14-3-3η proteins are potential candidates for diagnostic marker, marker of disease activity, and predictor of lymphoma in PSS patients.

EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) and Other Patient-Reported Outcomes in the Assessment of Glandular Dysfunction in Primary Sjögren's Syndrome.

The EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI), and other patient-reported outcomes (PROs), such as the visual analog scale (VAS) for symptoms and EULAR sicca score (ESS), are used to assess the disease activity of primary Sjögren's syndrome (pSS). Recently, Clinical ESSDAI (ClinESSDAI) and Clinical Trials ESSDAI (ClinTrialsESSDAI) were developed for objective clinical disease activity indexes. However, the relationship of ClinESSDAI and ClinTrialsESSDAI with PROs as well as that between ESSPRI and other PROs and the objective parameters of glandular function in pSS have not been established. Herein, we investigated the correlation of ESSPRI and other PROs with the objective parameters of glandular function and the relationship of PROs with ClinESSDAI and ClinTrialsESSDAI in 66 patients with pSS. Correlations were calculated with Spearman's correlation coefficient. ClinTrialsESSDAI was correlated with ESSPRI, dryness (ESSPRI-Dryness), fatigue, and pain domains of ESSPRI, VAS for oral dryness (oral-VAS), and patient's global assessment. Although ESSPRI did not correlate with the objective parameters of glandular function, ESSPRI-Dryness, ESS, and oral- and ocular-VAS did. These results suggest that ESSPRI-Dryness, ESS, and VAS for symptoms, but not ESSPRI, reflect the glandular dysfunction and that ClinTrialsESSDAI correlates with PROs for dryness in pSS.

Predictors for future development of systemic lupus erythematosus in Korean Sjögren's syndrome patients.

This study determined the impact of demographic factors, clinical manifestations, disease activity, and serological tests at baseline on future SLE development in Sjögren's syndrome (SS) patients. This retrospective study assessed 1,082 SS patients without other autoimmune diseases at baseline who visited our hospital between January 2012 and March 2021. We analyzed demographic features, extra-glandular manifestations (EGMs), clinical indices, and laboratory values at baseline between the two groups divided per future SLE development (SS/SLE group vs SS group). The probability and predictors of SLE development in SS patients were estimated using the Kaplan-Meier method and Cox proportional hazards models. The median follow-up duration was 1083.5days. Forty-nine patients (4.5%) developed SLE that met the 2012 Systemic Lupus International Collaborating Clinics or 2019 EULAR/ACR classification criteria. The baseline EULAR SS disease activity index (ESSDAI) score was significantly higher in the SS/SLE group (p < .001). The SS/SLE group had more lymphadenopathy and renal involvement (p = .015 and p = .017, respectively). Shorter SS disease duration (<3years) (hazard ratio [HR] = 2.12, p = .0328), high ESSDAI (HR = 8.24, p < .0001), leukopenia (HR = 4.17, p = .0005), thrombocytopenia (HR = 3.38, p = .0059), hypocomplementemia (HR = 29.06, p<.0001), and positive for anti-dsDNA (HR = 13.70, p < .0001), anti-ribonucleoprotein (RNP) (HR = 3.82, p = .0027), and anti-ribosomal P (HR = 6.70, p = .0002) at baseline were SLE development predictors in SS patients. Shorter disease duration and higher disease activity of SS at baseline may be risk factors for future SLE development. Serologic predictors of SLE development are hypocomplementemia, leukopenia, thrombocytopenia, and positivity for anti-dsDNA, anti-RNP, and anti-ribosomal P antibodies. If the above factors are observed, close monitoring will be necessary during the follow-up period, considering the possibility of future SLE development.