ESSDAI Score Research Articles

Hydroxychloroquine and Sjögren disease: Old friends

About 25–50% of patients with primary Sjögren's syndrome (SjD) take hydroxychloroquine (HCQ). Although it is widely prescribed, and recommended in international guidelines, its use is mostly based on expert opinion and personal experience. Our aim was to provide a comprehensive overview of the pathogenic mechanisms of HCQ, the current clinical evidence for its use, and its safety in primary SjD. HCQ plays an immunomodulatory and anti-inflammatory role, mainly by regulating some interferon proteins, chemokines, BAFF levels, and by modifying gut microbiota. It decreases immunoglobulins and ESR levels. In a Latin-American cohort, the main indications were arthritis, parotid gland enlargement and sicca-only symptoms. In the clinical setting, most studies showing a positive effect of HQC are open trials or retrospective cohorts. Some of these studies may be biased due to the use of non-validated outcomes, and a placebo response effect. To date, only 3 RCTs have investigated the benefits of HCQ, the JOQUER being the pivotal one. This study failed to improve oral/ocular symptoms or ESSDAI score. However, a re-analysis by symptomatology subgroups detected some differences in the ESSPRI. Recently, promising data from a small phase II RCT of the combination of HCQ/leflunomide was reported, but results should be replicated. Currently, the NECESSITY study is investigating treatment combinations that will provide new insights. In the meantime, HCQ plays a central role in the treatment of SjD due to its excellent benefit-risk profile. Data on damage accrual, quality of life, mortality and prevention of cardiovascular risks are also still lacking.

The impact of two different rituximab-based strategies in cryoglobulinaemic vasculitis secondary to Sjögren's disease: a monocentric cohort study.

To compare two different rituximab (RTX)-based therapeutic approaches on vasculitic and lymphoproliferative-related disease activity and on non-Hodgkin lymphoma (NHL) development in a cohort of patients affected by cryoglobulinaemic vasculitis secondary to Sjögren's disease (Sjögren-CryoVasc). Three Sjögren-CryoVasc treatment groups were identified: 1) early RTX induction followed by maintenance; 2) late RTX induction with possible on-demand retreatment; 3) no RTX treatment. The following outcomes were evaluated: a) changes in cumulative ESSDAI, considering vasculitic-related and lymphoproliferative-related domains and changes in ESSDAI specific to each single vasculitic-related and lymphoproliferative-related domain; b) development of NHL; c) occurrence of persistent hypogammaglobulinemia associated with serious infections. 13 Sjögren-CryoVasc patients were identified: 1) 5/13 treated earlier with RTX with subsequent maintenance; 2) 5/13 treated late with RTX with possible on-demand retreatment; 3) 3/13 not treated with RTX. The two RTX groups showed a decrease in the ESSDAI score with group 1 showing the most substantial reduction (p=0.028). Patients receiving RTX exhibited significant improvement in cutaneous, PNS, and articular vasculitic-related ESSDAI domains (p=0.007; p=0.006; p=0.03, respectively). By contrast RTX did not greatly affect the lymphoproliferative-related ESSDAI domains, even if an improvement was noted in the glandular and nodal domains for group 1 (p=0.03; p=0.03, respectively). No differences in NHL occurrence or safety concerns were observed among the groups. RTX is an effective and safe treatment to control Sjögren-CryoVasc disease activity with a greater impact when administered earlier with a maintenance regimen. RTX alone cannot, however, affect the possible evolution of Sjögren-CryoVasc into an overt NHL.

The role of imbalanced CD226/TIGIT on activated peripheral double-negative T cells in the pathogenesis of primary Sjögren's syndrome.

To explore whether the balance of CD226 and TIGIT is disturbed in CD3+CD56-TCRαβ+CD4-CD8- (DN) T cells and have a better understanding of the potential role of DN T cells in the pathogenesis of primary Sjögren's syndrome (pSS). The percentage of DN T cells as well as the expression of CD226 and TIGIT was identified by flowmetry. After in vitro stimulation, we further detected the expression of activation and cytotoxic marker, as well as intracellular cytokines secreted by DN T cells. DN T cells were found to expand in the peripheral blood of pSS patients (1.77±0.66%) and correlate with IgG (r=0.451, p<0.05), C3 (r=-0.438, p<0.05) and C4 (r=-0.470, p<0.05). Imbalanced CD226/TIGIT was observed on peripheral DN T cells of pSS patients, especially the overexpression of inhibitory immunoreceptor TIGIT. The expression ratio of TIGIT and CD226 on DN T cells was elevated in pSS patients and correlated with ESSDAI scores≥5 (r=0.743, p<0.05). Besides, these DN T cells were found to be activated and show strong cytotoxicity. The balance between CD226 and TIGIT on DN T cells was disturbed and correlated with the disease activity in pSS patients, which may be implicated in the pathogenesis of pSS.

Clinical stratification of 1318 Primary Sjögren's Syndrome patients

ObjectivePrimary Sjögren's Syndrome (pSS) is a complex autoimmune disorder characterized by diverse clinical manifestations yet lacking effective therapeutic strategies currently. This study aims to gain a thorough understanding of the clinical landscape of pSS and further delineate its clinical subtypes, thereby enabling the efficient management for pSS. MethodsWe conducted a cross-sectional observational study of 1318 pSS patients. The pSS patients were categorized and compared based on gender, anti-SSA antibodies, and labial salivary gland biopsies (LGSB). Unsupervised clustering analysis was employed to identify pSS subtypes using systemic involvement among patients. Furthermore, we assessed clinical and biological variances among these subtypes. ResultsThrough group comparisons, we observed more pronounced extraglandular manifestations among male patients, SSA-negative group, and those with positive LGSB results. Based on systemic involvement, pSS patients were categorized into four groups. C1 exhibited minimal systemic involvement, lacking hematologic or serologic manifestations, with the lowest ESSDAI scores. C2 presented with serologic changes in all patients, partial joint involvement, and no hematologic systemic manifestations. C3 lacked joint involvement but all members displayed hematologic systemic involvement, with higher rates of renal, cutaneous, and systemic manifestations. C4 encompassed patients with joint and hematologic involvement, displaying the highest ESSDAI scores. The positivity rates of antibodies, immunological parameters, and inflammatory markers exhibited significant differences among the groups. Furthermore, notable variances were observed in the expression of peripheral blood transcriptomic modules among these groups. ConclusionIn this cohort study, we summarized the clinical characteristics of Chinese patients with pSS and identified four distinct subgroups of pSS based on systemic involvement, revealing clinical and molecular disparities that unveil distinct pathobiological endotypes. Our findings hold significant implications for clinical management.

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

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

Inclusion-body myositis associated with Sjögren's disease: clinical characteristics and comparison with other Sjögren-associated myositis.

To describe the characteristics of patients with Sjögren's disease (SjD) and inclusion-body myositis (IBM), and how they compare to SjD patients with other inflammatory myopathies (IM). Patients were retrospectively recruited from 13 French centers and included if they met the ACR/EULAR criteria for SjD and for IM. They were categorized as SjD-IBM if sub-criteria for IBM were met, or as SjD-other IM if not. SjD-IBM patients (n = 22) were mostly females (86%), with a median [Q1; Q3] age of 54 [38.5; 64] years at SjD diagnosis, and 62 [46.5; 70] years at first IBM symptoms. Although most patients displayed glandular and immunological abnormalities, additional extra-glandular manifestations were uncommon, resulting in moderate disease activity at SjD diagnosis (ESSDAI 5.5 [1; 7.8]). Classic IBM features were frequent, such as progressive symptom onset (59%), asymmetrical (27%) and distal (32%) involvements, dysphagia (41%), low CPK (386.5 [221.8; 670.5] UI/l) and CRP (3.0 [3; 8.5] mg/l) levels. Immunosuppressants were reported as efficient in 55% of cases.Compared with SjD-IBM patients, SjD patients with other IM (n = 50) were significantly younger, displayed more frequent additional extra-glandular disease, higher ESSDAI score (11 [3; 30]), shorter delay between SjD diagnosis and myositis onset (0 [-0.5; 26]), more frequent CPK values over 1000 UI/l (36%), and less frequent classic IBM features. IBM can occur in SjD patients, with muscle features reminiscent of classic sporadic IBM characteristics, but mostly affecting women. In SjD patients with muscle involvement, extra-glandular manifestations, high ESSDAI score, elevated CPK values, and shorter delay after SjD diagnosis plead against IBM.

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

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

Exposure to air pollution as an environmental determinant of how Sjögren's disease is expressed at diagnosis.

To analyse how the potential exposure to air pollutants can influence the key components at the time of diagnosis of Sjögren's phenotype (epidemiological profile, sicca symptoms, and systemic disease). For the present study, the following variables were selected for harmonization and refinement: age, sex, country, fulfilment of 2002/2016 criteria items, dry eyes, dry mouth, and overall ESSDAI score. Air pollution indexes per country were defined according to the OECD (1990-2021), including emission data of nitrogen and sulphur oxides (NO/SO), particulate matter (PM2.5 and 1.0), carbon monoxide (CO) and volatile organic compounds (VOC) calculated per unit of GDP, Kg per 1000 USD. The results of the chi-square tests of independence for each air pollutant with the frequency of dry eyes at diagnosis showed that, except for one, all variables exhibited p-values <0.0001. The most pronounced disparities emerged in the dry eye prevalence among individuals inhabiting countries with the highest NO/SO exposure, a surge of 4.61 percentage points compared to other countries, followed by CO (3.59 points), non-methane (3.32 points), PM2.5 (3.30 points), and PM1.0 (1.60 points) exposures. Concerning dry mouth, individuals residing in countries with worse NO/SO exposures exhibited a heightened frequency of dry mouth by 2.05 percentage points (p<0.0001), followed by non-methane exposure (1.21 percentage points increase, p=0.007). Individuals inhabiting countries with the worst NO/SO, CO, and PM2.5 pollution levels had a higher mean global ESSDAI score than those in lower-risk nations (all p-values <0.0001). When systemic disease was stratified according to DAS into low, moderate, and high systemic activity levels, a heightened proportion of individuals manifesting moderate/severe systemic activity was observed in countries with worse exposures to NO/SO, CO, and PM2.5 pollutant levels. For the first time, we suggest that pollution levels could influence how SjD appears at diagnosis in a large international cohort of patients. The most notable relationships were found between symptoms (dryness and general body symptoms) and NO/SO, CO, and PM2.5 levels.

Influence of exposure to climate-related hazards in the phenotypic expression of primary Sjögren's syndrome.

To analyse how the key components at the time of diagnosis of the Sjögren's phenotype (epidemiological profile, sicca symptoms, and systemic disease) can be influenced by the potential exposure to climate-related natural hazards. For the present study, the following variables were selected for harmonisation and refinement: age, sex, country, fulfilment of 2002/2016 criteria items, dry eyes, dry mouth, and overall ESSDAI score. Climate-related hazards per country were defined according to the OECD and included seven climate-related hazard types: extreme temperature, extreme precipitation, drought, wildfire, wind threats, river flooding, and coastal flooding. Climatic variables were defined as dichotomous variables according to whether each country is ranked among the ten countries with the most significant exposure. After applying data-cleaning techniques and excluding people from countries not included in the OECD climate rankings, the database study analysed 16,042 patients from 23 countries. The disease was diagnosed between 1 and 3 years earlier in people living in countries included among the top 10 worst exposed to extreme precipitation, wildfire, wind threats, river flooding, and coastal flooding. A lower frequency of dry eyes was observed in people living in countries exposed to wind threats, river flooding, and coastal flooding, with a level of statistical association being classified as strong (p<0.0001 for the three variables). The frequency of dry mouth was significantly lower in people living in countries exposed to river flooding (p<0.0001) and coastal flooding (p<0.0001). People living in countries included in the worse climate scenarios for extreme temperature (p<0.0001) and river flooding (p<0.0001) showed a higher mean ESSDAI score in comparison with people living in no-risk countries. In contrast, those living in countries exposed to worse climate scenarios for wind threats (p<0.0001) and coastal flooding (p<0.0001) showed a lower mean ESSDAI score in comparison with people living in no-risk countries. Local exposure to extreme climate-related hazards plays a role in modulating the presentation of Sjögren across countries concerning the age at which the disease is diagnosed, the frequency of dryness, and the degree of systemic activity.

Mortality risk factors in primary Sjögren syndrome: areal-world, retrospective, cohort study.

What baseline predictors would be involved in mortality in people with primary Sjögren syndrome (SjS) remains uncertain. This study aimed to investigate the baseline characteristics collected at the time of diagnosis of SjS associated with mortality and to identify mortality risk factors for all-cause death and deaths related to systemic SjS activity measured by the ESSDAI score. In this international, real-world, retrospective, cohort study, we retrospectively collected data from 27 countries on mortality and causes of death from the Big Data Sjögren Registry. Inclusion criteria consisted of fulfilling 2002/2016 SjS classification criteria, and exclusion criteria included chronic HCV/HIV infections and associated systemic autoimmune diseases. A statistical approach based on a directed acyclic graph was used, with all-cause and Sjögren-related mortality as primary endpoints. The key determinants that defined the disease phenotype at diagnosis (glandular, systemic, and immunological) were analysed as independent variables. Between January 1st, 2014 and December 31, 2023, data from 11,372 patients with primary SjS (93.5% women, 78.4% classified as White, mean age at diagnosis of 51.1 years) included in the Registry were analysed. 876 (7.7%) deaths were recorded after a mean follow-up of 8.6 years (SD 7.12). Univariate analysis of prognostic factors for all-cause death identified eight Sjögren-related variables (ocular and oral tests, salivary biopsy, ESSDAI, ANA, anti-Ro, anti-La, and cryoglobulins). The multivariate CPH model adjusted for these variables and the epidemiological features showed that DAS-ESSDAI (high vs no high: HR=1.68; 95% CI, 1.27-2.22) and cryoglobulins (positive vs negative: HR=1.72; 95% CI, 1.22-2.42) were independent predictors of all-cause death. Of the 640 deaths with available information detailing the specific cause of death, 14% were due to systemic SjS. Univariate analysis of prognostic factors for Sjögren-cause death identified five Sjögren-related variables (oral tests, clinESSDAI, DAS-ESSDAI, ANA, and cryoglobulins). The multivariate competing risks CPH model adjusted for these variables and the epidemiological features showed that oral tests (abnormal vs normal results: HR=1.38; 95% CI, 1.01-1.87), DAS-ESSDAI (high vs no high: HR=1.55; 95% CI, 1.22-1.96) and cryoglobulins (positive vs negative: HR=1.52; 95% CI, 1.16-2) were independent predictors of SjS-related death. The key mortality risk factors at the time of SjS diagnosis were positive cryoglobulins and a high systemic activity scored using the ESSDAI, conferring a 2-times increased risk of all-cause and SjS-related death. ESSDAI measurement and cryoglobulin testing should be considered mandatory when an individual is diagnosed with SjS. Novartis.

Comparative Analysis of Hematological and Immunological Parameters in Patients with Primary Sjögren's Syndrome and Peripheral Neuropathy.

Primary Sjögren syndrome (pSS) is a multisystem disorder of autoimmune etiology, frequently involving peripheral nerves. Early detection of peripheral neuropathy (PN) manifestations might improve prognosis and disease control. The purpose of the study was to evaluate the predictive potential of hematological and immunological parameters associated with PN development in pSS patients. This single-center retrospective study included patients with pSS who were divided into two groups, according to the occurrence of neurological manifestations throughout the follow-up period. From the total of 121 pSS patients included in the study, 31 (25.61%) developed neurological manifestations (PN+ group) during the follow-up period. At the moment of pSS diagnosis, 80.64% of PN+ patients exhibited increased disease activity, with ESSDAI scores above 14 (p = 0.001), and significantly higher values for VASp score (p = 0.001), with a mean value of 4.90 ± 2.45, compared to 1.27 ± 1.32 in the PN- group. The hematological assessment at the moment of pSS diagnosis revealed that neutrophils and neutrophil-to-lymphocyte ratio (NLR) were significantly higher in the PN+ group (p = 0.001), while lymphocytes, monocytes and monocyte-to-lymphocyte ratio (MLR) were significantly lower (p = 0.025, p = 0.13 and p = 0.003, respectively). Immuno-inflammatory parameters-gammaglobulins, complement fractions C3, C4, total proteins and vitamin D were significantly lower in the PN+ patients' group. In multivariate analysis, the independent predictive character for PN development in pSS patients was confirmed for NLR (95% CI 0.033 to 0.263, p = 0.012), MLR (95% CI -1.289 to -0.194, p = 0.008), gammaglobulins (95% CI -0.426 to -0.088, p < 0.003), complement fraction C4 (95% CI -0.018 to -0.001, p < 0.030) and vitamin D (95% CI -0.017 to -0.003, p < 0.009). Readily available and frequently used hematological and immunological markers, such as NLR, MLR, gammaglobulins, C4 and vitamin D could be helpful in predicting the neurological involvement in pSS patients. These biological parameters might become useful tools for clinicians to monitor disease progression and identify potentially severe extraglandular manifestations in pSS patients.

Clinical Efficacy of Spleen and Yin Prescription in the Treatment of Primary Sjogren Syndrome and Its Impact on Disease Activity

Objective: To study the clinical efficacy of primary Sjogren syndrome and the effect of disease activity. Methods: The 60 patients from January 2021 to January 2022 respectively, and divided into two groups according to random numbers, hydroxychloroquine sulfate, 30 patients, clinical effect combined with hydroxychloroquine sulfate, inflammatory index, complement levels, and immunoglobulins (ESR, RF, CRP, C3, C4, IgG, IgA, IgM), ESSDAI, ESSPRI, and adverse effects. Results: The total response rate of the two groups was 86.67% (26/30) and 73.33% (22/30), respectively, comparing with the treatment group (P &lt;0.05). Comparison between groups found that no differences in CRP, C4, IgA, and IgM were significant (P&gt;0.05). After treatment, peripheral ESR, RF, IgG decreased, complement C3 levels increased (P &lt;0.05), the ESSDAI score and ESSPRI score of the two groups also decreased (P&lt;0.05). On the Traditional Chinese medicine symptom integral, the treatment group had better results in improving dry mouth, dry throat, dry eyes, dry skin, five upset heat, and joint pain(P&lt;0.05), and no adverse reactions were found in either group. Conclusion: The treatment group can effectively improve the clinical efficacy, reduce the level of inflammatory indicators and disease activity, and see no obvious adverse reactions, which can be effectively used in clinical practice.

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.

Impaired kynurenine metabolism in patients with primary Sjögren’s syndrome

ObjectivesPrimary Sjögren’s syndrome (pSS) is an autoinflammatory disease characterized by inflammation of the exocrine glands. Elevated inflammation causes an increase in kynurenine pathway (KP) metabolite levels by activating indoleamine 2,3-dioxygenase (IDO). The aim of this study was to measure serum KP metabolite concentrations in patients with pSS and to evaluate the relationship between these metabolites with disease activity score and clinical manifestations. Design & MethodsA total of 80 patients with pSS and 80 healthy controls were enrolled in this study. Serum tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxyanthranilic acid (3HAA), 3-hydroxykynurenine (3HK), quinolinic acid (QUIN) concentrations were quantified with liquid chromatography with tandem mass spectrometry (LC-MS/MS). Demographic characteristics, clinical manifestations and disease activity score (ESSDAI) of the participants were recorded. ResultsThe serum level of KYN and QUIN were significantly higher in patients with pSS with low and moderate activity compared those healthy controls, while the serum level of TRP, KYNA/KYN and 3HK/KYN were lower. In addition, the significant difference for the serum level of KYNA was only in patients with moderate activity from healthy controls, and the difference was higher in favor of pSS patients. Moreover, the KYN/TRP levels were significantly increased with disease activity. The ESSDAI score was positively correlated with KYN/TRP ratio, but negatively correlated with KYNA/KYN ratio. ConclusionsThese findings indicated that KP metabolites may play a role in the etiopathogenesis, activation and progression of pSS.

Abnormal expression of CXCL13, MIF and IL-35 in patients with primary Sjögren's syndrome and its relationship with disease severity.

The aim of the study was to detect the saliva chemokine (C-X-C motif) ligand 13 (CXCL13), macrophage migration inhibitory factor (MIF), and interleukin 35 (IL-35) levels in patients with primary Sjögren's syndrome (pSS) and pSS-associated interstitial lung disease (pSS-ILD), and to explore the relationship between CXCL13, MIF, IL-35 levels, and disease severity. ESSDAI score was used to evaluate the disease activity of pSS patients, and the levels of CXCL13, MIF and IL-35 in saliva of subjects were detected and analyzed, and the relationship between CXCL13, MIF, IL-35 and the occurrence of pSS was evaluated. Pearson's correlation coefficient was used to analyze the correlation between CXCL13, MIF, IL-35 and ESSDAI score. ROC curve analysis was conducted to assess the diagnostic value of CXCL13, MIF, IL-35 and their combined application in pSS. The levels of CXCL13, MIF, and IL-35 in saliva were positively correlated with ESSDAI score. Saliva CXCL13 and IL-35 are risk factors for the development of pSS into pSS-ILD. The ROC curve shows that the combination of saliva CXCL13, MIF and IL-35 has the highest diagnostic efficiency for pSS-ILD. CXCL13, MIF and IL-35 are related to the activity of pSS, and the combined diagnosis of these three indexes is expected to be an important method to predict the occurrence and development of pSS.

Hsa_circ_0008301 as a potential biomarker of disease activity for primary Sjogren's syndrome: Increased expression in peripheral blood of patients with primary Sjogren's syndrome

ObjectivesTo explore the expression level, association with disease activity and clinical significance of hsa_circ_0008301 in the peripheral blood of patients with primary Sjögren's syndrome (pSS). MethodsWe selected 70 pSS patients hospitalized under the Rheumatology service line at the General Hospital of Ningxia Medical University from September 2018 to June 2021 as the disease group, in which general data and clinical indicators were collected. Fifty-three patients with healthy physical examinations for the same period were selected as the healthy control group, and 32 patients with non-pSS rheumatic diseases were selected as the disease control group. We collected peripheral blood samples and used fluorescence quantitative PCR to detect the expression level of hsa_circ_0008301. In addition, we analyzed the association of the expression level of hsa_circ_0008301 with the clinical characteristics and disease activity of pSS patients. A receiver operating characteristic curve was used to evaluate the diagnosis and the disease activity value of hsa_circ_0008301 in patients with pSS. Meanwhile, we analyzed the differential expression of hsa_circ_0008301 in 24 pSS patients selected from the disease group before and after treatment. ResultsThe relative expression of hsa_circ_0008301 in the peripheral blood of pSS patients was significantly higher than that in the control groups including healthy control group and disease control group. The expression level of hsa_circ_0008301 was high in pSS patients with a course of disease ≥ 10 years, fatigue symptoms, platelets < 100*10^9/L, erythrocyte sedimentation rate ≥ 50 mm/h, immunoglobulin IgG > 16 g/L, complement C3 < 0.9 g/L, ESSDAI score ≥ 5 and positively correlated with the above groups. Furthermore, ROC analysis showed that hsa_circ_0008301 was statistically significant between pSS patients and healthy controls. We selected patients from the disease group before and after treatment and showed that the expression level of hsa_circ_0008301 decreased significantly after treatment, compared with before. The area under the curve (AUC) was 0.825 (95% CI: 0.754 ∼ 0.897; P < 0.0001). The AUC of hsa_circ_0008301 in pSS patients and the disease control group was 0.673 (95% CI: 0.563 ∼ 0.782; P = 0.005), the sensitivity was 40.00%, the specificity was 93.70%, the optimal truncation value was > 0.0420, and the maximum Youden index was 0.337. In addition, ROC analysis revealed that hsa_circ_0008301 was statistically significant between disease-active patients and stable patients. The AUC value was 0.681 (95% CI: 0.553 ∼ 0.809; P = 0.010), the sensitivity was 65.90%, the specificity was 72.40%, the optimal truncation value was > 0.0285, and the maximum Youden index was 0.383. ROC analysis indicated that hsa_circ_0008301 has some value in the diagnosis and disease activity of patients with pSS. Comparison of 24 pSS patients selected from the disease group before and after treatment showed that the expression level of hsa_circ_0008301 decreased significantly after treatment compared with before treatment (Z = − 4.257, P < 0.0001). ROC analysis indicated that hsa_circ_0008301 has some value in the diagnosis and disease activity of patients with pSS. ConclusionsHsa_circ_0008301 is expressed in higher levels in the peripheral blood of patients with pSS, which is related to the disease activity. It may be involved in the occurrence and development of pSS and may have a potential biomarker for the disease.

A Systematic Review and Meta-Analysis of 19 Randomized Controlled Trials of Iguratimod Combined With Other Therapies for Sjogren's Syndrome.

ObjectiveTo explore the efficacy and safety of Iguratimod intervention in Primary Sjogren’s syndrome (pSS).MethodsMany databases were searched to collect the RCTs. Three independent reviewers extracted data and assessed the quality of the studies based on the Cochrane Handbook. The statistical analysis was done by RevMan 5.3 and STATA. The quality of evidence was evaluated by GRADE tool.ResultsTwenty-nine RCTs with 2258 participants were included in this review. The meta-analysis shows that: iguratimod experiment group can reduce the ESSPRI score (WMD -1.93 [-2.33, -1.52], P<0.00001), ESSDAI score (WMD -1.39 [-1.81, -0.98], P<0.00001), Schirmer’s test (WMD 1.77 [0.85, 2.70], P=0.0002), RF (WMD -5.78 [-7.59, -3.97], P<0.00001), and decrease the ESR level (WMD -7.05 [-9.84, -4.26], P<0.00001). Meanwhile, the summary result showed the addiction of Iguratimod may not increase the adverse events. The adverse events were mainly gastrointestinal discomfort, abnormal liver function, and rash and itching. The quality of evidence of adverse events was moderate. Referring to minimal clinically important difference (MCID), the improvement of ESSPRI is clinically significant, and the improvement of ESSDAI for patients older than 60 years old may be clinically significant.ConclusionBased on current evidence, iguratimod can effectively reduce ESSPRI score, ESSDAI score, Schirmer’s test score and decrease systemic inflammatory response (such as ESR level and RF level) without increasing the probability of adverse events. The recommended course of treatment is at least 12 weeks.Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?, identifier CRD42020220770.

Circulating Th2 cell reduction and Th1/Th2 imbalance are correlated with primary Sjogren’s syndrome-associated interstitial lung disease

ObjectivePrimary Sjogren’s syndrome (pSS) is a heterogeneous chronic autoimmune disorder characterized by lymphocyte infiltration of the exocrine glands and the involvement and dysfunction of multiple organs and tissues. Interstitial lung disease (ILD) is the most common type of respiratory system damage. This study ascertained the factors related to ILD in patients with pSS (pSS-ILD), such as altered levels of circulating lymphocyte subtypes.MethodsEighty healthy controls and 142 patients diagnosed with pSS were included. The pSS patients were classified into groups with pSS-ILD or pSS without ILD (pSS-non-ILD). Baseline clinical and laboratory data were collected for all subjects, including the levels of lymphocytes measured by modified flow cytometry.ResultsThe pSS-ILD patients were older, had higher ESSDAI scores, had higher positivity rates for anti-SSB and anti-Ro52 antibodies, and had more frequent symptoms of respiratory system involvement than pSS-non-ILD patients. pSS-ILD patients had the lowest Th2 cell counts among the three groups. Although the absolute numbers of Treg and NK cells were lower in pSS patients with and without ILD than in the healthy controls, there was no significant difference between the two pSS groups. The Th1/Th2 ratio was significantly higher in patients with ILD than in patients without ILD. Further analysis showed that older age (OR=1.084), lower Th2 count (OR=0.947), higher Th1/Th2 ratio (OR=1.021), and positivity for anti-SSB (OR=3.620) and anti-Ro52 (OR=5.184) antibodies were associated with the occurrence of ILD in patients with pSS.ConclusionDecreased circulating Th2 cells and an elevated Th1/Th2 ratio may be the immunological mechanism underlying the development of ILD in pSS patients.

Maladie de Sjögren, syndrome asthénie polyalgie sécheresse (SAPS) et fibromyalgie

The combination of dry eyes and mouth, fatigue and pain in the limbs suggests Sjögren's syndrome, a systemic autoimmune disease. The association also characterizes the sicca, asthenia, polyalgia syndrome (SAPS), which is considered to be an equivalent of fibromyalgia and is common in fibromyalgia. These 2 entities have a high prevalence unlike Sjögren's syndrome. The distinction between these pathologies is made by applying the ACR/EULAR criteria for Sjögren's syndrome which require the presence of anti-SSA or a focus score≥1 on the labial salivary gland biopsy (LSGB). In the absence of anti-SSA and when the diagnostic probability is low, the salivary gland ultrasonography, which shows a high negative predictive value, could be an intermediate step before deciding on the LSGB, which is a little more aggressive. About 20% of patients with Sjogren's syndrome have concomitant fibromyalgia. These patients have a higher ESSPRI score (EULAR Sjögren's Syndrome Patient Related Index) (assessment by a VAS of pain, fatigue and dryness), while the ESSDAI score (EULAR Sjögren’ Syndrome Disease Activity Index) which measures systemic impairment, is no different from patients without fibromyalgia. In this population, unlike primary fibromyalgia, agreement between the fibromyalgia criteria is not good. The symptoms of fibromyalgia and Sjogren’ syndrome are very similar, and fibromyalgia criteria have difficulty discriminating between them.

Les complications systémiques de la maladie de Sjögren (ou syndrome de Sjögren primitif)

Primary Sjögren syndrome (pSS) is a progressive autoimmune disease characterized by sicca and systemic manifestations that are frequent and potentially severe, especially when related to B cell activity or the presence of cryoglobulinemia, but the pathological role of the anti-SSA antibodies has never been demonstrated. The frequency of the systemic manifestations in pSS is differentially evaluated related to disease duration or the methods used to detect them, but they are supposed to concern 20 to 70% of the patients. The systemic manifestations can be artificially divided in two types: the life-threatening manifestations (lymphoma, vasculitis with cryoglobulinemia, central nervous system involvement, ganglioneuronopathy and membranoproliferative glomerulonephritis) and the others manifestations. However, the mortality rate in pSS is similar to the general population. The more frequent and easy to evaluate systemic manifestations have been gathered in the ESSDAI score (EULAR Sjogren's Syndrome Disease Activity Index), an international consensual score used in clinical trials and recently incorporated in the STAR index (Sjogren's Tool for Assessing Response).