Janus kinase (JAK) inhibitors have emerged as a transformative therapeutic class across autoimmune diseases by targeting multiple cytokine networks implicated in inflammation and fibrosis. Beyond inflammatory arthritis, increasing evidence supports their potential efficacy in connective tissue diseases such as idiopathic inflammatory myopathies, systemic sclerosis, primary Sjögren's disease, and systemic lupus erythematosus. Through modulation of type I/II interferon and interleukin signaling, JAK inhibition exerts broad anti-inflammatory and antifibrotic effects, translating into clinical improvements in cutaneous, articular, and pulmonary domains. Early clinical trials and real-world data confirm meaningful responses in refractory disease, though randomized evidence remains limited. Overall, JAK inhibitors represent a promising, mechanistically grounded option for systemic autoimmune diseases, with ongoing studies expected to refine selectivity, indications, and long-term safety profiles.
Heart failure (HF) is an increasingly important cause of morbidity and mortality in patients with autoimmune rheumatic diseases. Despite advances in cardiovascular prevention and treatment, HF incidence continues to rise in this population, driven by chronic systemic inflammation, immune-mediated myocardial injury, microvascular dysfunction, fibrosis, and treatment-related cardiotoxicity. Epidemiological studies consistently demonstrate a markedly increased HF risk across a broad spectrum of rheumatic diseases—including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, idiopathic inflammatory myopathies, ankylosing spondylitis, and primary Sjögren syndrome—often manifesting at younger age and independently of traditional cardiovascular risk factors. Subclinical myocardial involvement is frequent and commonly precedes overt HF, with preserved ejection fraction representing the dominant phenotype, particularly in inflammatory arthritis and systemic sclerosis. Advances in speckle-tracking echocardiography, cardiac magnetic resonance, and circulating biomarkers such as natriuretic peptides and cardiac troponins have enabled earlier detection and refined risk stratification. Although anti-inflammatory therapies, including conventional and biologic disease-modifying antirheumatic drugs, may mitigate HF risk, optimal control of traditional cardiovascular risk factors and cautious use of cardiotoxic agents remain essential.
To investigate the clinical and immunological features of primary Sjögren's disease (pSjD) patients with anti-centromere protein B (CENP-B) antibody positivity and to evaluate its prognostic significance. This ambispective cohort study included 1,222 patients with pSjD from the China-Japan Friendship Hospital between February 2014 and February 2023, with follow-up through February 2024. Patients were categorized into anti-CENP-B positive and negative groups based on serum testing. Clinical characteristics, immunological features, and outcomes were compared between groups. A subgroup analysis compared patients with isolated CENP-B positivity to those with additional autoantibodies. Statistical analyses were conducted using SPSS 26.0 and R 4.2.3, including descriptive statistics, univariate tests, and Kaplan-Meier survival analysis. In this study, 100 patients (8.2%) were positive for anti-CENP-B antibody, while 1,122 patients (91.8%) were negative. Compared with the negative group, positive patients were older, more often female, and have higher rates of xerostomia and Raynaud's phenomenon, but lower frequency of dyspnea. They showed lower platelet counts, higher aspartate aminotransferase, gamma glutamyl transferase, lactate dehydrogenase, total bilirubin, and lower estimated glomerular filtration rate, with reduced frequencies of elevated Immunoglobulin (Ig) G, but increased IgM levels and slightly lower EULAR Sjögren's Syndrome Disease Activity Index scores. Among anti-CENP-B positive patients, those with isolated anti-CENP-B positivity had milder immunologic abnormalities than those with concomitant autoantibodies. Among patients with available LSGB data, focal lymphocytic infiltration counts were higher in the anti-CENP-B-positive group. Anti-CENP-B positivity was not significantly associated with mortality, cancer, or interstitial lung disease. Anti-CENP-B positivity in pSjD may identify a different baseline serological and clinical profile, characterized by relatively milder immunologic abnormalities and lower disease activity. However, its prognostic and clinical significance remains uncertain and requires further validation.
Rheumatic and musculoskeletal diseases (RMDs) confer an increased cardiovascular risk beyond traditional factors, with peripheral artery disease (PAD) being an important source of morbidity and disability in these patients. This review summarizes current evidence on PAD across RMDs, including rheumatoid arthritis, systemic lupus erythematosus, antiphospholipid syndrome, systemic sclerosis, polymyalgia rheumatica, psoriatic arthritis, and primary Sjögren's syndrome. Physiopathological mechanisms involved include persistent inflammation, immune dysregulation, and the presence of pathogenic autoantibodies. Protective humoral responses have also been linked to reduced CV risk and may serve as future biomarkers. Clinical studies reveal variable PAD prevalence across diseases but consistent high underdiagnosis. Optimal management requires aggressive CV risk control, including lipid-lowering, immunomodulatory, and biologic therapies. This review underscores PAD as a distinct and clinically relevant manifestation of systemic autoimmunity, calling for targeted screening and prevention strategies in rheumatic populations.
The identification of genetic risk factors could facilitate our understanding of the cause and pathogenesis of rheumatic diseases. Maps of susceptibility loci have been established for most complex diseases, including all major rheumatic diseases, but definitive causal variants have been identified only very infrequently. Here, we highlight the need to both position and confirm the role of causative polymorphisms in humans using experimental animals. The approach is best exemplified by the positional cloning of a causative single-nucleotide polymorphism (SNP) (rs201802280), which results in the substitution of arginine with histidine at position 90 in the NCF1 gene (neutrophil cytosolic factor 1, a component of the phagocyte NOX2 (Nicotinamide adenine dinucleotide phosphate oxidase 2) complex. This variant was independently identified and validated using 2 distinct approaches: by positioning the gene in animal models, followed by exon sequencing and validation of the identified SNPs, and by targeted resequencing and linkage disequilibrium mapping in multiethnic case-control studies. This causal SNP, located in a region with copy number variation, has emerged as a major susceptibility variant for multiple rheumatic diseases, including systemic lupus erythematosus, rheumatoid arthritis, primary Sjögren's disease, and systemic sclerosis. It represents the first major causal polymorphism conclusively linked to both increased susceptibility and disease severity across multiple rheumatic conditions, in both patients and animal models. The functional impact of the NCF1 variant has been explored mechanistically, and a viral infection has been identified as an interacting environmental factor contributing to lupus disease in animal studies. Importantly, the significance of the NCF1 polymorphism extends beyond rheumatic diseases-it has also been implicated in cancer, cardiovascular syndromes, infections, and physiological traits.
Dry mouth symptoms in patients with primary SS (pSS) may be associated with oral microbiome dysbiosis, which plays a critical role in the pathogenesis of pSS and potentially contributes to disease progression. This study systematically reviews and meta-analyses the latest research on the relationship between the oral microbiome and pSS to identify potential diagnostic biomarkers. A systematic search was conducted across nine international databases (PubMed, Cochrane Library, Embase, Web of Science, Scopus, VIP, CNKI, Wanfang, and SinoMed) up to 1 October 2024, using a combination of Medical Subject Headings (MeSH) and free-text terms: 'oral microbiome' OR 'oral flora' AND 'Sjögren's Syndrome' OR 'pSS'. Only studies analysing the oral microbiota of pSS patients were included. A random-effects meta-analysis was performed for quantitative synthesis, and funnel chart was used to assess the publication bias of the included articles. The conclusions are tempered by the moderate risk of bias in some of the included studies, the substantial heterogeneity (partly attributed to methodological heterogeneity), and the limited number of studies for certain subgroup analyses, which may affect the precision of the pooled estimates. A total of 833 studies were identified, 21 of which were included, with 16S rRNA sequencing being the most commonly used technique. Quantitative Insights Into Microbial Ecology (QIIME) is a mainstream bioinformatics analysis tool. Of the 21 studies (1094 participants) included, 19 provided data on α diversity. Overall, declines in the α diversity index were common in pSS [Chao1: SMD = -0.79, (95% CI = -1.381, -0.21), P < 0.001; Shannon index: SMD = -0.16, (95% CI = -0.53, -0.21), P = 0.400; Simpson index: SMD = -0.14, (95% CI = -0.79, -1.06)], P = 0.770. Ten of these studies provided data on β diversity, suggesting a clear difference between the pSS group and the healthy control (HC) group.
Primary Sjögren's disease (SD) is a systemic autoimmune disorder causing glandular dysfunction, sicca symptoms and extraglandular manifestations, which impair quality of life. Data on early irreversible damage and its predictors remain limited. We conducted a multicentre retrospective cohort study of 429 adult patients with SD from the Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale network with ≥1 year of follow-up. Baseline assessments included disease activity (European League Against Rheumatism (EULAR), Sjögren's Syndrome Disease Activity Index (ESSDAI)), patient-reported symptoms (EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI)), C reactive protein (CRP), Schirmer's test (ST) and autoantibody status. Irreversible damage was evaluated using the Sjögren's Syndrome Damage Index (SSDI) across ocular, oral and systemic domains. Predictors of damage accrual were analysed using Cox proportional hazards models and Kaplan-Meier curves. Exploratory Least Absolute Shrinkage and Selection Operator (LASSO) and principal component analysis (PCA) analyses assessed domain-specific contributions and relationships between subjective and objective measures. At baseline, 48% of patients had SSDI≥1: ocular 25.4%, systemic 22.5% and oral 14.3%. After 5 years, 65% had cumulative damage: ocular 34.2%, oral 21.7% and systemic 40.8%. Higher baseline ESSDAI predicted damage across all domains. Elevated ESSPRI was associated with oral damage, while abnormal ST strongly predicted ocular damage. Anti-Ro/La antibodies, elevated CRP and recurrent oral infections were linked to higher domain-specific damage. LASSO analyses showed glandular, peripheral nervous system and pulmonary ESSDAI domains independently contributed to systemic damage. PCA confirmed that patient-reported symptoms and systemic activity represent complementary, independent dimensions. Irreversible damage in SD occurs early, often present at diagnosis and affects multiple organ domains. Early identification of high-risk patients, based on clinical, serological and patient-reported measures, may enable timely interventions to prevent further damage, guide
To examine whether salivary gland ultrasonography (SGUS) and scintigraphy (SGS) reflect systemic disease activity (ESSDAI) and patient-reported index (ESSPRI) in primary Sjögren's disease (PSD). We retrospectively enrolled 118 patients undergoing SGUS and SGS during diagnostic workup of dryness symptoms, which ultimately led to labial biopsy-confirmed PSD. SGUS was scored using the Outcome Measures in Rheumatology Clinical Trials (OMERACT) system (range 0-12). SGS analysis relied on time-activity curve-derived parotid and submandibular uptake ratios and excretion fractions. Unstimulated salivary flow rate (USFR) was also assessed. Associations were evaluated using correlation and logistic regression. OMERACT scores showed a weak but significant correlation with ESSDAI (ρ = 0.329, p < 0.001), whereas SGS parameters were not associated with ESSDAI or ESSPRI (all p > 0.05). ESSDAI and ESSPRI were weakly correlated (ρ = 0.252, p = 0.006). OMERACT scores differed significantly across ESSDAI categories (p = 0.001), whereas SGS parameters did not. In multivariable analysis, anti-SSA/Ro positivity (p = 0.006) and higher OMERACT scores (p < 0.001) independently predicted moderate-to-high ESSDAI (ESSDAI ≥ 5). No imaging parameter predicted high ESSPRI (ESSPRI ≥ 5) (all p > 0.05); however, USFR was strongly associated with symptom burden (p < 0.001). The final models showed good discrimination (AUC 0.76 for ESSDAI and 0.74 for ESSPRI). SGUS reflects systemic disease activity, whereas SGS has limited clinical value. Patient-reported burden is more closely related to objective salivary hypofunction than to imaging findings. Integrating structural imaging, functional assessment, and patient-reported symptoms in PSD provides complementary information for disease assessment.
To assess the prevalence of organ-specific autoimmunity (OSA) among patients with primary Sjögren's disease (SjD), and its association with clinical and serological variables and disease activity. We included 328 patients with SjD according to ACR/EULAR criteria. We recorded the following types of OSA: gastrointestinal [primary biliary cholangitis (PBC), autoimmune hepatitis (AH), coeliac disease], haematological (pernicious anaemia, haemolytic anaemia, idiopathic thrombocytopenia purpura), neurological (myasthenia gravis), dermatological (vitiligo, alopecia areata), and endocrinological (autoimmune thyroid disease and type 1 diabetes). We also registered demographics, basal Schirmer I test, non-stimulated whole salivary flow, serological variables, treatment (ever), and basal and cumulative EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score at last follow-up. We found OSA in 122 patients (37.9%), the most frequent being autoimmune hypothyroidism (n = 56), PBC (n = 28), and AH (n = 8). OSA preceded SjD in 37 patients (30.3%), followed it in 62 (50.8%), and was concomitant in 23 (18.8%). In logistic regression analysis comparing patients with OSA (concomitant/post-SjD diagnosis) versus those without OSA, the variables associated with OSA were anti-Ro/SSA [odds ratio (OR) 0.44, 95% confidence interval (CI) 0.20-0.97, p = 0.04], disease duration (OR 1.03, 95% CI 1.005-1.06, p = 0.01), and use of methotrexate (OR 0.32, 95% CI 0.55-0.73, p = 0.007) and azathioprine (OR 2.12, 95% CI 1.14-3.84, p = 0.01). One-third of patients with primary SjD had OSA, with endocrine involvement being the most common. OSA may precede, follow, or accompany the diagnosis of SjD, and is not associated with higher disease activity. Monitoring for OSA is important as it contributes to comorbidity in these patients.
Primary Sjögren's syndrome (pSS) patients with low disease activity remain at risk for disease progression, yet predictive factors are poorly understood. We aimed to identify risk factors for disease worsening in pSS patients with initially low disease activity. We conducted a registry-based cohort study using prospectively collected data from the Chinese Rheumatism Data Center (CRDC). Patients with pSS meeting either 2002 AECG or 2016 ACR/EULAR classification criteria and baseline ESSDAI < 5 were included. Disease worsening was defined as ESSDAI increase ≥ 3 points during follow-up. Cox proportional hazards regression with LASSO selection identified independent risk factors. Among 745 patients (median age 46 years, 97.4% female), 214 (28.7%) experienced disease worsening during median follow-up of 36 months. Univariate analysis and LASSO regression selected 11 variables for multivariate analysis. Independent risk factors were renal involvement (HR = 6.18, 95%CI: 2.44-15.61, P < 0.001), anti-Sm positivity (HR = 2.10, 95%CI: 1.12-3.93, P = 0.020), and dry eye symptoms (HR = 1.46, 95%CI: 1.06-2.00, P = 0.022). Nearly one-third of pSS patients with low disease activity experience disease worsening. Renal involvement, anti-Sm antibodies, and dry eye symptoms independently predict progression. Risk stratification based on these factors can identify patients requiring closer monitoring and potentially more intensive therapeutic intervention. Key Points • This multicenter registry study of 745 primary Sjögren's syndrome patients with low disease activity found that 28.7% experienced disease worsening during follow-up, highlighting that low disease activity does not guarantee disease stability. • Three independent predictors of disease progression were identified: renal involvement (HR = 6.18), anti-Sm antibody positivity (HR = 2.10), and dry eye symptoms (HR = 1.46). • Conventional synthetic DMARDs were not significantly associated with reduced disease worsening in adjusted models, highlighting the need for randomized trials to properly evaluate therapeutic strategies.
The impact of primary Sjögren's syndrome (pSS) on adverse pregnancy outcomes remains a debated issue. Research suggests that newborns of mothers with pSS may be at a higher risk of developing heart conditions. This study aimed to examine the relationship between maternal pSS and the risk of cardiac disorders in neonates. A multicentre, retrospective cohort study was conducted with pSS patients treated between January 2015 and May 2024. Data on demographics, comorbidities, disease activity, pregnancy outcomes and treatments were collected. Associations between adverse pregnancy outcomes and preconception characteristics were analysed. Among 169 newborns from pSS mothers, 49 had heart diseases, while 120 did not. Newborns with cardiac conditions had higher rates of premature birth (P = 0.002), lower birth weight (P = 0.012) and increased risk of neonatal asphyxia (P = 0.009), brain injury (P < 0.001) and neonatal infections (P < 0.001). Mothers who delivered babies with heart conditions had more umbilical cord abnormalities (P = 0.002) and threatened preterm labor (P = 0.008). Lower C3 and C4 levels (P = 0.022, P = 0.033) and use of glucocorticosteroids (P = 0.005) and ciclosporin A (P = 0.036) were linked to neonatal heart diseases. High EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) scores increased the risk of heart disease in newborns [OR 1.503, 95% CI (1.148, 1.966), P = 0.003]. Maternal pSS, especially with high disease activity, elevates the risk of neonatal heart disease, highlighting the need for careful monitoring during pregnancy.
Adverse pregnancy outcomes in women with primary Sjögren's syndrome have only been evaluated retrospectively using heterogeneous methods and with contradictory results. We aimed to describe adverse pregnancy, delivery, and birth outcome risks in pregnant women with primary Sjögren's syndrome compared with those of a matched general population in France, and to identify factors predictive of disease flares or adverse pregnancy outcomes. We conducted a multicentre, prospective, cohort study in France using the GR2 (Groupe de Recherche sur la Grossesse et les Maladies Rares) registry. Women from the GR2 study were eligible if they had conceived before March, 2021, had primary Sjögren's syndrome according to the American College of Rheumatology and European Alliance of Associations for Rheumatology (EULAR) 2016 classification criteria, and had an ongoing pregnancy at 12 weeks of gestation. In women who entered in the registry with pregnancies before 18 weeks of gestation, we sought to identify factors associated with primary Sjögren's syndrome flare (≥3-point increase in EULAR Sjögren's Syndrome Disease Activity Index [ESSDAI] score) or adverse pregnancy outcomes (fetal or neonatal death, placental insufficiency leading to a preterm delivery [<37 weeks of gestation], or small-for-gestational-age birthweight). A matched controlled study compared adverse pregnancy, delivery, and birth outcome rates between pregnant women with primary Sjögren's syndrome from the GR2 registry and matched controls from the general population included in the last French perinatal survey (Enquête Nationale Périnatale 2016). 1944 pregnancies were identified in the GR2 cohort, of which 106 pregnancies in 96 women with primary Sjögren's syndrome were included in this analysis. The median age at pregnancy onset was 33 years (IQR 31-36). 87 (83%) of 105 pregnancies (with ethnicity data) were in White women, 18 (17%) were in
To compare immune cell subsets and interferon (IFN) expression in placentas from patients with systemic lupus erythematosus (SLE), primary Sjögren's disease (pSjD), antiphospholipid syndrome (APS), healthy controls (HC) and of women with adverse pregnancy outcomes (APO) without these systemic rheumatic diseases (SRD). Placenta biopsies from HC, SLE, pSjD, APS, and patients with fetal growth restriction (FGR), spontaneous preterm birth (PTB), or FGR and preeclampsia (FGR/PE) attended between 2008 and 2022 were recovered from the pathology biobank of the University Medical Center Groningen. Clinical characteristics and APO were retrieved from medical records. Immunohistochemistry was performed for Myxovirus resistance protein 1 (MxA), CD3, CD20, CD56, CD68, CD123, and Foxp3. The proportion of positive cells was established using an automated detection classifier, while MxA expression was assessed semi/quantitatively discriminating between maternal (decidua) and fetal (villi) tissue. Finally, placental lesion classification was performed. Our study included placentas from 11 SLE, 4 pSjD, 8 APS, 4 PTB, 8 FGR, 8 FGR/PE patients and 11 HC. A high rate of APO (70%) was identified in SRD patients. Patients with SRD had a higher macrophage (CD68+) count in decidua and villi than HC, but no differences were observed in T (CD3+), B (CD20+), NK (CD56+) and T regulatory (Foxp3+) cell count. No plasmacytoid dendritic cells (CD123+) were identified. Furthermore, patients with these SRD had higher MxA values than HC in villi but not in decidua. SLE, pSjD and APS patients have an increased macrophage count and interferon upregulation in the placenta compared to HC. Therefore, a pro-inflammatory environment might be key inducing placental dysfunction, which may lead to subsequent APO development.
Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease where cardiac involvement is increasingly recognized but challenging for screening and detection. Cardiac magnetic resonance (CMR) is a powerful tool for identifying such impairments but had limited clinical application. Therefore, this study investigated the relationship between clinical characteristics particularly pulmonary function tests (PFTs) and cardiac MRI parameters for identifying pSS patients at risk of subclinical myocardial injury. This cross-sectional study included 48 pSS patients without overt cardiac symptoms who underwent both CMR and PFTs. According to interstitial lung disease (ILD) status, patients were categorized into the pSS-ILD group (ILD, n = 37) and the pSS-nonILD (n = 11) group based on high-resolution CT results. The clinical and CMR parameters were also analyzed. Impaired PFT was defined as predicted diffusing capacity for carbon monoxide (DLCO) < 70% or forced vital capacity (FVC) < 80%. Correlation analysis, univariate and multivariate linear regression analyses were performed to assess associations between PFT results, inflammatory markers, and myocardial tissue characteristics. Patients in the pSS-ILD group had significantly worse PFT results than the pSS-nonILD group. Impaired PFT and an elevated erythrocyte sedimentation rate (ESR) were independently associated with higher native T1 values after adjustment for age, sex, BMI, disease duration, and disease activity (impaired PFT: β = 103.49, P = 0.013; abnormal ESR: β = 84.63, P = 0.001). Among PFT parameters, DLCO showed the strongest negative correlation with native T1 (r = - 0.458, P = 0.001). Subgroup analysis confirmed that impaired PFT was correlated with higher T1 values in both ILD and nonILD pSS patients. The preliminary study revealed that impaired pulmonary function and abnormal ESR are independently associated with increased cardiac T1 mapping in pSS. Although future large-scale studies should be performed to validate the results, this study suggested that pSS patients with specific
To explore the pathological changes of peripheral neuropathy in Sjogren's syndrome and the role of macrophages in it. Methods: Sural nerve biopsy was performed in 12 patients diagnosed with primary Sjogren's syndrome associated peripheral nervous system involvement (pSS-PN) and 3 traumatic amputees. First, we collected clinical data and electromyography (EMG) findings from 12 pSS-PN patients. Histological assessment of sural nerve specimens was subsequently performed using hematoxylin-eosin (HE) and neurofilament protein (NF) staining under light microscopy. The ultrastructural changes of peripheral nerves were observed by transmission electron microscopy (TEM). Macrophage types were labeled with CD206 and iNOS antibodies by immunohistochemistry and immunofluorescence. The 3 control cases underwent HE staining, CD68 IHC, and TEM. Patients with pSS-PN typically present with symptoms such as neuropathic pain, limb weakness, and sensory disturbances. HE and NF staining revealed mild-to-severe damage to both myelinated and unmyelinated fibers in peripheral nerves, with some cases showing predominant small‑vessel inflammation. Immunohistochemistry and immunofluorescence demonstrated infiltration of CD68⁺ macrophages-predominantly of the M2 phenotype-around small vessels and within nerve bundles. Electron microscopy further illustrated that macrophages progressively strip and engulf myelin sheaths, leaving bare axons. In addition, inflammatory cell infiltration within vasa nervorum led to blood‑cell stasis, endothelial damage, platelet aggregation, and eventual vascular obstruction and collapse. These clinicopathological observations establish vasculitic peripheral neuropathy as the predominant form of pSS‑PN. This prominent infiltration of M2 macrophages in the affected nerves suggests that they play a pivotal role in the pathogenesis of pSS‑PN, potentially offering a novel therapeutic direction for this condition. Key Points • Vasculitic peripheral neuropathy is the main pattern of pSS‑PN, with M2 macrophages heavily infiltrating affected nerves. • Ultrastructural evidence shows macrophages actively stripping myelin sheaths, leading to
This study aimed to identify risk factors contributing to diverse pregnancy outcomes in primary Sjögren's syndrome (pSS) cases. A retrospective analysis was conducted on pregnant individuals with pSS, who received outpatient or inpatient care across multiple hospitals in Anhui Province, China, from January 2015 to December 2022. This study included 164 pregnant women with pSS and 328 control subjects, with no statistically significant difference in average age between the two groups. Analysis of pregnancy outcomes revealed that, compared with the control group, pregnant women in the pSS group were more likely to experience miscarriages, both spontaneous (12.80% vs 1.52%, p<0.001) and therapeutic (6.10% vs 0.91%, p<0.05). The proportion of placental abnormalities detected during prenatal ultrasound in women from the pSS group was higher (14.63% vs 6.40%, p<0.05). In the analysis of pregnancy outcomes for live-born neonates, a higher incidence of congenital heart abnormalities was observed in the pSS group (27.34% vs 12.03%, p<0.05). While there were no significant differences between the pSS pregnancies in terms of both normal and adverse pregnancy outcomes, a comparison of fetal survival and fetal loss in pSS pregnancies revealed a greater use of prophylactic anticoagulant therapy in the fetal survival group. Notably, the application of low molecular weight heparin (LMWH) emerged as an independent protective factor for fetal survival. Compared with non-autoimmune controls, pregnancy in women with pSS presents more challenges. Importantly, we observed that the use of LMWH as anticoagulant therapy is an independent protective measure for fetal survival.
This study aimed to evaluate the diagnostic performance of the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR-2019) classification criteria of systemic lupus erythematosus (SLE) and to clarify the clinical characteristics of Japanese childhood-onset SLE (cSLE). We retrospectively analyzed clinical data registered in the Paediatric Rheumatology International Collaboration Unit Registry (PRICURE) version 2 up to March 31, 2023. Frequencies of individual items within the EULAR/ACR-2019 criteria were compared with those observed in a Japanese adult SLE cohort. A total of 105 patients with cSLE, 19 with Juvenile dermatomyositis (JDM), 27 with primary Sjögren's disease (pSjD), and 9 with mixed connective-tissue disease (MCTD) were included. The sensitivity of the EULAR/ACR-2019 criteria was 97.1%. The specificity was 94.7% for JDM, 92.6% for pSjD, 55.6% for MCTD, and 87.3% for all disease controls. cSLE patients in this cohort more frequently exhibited renal involvement, low serum C3 or C4 levels, and positivity for antiphospholipid and anti-double-stranded DNA antibodies, but joint symptoms were less common than in adult SLE patients. Although the EULAR/ACR-2019 criteria are generally applicable, the limited specificity for MCTD necessitates careful differential diagnosis. Japanese cSLE is commonly characterized by renal involvement, hypocomplementemia, and SLE-related autoantibody positivity.
Tumour markers may correlate with interstitial lung disease (ILD). We conducted a large, population-based retrospective study to investigate the relationship between serum carcinoembryonic antigen (CEA) levels and disease severity and 1-year mortality in different ILD subtypes. ILD patients treated at Nanjing Drum Tower Hospital from 2014 to 2022 were included. The primary end point was 1-year mortality. Cox regression and receiver operating characteristic analyses were used to identify independent risk factors and determine the optimal CEA cut-off. Overall, 1209 ILD patients were enrolled. Serum CEA levels correlated with the composite physiological index (CPI) in idiopathic pulmonary fibrosis (IPF) (r = 0.170, P = 0.007), idiopathic inflammatory myopathy-associated ILD (IIM-ILD) (r = 0.222, P < 0.001), primary SS-associated ILD (pSS-ILD) (r = 0.179, P < 0.001) and undifferentiated connective tissue disease-associated ILD (r = 0.146, P = 0.042). Subgroup analysis showed higher CEA in acute exacerbations of IPF [5.44 vs 2.49 ng/ml, P = 0.009], anti-melanoma differentiation-associated gene 5-positive IIM-ILD [3.62 vs 1.47 ng/ml, P < 0.001] and rapidly progressive IIM-ILD [4.88 vs 1.48 ng/ml, P < 0.001]. After adjustment for age, sex, smoking history and CPI, elevated CEA was independently associated with increased 1-year mortality in IPF (HR 1.118; 95% CI 1.031-1.212; P = 0.007), IIM-ILD (HR 1.225; 95% CI 1.160-1.293; P < 0.001) and pSS-ILD (HR 1.295; 95% CI 1.091-1.538; P = 0.003). Moreover, CEA ≥2.835 ng/ml was associated with increased 1-year mortality in IPF (HR 3.230; 95% CI 1.492-6.994; P = 0.003) and IIM-ILD (HR 13.022; 95% CI 5.272-32.165; P < 0.001). Serum CEA levels are associated with disease severity and 1-year mortality across ILD subtypes, supporting its potential as a reliable prognostic biomarker.
Early-onset primary Sjögren's disease (pSjD) represents a specific clinical phenotype with poorer prognosis. We aim to compare early- and late-onset pSjD immunophenotypes to identify key distinct immunological features. We retrospectively studied 204 newly diagnosed, untreated pSjD patients categorized by age at diagnosis (≤35 years). Clinical features, peripheral lymphocyte profiles, CD4+ T cell subsets and cytokine levels were compared. Key immune variables were screened via random forest and LASSO regression. LASSO-selected variables were analysed using forward stepwise logistic regression to determine independent immune factors associated with early-onset pSjD. Among 204 enrolled patients, 43 (21.08%) were classified as early-onset pSjD and 161 (78.92%) as late-onset pSjD. Compared with the late-onset group, early-onset patients showed significantly lower CD4+ T cell counts [442.62 (236.92-558.89) vs 563.11 (386.98-762.60), P = 0.005] and NK cell counts [71.36 (51.69-134.58) vs 138.05 (91.65-241.90), P < 0.001]. In terms of CD4+ T cell subsets, the early-onset group exhibited higher Th17/Treg cell ratios [0.42 (0.33-0.59) vs 0.30 (0.21-0.46), P = 0.006] and lower Treg cell counts [22.07 (12.89-34.96) vs 28.00 (20.35-38.93), P = 0.032]. Three independent factors for early-onset disease were identified: NK cell counts (OR = 0.993, P = 0.010), CD4+ T cell percentage (OR = 0.947, P = 0.019) and Th17/Treg cell ratios (OR = 5.215, P = 0.029). This study characterizes the distinct peripheral immunological landscapes of early- and late-onset pSjD and identifies an immunological triad that may represent a unique 'immune endotype' for early-onset disease, offering insights into targeted monitoring and therapies.
To investigate the relationship between maternal disease, anti-rheumatic treatment, autoantibody levels and foetal atrioventricular (AV) conduction. A total of 324 pregnancies from two groups of anti-Ro/La autoantibody-positive women were included. The Surveillance group consisted of pregnancies with known anti-Ro positivity followed from early pregnancy; n = 302, including nine with AV block (AVB), and the Bradycardia group with no prior knowledge of anti-Ro/La autoantibodies and referred upon detection of foetal bradycardia, with a subsequent AVB II-III diagnosis (n = 22). Foetal AV conduction and routine anti-Ro52, anti-Ro60 and anti-La autoantibody levels were analysed. Women with primary Sjögren disease (SjD) had longer foetal AV time intervals (130.5 ± 11.9 vs 125.8 ± 8.7 ms, P = 0.002) compared with autoantibody-positive women with neither SjD nor SLE. Notably, AZA, mostly used in women with SLE, was associated with shorter foetal AV time intervals compared with autoantibody-positive pregnancies without AZA treatment (122.5 ± 8.9 vs 128.7 ± 11.0 ms, P = 0.038). For antibody-based prediction, anti-Ro52, anti-Ro60 and anti-La antibody levels obtained from routine assays could identify nearly 20% of pregnancies as low risk, and high levels (≥8 U/ml) of anti-La antibodies were associated with an increased risk of AVB I-III (OR = 6.0, 1.26-28.5). However, the positive predictive value for AVB II-III of the three autoantibodies did not reach 5% for a sensitivity of 100%. This report, based on over 20 years of surveillance of anti-Ro positive pregnancies, identifies associations between maternal disease, their treatments and foetal AV conduction. Routine detection assays for anti-Ro/La antibodies had low performance in predicting AVB among an anti-Ro/La positive population.
Anti-Ro52 and anti-Ro60 antibodies are key serological markers for primary Sjögren's disease (pSjD), yet their association with specific clinical phenotypes remains unclear. This study aimed to define the predictive value of anti-Ro profiles for systemic involvement in pSjD. In this retrospective study of 725 pSjD patients, we categorized patients into four subgroups based on their anti-Ro52/Ro60 status. Multivariable logistic regression, adjusted for confounders via LASSO, assessed independent associations. Relative excess risk due to interaction (RERI), attributable proportion of interaction (AP) and synergy index (SI) were calculated to determine the additive interaction between anti-Ro52 and anti-Ro60. The cohort consisted of 21.5% Ro52-Ro60-, 17.7% Ro52+Ro60-, 10.2% Ro52-Ro60+, and 50.6% Ro52+Ro60+ patients. Anti-Ro52 positive groups (Ro52+Ro60- and Ro52+Ro60+) exhibited significantly higher ESSDAI scores. After adjustment, the Ro52+Ro60+ profile was independently associated with renal involvement (OR=5.53, 95%CI 2.56-11.97, p<0.001), cutaneous involvement (OR=2.49, 95%CI 1.08-5.75, p=0.032), hyperglobulinemia (OR=5.19, 95%CI 2.96-9.10, p<0.001), and low complement levels (OR=1.70, 95%CI 1.07-2.71, p=0.025). In contrast, the Ro52+Ro60- profile was specifically linked to interstitial lung disease (ILD) (OR=4.17, 95%CI 2.33-7.46, p<0.001). A significant synergistic interaction between anti-Ro52 and anti-Ro60 was identified for hyperglobulinemia (adjusted RERI=3.00, 95%CI 0.87-5.14; AP=0.58, 95%CI 0.31-0.84; SI=3.52, 95CI 1.04-11.94). Anti-Ro52 and anti-Ro60 profiles delineate distinct clinical subsets of pSjD. Anti-Ro52 positivity is associated with greater disease severity, while double positivity defines a unique subgroup with multi-organ involvement and immune hyperactivation, highlighting the clinical utility of comprehensive anti-Ro testing.
To evaluate whether low-to-moderate dose glucocorticoids provide additional benefit in primary Sjögren's syndrome patients treated with hydroxychloroquine and/or iguratimod. Using the Chinese Rheumatism Data Center database, we emulated a pragmatic trial including 395 patients with primary Sjögren's syndrome treated between May 2016 and August 2025. All patients received hydroxychloroquine and/or iguratimod as background therapy. Patients were categorized by glucocorticoid use: HCQ/IGU plus glucocorticoid group (≤ 30 mg/day prednisone equivalent, n = 188) or HCQ/IGU group (n = 207). Primary outcome was ESSDAI score change at 1 month. Secondary outcomes included ESSPRI scores and laboratory parameters. Treatment effects were estimated using overlap weighting of propensity scores. Stratified analyses examined subgroups by baseline ESSDAI, IgG levels, and arthritis status. After propensity score weighting, baseline characteristics were well-balanced. At 1 month, glucocorticoids provided no additional benefit in ESSDAI change compared to hydroxychloroquine/iguratimod (Cohen's d =  - 0.12; 95% CI, - 0.32 to 0.08; p = 0.270). ESSPRI scores showed no improvement (Cohen's d =  - 0.20; 95% CI, - 0.39 to 0.00; p = 0.077). While glucocorticoids increased white blood cell counts (Cohen's d = 0.57; p < 0.001) and decreased IgG levels (Cohen's d =  - 0.33; p = 0.004), these changes did not translate into clinical benefits. Stratified analyses revealed no additional benefit from glucocorticoids in any subgroup, including patients with higher disease activity (ESSDAI ≥ 5), elevated IgG, or arthritis. Low-to-moderate dose glucocorticoids (≤ 30 mg/day prednisone equivalent) provide no additional short-term clinical benefit at 1-month follow-up in primary Sjögren's syndrome patients receiving background hydroxychloroquine and/or iguratimod therapy. Key Points • Low-to-Moderate dose glucocorticoids show no additional benefit over hydroxychloroquine/iguratimod therapy in primary Sjögren's syndrome patients.
Systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), and systemic sclerosis (SSc) are systemic autoimmune diseases characterized by marked heterogeneity in clinical presentation, organ involvement, and disease course. Their management remains challenging, particularly in patients with multi-organ involvement or overlapping autoimmune conditions. Emerging metabolomic studies indicate that distinct molecular signatures are closely linked to disease phenotypes and can reliably distinguish patients from healthy controls, underscoring their potential clinical relevance. This review aims to synthesize current metabolomics research on SLE, pSS, and SSc. We first consolidate knowledge on metabolic alterations by identifying pathways that differentiate patients from controls. We then highlight metabolites associated with organ involvement and disease activity and compare shared and disease-specific metabolic features across the three conditions. Metabolites reported in published metabolomics studies of SLE, pSS, and SSc were systematically mapped to the KEGG database (MetaboAnalyst 6.0) to perform pathway enrichment analysis, providing an integrated overview of disease-associated metabolic pathways. Analysis revealed substantial overlap in metabolic alterations across the three diseases. Amino acid metabolism emerged as a core feature of systemic autoimmunity, whereas lipid-related pathways showed greater disease- and organ-specificity. SLE and pSS are metabolically similar, reflecting their clinical overlap, yet glycerophospholipid metabolism may distinguish pSS. SLE was the most extensively studied disease, with glycine, serine, and threonine metabolism showing particularly pronounced alterations. Altered metabolomic profiles provide insight into shared and disease-specific mechanisms underlying SLE, pSS, and SSc. Systematic integration of metabolomics data may reduce study-specific variability and identify robust metabolic pathways relevant for diagnosis and personalized management. However, further analytical validation and clinical translation are required before these metabolites can be implemented in routine diagnostic and stratification strategies.
Rheumatic diseases (RDs) are chronic immune-mediated disorders associated with disproportionately increased cardiovascular morbidity and mortality. Accelerated atherogenesis in these diseases is driven by persistent systemic inflammation, autoantibody-mediated endothelial injury, oxidative stress, and dysregulated lipid metabolism, resulting in premature vascular remodeling manifested by increased carotid intima-media thickness, arterial stiffness, impaired flow-mediated dilation, and coronary artery calcification. This review synthesizes evidence regarding subclinical atherosclerosis and cardiometabolic risk across common RDs. In rheumatoid arthritis and systemic lupus erythematosus, vascular alterations correlate with inflammatory burden, disease duration, autoantibody profiles, renal involvement, and glucocorticoid exposure. Emerging biomarkers-including apolipoprotein B48, FIB-4 index, asymmetric dimethylarginine, and adhesion molecules-provide incremental prognostic value beyond traditional lipid parameters. Advanced imaging modalities, such as ^18F-sodium fluoride PET/CT and vascular elastography, enhance early detection of arterial calcification and stiffness. Growing evidence in primary Sjögren syndrome, Behçet disease, systemic sclerosis, and ankylosing spondylitis similarly confirms increased subclinical atherosclerosis and endothelial dysfunction. Importantly, tight disease control and targeted immunomodulatory therapies-including methotrexate, biologic agents, antimalarials, and cytokine-directed treatments-are associated with improved vascular and metabolic profiles and attenuation of disease progression. Subclinical atherosclerosis represents a critical interface between autoimmunity and cardiovascular disease in RDs. Early vascular assessment integrated with disease-specific and metabolic risk stratification is essential to implement precision-based cardiovascular prevention in this high-risk population.
Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and primary Sjögren's syndrome (pSS) frequently share overlapping clinical features, yet exhibit substantial intradisease heterogeneity in organ involvement and severity. This study aimed to define conserved molecular subtypes across these systemic autoimmune diseases (SADs) and delineate their transcriptional and epigenetic underpinnings. We profiled 262 treatment-naïve Chinese Han patients (RA: n = 109; SLE: n = 69; pSS: n = 84), predominantly female (83.2%), who were divided into discovery (n = 119) and validation (n = 143) cohorts. Bulk RNA sequencing defined molecular subtypes, which were correlated with clinical phenotypes. Chromatin accessibility and super-enhancer landscapes were mapped by Assay for Transposase-Accessible Chromatin with high-throughput sequencing and cleavage under targets and tagmentation, and single-cell RNA sequencing (scRNA-seq) was performed to delineate subtype-specific cellular compositions. Integrative analyses uncovered 2 robust and reproducible molecular subtypes, megakaryocyte-enriched and B-cell-enriched, which were consistent across all 3 SADs and both cohorts. The megakaryocyte-enriched subtype was associated with higher platelet counts, greater disease activity, and broader organ involvement. Epigenomic profiling identified distinct chromatin accessibility and regulatory architectures, with megakaryocyte-associated genes (eg, ZFP36L1 and RAD51B) linked to active superenhancers in the megakaryocyte-enriched subtype, and B-cell-associated genes (eg, MAF and PRDM1) in the B-cell-enriched subtype. scRNA-seq confirmed expansion of platelet-producing megakaryocytes and enhanced B-cell-activation signatures in their respective subtypes. Integrative multiomics profiling defines 2 conserved molecular subtypes across RA, SLE, and pSS with distinct cellular and regulatory programmes. This cross-disease taxonomy may inform precision stratification and the development of lineage-targeted therapies in SADs. Further multicentre validation and investigation of the epigenetic mechanisms underlying molecular subtypes are warranted.
Primary Sjögren disease (pSjD) is a systemic autoimmune disease with heterogeneous clinical, serological, and hematological manifestations. Because symptom onset and diagnostic delay may be difficult to determine retrospectively, age at diagnosis may provide a pragmatic framework for describing clinical heterogeneity. This study compared clinical, serological, and hematological profiles across diagnosis-age groups in pSjD. This retrospective cross-sectional study included 258 patients with definite primary Sjögren disease fulfilling the 2016 ACR/EULAR classification criteria after exclusion of cases with uncertain primary/secondary status. Patients were stratified according to age at diagnosis into young-adult (< 40 years, n = 54), middle-age (40-59 years, n = 137), and late (≥ 60 years, n = 67) groups. Demographic, clinical, serological, hematological, and composite inflammatory indices were compared. Logistic regression was used to evaluate exploratory sex-adjusted associations with pulmonary involvement. ROC analysis was performed to evaluate the modest discriminative performance of RDW-SD for late versus young-adult diagnosis-age groups. Pulmonary involvement was observed in 2/54 (3.7%) young-adult, 7/137 (5.1%) middle-age, and 19/67 (28.4%) late diagnosis-age patients (p < 0.001). In exploratory sex-adjusted logistic regression, late diagnosis-age was associated with pulmonary involvement compared with young-adult diagnosis-age (OR 8.20, 95% CI 1.75-38.32), whereas middle-age diagnosis was not (OR 1.34, 95% CI 0.26-6.83). Extraglandular involvement also differed across groups (31.5%, 16.8%, and 35.8%, respectively; p = 0.006). Corticosteroid exposure was more frequent in the late diagnosis-age group (7.4%, 18.2%, and 32.8%; p = 0.002), but was interpreted as a treatment variable rather than an intrinsic disease phenotype. CRP, neutrophil count, monocyte count, RDW-SD, NLR, SIRI, SII, and AISI differed across groups. RDW-SD showed only modest discriminatory ability for late versus young-adult diagnosis-age groups (AUC 0.645, 95% CI 0.538-0.746). Autoantibody profiles were broadly
ABSTRACT Objective This study tested the reliability of an ultrasound scoring system (0-3) for lacrimal glands using an OMERACT semi-quantitative ultrasound scoring system developed for salivary glands in primary Sjögrens Disease pSjD). Methods Fourteen rheumatologists participated in a static image exercise on ultrasound images in order to evaluate the reliability of the existing salivary gland ultrasound (SGUS) scoring system when applied to lacrimal glands. All images were obtained from patients with suspected pSjD using a 6-24 MHz linear hockey stick transducer. One hundred images representing different grades of parenchyma changes in the lacrimal glands were collected for the inter-observer analyses and 32 of these were repeated to assess intra-observer reliability. Kappa statistics were applied. Results Participants had musculoskeletal ultrasound experience ranging from 2–28 years, and SGUS experience from 0–12 years. The majority (11/14) had no prior experience in lacrimal gland ultrasound but 13/14 had experience in SGUS. Intra-observer reliability was good to excellent, with kappa values ranging from 0.63 to 1.00 (95% CI: 0.77–0.89). Inter-observer reliability showed good agreement, with a kappa of 0.63 (95% CI: 0.61–0.65). Conclusion The consensus-based semi-quantitative ultrasound scoring system for salivary glands showed good to excellent intra-observer and good inter-observer reliability when applied to the lacrimal glands using static images. The next step is to assess the reliability when scoring lacrimal glands in video-clips and in live exercises.