PURPOSE OF REVIEW: Genetic autoinflammatory conditions constitute an increasing field. Among them, type I interferonopathies (IFNp-I) were conceptualized 15 years ago as inborn errors of immunity due to chronic activation of the type I interferon (IFN-I) signalling pathway. Here, we provide recent insights in genetic mechanisms, clinical phenotypes and therapeutic options for these severe and rare disorders. RECENT FINDINGS: We will cover the novel findings into disease mechanisms, particularly the role of PTP1B in STING and IFNAR signalling, as well as the contribution of endosomal TLR pathways. We will also discuss the expanding phenotypic spectrum highlighted by recent case reports and cohort studies, together with the topic of clinical expressivity, including clinical non-penetrance, and possible mechanistic explanations such as monoallelic expression, the STING HAQ haplotype, and innovative approaches to characterise disease variability. Finally, we discuss current targeted therapeutic approaches for these disabling conditions, as well as potential new treatments for the future. SUMMARY: Overall, these findings highlight the need to consider these rare diseases across a wide range of clinical phenotypes. Advances in next-generation sequencing have enabled a genetic diagnosis in suspected cases and the implementation of targeted treatments, thereby reducing diagnostic uncertainty and providing the possibility of genetic counselling.
Incomplete lupus erythematosus (ILE) and non-Sjögren’s disease sicca (nSjD-sicca) are clinically heterogeneous, incompletely classified autoimmune conditions that share features with systemic lupus erythematosus (SLE) and Sjögren’s disease (SjD), respectively. Although some patients progress to classified disease, many remain stable. The immunologic features distinguishing incomplete from established autoimmune disease remain poorly defined. We sought to characterize and compare autoantibody immune signatures across ILE, SLE, nSjD-sicca, and SjD using expanded autoantibody profiling. Serum samples were obtained from patients with ILE (n=80), SLE (n=80), nSjD-sicca (n=52), SjD (n=60), and matched healthy controls (n=79). Initial screening was performed using the Bio-Rad BioPlex 2200. Expanded profiling utilized the GeneCopoeia Human Autoimmune Array (120 autoantigens) with parallel IgM and IgG detection. Traditional screening demonstrated expected patterns: ILE (anti-nRNP 26.3%; anti-chromatin 25.0%), SLE (anti-SmRNP 40.0%; anti-dsDNA 31.3%), nSjD-sicca (anti-La 9.6%), and SjD (anti-Ro/SSA 53.3%). Expanded analysis revealed significantly increased IgM autoreactivity in ILE compared with SLE (BH-FDR-adjusted p<0.05), targeting nuclear (KU, Nup62, CENP-A/B), cytokine (IFN-α1, IFN-ϵ, IL-15, GM-CSF), mitochondrial (M2), extracellular matrix (collagen IV, fibrinogen), vascular (β2-glycoprotein I, AGTR), and gut-associated antigens (tissue transglutaminase, intrinsic factor). In contrast, SLE demonstrated enriched IgG responses to canonical nuclear antigens, including core histone and dsDNA. Within the sicca spectrum, Ro52 (TRIM21) IgG autoantibodies were significantly increased in SjD compared to nSjD-sicca. These findings indicate that incomplete autoimmune disease states exhibit distinct IgM-dominant autoantibody profiles rather than simply attenuated versions of the IgG dominant responses in classified disease, highlighting the potential value of isotype-specific profiling for disease classification.
Objective Sjögren disease (SjD) is characterized by autoimmune lymphocytic infiltration of lacrimal and salivary glands, leading to dry eye and dry mouth. This study aimed to investigate the features and diagnostic value of lacrimal gland ultrasonography (LGUS) for distinguishing SjD from undifferentiated connective tissue diseases (UCTDs). Methods This prospective cohort study enrolled 80 patients, including 46 with SjD and 34 with non-SjD UCTDs. All participants underwent LGUS, scored according to the OMERACT guidelines for greyscale and color Doppler systems, alongside salivary gland ultrasonography (SGUS) and objective dry eye tests. Diagnostic performance was assessed using receiver operating characteristic (ROC) analysis. Results The ocular surface evaluation including tear break-up time (BUT), Schirmer test (ST), ocular staining score (OSS), and LGUS greyscale score of patients with SjD showed significant differences as compared with non-SjD patients, while no difference was found in morphology and color Doppler ultrasound score between the two groups. The ROC of LGUS has an AUC of 0.70 (95% CI 0.579–0.810) compared to other CTD patients; the combined LGUS and SGUS model achieved an AUC of 0.76, while a multivariate nomogram incorporating LGUS, SGUS, Schirmer, and OSS yielded an AUC of 0.792 (95% CI 0.693–0.891). Besides, a significant correlation was found between the LGUS greyscale score and salivary gland involved, anti-SSA antibody, and the ocular surface parameters. Conclusion LGUS is a non-invasive, cost-effective adjunct for early SjD diagnosis. It can be an additional tool integrated with SGUS and clinical tests, substantially improving diagnostic performance. Key Points • SjD patients showed significantly higher LGUS greyscale score than non-SjD UCTD patients. • LGUS may aid early SjD identification when used alongside ocular surface tests (Schirmer test and ocular staining score), with high specificity
Protein-losing enteropathy (PLE) is characterized by excessive gastrointestinal protein loss, yet systematic comparative studies across etiologies remain limited. This study aimed to characterize the confirmed PLE cohort in our center, with a focused comparison between connective tissue disease-associated PLE (CTD-PLE) and lymphatic drainage disorder-associated PLE (LDD-PLE), describe follow-up observations, and explore routine clinical indicators that may assist etiologic differentiation. This retrospective study included 146 patients admitted to Beijing Shijitan Hospital between January 2014 and December 2024 with PLE confirmed by 99mTc-HSA scintigraphy. Patients were classified as CTD-PLE or LDD-PLE according to the final clinical diagnosis. Clinical features, laboratory findings, and available follow-up data were analyzed, and logistic regression together with receiver operating characteristic (ROC) analyses were used to explore factors associated with CTD-PLE. The cohort included 146 patients (median onset age 26 years; 30 CTD-PLE and 116 LDD-PLE). Edema (84.2%) and serous cavity effusions (76.7%) were the most frequent manifestations. Comparative analysis showed that CTD-PLE patients were older, predominantly female, and had more frequent thrombosis and higher D-dimer levels than LDD-PLE patients. CTD-PLE also showed distinct laboratory features, including higher total cholesterol, triglycerides, and globulin levels, whereas LDD-PLE was associated with lower lymphocyte counts and more frequent diarrhea. Multivariate analysis identified age at onset, Hb, and total cholesterol as independent predictors of CTD-PLE. The three-variable model showed good apparent discrimination in this single-center cohort (AUC = 0.890), while C3 showed the best single-variable discrimination. Among patients with available follow-up, 19/20 CTD-PLE patients receiving glucocorticoids plus immunosuppressants achieved symptom remission with a median ALB improvement of 9.5 (3.8, 19.6) g/L, whereas 23/43 surgically treated LDD-PLE patients achieved symptom remission with a median ALB improvement of 2.0 (-0.5, 5.8) g/L. PLE with different etiologies
To understand the ordering patterns of antinuclear antibody (ANA) multiplex testing in a single, large US Department of Defense (DoD) tertiary healthcare system. Records of patients with an ANA multiplex assay ordered over a 1-year period were evaluated in a large DoD hospital system. Duplicate tests and patients with a previously established autoimmune rheumatic disease (ARD) prior to the year of study were excluded. The remaining 2499 patients' charts were reviewed for clinical presentation, ordering specialty, ordering rationale, and whether subsequent rheumatology evaluations resulted in a new ARD diagnosis. The ANA multiplex assay was ordered most often by primary care and medicine subspecialties for > 100 reasons. In the ANA multiplex assay-negative group, 37/2228 (1.66%) individuals were diagnosed with a new ARD. In the ANA multiplex assay-positive group 37/271 (13.7%) individuals were diagnosed with a new ARD. Sjögren disease, systemic lupus erythematosus, and undifferentiated connective tissue disease were the most common newly diagnosed ARDs in the ANA multiplex assay-positive group. Rheumatoid arthritis and seronegative spondyloarthritis were the most common new ARD diagnoses in the ANA multiplex assay-negative group. In this study, 97% of the ordered ANA assays did not lead to an ARD diagnosis. This study demonstrates frequent utilization of the ANA multiplex assay in the evaluation of nonspecific signs and symptoms, with a low rate of ANA-associated ARDs suggesting a need for implementation of strategies to improve understanding of appropriate clinical contexts that warrant ANA testing.
Anti-Ro/SS-A antibodies are prevalent across systemic autoimmune rheumatic diseases (SARDs) and may signify a distinctive phenotype. This study aimed to identify protein biomarkers associated with symptom burden and health-related quality of life (HR-QoL), and use protein-based stratification to identify clinically meaningful clusters and inflammatory pathways implicated. Anti-Ro positive SARD patients were enrolled in a 6-month pilot study. HR-QoL was determined using a patient-reported visual analogue scale, and symptom burden was assessed with the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI). Proximity extension immunoassays measured normalized protein expression (NPX) across 92 inflammatory proteins. Linear regression identified proteins linked to patient outcomes. Unsupervised hierarchical clustering of baseline NPX identified patient clusters. Functional protein association networks were visualized using String V.12.0. Diagnostic groups showed no differences in HR-QoL or physician global assessment (PhGA). Poor HR-QoL and high symptom burden correlated with downregulated inflammatory proteins, while PhGA correlated with upregulated proteins. Two distinct clusters were identified; Cluster 1, 'low expression cluster' exhibited higher symptom burden and more impaired HR-QoL, while Cluster 2, 'high expression cluster' correlated with a higher physician global assessment (PhGA). Key hub proteins included TGF-β1, CXCL-8, and CCL-2. This study identified patient clusters across the Ro-positive SARD, linking symptom burden to specific proteomic profiles. Unraveling novel protein networks associated with symptom burden and poor HR-QoL may identify therapeutic targets, which address patient-reported outcome measures (PROMs) across several disease indications.
Fetal autoimmune congenital heart block is a rare but life-threatening condition that is difficult to predict. This study sought to identify a serological biomarker predictive of autoimmune congenital heart block in pregnancies at risk due to maternal systemic lupus erythematosus, Sjögren's disease, undifferentiated connective tissue disease, or a history of congenital heart block offspring. This case-control study analysed maternal blood samples from pregnancies affected and unaffected by autoimmune congenital heart block from two centres (The Hospital for Sick Children, Canada, and The University of Padua, Italy). Serum samples collected across varying gestational ages were used for biomarker discovery, verification, and validation. The key inclusion criterion was a positive clinical test for maternal anti-Sjögren's syndrome-related antigen A/Ro autoantibodies, and the key exclusion criterion was structural congenital heart disease associated with heart block. Cases were pregnancies that resulted in fetal or neonatal congenital heart block and controls were pregnancies that resulted in offspring with a normal heart rhythm. Two-dimensional western blotting was used to identify maternal autoantibodies targeting fetal cardiac proteins, using fetal heart tissue and stem-cell-derived cardiomyocytes. Findings were validated using commercial proteins. Sensitivity and specificity for predicting fetal heart block outcomes were assessed using receiver-operating characteristic curves. The primary study outcomes were the presence and specificity of anti-cardiac autoantibodies in autoimmune congenital heart block cases versus controls, the association between specific autoantibodies and congenital heart block development, and the predictive accuracy of identified autoantibodies. This study did not involve individuals with lived experience in the study design or implementation. Serum samples were collected between Jan 1, 2010, and Dec 31, 2020, in the discovery cohort (The Hospital for Sick Children), between Aug 1, 1999, and Dec 31, 2019 in the
Systemic Lupus Erythematosus (SLE) presents a significant diagnostic challenge for clinicians due to its diverse clinical manifestations and overlap with other autoimmune conditions. Large Language Models (LLMs) are currently regarded as having the potential to assist clinicians in expediting decision-making. This study aimed to evaluate the performance of four LLMs in differentiating SLE from clinically mimicking conditions. A retrospective diagnostic accuracy study was conducted involving 100 patients at a rheumatology center: 50 patients with confirmed SLE and 50 non-SLE patients with conditions including rheumatoid arthritis, systemic sclerosis, axial spondyloarthritis, psoriatic arthritis, myositis, ANCA-associated vasculitis, mixed connective tissue disease, undifferentiated connective tissue disease, and fibromyalgia. Four LLMs were evaluated: Deepseek, ChatGPT 4.0, Claude Sonnet 4, and Gemini. The 2019 European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) classification criteria were applied. Diagnostic accuracy, positive predictive value (PPV), negative predictive value (NPV), and Area Under the Receiver Operating Characteristic Curve (AUC) were calculated. IBM SPSS Statistics version 25 was used for all analyses. Gemini achieved the highest performance score, with an accuracy of 96% (95% CI: 91.2-100.0%), sensitivity of 94% (95% CI: 89.3-98.7%), specificity of 98% (95% CI: 93.1-100.0%), and an AUC of 0.960. ChatGPT 4.0 and Claude Sonnet 4 exhibited comparable accuracy. Deepseek recorded the lowest performance score. Gemini demonstrated significant potential to assist clinicians in differentiating SLE from mimicking conditions. Nevertheless, prospective validation in real-world clinical settings is required before these tools can be reliably integrated into clinical practice.
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.
Undifferentiated connective tissue disease (UCTD) is a condition characterized by serological evidence of autoimmunity and occurrence of clinical symptoms suggestive for systemic autoimmune diseases, yet not fulfilling specific classification/diagnostic criteria. In the present longitudinal, observational, retrospective study, we aimed at analysing the evolution of UCTD course, focussing on the impact of 2019 EULAR/ACR classification criteria for systemic lupus erythematosus (SLE). Since 2008 we consecutively collected data about UCTD patients. All subjects were evaluated every six months, to record the development of clinical and laboratory features suggestive for specific autoimmune diseases. Finally, we retrospectively applied the 2019 EULAR/ACR SLE classification criteria at the first and last visit in our outpatient clinic. All the patients included in the study had been evaluated at our Lupus Clinic before the release of 2019 EULAR/ACR criteria. We included 201 UCTD patients [F/M 191/10, median age at first visit 46 years (IQR 21), median disease duration at first visit 3 years (IQR 9)]. At the first visit, 27 patients (13.4%) already met 2019 EULAR/ACR SLE classification criteria. Logistic regression analysis demonstrated the association between SLE classification and thrombocytopenia, anti-dsDNA/anti-Sm positivity, low C4 levels, joint involvement. During a mean observation period of 45.9 ± 35.6 months, 18.9% of patients were lost to follow-up, while 141 patients were followed. At last visit, additional 11 patients (7.8%) could be classified as having SLE. A relevant proportion of UCTD patients could be reclassified as having SLE according to the most recent classification criteria. Thrombocytopenia, anti-DNA/anti-Sm positivity and low C4 levels represent the most associated factors.
To explore self-reported cognitive dysfunction, including memory impairment, across systemic autoimmune rheumatic diseases (SARDs) and examine its impact and associations with demographic, clinical and psychosocial factors. A mixed-methods approach was employed, surveying 1853 SARD patients and 463 controls using validated instruments including the Everyday Memory Questionnaire-Revised (EMQ-R). Kruskal-Wallis tests and Spearman's rank correlations were used to compare the groups. Additionally, 67 in-depth interviews were conducted for qualitative thematic analysis. Systemic lupus erythematosus (SLE), undifferentiated connective tissue disease (UCTD) and Sjögren's patients reported significantly higher rates of memory impairments than other groups. There was no evidence of increased self-reported memory impairment with disease duration or age. Moderate positive associations were found between EMQ scores and the lifetime frequency of all other neuropsychiatric symptoms. EMQ-R was positively associated with self-assessment of overall disease activity (r = 0.291, P < 0.001) and negatively correlated with well-being (r = -0.397, R2 = 0.159). Expanding on the quantitative findings, qualitative analyses highlighted the adverse impact of cognitive dysfunction on daily participation in activities, social isolation, self-esteem and mental well-being, and the potential underreporting of these symptoms to clinicians. This study highlights a significant impairment of memory in SARDs, notably in SLE, UCTD and Sjögren's, and the impact of cognitive impairment on daily lives and well-being. The positive associations with disease activity and neuropsychiatric symptoms, and negative association with well-being emphasizes the need for targeted interventions. Future research should prioritize developing pharmacological and psychosocial interventions to address cognitive dysfunction in SARD patients. While reassuringly there was no evidence of worsening memory impairment over time, the underreporting of symptoms also suggests that cognitive issues may be more prevalent than clinical records indicate and thus emphasize the importance of thorough
To investigate whether in undifferentiated arthritis (UA) it is beneficial to start early treatment with disease-modifying antirheumatic drugs (DMARDs) compared with symptomatic therapy. The Induction of Cure in Early Arthritis study is a 3-month multicentre single-blinded randomised controlled trial followed by a 9-month observational period. Patients with early DMARD-naïve UA (arthritis ≥2 joints, not fulfilling American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2010 Rheumatoid Arthritis criteria) received a glucocorticoid injection (40 mg intra-articular or intramuscular) and were randomised (1:1:1) to a 3-month intervention with (1) non-steroidal anti-inflammatory drugs (NSAIDs) in standard daily dose or (2) methotrexate (MTX) 15 mg/week increased to 25 mg/week or (3) baricitinib 4 mg/day. Primary endpoint was Disease Activity Score (DAS) (44/53 joints) improvement at 3 months. Differences between treatment arms were assessed with analysis of covariance, adjusted for baseline DAS. Patients were randomised to NSAID (n=29), MTX (n=28) or baricitinib (n=28). After 3 months, baricitinib gave a significant improvement in DAS compared with NSAIDs: adjusted mean change in DAS: -0.52 (95% CI -0.93 to -0.11; p=0.01). MTX gave a numerically similar improvement: -0.39 (95% CI -0.84 to 0.06, p=0.09). Although non-significant, at 12 months DAS was lowest in the MTX treatment arm 1.3 (SD 0.7), NSAID 1.6 (SD 0.9), baricitinib 1.7 (SD 0.9), p=0.38. Incidence rates of severe adverse events remained low during the study across all treatment arms. In patients with UA, early DMARD treatment led to greater improvement in disease activity over 3 months compared with NSAIDs, with the improvement for baricitinib reaching statistical significance. Over 12 months, disease activity was not significantly different across treatment arms, with overall favourable outcomes.