To co-develop disease-specific patient questions for connective tissue diseases (CTDs), compare patient/rheumatologist ratings of answers from language models (LLMs) versus Google Search, and quantify EULAR coverage of these patient-prioritized questions. In this prospective single-center observational study, reported in accordance with STROBE, patient advocacy groups curated 20 frequently asked questions (FAQs) for each CTD (systemic lupus erythematosus, idiopathic inflammatory myopathy, Sjögren disease, systemic sclerosis). Questions were submitted to Claude 4.0 Sonnet, ChatGPT-5, Gemini 2.5 Pro, and Google Search. Five patients per disease and five rheumatologists rated blinded outputs using forced-rank preference and 5-point Likert scales (patients: empathy, trustworthiness, comprehensibility; physicians: medical correctness, empathy, comprehensibility). Guideline mapping assessed whether EULAR recommendations addressed each question. All three LLMs answered 100% of questions (80/80), whereas Google Search answered 90% (72/80). Across CTDs, patients rated LLM outputs favorably for empathy (mean 1.40-2.77), trustworthiness (1.47-2.6), and comprehensibility (1.33-2.27), and rheumatologists for medical correctness (1.23-1.98). Patients and physicians most often ranked Gemini 2.5 Pro best overall (rank 1: 59% and 63%), and Google Search most often worst (rank 4: 55% and 57%). Cluster analyses showed no consistent differences across five clusters. Guideline mapping revealed substantial gaps: 40-55% of prioritized FAQs were not addressed by EULAR recommendations, with largest gaps in cluster E, life impact, psychosocial aspects and family planning (75-100% not addressed; 0% fully addressed). In this blinded evaluation, LLMs produced CTD FAQs responses patients perceived as empathic, trustworthy and rheumatologists rated medically correct, with Gemini 2.5 Pro most consistently preferred overall. However, the mismatch between prioritized questions and guideline coverage underscores the need for patient-centered, evidence-grounded information resources.
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.
OBJECTIVES: Laboratory detection of myositis-specific autoantibodies (MSAs) utilises enzyme-linked immunosorbent assays (ELISA) and multianalyte line blot assays (LBA). We sought to evaluate the concordance and reliability of these two commercial assays. METHODS: Serum samples from patients with idiopathic inflammatory myopathies (IIM) were obtained from 7 countries across the Asia-Pacific region. Anti-Jo-1, anti-EJ, anti-PL-7, anti-PL-12, anti-MDA5, anti-Mi-2, and anti-TIF1-γ antibodies were centrally measured with commercial ELISA and LBA kits. The positive percentage agreement (PPA), negative percentage agreement (NPA), and Cohen's kappa were calculated by comparing the two assays. Sera with discordant results were subjected to "gold-standard" immunoprecipitation (IP) assays. RESULTS: Serum samples obtained from 485 patients with IIMs, including 180 with dermatomyositis, 44 with amyopathic dermatomyositis, 7 with juvenile dermatomyositis, 197 with polymyositis or immune-mediated necrotising myopathy, and 57 with inclusion body myositis, were subjected to ELISA and LBA. The PPA was the highest for anti-Jo-1 at 0.98, followed by 0.94 for anti-PL-7, 0.93 for anti-EJ, 0.93 for anti-MDA5, 0.89 for anti-TIF1-γ, 0.78 for anti-PL-12, and 0.67 for anti-Mi-2, whereas the NPA was high (ranging from 0.97-1 for all MSAs). Kappa values exceeded 0.80 for anti-Jo-1, anti-EJ, anti-MDA5, and anti-TIF1-γ, whereas anti-PL-7, anti-PL-12, and anti-Mi-2 exhibited low values. IP assays using sera with discordant results revealed a high rate of false positives for anti-PL-7 and anti-Mi-2 in LBA. CONCLUSION: Discrepancies in the measurement results were observed between commercially available ELISA and LBA, especially for anti-PL7 and anti-Mi-2. ELISA is more accurate than LBA.
OBJECTIVE: Little is known as to whether the American College of Rheumatology/European Alliance of Associations for Rheumatology Total Improvement Score (TIS) reflects how patients in the autoimmune inflammatory myopathies (AIM) spectrum feel and function. We assessed the associations between TIS and changes in the scores of a wide range of patient-reported outcomes (PROs). METHODS: Adult AIM subjects with active disease at baseline visit and a 1-year follow-up were identified from a research cohort. PROs included a numerical rating scale for pain, the Functional Assessment of Chronic Illness Therapy (FACIT)-fatigue, the PROMIS Short Form v1.0-Fatigue 8a, the Patient Health Questionnaire (PHQ-9), and the Medical Outcomes Trust Short Form-36 (SF-36) Physical and Mental Component Summary (PCS/MCS). Multivariable linear regression models were generated to determine the absolute change in PROs for each increase of 20 units in absolute TIS. RESULTS: We identified 65 subjects with active disease for which TIS could be calculated. At year- 1, 40% did not improve, 34% achieved minimal improvement and 26% moderate improvement. In adjusted models, increase in absolute TIS was associated with a statistically significant improvement in pain, PROMIS-fatigue, FACIT-fatigue, and SF-36 PCS. For the FACIT-fatigue, a significant interaction was identified between age and TIS. In stratified analyses, only patients with shorter disease duration significantly improved in pain and FACIT-fatigue scores. CONCLUSION: The findings from this cohort study support the use of the TIS in AIM research, but also highlight some of its possible limitation in the greater spectrum of AIM especially older individuals and those with longer disease duration.
OBJECTIVES: Discordance between patient and physician perspectives on disease activity in idiopathic inflammatory myopathies (IIM) can compromise treatment outcomes. This study aimed to characterize patterns of discordance and distinct longitudinal trajectories in the MyoCite IIM cohort. METHODS: Discordance was defined as a difference between patient (PtGA) and physician (PhGA) global assessments (0-10cm scale) of ≥ ±1cm. Prevalence was assessed at baseline (n = 244) and longitudinally at 6, 12, and 24 months (n = 128). Linear mixed-effects (n = 191) and bidirectional mediation models identified independent drivers and causal pathways. RESULTS: Clinically significant baseline discordance occurred in 19.3% of patients, predominantly manifesting as positive discordance (PtGA>PhGA; 16.8%) across IIM subtypes (dermatomyositis, polymyositis, overlap myositis, anti-synthetase syndrome). Over 24 months, discordance narrowed with treatment. Baseline positive discordance strongly predicted poorer functional capacity (HAQ) at 1 year (p= 0.034). While objective muscle weakness statistically drove the gap (MMT-8: β = -0.013, 95% CI - 0.022 to - 0.004; standardised β = -0.155, p= 0.006), fluctuations had minimal absolute impact. A distinct subset (25%) maintained persistent discordance, exhibiting high subjective pain despite normalized muscle enzymes. Bidirectional mediation analysis revealed discordance unidirectionally drives future functional disability through unmanaged pain (32.1% mediated, p< 0.001) while reverse mediation (HAQ driving discordance via pain) was not statistically significant. CONCLUSION: Patient-physician discordance in IIM is an active, upstream driver of future functional loss, mediated significantly by pain, rather than a mere reflection of existing objective damage. It serves as a critical marker requiring early targeted pain intervention and integration of patient-reported outcomes into routine clinical monitoring.
Objective Individuals with systemic autoimmune rheumatic diseases (SARDs) are at risk for worse acute and post–acute COVID‐19 outcomes, though whether individuals with SARDs have longer persistence of viral antigens after COVID‐19 has not been studied. Methods This retrospective cohort study evaluated post–COVID‐19 differences in SARS‐CoV‐2 antigen (spike, spike protein that contains the receptor‐binding domain, and nucleocapsid) positivity between individuals with SARDs (COVID‐19 and Rheumatic Diseases [RheumCARD]) and without SARDs (Researching COVID to Enhance Recovery [RECOVER]–Adult). SARS‐CoV‐2 antigens were measured in collected samples using a validated ultrasensitive single molecule array. This digital enzyme‐linked immunosorbent assay used antibody‐coated magnetic beads to capture antigen molecules, which were loaded into microwell arrays and detected through enzymatic cleavage of a fluorescent substrate. We used logistic regression to estimate unadjusted and adjusted (for age, sex, infection year, vaccination status, and COVID‐19 treatment) odds ratios for SARS‐CoV‐2 antigen positivity at months 3 and 6 following COVID‐19. Results Among 210 individuals with SARDs in RheumCARD and 348 individuals without SARDs in RECOVER‐Adult, any SARS‐CoV‐2 antigen positivity was more common in those with SARDs (36.7% in RheumCARD vs 18.9% in RECOVER‐Adult; P < 0.001). Those with SARDs had higher odds of nucleocapsid antigen positivity (adjusted odds ratio [aOR] 3.73, 95% confidence interval [CI] 1.28–10.85) or any antigen positivity (aOR 2.89, 95% CI 1.43–5.85) three months after COVID‐19 infection and higher odds of nucleocapsid antigen positivity (aOR 6.62, 95% CI 1.09–40.30) six months after COVID‐19 infection. Conclusion Individuals with SARDs were more likely to have SARS‐CoV‐2 antigen positivity at months 3 and 6 following COVID‐19 infection compared with individuals without SARDs, not explained by demographics, variant, vaccination, or treatment.
Although statin-induced muscle toxicity was recognized, a subset of patients presented with severe, persistent necrotizing myopathy despite statin withdrawal. Recognized initially through the serendipitous aggregation of cases in the longitudinal myositis cohort at the Johns Hopkins Myositis Center, the anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibody was identified in patients with previously seronegative necrotizing myopathy who shared a significant history of statin exposure. The autoantigen is the statin's pharmacological target, providing a specific biomarker and a compelling mechanistic link to the drug. Subsequent investigation has delineated a complex, self-perpetuating pathogenesis, in which statin exposure upregulates HMGCR expression on regenerating muscle fibers in genetically susceptible individuals, sustaining the autoimmune response. Pathogenic IgG antibodies drive myofiber necrosis through complement activation on the myofiber surface, and recent evidence indicates that internalized autoantibodies disrupt HMGCR function, leading to pathological lipid accumulation and necrosis. Curiously, the disease also occurs in statin-naïve patients, including children, where it can clinically mimic muscular dystrophy, and the trigger remains unknown. HLA-DRB1*11:01 is a strongly associated risk allele, and certain Indigenous populations have been shown to be at a substantially increased risk. Anti-HMGCR myopathy is distinguished from self-limited toxic myopathy by its persistence- generally presenting years rather than weeks or months after stain exposure-and its response to immunotherapy. Intravenous Ig and rituximab are cornerstone treatments, with emerging therapies targeting the neonatal Fc receptor. Targeting complement in a clinical trial yielded unexpected negative results. This review traces the scientific journey from a clinical conundrum to a paradigm-shifting discovery, highlighting key milestones and future directions.
Objective We evaluated remission rates and predictors across idiopathic inflammatory myopathy (IIM) subgroups using data from a prospective registry. Methods Adult patients with IIM with ≥ 1 year of disease duration, enrolled between 2000 and 2019, were analyzed. Subgroups included dermatomyositis (DM), antisynthetase syndrome (ASyS), and immune-mediated necrotizing myopathy (IMNM). Remission was defined as the absence of disease activity by expert assessment. Drug-free remission (DFR) and International Myositis Assessment and Clinical Studies Group (IMACS) remission (≥ 6 months of DFR) were also evaluated. Cumulative incidence of remission and flare was estimated using the cumulative incidence function. Remission predictors were evaluated using cause-specific Cox proportional hazards models. The association between remission and mortality was assessed using Cox models, with remission treated as a time-dependent covariate. Results The cohort (n = 393) was 67.2% female, with a mean age of 50.1 years. At 10 years, cumulative probabilities of remission, DFR, and IMACS remission were 40.3%, 23.3%, and 18.1%, respectively. Remission rates were highest in DM (47.4%) and lowest in ASyS (30.1%). Median time to first remission was 3.7 years. The 10-year cumulative incidence of flare following remission was 40.6%. Anti–Mi-2 antibody predicted a higher likelihood of remission (hazard ratio 2.08, P = 0.02). Remission and DFR were associated with improved survival. Conclusion Remission rates differed across IIM subgroups, with the highest in DM and lowest in ASyS. Anti–Mi-2 antibody was associated with a higher likelihood of remission.
Objective Steroid‐induced osteonecrosis of the femoral head (SONFH) is a refractory skeletal disorder influenced by genetic and environmental factors. However, conclusive pathogenic genetic evidence remains elusive due to the limited exploration of rare damaging variants. In this study, we aimed to identify rare variants associated with SONFH. Methods We conducted whole‐exome sequencing (WES) in a SONFH case‐control study comprising 174 systemic lupus erythematosus (SLE) patients on steroids. Followed by comparing the cases with an ethnically matched healthy population and validation in an additional SONFH cohort of 246 patients without SLE. Rare damaging variants were identified via genetic burden analysis and confirmed by Sanger sequencing and pedigree studies. The functional assessments of the erythrocytes on target variants were performed. Results We identified 10 heterozygous ANK1 and EPB41 rare variants in 9 (10.8%) of 83 SONFH patients compared with 0 (0%) of the 91 non‐SONFH controls.The burden effect of them remained robust after adjusted analysis (aOR [Firth's logistic regression adjusted odds ratio] ANK1 11.3; aOR EPB41 32.3; both p<0.05). The variants were detected in 10 (4.1%) of the validated SONFH cohort with 246 non‐SLE conditions. Functional analyses revealed that the variants result in membrane dysfunctions in the patients’ erythrocytes, characterized by reduced ANK1 expression, abnormal morphology, and increased hypotonic hemolysis. Conclusion These findings suggest that the rare variants in ANK1 and EPB41 are novel SONFH disease risk factors which compromise erythrocyte membrane integrity, exacerbating microcirculatory damage in the presence of glucocorticoid as a second hit.
Objectives To systematically evaluate the efficacy and safety of plasma exchange (PE) in adult patients with idiopathic inflammatory myopathies (IIM). Methods A systematic review was conducted in accordance with PRISMA guidelines and registered on PROSPERO. MEDLINE, Embase and Web of Science were searched from inception to 17 January 2025. Studies involving adult patients with IIM treated with PE were included. Baseline demographics, clinical characteristics, treatment outcomes and adverse events were extracted. Results Thirty-five studies involving 473 patients were included, of whom 361 received PE. Most studies were observational, and PE was predominantly used as adjunctive or rescue therapy alongside immunosuppressive treatment. Across included studies, PE was reported to be associated with improvements in organ-specific outcomes, including muscle strength, dysphagia, pulmonary manifestations and biochemical markers such as creatine kinase, ferritin, KL-6 and myositis-specific autoantibody titres. A meta-analysis of seven comparative studies did not demonstrate a statistically significant mortality benefit associated with PE in patients with refractory or rapidly progressive interstitial lung disease (RR 0.41, 95% CI 0.16–1.06, I2 = 70%). In immune-mediated necrotising myopathy, PE was frequently associated with clinical improvement and reductions in anti-HMGCR antibody titres. Reported adverse events were generally mild to moderate, with no procedure-related mortality. Conclusion PE has a biologically plausible but clinically selective role in adult IIM and is most commonly used as an adjunctive therapy in severe or refractory disease. Evidence is heterogeneous and largely observational, limiting causal inference. Prospective studies with standardised outcome measures are required to better define the role of PE in IIM.
In DM/PM hospitalizations, malnutrition was associated with higher odds of major complications and greater healthcare resource utilization. These findings suggest that inpatient nutritional risk assessment may help inform risk stratification during hospitalization for DM/PM. Key Points • In DM/PM hospitalizations, malnutrition occurred in 12.9% of admissions (NIS 2016-2022). • In matched DM/PM analyses, malnutrition was associated with higher in-hospital mortality and major complications. • Malnutrition was associated with greater resource utilization in DM/PM admissions.
This study provides a detailed clinical-serological characterization of IIMs in a Mexican cohort. Our findings reinforce recognized clinico-serological phenotypes and suggest regional patterns, including the high prevalence of anti-Ro52. These results underscore the need for broader autoantibody testing and contribute to the understanding of IIM heterogeneity in underrepresented populations.
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.
Objective Regeneration and expansion of regulatory T cells (Treg) by low‐dose interleukin‐2 (IL‐2) therapy is considered a potential treatment strategy for a wide range of autoimmune diseases. To provide a pathophysiologically‐based rationale for low‐dose IL‐2 therapy, we investigated whether reversible defects in the Treg‐IL‐2 axis emerge in inflammatory myopathies. Methods CD4+ T cell subsets from patients with polymyositis (PM) or dermatomyositis (DM) (n=20) and healthy controls (HC; n=19), and PBMC from 8 patients, that were stimulated in vitro for 24 hours with different concentrations of recombinant human IL‐2, were analyzed by multicolor flow cytometry. mRNA expression of IL2RA, IL2RB, IL2RB, ENTPD1, IKZF2, and CTLA4 was quantified by real‐time PCR in IL‐2 stimulated PBMC (n=6). Two patients with refractory PM/DM were treated with low‐dose IL‐2 therapy for 8 weeks and monitored for clinical responses and changes in Treg subsets. Results Frequencies of Treg expressing CD25 at high levels (CD25hi Treg) and of CXCR5+ Treg were reduced in PM/DM patients compared to HC (p=0.0052; p=0.0661), particularly in active myositis (p=0.0036; p=0.0335). Stimulation with low doses of IL‐2 selectively enhanced expression of CD25 molecules by Treg, leading to an increase in the CD25hi Treg subset (p<0.05), and augmented mRNA expression of several immunoregulatory molecules (p<0.05). Low‐dose IL‐2 therapy induced decreases in muscle enzymes that were accompanied by a sustained expansion of CD25+ Treg. Conclusion Our data suggest that shortage of IL‐2 is pathophysiologically relevant in PM/DM. Recovery and expansion of Treg by low‐dose IL‐2 therapy could thus be a promising targeted treatment option. image
Inborn errors of metabolism comprise a clinically diverse group of conditions that arise from the decreased activity of an enzyme or metabolite transporter and subsequent blockade in a metabolic pathway. These disorders are typically considered in the differential diagnosis of critically ill neonates or young children presenting with hypoglycaemia, metabolic acidosis or hyperammonaemia. However, beyond these classic presentations, a broader group of inborn errors of metabolism can manifest more subtly, with progressive articular and multi-systemic involvement that mimics or overlaps with typical features of rheumatological disease. Consequently, these conditions might be misdiagnosed for years as rheumatological diseases, including juvenile idiopathic arthritis, systemic sclerosis, idiopathic inflammatory myopathies and systemic lupus erythematosus. Moreover, these disorders provide unique opportunities to understand the complex interplay between metabolism and immune function. With the growing availability of disease-modifying therapies for inborn errors of metabolism, rheumatologists must be able to recognize these disorders, particularly in patients with atypical features or treatment-refractory disease.
A newsletter aborda o risco quase dobrado de câncer em pacientes com Síndrome VEXAS, destacando a importância da genotipagem de UBA1 e marcadores inflamatórios. Apresenta o novo guideline brasileiro para fibromialgia com recomendações atualizadas e analisa um ensaio clínico sobre o abatacepte em miopatias inflamatórias, que sugeriu benefício clínico em subtipos específicos como polimiosite e miopatia necrosante.
Idiopathic inflammatory myopathies (IIMs) are being increasingly recognized as disorders driven by profound disturbances in cellular energy metabolism rather than inflammation alone. Recent studies have highlighted mitochondrial dysfunction, oxidative stress, and metabolic reprogramming across glucose, lipid, and amino acid pathways as central mechanisms linking energy metabolism dysregulation to sustained muscle injury. Defective mitophagy, mitochondrial DNA (mtDNA) depletion, and excessive reactive oxygen species (ROS) production create a self-amplifying loop with interferon-driven inflammation, whereas abnormal glycolysis, impaired fatty acid oxidation, and dysregulated tryptophan-kynurenine metabolism further shape the immunometabolic landscape of IIMs. These metabolic shifts not only contribute to muscle weakness and tissue degeneration but are also correlated with disease severity, autoantibody profiles, and treatment resistance. Emerging therapeutic strategies, including antioxidant approaches, mitochondrion-targeted agents, metabolic modulators, and exercise-based interventions, underscore the translational potential of targeting energy homeostasis. This review synthesizes current evidence on energy metabolism abnormalities in IIMs, integrates molecular findings with clinical implications, and highlights future directions for immunometabolic-based precision therapies.
While Sjögren disease (SjD) overlap is known to modulate the clinical-serologic manifestations of other connective tissue diseases, the association with anti-synthetase syndrome (ASyS) has been seldom described in Caucasian cohorts. Anti-Ro52 autoantibodies, shared by both conditions, may blur early diagnostic attribution, particularly when glandular symptoms precede myositis-spectrum features. To characterize the clinical phenotype, serological profile, and disease trajectory of patients fulfilling classification criteria for both SjD and ASyS. We conducted a multicentre retrospective study (2018-2025) across three Italian referral centres, including patients meeting both the 2016 ACR/EULAR SjD criteria and the Connor's/provisional CLASS classification criteria for ASyS. Clinical features, serology, interstitial lung disease (ILD) characteristics, treatments, and outcomes were systematically collected. SjD activity was assessed using the ESSDAI and an adapted ESSDAI excluding the classic ASyS triad (pulmonary, articular and muscular domains). Seventeen female patients of Caucasian ethnicity were identified. At the time of connective tissue disease diagnosis, 7 were classified as SjD and 10 received concomitant diagnoses; all reported early sicca symptoms. Regarding serology, anti-Ro52 antibodies were detected in all patients, most often (88%) in the absence of anti-Ro60 antibodies. Anti-synthetase antibodies were present in all cases, mainly non-Jo-1 specificities (77%), while anti-Jo-1 was observed in a minority of patients (23%). ILD was the leading organ involvement (14/17, 82%), typically with acute/subacute onset and NSIP or NSIP/OP patterns. ILD drove treatment decisions and accounted for four deaths, whereas most survivors showed stabilization or mild improvement under immunosuppressive treatment. Systemic assessment indicated a predominantly ASyS-driven phenotype: although ESSDAI was moderately elevated (median 15, IQR 7.5-21), the adapted ESSDAI markedly decreased (median 5, IQR 0-6.5), reflecting limited SjD-specific systemic activity. The SjD-ASyS overlap seem characterized by a coherent clinical-serological phenotype, defined
To investigate the clinical, immunological, and metabolomic factors associated with fibromyalgia (FM) in patients with idiopathic inflammatory myopathies (IIM) who are in clinical remission or complete response. In this cross-sectional, 49 patients with IIM meeting remission and/or complete clinical response criteria were evaluated with the PROMIS Pain Interference Short Form 8a as an initial screening tool and patients with clinically significant pain interference subsequently underwent assessment with the 2016 ACR criteria. Clinical data, flow cytometry of peripheral blood mononuclear cells, multiplex cytokine assays, and untargeted metabolomic profiling by GC-MS were performed. Multivariate logistic regression was used to identify variables associated with FM. The prevalence of FM in this IIM cohort was 40.8%. FM was associated with higher patient global assessment scores, increased muscle damage, current prednisone use, and elevated serum levels of IL-6 and MCP-1. Immunophenotyping revealed reduced numbers of non-classical monocytes, CD8+ T cells, and B lymphocytes in FM patients. Metabolomic analysis identified lower concentrations of tryptophan and nonanoic acid in the FM group, suggesting altered pathways of immune regulation and nociplastic pain. Patients with IIM in remission and/or complete clinical response can present with clinical significant FM, which is associated with immune dysregulation and metabolic alterations. These findings highlight the need for routine FM screening in IIM and support the use of patient-reported outcomes to distinguish between inflammatory and nociplastic symptoms in clinical practice.
The frequency of extractable nuclear antigen (ENA) seropositivity in patients with negative antinuclear antibodies (ANA) by indirect immunofluorescence (IIF) remains insufficiently characterized. We aimed to estimate the frequency of ENA seropositivity among ANA-IIF-negative individuals (ENA+/IIF-), and to identify associated clinical and methodological determinants. A systematic search of PubMed, EMBASE, Web of Science, and Scopus was conducted for studies published up to January 31, 2025. Studies evaluating ENA seropositivity in ANA-IIF-negative patients using HEp-2 or HEp-2000 substrates were included. Meta-analysis was performed using the Freeman-Tukey double arcsine transformation and random-effects models. Twenty-eight studies, comprising 33 distinct patient groups and 28,552 ANA-IIF-negative samples, were included. The pooled proportion of ENA+/IIF- was 14.1% (95% CI: 10%-18.7%), with substantial heterogeneity (I² = 99%). Subgroup analysis demonstrated significant variation according to clinical indication: 1.4% (95% CI: 1.1%-1.9%) in unspecified indications, 8.1% (95% CI: 6%-10.5%) in suspected connective tissue disease (CTD), and 44.1% (95% CI: 32.3%-54.6%) in confirmed CTD (p < 0.0001). Multivariable meta-regression identified the IIF cut-off dilution, anti-SSA/Ro antibodies, and anti-tRNA synthetase antibodies as significant determinants of ENA+/IIF- frequency. This meta-analysis confirmed that ENA seropositivity is not uncommon in ANA-IIF-negative individuals, and it varies according to clinical context. A negative ANA-IIF result does not reliably exclude CTD, particularly in patients with strong clinical suspicion of CTD. These findings support a targeted, clinically driven ENA testing strategy, especially in conditions such as Sjögren syndrome and inflammatory myopathies. https://www.crd.york.ac.uk/PROSPERO/view/, identifier CRD420250654499.
Chimeric antigen receptor T-cell (CAR-T) therapy has expanded beyond oncology and is emerging as a promising strategy for autoimmune diseases. Early clinical experience, particularly with CD19-directed CAR-T cells, has shown that deep remission can occur in refractory disorders such as systemic lupus erythematosus, inflammatory myopathies, and systemic sclerosis. These observations are consistent with an immune-reset-like process, although its durability, cellular basis, and disease-specific mechanisms remain incompletely defined. However, the clinical development landscape remains uneven. Based on an April 2026 Trialtrove snapshot, the field is growing rapidly but remains concentrated in a limited number of countries, diseases, and target classes, with most studies in early-phase development. These features suggest that autoimmune CAR-T therapy has moved beyond proof of concept, but has not yet reached a mature, indication-optimized stage of clinical translation. In this Perspective, we argue that the next phase of progress will depend less on increasing trial numbers than on improving biological precision, platform diversity, and trial design. The current pipeline is dominated by CD19-centered programs and diseases in which B-cell depletion appears biologically plausible, but this approach is unlikely to be equally informative across autoimmune disease. Key questions remain regarding remission durability, relapse after B-cell reconstitution, patient selection, toxicity management, and scalability. Looking ahead, major opportunities include plasma cell-directed approaches, dual-target strategies, chimeric autoantigen receptor platforms, tolerance-oriented cell therapies, off-the-shelf products, and in vivo engineering. The near-term readout window will be critical in determining whether autoimmune CAR-T therapy becomes broadly deployable or remains limited to selected indications and settings.
Preliminary evidence suggests sex-related variations in clinical and serological features in idiopathic inflammatory myopathies (IIMs), yet comprehensive cohort studies, particularly within the Italian population, remain scarce. The aim of this study is to assess sex differences in clinical phenotype, serological features, and disease activity, and to identify independent associated factors of disease activity in a well-characterised multi-centre Italian IIMs cohort. A total of 228 IIMs patients from 5 tertiary Rheumatology Units across Italy were included. Demographic, clinical, serological, and treatment data were collected. Continuous variables are reported as mean ± SD or median (IQR), categorical variables as n (%). Comparisons between the 2 sexes were assessed by Student's t-test, Mann-Whitney U test, χ², or Fisher's exact test. Independent associated factors of disease activity (MYOACT) were assessed through multivariable linear regression analysis. Of 228 patients, 157 (68.9%) were female, and 71 (31.1%) were male. Age at diagnosis was similar between sexes. Males showed significantly higher disease activity measured by the MYOACT index. Multivariable analyses identified male sex, MDA5 autoantibody positivity, and greater disease damage extent as independent associated factors of higher disease activity, whereas dermatomyositis and polymyositis were associated with lower disease activity. Furthermore, MYOACT showed good predictive ability to define patients at risk for intensive care unit admission with an optimal threshold of 0.23. These findings highlight relevant sex-related differences in clinical expression and may support more personalised management strategies.
To examine national trends and disparities in cardiovascular mortality associated with systemic connective tissue disorders (CTDs) in the United States from 1999 to 2020. We analyzed mortality data from the CDC WONDER database. Deaths were included where CTD (ICD-10: M05, M06, M30-M35) was the underlying cause and cardiovascular disease was a contributing cause. Age-adjusted mortality rates (AAMRs) per 1 000 000 were calculated using the 2000 US Standard Population. Joinpoint regression identified annual and average annual percentage changes. Analyses were stratified by sex, race/ethnicity, census region, and urbanization. Disease subgroup and state-level analyses were performed. Between 1999 and 2020, 47 752 cardiovascular deaths occurred among individuals with systemic CTDs. The national AAMR declined from 14.4 to 8.2 per 1 000 000 (AAPC: -2.68%, 95% CI: -2.89 to -2.47, p < 0.001). Females had consistently higher mortality than males (average AAMR: 13.5 vs. 5.9 per 1 000 000; p < 0.001). Non-Hispanic Black individuals had the highest rates (average AAMR: 14.9 per 1 000 000), with widening disparities after 2008. Rural areas had higher mortality than urban areas (average AAMR: 11.4 vs. 9.9 per 1 000 000; p = 0.01). Subgroup analyses revealed heterogeneous trends across CTD subtypes, with SLE showing the slowest improvement (AAPC: -1.87%) and dermatomyositis the steepest decline (AAPC: -4.98%). State-level AAMRs ranged 2.2-fold, from 6.3 (District of Columbia) to 13.6 (Montana) per 1 000 000. Cardiovascular mortality associated with systemic CTDs has declined significantly over two decades; however, persistent racial disparities, urban-rural differences, heterogeneous disease-specific trends, and substantial geographic variation underscore the need for targeted, equitable interventions in this high-risk population.
The objective of this study was to compare the efficacy of adjunct plasma exchange (PE) therapy with standard therapy in idiopathic inflammatory myopathy (IIM) with anti-signal recognition particle (SRP) antibodies. Anti-SRP-positive myositis patients were consecutively enrolled and followed up. Two-way ANOVA was performed to compare the pre- and post-treatment changes in myositis disease activities between the two groups. The Kaplan-Meier method was used to compare the composite end point of all-cause death and relapse after propensity score matching (PSM) and inverse probability weighting (IPW) analyses. Cox regression analyses were performed to screen long-term prognostic factors. In total, 53 patients were included (35 received standard therapy, 18 received adjunct PE therapy). The PE therapy group tended to have severer muscle weakness (P = 0.027), higher levels of anti-SRP antibody titres (P = 0.001), and creatine kinase (P < 0.001), as well as higher doses of CS administration (P = 0.038). At the 4-week follow-up point, both groups achieved remarkable remission, as indicated by significant improvements in the six core set measures (CSMs), and the changes in the six CMSs were more prominent in the PE therapy group (all P < 0.001). During a median follow-up of 15 months, 26 patients reached the composite end point, and the PE therapy group had significantly better prognosis after IPW analysis (P = 0.029). In the multivariate Cox regression analyses, PE therapy [hazard ratio: 0.14 (0.03-0.57), P = 0.006] and interstitial lung disease [HR: 4.82 (1.22-19.12), P = 0.025] turned out to be independent predictors for long-term prognosis. Adjunct PE therapy provided quick remission and sustained benefits for IIM with anti-SRP antibodies.
Interstitial lung disease (ILD) is a major pulmonary complication of idiopathic inflammatory myopathy (IIM), where early diagnosis improves outcomes. While high-resolution CT (HRCT) remains the gold standard, its radiation exposure poses concerns. Serum Krebs von den Lungen-6 (KL-6) and lung ultrasound (LUS) B-lines offer non-invasive alternatives, though their optimal diagnostic cut-offs and combined utility for IIM-ILD remain undefined. This study aimed to establish these cut-offs, evaluate diagnostic performance and develop a clinical prediction model. In this single-centre observational study, 162 patients diagnosed with IIM between 2020 and 2024 were enrolled. All underwent serum KL-6 testing, and 120 received systematic 50-point LUS examinations. Using HRCT as the reference standard for ILD diagnosis, receiver operating characteristics (ROC) curve analysis was used to determine optimal cut-offs and construct a combined nomogram. KL-6 levels were significantly elevated in the ILD group (n=113) compared with non-ILD (n=49). The optimal KL-6 cut-off was 553 U/mL (area under the curve (AUC)=0.895, sensitivity 69%, specificity 95.9%). For LUS B-lines number, 25 was recommended as the clinical threshold (sensitivity 98.8%). Their combination enhanced diagnostic performance (AUC=0.984). An online prediction model demonstrated strong clinical applicability. In an exploratory analysis of the rapid-progressive ILD subgroups, KL-6 and B-lines showed only modest predictive value (AUC ≈ 0.65). KL-6 ≥553 U/mL and B-lines ≥25 are effective screening thresholds, with combined use significantly improving diagnostic accuracy. The prediction model provides a practical tool for early identification in similar clinical settings. To optimise and generalise its use, external validation in multicentre cohorts is warranted.
To characterize the clinical and serological correlates of cardiovascular magnetic resonance (CMR)-confirmed myocarditis in idiopathic inflammatory myopathies (IIM), evaluate the diagnostic performance of high-sensitivity cardiac troponin I (hs-TnI), and quantify the independent prognostic impact of myocarditis relative to interstitial lung disease (ILD). Single-center retrospective cohort study (STROBE-compliant) of 142 consecutive adults with IIM (2019-2025). Myocarditis was confirmed by CMR according to the 2018 Lake Louise Criteria, performed both at diagnosis and during follow-up (with or without immunosuppression) upon clinical suspicion and/or elevated hs-TnI. Myositis-specific antibodies (MSA), myositis-associated antibodies (MAA), anti-Ro52 and antiphospholipid antibodies (aPL, Sydney criteria: ≥40 GPL/MPL units confirmed at ≥ 12 weeks) were systematically recorded. Associations were assessed with Fisher's exact test and logistic regression; multivariable models were pre-specified as parsimonious (two predictors) given the limited event count. Overall survival was analyzed with Kaplan-Meier curves, the log-rank test and Cox proportional-hazards regression. Myocarditis was confirmed in 9/142 patients (6.3%), without significant association with IIM class (P = 0.303) or with the antisynthetase antibody subgroup (anti-Jo-1 + PL-12 + PL-7 + EJ; 5.8% vs. 6.7%, P = 1.000). In univariable analyses, myocarditis was associated with Raynaud phenomenon (OR 13.6, 95% CI 2.3-80.0), aPL positivity (OR 10.7, 95% CI 2.6-43.9), anti-Ro52 coexisting with MSA/MAA (OR 8.7, 95% CI 2.2-34.8), anti-PM/Scl (OR 7.1, 95% CI 1.6-30.3), fever (OR 7.1, 95% CI 1.6-30.3) and ILD (OR 4.7, 95% CI 1.1-20.3). hs-TnI was markedly higher in myocarditis (median 366 vs. 3.5 ng/L; P < 0.001) with an area under the receiver-operating characteristic curve (AUROC) of 0.91 (95% CI 0.83-0.98). In the event-constrained multivariable model, Raynaud phenomenon (adjusted OR 13.1, 95% CI 1.5-112.7) and aPL (adjusted OR 7.2, 95% CI 1.4-36.0) remained independently associated. All-cause mortality was higher in myocarditis (44% vs. 9%; OR 7.95, 95% CI
To investigate soluble circulating sialic acid-binding Ig-like lectin 1 (scSIGLEC1), a surrogate biomarker for type I IFN, as a novel biomarker for idiopathic inflammatory myopathies (IIM) disease activity. Patients enrolled in a Canadian multicentre cohort of IIM patients with biobanked serum samples and clinical data at baseline and 1-year follow-up were included. Serum scSIGLEC1 levels at baseline were tested using a capture immunoassay and evaluated in relation to disease activity, defined using patients' Physician Global Activity (PGA) scores, Total Improvement Scores (TIS) and visual analogue scale scores for the six organ systems included in the Myositis Disease Activity Assessment Visual Analogue Scales (MYOACT): constitutional, cutaneous, skeletal, gastrointestinal, pulmonary and cardiovascular. Performance of scSIGLEC1, MYOACT and creatine kinase to assess disease activity were compared [area under the receiver operating characteristic curve (ROC AUC)]. A total of 87 IIM patients (67.8% female, mean age 54.4 ± 14.3 years) were included. Higher scSIGLEC1 levels differentiated between active and inactive disease on the PGA (difference 2.7 ng/ml; 95% CI 0.7-4.8). Higher scSIGLEC1 levels were found among patients with cutaneous (difference 1.7 ng/ml; 95% CI 0.1-3.4), skeletal (difference 2.0 ng/ml; 95% CI 0.1-3.9) and gastrointestinal (difference 2.2 ng/ml; 95% CI 0.5-3.9) disease activity compared with patients without disease activity in these extramuscular organs, and were associated with lower TIS scores at 1-year follow-up. scSIGLEC1 levels (ROC AUC 0.74; 95% CI 0.61-0.86) matched MYOACT performance and outperformed creatine kinase in assessing disease activity. scSIGLEC1 levels are a promising biomarker for monitoring overall IIM disease activity, as well as activity involving the cutaneous, musculoskeletal and gastrointestinal systems.
To assess the efficacy and safety of upadacitinib (UPA) in patients with refractory idiopathic inflammatory myopathy-associated interstitial lung disease (IIM-ILD) following conventional therapy failure. We conducted a single-centre retrospective cohort study of IIM-ILD patients initiating UPA after conventional therapy failure. Clinical characteristics, pulmonary function tests (PFTs), high-resolution CT (HRCT) Warrick scores and therapeutic regimens were collected at baseline and follow-ups. Patients receiving conventional treatment were included as the control group following propensity score matching (PSM, 1:2). Treatment responses and adverse events were analysed and compared. Among 28 UPA-treated patients (mean age 57, 87.5% female), 16 had complete paired data of PFTs and/or HRCT both at baseline and after treatment. After mean 7.4 months, lung function improved: the mean FVC increased from 1.84 to 2.13 l (P = 0.0069), FVC% from 63.5% to 76.77% (P = 0.0004). HRCT Warrick scores remained stable overall, with some patients showing radiographic improvement. Inflammatory indicators, including IL-6 (14.06-8.44 pg/ml, P = 0.039) and serum ferritin (240.30-188.15 µg/l, P = 0.018), decreased significantly after treatment. Further PSM analysis (n = 16 UPA vs 32 controls) showed notably lower post-treatment IL-6 (8.44 vs 20.60 pg/ml, P = 0.0012) and lower glucocorticoid dose (7.50 vs 12.50 mg, P = 0.017). No significant differences in PFTs or HRCT scores were found between the groups. Infections occurred in 6/28 (21.4%), all recovered well. UPA significantly improved lung function, reduced glucocorticoid dependence and suppressed systemic inflammation in refractory IIM-ILD with acceptable safety, supporting its use as a promising therapeutic option in IIM-ILD patients after conventional treatment failure.
To assess the risk of second primary cancer and death in patients who has a cancer diagnosis following idiopathic inflammatory myopathies (IIM). Using nationwide Swedish healthcare and population registers, we identified 2346 patients diagnosed with IIM ≥18 years of age between 1998 and 2024. Patients were followed for up to 27 years for first and second post-IIM primary cancers and death. Cumulative incidence function and incidence rate of second primary cancer and death were estimated. A flexible parametric multistate model was used to estimate transition probabilities to cancer and death. Furthermore, risk and prognostic factors for second primary cancer and subsequent death were assessed using multivariable models. Of 326 patients diagnosed with cancer at or after IIM diagnosis, 37 developed a second primary cancer during a mean follow-up of four years (maximum 19 years). The cumulative incidence of second primary cancer over the entire follow-up period was 22% (95% CI 14-33%) while the absolute risk within four years after a first post-IIM cancer was below 5%. Being male (hazard ratio, HR=3.2, 95% CI 1.6-6.5) and having a cancer history (HR=3.4, 95% CI 1.5-8.0) were significant risk factors of second primary cancers. The three-year all-cause mortality risk after a second primary cancer was 46% (95% CI 44%-70%). Patients with dermatomyositis had a markedly elevated mortality risk following a second primary cancer diagnosis compared to non-dermatomyositis subtypes (HR=3.77, 95% CI 1.46-9.75). These findings provide new insight into the burden of subsequent cancers among IIM cancer survivors and highlight the need for close clinical monitoring for patients with dermatomyositis to reduce premature mortality.
Myositis specific antibodies are clinically useful biomarkers in inflammatory myositis. Although immunoprecipitation is regarded as the gold standard, line immune assay (LIA) is widely used in practice. However, LIA is limited by multiple MSA positivity in up to 15% of patients, which limits its applicability in diagnosis and prognostication. We sought to interrogate the subset of patients with multiple antibody positivity on LIA to determine a new positive control band index with high specificity for the diagnosis of myositis. We retrospectively reviewed all samples tested for MSA (EUROLINE DL 1530-1601-4G) between April 2023 to April 2025. We calculated the PCBI (test reading/positive control) and compared it with optimal cutoffs as per EUROLINE and how it impacted multiple antibody positivity. Diagnosis of myositis subtype was confirmed by 2 rheumatologists. We retrieved records of 235 patients, 59.6% females with a mean age of 46.1 years. The underlying diagnosis was dermatomyositis (8.5%), juvenile dermatomyositis (2.1%), anti-synthetase syndrome (7.7%), necrotizing myopathy (2.6%), malignancy associated (4, 1.7%), MSA negative IIM or polymyositis (8, 3.4%) and CTD associated myositis (12, 5.1%) and ILD for IPAF evaluation (139, 59.1%). Multiple MSA positivity was seen in 25 patients (10.6%) with EuroLine, Using the revised PCBI cutoffs, we could discriminate between 14 of these MSA's and 11 remained positive for multiple antibodies. On correspondence analysis, both Euroline cutoffs and PCBI showed association between antibody positivity and clinical diagnosis (Chisq p values < 0.001). However, using the PCBI, 73.4% of the variability in the data compared to 69.13% with Euroline cutoffs. Rather than a single uniform cut off for all patients, a phenotype specific cut off for each clinical phenotype at the time of clinical assessment might offer a higher specificity for MSA with line
To evaluate the diagnostic performance of BioPlex 2200 multiplex immunoassay (BI) for detecting antinuclear antibodies (ANA), compared with the gold standard, the indirect immunofluorescence assay (IIF), as a screening methodology for autoimmune diseases within a general population. Cross-sectional, database-based analysis of the Clalit Health Services nationwide registry. Data were extracted from the Clalit Health Services database between 2014 and 2023. We included adult outpatients without a known rheumatic disease who underwent both IIF and BI testing simultaneously, ordered for nonspecific signs and symptoms primarily by primary-care physicians. Among the 391,366 individuals tested, 67% were female, and the median age at testing was 49 years. Annual ANA testing volume increased from 23,802 in 2014 to 76,898 in 2023 (3.2-fold). Of the total, 33,234 (8.4%) tests were false negatives (BI-negative while IIF-positive), 42,021 (10.7%) were false positives (BI-positive while IIF-negative), 302,439 (77.2%) were true negatives, and 13,672 (3.5%) were true positives. BI demonstrated a sensitivity of 29.1% (95% CI: 28.7-29.6) and a specificity of 87.8% (95% CI: 87.7-87.9). The positive predictive value was 24.5% and the negative predictive value 90.1%. Our findings do not support the use of the BI multiplex immunoassay as a primary ANA screening tool in the primary-care setting. On the basis of these findings, the Clalit Health Services laboratory network discontinued simultaneous IIF and BI testing. The BI showed low sensitivity despite relatively high specificity, resulting in a substantial proportion of false-negative results compared with IIF. These findings indicate that it is not suitable as a primary screening tool for ANA in the primary-care setting.
Data on interstitial lung disease (ILD) in Indian patients with idiopathic inflammatory myopathy (IIM) is limited. We aimed to determine the characteristics of ILD, and factors associated with the progression of ILD in Indian patients with IIM. A prospective single centre cohort of 86 consecutive adult-onset IIM patients recruited between October 2020 and December 2025 were studied. The diagnosis of IIM related ILD (IIM-ILD) was made after high resolution CT Thorax. Progression of ILD was defined as per the 2022 ATS/ERS/JRS/ALAT guidelines for progressive pulmonary fibrosis (PPF). Multivariate logistic regression was done to identify independent factors associated IIM-ILD. Comparisons were made between patients with PPF and those without PPF. Of the 86 IIM patients, ILD was seen in 59.3% of patients (n = 51). The most common radiological patterns were non-specific interstitial pneumonia (58.8%), organizing pneumonia (21.6%), usual interstitial pneumonia (13.7%), and overlap of NSIP-OP (5.9%). The most common subsets were anti synthetase syndrome (66.6%, 34/51), dermatomyositis (23.5%, 12/51) and overlap myositis (7.8%, 4/51). The most common myositis specific autoantibody was anti-Jo1 (27.4%, 14/51) and the most common myositis associated autoantibody was anti-Ro52 (58.8%, 30/51). On multivariate logistic regression, heliotrope rash (OR 0.25, 95% CI 0.06-0.96, p = 0.04), arthritis (OR 3.57, 95% CI 1.15-11.07, p = 0.03) and anti-Ro52 (OR 4.37, 95% CI 1.40-13.40, p = 0.01) were associated with ILD. Of the 37 patients with IIM-ILD evaluated for progression, 18.9% (n = 7) developed PPF within 1 year of follow up. Amyopathic presentation and NSIP/OP pattern were associated with PPF (p = 0.02, p = 0.03 respectively). The frequency of ILD is high in Indian patients with IIM (59.3%, 51/86) and of the IIM-ILD evaluated for progression, around one fifth developed PPF (18.9%, 7/37). A baseline screening for ILD is mandatory in IIM
Line blot assays (LBA) have several limitations regarding diagnostic validity, as sensitivity and specificity vary considerably among antigens. The aim of this study was to assess whether the adjustment of each specific band intensity (BI) relative to the positive control band (PCB), combined with increasing the cut-off value from 15 to 20, improves the diagnostic performance of the LBA for detecting autoantibodies related to idiopathic inflammatory myopathies in our patient cohort. We included all serum samples tested for myositis‑specific antibodies (MSA) and myositis‑associated antibodies (MAA) between January 2022 and April 2023 at the Immunology Department of Hospital Clínic of Barcelona. Two analyses were performed: Analysis A, using the manufacturer's recommended cut-off (BI ≥ 15), and Analysis B, applying the proposed BI adjustment relative to the PCB and raising the cut-off to 20 in samples that were positive in Analysis A. A total of 939 patients were included. Using Analysis A, 280/939 (29.8%) patients had at least one positive result, whereas 659/939 (70.2%) were negative for all MSA and MAA. After applying Analysis B, 151/280 (53.9%) remained positive, while 129/280 (46.1%) became negative. With Analysis A, sensitivity was 76%, specificity 75%, positive predictive value (PPV) 24%, and negative predictive value (NPV) 96%. Under Analysis B, sensitivity was 70%, specificity 89%, PPV 41%, and NPV 96%. Applying the proposed BI adjustment effectively removes weakly positive results with low specificity in an objective and reproducible manner, thereby increasing the overall specificity of the LBA. Key Points • Applying the proposed band intensity removes weakly positive results. • This approach enhances the specificity, and positive predictive value of a commercial line blot assay.
Cardiac involvement in patients with idiopathic inflammatory myopathies (IIM) is often subclinical but associated with poor prognosis. This study aimed to evaluate the diagnostic utility of cardiac troponin T (cTnT) for identifying myocardial involvement in IIM, using cardiac magnetic resonance (CMR) imaging. One hundred and sixteen IIM patients underwent clinical evaluation, laboratory tests, electrocardiogram (ECG), and CMR. The diagnostic performance of cTnT was assessed using receiver-operating characteristic (ROC) curves, while linear regression was used to explore associations between cTnT and myocardial involvement markers. Myocardial involvement, detected by late gadolinium enhancement (LGE) on CMR, was present in 63.8% of patients. Those with cardiac involvement exhibited significantly elevated cTnT levels (> 157.85 ng/L), which correlated with native T1, native T2, and extracellular volume (ECV) values. The cTnT threshold of 157.85 ng/L demonstrated sensitivity and specificity of 62.2% and 92.9%, respectively. Elevated cTnT levels (> 157.85 ng/L) are associated with cardiac involvement in IIM patients and could serve as a valuable non-invasive biomarker for early detection, particularly in subclinical cases. Further investigations are warranted to refine its clinical applicability. Key Points • A specific cTnT threshold (> 157.85 ng/L) demonstrates high sensitivity (62.2%) and specificity (92.9%) for identifying cardiac involvement. • Utilization of cardiac magnetic resonance imaging (CMR) as a reference standard enhances diagnostic accuracy for subclinical myocardial injury. • Findings support cTnT as a practical, non-invasive screening tool, guiding early detection and management of cardiac involvement in IIM.
ICI-induced inflammatory myositis (IIM) is a recognized irAE with significant morbidity and potential for life-threatening overlap syndromes. Whether polymyositis (PM) and dermatomyositis (DM) carry differential pharmacovigilance signals across ICI drug classes has not been systematically examined. A disproportionality analysis of FAERS was conducted to quantify reporting odds ratios across twelve approved ICI agents. Adverse event reports were extracted from FAERS through March 2026 using OpenVigil 2.1. RORs with 95% CIs were calculated for twelve ICI agents spanning PD-1, PD-L1, CTLA-4, and LAG-3 classes. Primary MedDRA endpoints were myositis, immune-mediated myositis, polymyositis, and dermatomyositis. Significant disproportionality for broad myositis was identified across all adequately powered ICI agents (PD-1, PD-L1, CTLA-4, LAG-3 classes), with RORs ranging 12- to 47-fold above background. The largest adequately powered signals were observed for pembrolizumab (ROR 18.34, n = 258), nivolumab (ROR 18.65, n = 256), atezolizumab (ROR 22.22, n = 132), and ipilimumab (ROR 15.11, n = 73); cemiplimab (ROR 46.89), relatlimab (ROR 44.68), and dostarlimab (ROR 33.48) produced high-magnitude estimates with smaller case counts. The immune-mediated myositis Preferred Term generated the largest estimates: pembrolizumab (ROR 45.64, n = 187), nivolumab (ROR 33.11, n = 137), and ipilimumab (ROR 25.40, n = 38). Significant dermatomyositis signals were identified in five agents, with atezolizumab producing the largest powered estimate (ROR 15.53, n = 29); DM RORs consistently exceeded PM RORs across agents, though ascertainment and coding bias likely contribute to this pattern. IIM is a pharmacovigilance signal of substantial magnitude across all ICI drug classes. The DM phenotype is more consistently disproportionate than PM across classes, with mechanistic plausibility given PD-L1's role in restraining interferon-producing plasmacytoid dendritic cells. The immune-mediated myositis MedDRA term captures the most statistically robust signal, reflecting a distinct ICI-associated coding pattern in spontaneous reporting.
The reported incidence and mortality of connective tissue diseases (CTDs) in England has been inconsistent in the literature. Our objective was to describe current trends in the incidence and mortality of systemic lupus erythematous (SLE), Sjögren's disease (SjD), systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIM) and mixed connective tissue disease (MCTD). We conducted a retrospective population-level study using primary care records in England via the Clinical Practice Research Datalink. We included individuals ≥18 years old with new CTD diagnoses between 2012 and 2023. Our outcomes were incidence and all-cause mortality, which included age-standardized mortality rates (ASMRs), standardized mortality ratios and hazards over time using flexible parametric models. There was a total of 22 829 incident CTD diagnoses (81.1% female, median age 57). The age and sex-standardized incidence of SLE and SSc fell over the study period 2012-2023 (SLE: 4.32-3.29 per 100 000 person years [py] and SSc: 2.33-1.86 per 100 000 py), whereas SjD and MCTD incidence remained relatively stable. In contrast, IIM diagnoses rose from 3.23 to 4.31 per 100 000 py. ASMRs across the study period were highest for IIM (27.83 per 1000 py), followed by SSc (24.43), SLE (16.74), MCTD (16.27) and lowest for SjD (9.70). Our findings indicated a fall in the incidence of SLE, a simultaneous rise in IIM incidence, and high all-cause mortality within IIM and SSc cohorts. Our study acknowledges the changing landscape of CTDs in England and will aid healthcare resource planning for this vulnerable population.
This study aimed to investigate the relationship between specific autoantibodies, particularly anti-Ro52, and the development of interstitial lung disease (ILD) in patients with autoimmune diseases (AID), with the goal of identifying potential biomarkers for the early detection and management of ILD. A retrospective cohort study was conducted at Peking Union Medical College Hospital, involving 2,021 AID patients who underwent antinuclear antibody (ANA) testing between 2017 and 2019. Clinical and serological data were collected to assess the presence of ILD and its association with specific autoantibodies. Least absolute shrinkage and selection operator (LASSO) regression was used to identify predictors of ILD. Among the 2,021 patients, ILD prevalence varied across AID subgroups, with the highest rates observed in idiopathic inflammatory myopathies (IIM), overlap syndrome, and systemic sclerosis. Anti-Ro52 was significantly more frequent in IIM patients with ILD compared to those without ILD (83.0% vs. 37.8%, p<0.0001). Anti-RNP was detected at a significantly higher rate in lupus-ILD patients. Additionally, positivity rates of anti-SSA/Ro60 and anti-CENP B were inversely associated with ILD in Sjögren's disease and systemic sclerosis, respectively. LASSO regression analysis identified anti-Ro52, age, and anti-MDA5 as significant predictors of ILD development in IIM. Anti-Ro52 positivity was associated with a more than two-fold increased risk of ILD progression in mixed connective tissue disease. Anti-Ro52, together with age and anti-MDA5, was identified as a significant predictor of ILD in IIM patients. This study highlights the potential of autoantibodies as biomarkers for early detection and management of ILD in AID patients.
To investigate respiratory syncytial virus (RSV) vaccine uptake, associations, and breakthrough infection among patients with systemic autoimmune rheumatic diseases (SARDs). We performed a retrospective cohort study investigating RSV vaccination among patients with SARDs at Mass General Brigham (Boston, Massachusetts, USA). We identified all patients with SARDs who were aged ≥ 60 years and thus eligible to receive the RSV vaccine between May 2023 and February 2025. We used multivariable logistic regression to identify factors associated with RSV vaccination. Among the vaccinated, we described documented cases of laboratory-confirmed breakthrough RSV infection. Among 10,587 patients with SARDs (median age 71.7 years, 72.4% female) eligible for RSV vaccination, 1075 (10.2%) received RSV vaccination. Factors associated with higher odds of RSV vaccination included higher median census-tract household income and comorbidities, such as cancer and interstitial lung disease. Associations with lower odds of RSV vaccination included Black race, lack of previous influenza or COVID-19 vaccinations, and glucocorticoid use. RSV vaccination was not associated with specific SARD types or disease-modifying antirheumatic drugs (DMARDs), including CD20 inhibitors. Among the 1075 who were vaccinated, there were 9 (0.8%) documented cases of RSV breakthrough infection (2 hospitalizations and no deaths).  CONCLUSION: Only 10.2% of eligible patients with SARDs received RSV vaccination. Glucocorticoid users were less likely to receive RSV vaccination, whereas specific SARD types and DMARDs were not associated. Although some predictors of vaccine uptake were observed in this dataset, there are many unmeasured factors that may play a role in vaccine uptake. There were few documented breakthrough infections and no deaths. Future studies are needed to optimize RSV vaccine use and establish safety and efficacy in this vulnerable population.
To describe clinical characteristics and post-lung transplant outcomes of patients with idiopathic inflammatory myopathies (IIM), SSc and idiopathic pulmonary fibrosis (IPF). We retrospectively analysed interstitial lung disease (ILD) patients with IIM (n = 22), SSc (n = 32) and IPF (n = 64) who underwent lung transplantation (2012-24) at two Canadian centres, Vancouver and Montréal. Among IIM patients, 41% were clinically amyopathic at presentation, and 45% had anti-melanoma differentiation-associated protein 5 (anti-MDA5) DM, all with rapid progressive (RP)-ILD, 32% anti-synthetase syndrome, 14% overlap myositis and 9% other DM. In SSc, 88% had pulmonary hypertension (PH) (31% severe) and 78% had oesophageal dysmotility. IIM patients required more frequent pre-transplant intensive care unit (ICU) admission and emergency transplantation. Post-transplant, IIM patients had longer ICU/hospital stays. There were no significant differences in 1-year survival, survival at last follow-up (median: 2.8 years for IIM, 2.5 years for SSc and 3.6 years for IPF), incidence of chronic lung allograft dysfunction or malignancy. Subgroup analyses of IIM [stratified by transplant urgency, extracorporeal membrane oxygenation (ECMO) support and amyopathy] and SSc (stratified by severe PH, oesophageal dysmotility and transplant urgency) showed no significant differences in long-term survival. No autoimmune disease recurrence was observed. Despite their underlying autoimmune diseases, post-transplant survival outcomes of selected IIM and SSc patients did not differ significantly from those with IPF. IIM patients with RP-ILD necessitating emergency transplantation and ECMO support exhibited survival similar to those without such complications. However, their more complex pre- and post-transplant courses emphasize the necessity for individualized lung transplant strategies and a multidisciplinary management approach.
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.
This study systematically compares the efficacy and adverse events of rituximab (RTX) and cyclophosphamide (CYC) in patients with connective tissue disease-related interstitial lung disease (CTD-ILD). The EMBASE, Cochrane, and PubMed databases were systematically searched to find all relevant studies. Quality assessment, study selection, and data extraction were independently conducted by two reviewers. The mean changes in percentage of predicted forced vital capacity (FVC%) and percentage of predicted diffusing capacity for carbon monoxide (DLco%) of the patients were selected to be primary outcome measures. RevMan 5 software was used for the pooled analysis. Among 1106 titles screened from multiple databases, six studies met the inclusion criteria (two randomized controlled trials and four retrospective observational studies). Patients of four studies were systemic sclerosis-related interstitial disease(SSc-ILD), one study was anti-synthetase syndrome-related interstitial lung disease (AsyS-ILD), and one study was CTD-ILD (included idiopathic inflammatory myositis (IIM), systemic sclerosis (SSc) or mixed connective tissue disease (MCTD), rheumatoid arthritis(RA)). The summary weight mean difference of FVC% change in the RTX group compared with the CYC group was 0.86 (95% CI:-1.51,3.24; P = 0.48), and the summary weight mean difference of DLco% change in the RTX group compared with the CYC group was 6.43 (95% CI: 1.62, 11.23; P = 0.009). Our pooled analysis suggested no significant difference in FVC% improvement between RTX and CYC. RTX seems to be slightly superior to CYC in terms of DLco% improvement in our meta-analysis. However, only three out of six enrolled studies provided data on DLco% change. Therefore, the results for DLco% change should be cautiously interpreted. Studies enrolled showed that adverse events were fewer in the RTX group. RTX appears to offer a favorable balance between efficacy and safety. RTX demonstrated similar efficacy
We provide evidence-based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease. We developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation. Fifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high-resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6-minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs. This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs.
Interstitial lung disease (ILD) is a frequent manifestation of connective tissue diseases (CTDs) and is associated with high morbidity and mortality. Clinical practice guidelines to standardise screening, diagnosis, treatment and follow-up for CTD-ILD are of high importance for optimised patient care. A European Respiratory Society and European Alliance of Associations for Rheumatology task force committee, composed of pulmonologists, rheumatologists, pathologists, radiologists, methodologists and patient representatives, developed recommendations based on PICO (Patients, Intervention, Comparison, Outcomes) questions with grading of the evidence according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) methodology and complementary narrative questions agreed on by both societies. For both PICO and narrative questions, the Evidence to Decision framework was used to formulate the recommendations. The task force committee concluded with recommendations for 25 PICO and 28 narrative questions, regarding ILD in the context of systemic sclerosis, rheumatoid arthritis (RA), idiopathic inflammatory myopathies, Sjögren disease (SjD), systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). In four narrative questions, regarding screening and assessment of risk for ILD progression in MCTD, SjD and SLE and one PICO question regarding pirfenidone in CTD-ILD other than RA-ILD, the task force had insufficient evidence to support recommendations. Screening, diagnostic, monitoring and treatment algorithms were developed based on the recommendations and usual clinical practice. We provide practical guidance by evidence-based recommendations to clinicians for each of the CTDs. In many cases there is low certainty or absence of evidence and we encourage further research to fill these gaps.
Alemtuzumab is a humanized monoclonal antibody targeting CD52, a glycosylphosphatidylinositol-anchored surface antigen broadly expressed on lymphocytes and other immune cells. Although currently approved for multiple sclerosis and used in selected transplantation settings, alemtuzumab was among the earliest lymphocyte-depleting biologics explored across a wide spectrum of autoimmune rheumatic diseases. With renewed interest in deep immune-depleting strategies, including CAR-T cells and bispecific T-cell engagers, revisiting the immunobiology and clinical experience of alemtuzumab is timely. This review summarizes current knowledge of CD52 structure, expression, and immunological function, highlighting its dual role as both a co-stimulatory and immunoregulatory molecule. We examine the mechanisms underlying alemtuzumab-induced lymphocyte depletion, subsequent immune reconstitution, and the paradoxical development of secondary autoimmunity. Clinical evidence for alemtuzumab use in rheumatic diseases, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, vasculitis, idiopathic inflammatory myopathies, ocular inflammatory disease, and Behçet's syndrome, is reviewed, with emphasis on efficacy, durability of response, and safety outcomes. Across multiple refractory disease settings, alemtuzumab has demonstrated the capacity to induce rapid clinical improvement and, in some cases, prolonged drug-free remission. However, treatment is limited by risks of infection, delayed immune reconstitution, and immune dysregulation. We conclude that alemtuzumab remains a potent immunomodulatory option in selected refractory rheumatic diseases, provided that careful patient selection, cautious monitoring, and long-term follow-up are implemented.
Chimeric antigen receptor (CAR)-T cell and natural killer cell therapies are emerging as treatments for autoimmune diseases (AIDs), capable of inducing immune reprogramming and drug-free remission. However, their efficacy, safety, and durability across AIDs remain incompletely defined. We performed a systematic review and meta-analysis of proportions to evaluate the efficacy and safety of CAR-based therapies in AIDs. PubMed, Embase, and CENTRAL were searched from January 1, 2010, to October 20, 2025. The primary outcome was medication-free remission (MFR); secondary outcomes included disease-specific remission indices, incidence of adverse events and their severity. Subgroup and meta-regression analyses were conducted. Of 3367 records screened, 56 studies met the inclusion criteria (15 eligible for meta-analysis; 41 synthesized qualitatively). For CAR-T cell therapies, among SLE patients, pooled MFR was 0·76 and DORIS remission 0·75. Subgroup analyses revealed a longer disease duration was associated with lower remission rates. From the qualitative analysis, CAR-T cell therapies demonstrated promising clinical efficacy and seroconversion rates in other AIDs, such as systemic sclerosis, myositis and myasthenia gravis. Across all AIDs, CRS of any grade occurred in 0·63, but grade ≥ 3 CRS and any grade of ICANS were negligible (both 0·00). Hypogammaglobulinaemia of any grade occurred in 0·47, while grade ≥ 3 events were rare. Cytopenias were common: neutropenia and anemia of any grade were most frequent. Severe cytopenias occurred in ≤0·3. Infection within 3 months occurred in 0·29. CAR-T cell therapies targeting CD19 or BCMA appear highly effective in inducing remission in refractory autoimmune diseases, with predominantly mild CRS and negligible neurotoxicity.
AIM: Current ultrasound grading tools do not fulfil the criteria of the OMERACT Filter 2.1 Instrument Selection Algorithm (OFISA)and are not idiopathic inflammatory myopathies (IIM)-specific, prompting further work by the OMERACT US Working Group. The aim of this study was, therefore, to develop consensual definitions of elementary US lesions specific to IIM, using a structured methodological approach. METHODS: A multicentre group of 21 international experts from the OMERACT US in myositis subgroup participated in a multi-round Delphi survey followed by a web-based reliability exercise. RESULTS: The group participated in five Delphi rounds, followed by a web-based reliability exercise. Preliminary broad domains of "inflammation" and "damage" resulted in substantial intra-rater reliability testing (kappa: 0.662 and 0.620, respectively) but poor inter-rater reliability testing (kappa: 0.142 and 0.112, respectively). A further two Delphi rounds resulted in a consensus to revise the broad domains to a single domain of "muscle inflammation and damage", with elementary components including echogenicity and fascial thickness. A categorical morphological grading system was then tested in a web-based reliability exercise, which resulted in substantial intra-rater reliability testing (kappa: 0.706, min: 0.051, max: 1.000, SD: 0.295) and an improved moderate inter-rater reliability testing (kappa: 0.506, min: 0.421, max: 1.000, SD: 0.167). CONCLUSION: The systematic approach by the OMERACT US in the myositis subgroup has developed a categorical morphological scoring system, which showed moderate inter-rater reliability using consensus-derived definitions of US domains in IIM.
ABSTRACT Background Idiopathic inflammatory myopathies (IIM) are autoimmune diseases characterized by chronic muscle inflammation leading to impaired physical function and strength. Despite the importance of functional assessment, only few validated tools exist for this population. The Health Assessment Questionnaire-II (HAQ-II), a streamlined 10-item version of the HAQ, may provide an efficient instrument. This study aimed to evaluate the measurement properties of HAQ-II in patients with IIM. Methods Adults with IIM enrolled in Forward Databank (2005–2023) with available data on HAQ-II were included. Patients completed HAQ-II along with assessments of disease activity, pain, fatigue, quality of life (SF-36), and comorbidities. Internal consistency of HAQ-II was assessed using Cronbach’s α. Floor and ceiling effects, discriminant and construct validity (based on a priori hypotheses), and responsiveness (via linear mixed models adjusted for age, sex, and obesity) were evaluated. Results A total of 192 IIM patients (mean age 54.8 years; 79.3% female) were included. HAQ-II demonstrated high internal consistency (α = 0.93), no significant floor or ceiling effects. Discriminant validity was supported by significant score differences across groups stratified by SF-36 physical function, pain, fatigue, and disease activity (all p<0.0001). Fifteen of 17 a priori hypotheses for construct validity were met. Longitudinal changes in HAQ-II scores were significantly associated with changes in pain, fatigue, global disease activity, and SF-36 physical component scores. Conclusion HAQ-II demonstrated high internal consistency, no significant floor or ceiling effects, adequate validity and responsiveness for assessing physical function in patients with IIM and could be appropriate for both clinical and research settings.