Para médicos · reumatologia
Resumos de artigos, podcasts e newsletters sobre Esclerose Sistêmica, para atualização médica.
A newsletter destaca a revisão do índice de dano (SDI) no Lúpus Eritematoso Sistêmico, que busca maior precisão clínica ao remover itens de atividade inflamatória e incluir critérios de gravidade. Além disso, apresenta novos guidelines da EULAR para vasculites e polimialgia reumática, e discute evidências recentes sobre terapias biológicas e inibidores de fosfodiesterase em doenças autoimunes.
A newsletter analisa um estudo populacional que revela alta prevalência de edema ósseo sacroilíaco em indivíduos saudáveis, alertando para a necessidade de contexto clínico no diagnóstico de espondiloartrites. Além disso, discute as divergências entre diretrizes globais para esclerose sistêmica e apresenta avanços em novas terapias biológicas para o lúpus.
OBJECTIVE: Interstitial lung disease (ILD) is the leading cause of mortality in systemic sclerosis (SSc). The Warrick semiquantitative scoring system and the Goh staging algorithm provide different approaches for assessing lung involvement on high-resolution computed tomography (HRCT). We compared their sensitivity for detecting radiological progression in SSc-ILD. METHODS: We retrospectively analyzed 33 patients with SSc-ILD who underwent serial HRCT examinations. Each scan was evaluated using the Warrick score (0-30) and Goh staging (limited/extensive). Progression was defined as an increase of ≥ 3 points in the Warrick score or transition from limited to extensive disease by Goh staging. Comparative progression analysis was restricted to the 24 patients with baseline limited disease, as only these patients were eligible for Goh-defined progression. Progression rates were compared using the McNemar test, and receiver operating characteristic (ROC) analysis assessed Warrick score thresholds for identifying Goh-defined extensive disease. RESULTS: The cohort included 33 patients (85% female; mean age 53.2 ± 8.9 years), all with diffuse cutaneous SSc. At baseline, 24 (73%) had limited disease and 9 (27%) had extensive disease. Among patients with baseline limited disease, Warrick scoring identified progression in 15 (62%) compared with 8 (33%) by Goh staging (McNemar χ² = 7.00, P = 0.01). All Goh progressors also fulfilled Warrick progression criteria, whereas 7 additional patients showed Warrick progression without stage transition. Among baseline extensive patients, 6 (67%) demonstrated further radiological worsening according to Warrick scoring. Follow-up Warrick scores showed excellent discrimination for Goh-defined extensive disease (AUC 0.94, 95% CI 0.86-1.00), with an optimal threshold of 20 points (sensitivity 88%, specificity 88%). Agreement between methods was substantial (κ = 0.76). CONCLUSION: Warrick scoring was significantly more sensitive than Goh staging for detecting radiological
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.
A newsletter apresenta os destaques do EULAR 2026, focando em novas evidências para o tratamento da Artrite Reumatoide e Espondiloartrite Axial. São discutidos estudos inovadores sobre o uso de tocilizumabe na depressão inflamatória, o efeito da tirzepatida no ácido úrico e a eficácia do upadacitinibe após falha terapêutica. O conteúdo também aborda o papel da IA no suporte a pacientes com esclerose sistêmica e um caso clínico de Doença de Vogt-Koyanagi-Harada.
A newsletter aborda inovações do EULAR 2026, destacando a embolização da artéria genicular como uma alternativa promissora e segura para o manejo da dor na osteoartrite de joelho refratária. O conteúdo também analisa a persistência da sarcopenia em pacientes com artrite reumatoide controlada e os desafios da inércia terapêutica no tratamento da hipertensão arterial pulmonar em pacientes com esclerose sistêmica.
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.
Randomized trials have demonstrated that nintedanib is beneficial for Systemic Sclerosis-associated interstitial lung disease (SSc-ILD) with an acceptable safety profile. We evaluated the long-term safety and efficacy of nintedanib in a real-world SSc-ILD cohort. Medical records of SSc patients receiving nintedanib for newly diagnosed fibrotic or progressive ILD between 2020 and 2025 in our center were retrospectively reviewed. Forced vital capacity (FVC%) and diffusing capacity for carbon monoxide (DLCO%), were recorded 12 months before and 12/24/36 months after nintedanib initiation and compared by Wilcoxon signed-rank test. Safety analyses included all treated patients; efficacy analyses excluded patients initiating immunosuppression simultaneously with nintedanib. Fifty-one patients (41 female; 34 diffuse SSc; median age and disease duration of 53 and 6 years, respectively) received nintedanib for a median of 33 months (range 4-60). Diarrhea was the most frequent adverse event leading to dosage reduction in 31% and permanent discontinuation in 14% of patients, respectively. No additional safety signals emerged in patients receiving mycophenolate (n = 18), tocilizumab (n = 14), rituximab (n = 1), mycophenolate plus tocilizumab (n = 5) or mycophenolate plus rituximab (n = 2). FVC% and DLCO%, that had declined significantly during the preceding year, remained stable after nintedanib initiation in 23/35 patients with median FVC changes of + 1% and - 3% and median DLCO% changes of -2% and - 4% after 24 and 36 months, respectively), including patients on reduced dosage. Real-world data show that nintedanib seems to stabilize pulmonary function in progressive SSc-ILD, even at reduced doses, during 3 years of follow-up in about half of patients, without safety concerns when combined with biologic agents.
OBJECTIVES: Calcinosis cutis (CC) is disabling for systemic sclerosis (SSc) patients, and quantitative outcomes and treatments are needed. We performed computer-assisted mapping of CC lesions on computed tomography (CT) exams and quantified CC during sodium thiosulfate (STS) treatment. METHODS: In a pilot study, SSc-CC patients underwent CT imaging of a painful lesion followed by 6-12 month 25% STS, intradermal monthly injections or twice daily cream, treatment. Post-treatment CT exams were obtained, and three assessors used open-source software (BIS Web) to map and quantify CC volume, termed Scleroderma Calcinosis Cutis Score (SC2S). Results were compared to the Scleroderma Clinical Trials Consortium Radiologic Scoring System for Hand Calcinosis as appropriate. RESULTS: Five women with SSc-CC involving the arm, ischial tuberosities, hands (two patients) and patellae, received topical (n = 2) or intradermal (n = 3) STS. Lesion mapping with BIS Web showed high inter-rater agreement between independent assessors (intraclass correlation coefficient = 0.93). SC2S revealed 75% and 10% reductions in left and right buttock, respectively; 28% reduction in arm; 18% increase in left forefinger; 27% increase in right hand; and 12% reduction in left, and 4% increase in right, patellae, respectively. CC volume differences on repeated measures one-week apart were ≤3%. Mapping time ranged from 4h for finger/hand and patellae. CONCLUSION: SC2S may be a highly reproducible, broadly applicable, quantitative outcome that is sensitive to CC change. SC2S highlights the variable response of SSc-CC to STS treatment. Future work to automate CC mapping will reduce lesion mapping time.
A newsletter apresenta os principais destaques do congresso EULAR 2026, abordando desde a eficácia da manutenção do alopurinol na gota até novos alvos terapêuticos para a Síndrome de Sjögren. Além das atualizações clínicas, explora como fatores psicossociais e a satisfação conjugal influenciam diretamente o prognóstico e a saúde mental de pacientes com doenças reumáticas crônicas.
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.
Objective To assess the diagnostic accuracy of two lung ultrasound (LUS) scores (≥ 10 B-lines and pleural line abnormalities according to Fairchild's criteria) for detecting interstitial lung disease (ILD) in systemic sclerosis (SSc), when applied independently at two referral centers using a shared standardized protocol. Secondary aims included evaluating the diagnostic performance of their combined use and their association with ILD severity. Methods This cross-sectional bi-center study included same-day LUS and high-resolution computed tomography (HRCT), using a 14-zone scanning protocol. ILD was defined as ≥ 10% lung involvement on HRCT. The diagnostic performance of each LUS score and their combination was assessed using OR and AND rules (the OR rule indicating positivity for either criterion, and the AND rule requiring both to be positive). Associations with disease severity, based on the Goh classification, were also explored. Results ILD was present in 68% of the 108 patients included. The ≥ 10 B-lines cut-off showed 90.5% sensitivity and 84.4% specificity (AUC 0.875), while Fairchild's criteria achieved 93.2% sensitivity and 93.8% specificity (AUC 0.935). The OR rule yielded the highest sensitivity (95.9%) and NPV (89.7%), while the AND rule provided the highest specificity (96.9%) and PPV (98.5%). All patients with extensive ILD were positive for both scores. Conclusions In this real-life multicenter setting, both LUS scores showed high and complementary diagnostic performance when applied within a standardized protocol. Their consistent association with ILD extent supports their clinical use as non-invasive tools for routine SSc-ILD assessment. Key Points • Lung ultrasound shows high diagnostic accuracy for SSc-ILD across two international referral centres. • A standardized 14-zone protocol supports reproducible LUS performance. • ≥ 10 B-lines and Fairchild’s criteria provide complementary diagnostic information. • Combining
A newsletter destaca os resultados do estudo de fase 3 VALOR, que comprovou a eficácia do brepocitinibe na melhora cutânea e muscular da dermatomiosite, permitindo o desmame de corticoides. São discutidas também inovações como o uso de blinatumomabe para restaurar a responsividade terapêutica na artrite reumatoide e a aplicação de células CAR-T em casos refratários, além de novos escores para estratificação de risco gestacional.
OBJECTIVE: Autologous hematopoietic cell transplantation (HCT) is an effective treatment for a subset of systemic sclerosis (SSc) patients. Unfortunately, relapse is a significant problem, with no available tests to predict relapse. We studied whether relapse is associated with pre- or post-HCT serum levels of SSc-related autoantibodies. METHODS: The cohort comprised 38 consecutive evaluable SSc patients who underwent HCT at a single center, who were followed for median 33 months. Sixteen (42%) patients developed relapse at median 14 months post-HCT. Autoantibody levels were determined by immunoassays. RESULTS: Regarding pre-HCT autoantibodies, in univariate analyses, the cumulative incidence of relapse (CIR) was lower in anti-RNA polymerase III (ARA) positive than negative patients (Hazard ratio (HR)=0.2, P=.04). Conversely, there was a non-significant trend towards higher CIR in patients with positive anti-Ro52 (HR=2.9, P=.05). The CIR was similar in patients positive and negative for anti-topoisomerase antibody (ATA, i.e., Scl70) or anti-nuclear antibody (ANA). In bivariate analyses that included older age as a risk factor for relapse, pre-HCT ARA was still associated with relapse (HR=0.2, P=.04). This was not the case for Ro52 (HR=2.21, P=.16) Regarding post-HCT autoantibody level trajectory, there was no significant difference between patients with vs without relapse. CONCLUSION: In conclusion, positive ARA pre-HCT is associated with reduced relapse risk, and post-HCT autoantibodies do not appear to be associated with relapse risk.
A newsletter aborda a importância da reabilitação imunológica pós-transplante renal em pacientes com doenças reumáticas, focando no equilíbrio entre evitar a rejeição e prevenir a recorrência da doença de base. Destaca o sucesso do brepocitinibe (inibidor de TYK2/JAK1) no tratamento da dermatomiosite refratária e discute o uso de terapias biológicas combinadas para artrite psoríasica. O conteúdo também revisa biomarcadores preditivos e estratégias de monitoramento personalizado para otimizar a sobrevida do enxerto e do paciente.
Objective Systemic sclerosis (SSc) is characterized by dysregulated immunity, microvascular damage, and progressive fibrosis. SSc‐related interstitial lung disease (SSc‐ILD) is the leading disease specific cause of mortality; it is therefore important to identify biomarkers associated with SSc‐ILD. We hypothesized that the skin transcriptome would provide mechanistic clues that could further our understanding of lung impairment in SSc‐ILD. Methods We conducted a multi‐stage analysis of SSc transcriptomes using weighted gene correlation analysis, gene set enrichment analysis and single cell RNA sequencing. Results We identified seven modules correlated with skin and lung function involvement. Unsupervised clustering of these genes classified patients into two groups, one of which showed severe multiorgan involvement characterized by increased skin fibrosis and decreased lung function (p < 0.05). The KRAS pathway was enriched in the severe cluster. Deconvolution of the severe cutaneous signature in SSc skin and lungs showed increased expression in stromal cells and monocytes whereas the KRAS pathway was enriched in stromal cells only. Profiling KRAS and downstream signaling in lungs from SSc‐ILD demonstrated activation of these pathways (p < 0.05). Conclusion We found a severe cutaneous transcriptomic signature of SSc associated with multiorgan involvement. By deconvoluting the severe cutaneous signature, we have identified pathways enriched in specific cell types including KRAS in stromal cells, and a combination of stromal and immune cells in the severe signature. The severe SSc signature can provide a framework for understanding shared mechanisms in skin and lung fibrosis and may help identify additional molecular pathways.
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.
Arthritis &amp;Rheumatology, Volume 78, Issue 3, Page 713-723, March 2026.
Arthritis &amp;Rheumatology, Volume 78, Issue 3, Page 705-712, March 2026.
Arthritis &amp;Rheumatology, Volume 78, Issue 3, Page 566-581, March 2026.
Objective Juvenile Systemic Sclerosis (JSSc) is characterized by vascular manifestations, including Raynaud's phenomenon (RP) and vascular disease–related internal organ damage. We describe the clinical features of a subgroup of JSSc patients without clinical vascular manifestations, as a hypothesis-generating analysis of a possible new subtype. Methods Single center cohort study of consecutive patients with JSSc diagnosed since 2004. Data on demographic, clinical, autoantibody profile and treatment were collected in a standardized method. Disease severity was periodically evaluated by the J4S severity score and outcome was categorized as clinical remission (CR), clinical remission on-medication (CRM) or active/progressive disease (AP). Results Of 45 patients, 38 with at least four years follow up were included in the study. The mean age at onset was 10.3 years, mean follow up time 8.2 years and 61% were female. Thirty-three (87%) presented with Raynaud phenomenon and five (13%), all with diffuse cutaneous involvement, did not. The latter subgroup of patients, which we term "fibrotic subtype" (fJSSc), had predominant skin involvement and mild internal organ involvement (gastrointestinal in all, pulmonary in two). While ANA were positive in all fJSSc patients, none had SSc-specific autoantibodies and two had SSc-associated autoantibodies. Scleroderma pattern on capillaroscopy was detected in 4/5 patients. At the last follow-up visit, no fJSSc patient had active/progressive disease, three were in CR and two in CRM for mild pulmonary disease. Conclusion This proof-of-concept study describes a potential new clinical phenotype, which we term Fibrotic JSSc, characterized by predominant skin involvement, absence of SSc-specific autoantibodies and favorable outcome.
Objective Systemic sclerosis (SSc) is associated with substantial morbidity and mortality, prompting the development of internationally endorsed quality indicators (QIs). However, real-world adherence to these standards remains incompletely characterized. We evaluated adherence to baseline and longitudinal SSc QIs and identified predictors of adherence in a specialized clinical practice. Methods We conducted a retrospective cohort study including all patients with SSc managed at a tertiary SSc clinic between January 2016 and December 2024. Adherence to QIs was assessed across baseline screening (interstitial lung disease and pulmonary hypertension), longitudinal monitoring (pulmonary function testing, echocardiographic follow-up, skin assessment, and clinical documentation), and treatment and referral practices (digital ulcer management and rehabilitation). Multivariable logistic regression identified independent predictors of adherence. Results Among 66 patients (mean age 46.2 ± 12.9 years, 92% female), adherence to baseline screening was high, including high-resolution computed tomography (86%) and transthoracic echocardiography (84%). Baseline treatment adherence was also high, with vasodilator therapy for all patients with active digital ulcers (100%). In contrast, longitudinal follow-up adherence was suboptimal, including annual pulmonary function testing (35%), follow-up echocardiography after a new DLCO decline (36%), dyspnea documentation (63%), chest auscultation (27%), annual modified Rodnan skin score (19%), and physical therapy referral (37%). Older age, longer disease duration, diffuse cutaneous subtype, and pulmonary hypertension independently predicted lower adherence. Conclusion Despite strong baseline adherence, major gaps persist in longitudinal monitoring, documentation, and rehabilitation, highlighting key targets for quality improvement.
Vaccination uptake was relatively low in this vulnerable population. Strategies promoting discussion with the rheumatologist about vaccination and before treatment could play a pivotal role in improving vaccination uptake among patients with AIIRD.
Lung transplantation represents a potential life-extending therapy for patients with advanced CTD-ILD. This study aims to characterize lung transplant listing outcomes among CTD-ILD patients over a 20-year period using the Organ Procurement and Transplantation Network (OPTN) national database. Data analyzed from the OPTN between 2003-2023 included adults ≥18 years of age with CTD-ILD listed for lung transplantation. Patients were categorized into six diagnoses: scleroderma, lupus, rheumatoid arthritis (RA), myositis, Sjögren’s, and "Other" (including mixed connective tissue disease, CTD, etc.). Disease and patient specific data were obtained. Trends in listing and outcomes were analyzed in four time periods across the 20 years and among various diagnoses. We used descriptive summary statistics to characterize the sample, and univariate and multivariable logistic regression models to identify factors associated with undergoing lung transplantation. A total of 1,977 CTD-ILD patients were listed. Scleroderma constituted the majority (47%). Listings increased fourfold (185 to 744) from the first to last time periods. Listings for all diagnoses increased with time, with rising representation of non-White patients. Trend noted towards listing patients with more advanced lung disease with time. Transplant rates rose, while wait times, and waitlist mortality declined overtime. All diseases received transplants at comparable rates. Older age, lower lung allocation scores, and male sex were associated with higher odds of transplantation, female sex with lower odds. Over two decades, CTD-ILD transplant listings have increased in volume, matched with substantially improved outcomes. This reflects the evolution of listing practices and a growing confidence in lung transplantation as a viable option for CTD-ILD.
Incorporating baseline NFC into SCORE2 improves CV stratification in patients with SSc, and may support more individualized CV prevention strategies in SSc.
Background Liver involvement, particularly autoimmune hepatitis (AIH) overlap, is a rare but clinically important manifestation of systemic sclerosis (SSc). This study aimed to assess the prevalence, clinical characteristics, and diagnostic utility of laboratory parameters for identifying AIH in a cohort of patients with SSc. Methods We retrospectively analyzed 111 patients with SSc. Clinical characteristics, autoantibody profiles, and laboratory parameters were compared between patients with and without AIH. AIH diagnosis was confirmed by liver biopsy in all cases. Given the small number of events, Firth’s penalized likelihood logistic regression was applied to identify independent risk factors. The diagnostic performance of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum IgG levels was evaluated using receiver operating characteristic (ROC) curve analysis. Prior methotrexate (MTX) exposure was recorded, and the potential confounding effect of MTX-induced liver enzyme elevations was assessed. Results Autoimmune hepatitis (AIH) was identified in 8 of 111 patients (7.2%). All AIH-positive patients showed interface hepatitis on liver biopsy. There were no significant differences between AIH-positive and AIH-negative patients regarding age, systemic sclerosis subtype, or presence of interstitial lung disease (all p > 0.05). Firth’s penalized logistic regression indicated that diffuse cutaneous SSc, anti–Scl-70 positivity, and interstitial lung disease were not independent predictors of AIH overlap. In receiver operating characteristic analysis, alanine aminotransferase (ALT) demonstrated the highest diagnostic performance (AUC 0.88, 95% CI 0.76–0.99; p 34.5 U/L. Aspartate aminotransferase (AST) (AUC 0.86) and serum IgG (AUC 0.74) also showed significant but lower discriminatory ability. ALT retained high specificity for AIH even among patients with prior MTX exposure, supporting its utility as a non-invasive screening tool in SSc. Conclusion Autoimmune hepatitis is a rare overlap syndrome in systemic sclerosis that occurs independently of
Objectives This study aimed to evaluate the global trends in systemic sclerosis (SSc)-related mortality by age, sex, and geographic region. SSc is a multisystem autoimmune disease characterized by tissue fibrosis, vascular dysfunction, and multi-organ involvement, which is associated with a high mortality risk. Methods Using the World Health Organization Mortality Database, we examined trends in SSc-related crude mortality rates (SSc-CRs) and age-standardized mortality rates (SSc-ASMR) per 1,000,000 population from 2001 to 2023. Locally weighted regression was applied to visualize long-term patterns, and Joinpoint regression was used to assess the national trends from 2010 to 2023. Results Across 74 countries, 85,291 SSc-related deaths were reported, with 79.41% occurring in females. The SSc-CR steadily increased from 1.97 (95% confidence interval [CI]: 1.71–2.23) in 2001 to 2.34 (95% CI: 2.01–2.68) in 2023, while the SSc-ASMR decreased from 1.58 (95% CI: 1.42–1.74) to 1.29 (95% CI: 1.08–1.50), respectively. Regionally, mortality was the highest in the Western Pacific region and declined in the Americas and Europe, with temporal fluctuations. The SSc-ASMR was highest in countries with a middle sociodemographic index (SDI). Conclusions While overall age-standardized mortality from SSc has declined in many regions, disparities persist. These results underscore the importance of sustaining research and enhancing disease awareness, as well as developing strategies to reduce mortality in high-risk populations and regions. Key Points • First global analysis of mortality trends across 74 countries (2001–2023) • Age-standardized mortality declined globally, but crude mortality increased, with persistent female predominance • Findings highlight need for targeted strategies, early diagnosis, and improved care to reduce mortality
Objective To evaluate the relationship of skin fibroblast CD34 and α‐smooth muscle actin (α‐SMA) and immune cell infiltration with disease duration in diffuse cutaneous systemic sclerosis (dcSSc) and identify predictors of improvement. Methods Skin biopsies and clinical data were analyzed from patients with dcSSc enrolled in lenabasum (n = 79), belimumab (n = 18), or nilotinib (n = 8) trials. CD34 and α‐SMA were scored semiquantitatively. Immune cells (CD20+, CD3+, and CD123+) were counted. Clinical and histologic features were compared between those with early ( 5‐point decrease in modified Rodnan skin score (mRSS) at 52 weeks. An Akaike's information criterion–optimal multiple logistic regression model for clinical improvement among 68 mycophenolate mofetil (MMF) users was developed. Fibroblast spatial organization was visualized using imaging mass cytometry (IMC) in a representative sample. Results Despite similar baseline mRSS, early disease was associated with lower CD34, higher α‐SMA, increased B cells, and greater mRSS improvement compared with later SSc. IMC demonstrated regions of CD34+ fibroblasts in superficial dermis and α‐SMA+ fibroblasts in deeper, collagen‐dense regions. Among MMF users, high CD34 and α‐SMA predicted improvement in early SSc; however, high α‐SMA predicted lower odds of improvement in later SSc. The probability of improvement was lowest in early SSc with α‐SMA low /CD34 low immunophenotype and later SSc with α‐SMA high . In later SSc, B cells were higher in α‐SMA high versus α‐SMA low skin. Conclusion Fibroblast immunophenotype varied by baseline disease duration and improved model performance for identifying those with improvement on MMF. Skin biopsies may be useful for refining prognosis and guiding patient management decisions. image
Objective Peripheral blood leukocyte telomere length (PBL‐TL) shortening is associated with systemic sclerosis–related interstitial lung disease (SSc‐ILD). However, its association with other organ involvement, disease severity, and survival remains unclear. This study aimed to define the relationship of TL with SSc‐specific disease manifestations and outcomes. Methods PBL‐TL was measured by quantitative polymerase chain reaction in 244 patients with SSc and 314 healthy controls. Multivariate modeling was used to assess the association of PBL‐TL with disease severity and event‐free survival. Longitudinal changes in PBL‐TL were measured in a subset of patients. TL was quantified in SSc skin and lung tissues by telomere fluorescence in situ hybridization. Results PBL‐TL was significantly shorter in patients with SSc than healthy controls. Shortened PBL‐TL was associated with presence and severity of ILD and pulmonary hypertension (PH), with the shortest PBL‐TL found in subjects with concurrent ILD and PH ( P = 0.04). PBL‐TL was not associated with skin disease or peripheral vascular disease. Shorter PBL‐TL was associated with hospitalizations ( P < 0.01) and worse event‐free survival ( P = 0.03). Patients with early SSc had a faster rate of PBL‐TL shortening compared with patients with longer disease duration ( P = 0.04). TL was shorter in SSc‐ILD lung epithelial cells ( P = 0.01), whereas no difference was found in epithelial cells of SSc skin ( P = 0.82). Conclusion Short PBL‐TL is associated with pulmonary disease severity and predicts worse SSc clinical outcomes. This study provides rationale to further investigate the role of telomere dysfunction in SSc pathogenesis and validate TL as a prognostic biomarker in SSc.
Objective To evaluate dynamic changes in autoantibody and proteomic profiles in treatment‐naïve patients with systemic sclerosis (SSc) and to identify biomarkers and mechanisms associated with disease progression. Methods Serum samples from 30 baseline and 49 follow‐up patients with SSc, along with 38 controls, were analyzed. Autoantibody profiles were assessed using an autoantigen microarray targeting 120 autoantibodies, whereas proteomic analysis was conducted via liquid chromatography mass spectrometry in data‐independent acquisition mode. Cox proportional hazards models were used to assess associations with disease progression, and Spearman's correlation was applied to analyze antibody–protein interactions. Results Baseline autoantibody profiling identified two patient subgroups: high expression (SSc_high) and low expression (SSc_low), though their clinical characteristics were similar. Longitudinal analysis revealed that 88.9% of patients with rising autoantibody titers experienced disease progression, whereas 60% of those with decreasing titers showed clinical improvement. Notably, increased CENP‐B titers (hazard ratio 5.036) were strongly linked to disease progression. Proteomic analysis identified 112 proteins involved in tissue repair and immune modulation in patients with declining titers and clinical improvement, whereas 46 proteins linked to lipid metabolism and oxidative stress were enriched in those with rising titers and disease progression. SERPINA10 emerged as the strongest risk factor for progression, whereas ENTPD5 was most protective. Antibody–protein correlations that highlight key molecular interactions, including SERPINE1 and muscarinic receptor antibodies, were identified. Conclusion Dynamic changes in autoantibody titers, rather than baseline levels, were more strongly associated with SSc trajectory. Proteomic signatures suggest lipid metabolism and oxidative stress as potential drivers, highlighting novel biomarkers and therapeutic targets for personalized SSc management.
A newsletter discute como o sequenciamento genômico pode revelar doenças raras monogênicas disfarçadas de condições comuns, explicando casos de refratariedade ao tratamento. Apresenta atualizações cruciais na Doença de Sjögren, destacando a estratificação por clusters de risco e a emergência de novas terapias como o dazodalibep. Além disso, alerta para a toxicidade renal por antimaláricos e o uso de proteômica urinária para monitorar a inflamação na nefrite lúpica.
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.
Abstract Objectives Systemic sclerosis (SSc) heart involvement (SHI) is an enigmatic disease manifestation associated with high mortality. The Scleroderma Clinical Trials Consortium (SCTC) Cardiac Working Group developed SHI classification criteria to enable systematic investigation of this condition. Methods An international, inter-disciplinary working group was assembled. Using consensus methods and existing literature, provisional SHI classification criteria items were developed. Continuous consensus exercises and a discrete choice experiment were performed to reduce items and derive individual item weights. The sensitivity and specificity of the classification criteria were tested in an independent cohort (n = 168) of SHI (cases) and non-SSc heart disease (controls). Results The working group agreed that the SCTC SHI Classification Criteria should identify the direct effects of SSc on the heart and exclude the complications of other SSc manifestations or cardiac co-morbidities. The final classification criteria include 23 items measuring cardiac fibrosis, inflammation, arrhythmias and small vessel vasculopathy. No single item is pathognomonic for SHI, with a requirement for the presence of abnormalities across multiple histopathological, imaging, serological and, or clinical domains to be present to secure a diagnosis. A classification criteria score of ≥11 identified SHI with a sensitivity of 78% and specificity of 96%, with an area under the curve of 0.87 (0.80–0.93). This threshold correctly identified >90% of cases of SHI. Conclusion The newly derived SCTC SHI Classification Criteria have high sensitivity and specificity for SHI. Application of these criteria will enable standardised classification of patients in studies to facilitate future investigation of this important disease manifestation.
Objective Complement component 4 (C4), encoded by C4A and C4B within the major histocompatibility complex (MHC) on chromosome 6, regulates the immune response and clears immune complexes. The variable copy number (CN) of C4 genes and retroviral human endogenous retrovirus K (HERV‐K) element influence its function. Given the relationship of C4 CN with systemic sclerosis (SSc) risk, we assessed associations with SSc clinical and serologic subtypes. Methods We compared imputed C4 CNs across SSc subgroups (4,049 anticentromere positive [ACA + ]; 2,200 anti–topoisomerase I [ATA + ]; 577 anti‐RNA polymerase [ARA + ]; 1,078 triple‐negative [TN] patients; 6,295 limited cutaneous SSc [lcSSc]; and 2,946 diffuse cutaneous SSc [dcSSc]) and 17,991 controls. We evaluated associations with SSc subtypes, identifying C4 ‐independent HLA alleles. Results Lower C4 CN and higher HERV‐K CN were associated with increased risk in all SSc subgroups. ATA + patients showed the strongest association, particularly with C4A (odds ratio = 1.88), and differences in C4A CN association were more pronounced between autoantibody subgroups (ATA + vs ACA + , P = 4 × 10 −11 ) than between clinical subgroups (dcSSc vs lcSSc, P = 1 × 10 −4 ). In ACA + patients, only low C4B CN showed a significant association to SSc risk ( P = 1.23 × 10 −5 ). We also observed sex‐biased associations: dcSSc, ATA + , and ARA + male patients showed stronger effects for C4A and ACA + and lcSSc female patients for C4B . Finally, our results suggest that the HLA alleles associated with SSc subgroups are independent of C4 CN. Conclusion This study highlights distinct genetic contributions of C4A and C4B in SSc subtypes susceptibility. Our findings suggest that
A newsletter destaca a importância do anticorpo anti-nucleossomo como marcador complementar no lúpus, especialmente para manifestações neuropsiquiátricas e renais onde o anti-dsDNA pode ser negativo. Além disso, aborda a segurança dos DMARDs na artrite reumatoide com doença pulmonar intersticial, indicando que biológicos não-TNF podem estar associados a um maior risco de hospitalização por pneumonia.
Systemic sclerosis (SSc) is a prototypical systemic immune-mediated fibrosing disease that affects the skin, the lungs, the heart, the kidneys and the intestinal tract. Similar to many other fibrotic diseases, SSc is associated with high morbidity and mortality and therapeutic options are limited. Fibrosis arises from a complex interplay of vascular damage, inflammation and prolonged, misdirected repair responses. The progressive accumulation of extracellular matrix perturbs the physiological tissue architecture and commonly leads to failure of the affected organs. Understanding the mechanisms of fibrotic tissue remodelling can lead to the identification of preclinical targets. Novel fibrosis-promoting cell subpopulations, the interplay of fibroblasts with B cells and macrophages, the nerve–fibroblast axis, matrikines and matricryptins, senescence, profibrotic transcription factors, developmental pathways and epigenetic tissue memory are all important drivers of fibrotic tissue remodelling that might offer potential for novel therapies to improve outcomes for patients with SSc and possibly other fibrotic conditions.
Systemic sclerosis (SSc) is a prototypical systemic immune-mediated fibrosing disease that affects the skin, the lungs, the heart, the kidneys and the intestinal tract. Similar to many other fibrotic diseases, SSc is associated with high morbidity and mortality and therapeutic options are limited. Fibrosis arises from a complex interplay of vascular damage, inflammation and prolonged, misdirected repair responses. The progressive accumulation of extracellular matrix perturbs the physiological tissue architecture and commonly leads to failure of the affected organs. Understanding the mechanisms of fibrotic tissue remodelling can lead to the identification of preclinical targets. Novel fibrosis-promoting cell subpopulations, the interplay of fibroblasts with B cells and macrophages, the nerve–fibroblast axis, matrikines and matricryptins, senescence, profibrotic transcription factors, developmental pathways and epigenetic tissue memory are all important drivers of fibrotic tissue remodelling that might offer potential for novel therapies to improve outcomes for patients with SSc and possibly other fibrotic conditions.
Objective The treatment landscape for systemic sclerosis‐associated interstitial lung disease (SSc‐ILD) has evolved with increasingly available immunosuppressive therapies (ISTs) and antifibrotic treatments. However, their real‐world use remains unclear. The objective of this study was to analyze treatment trends and the effect of IST and antifibrotic treatments on ILD progression using the European Scleroderma Trials and Research database. Methods We included patients with SSc‐ILD meeting the 2013 American College of Rheumatology/EULAR criteria with high‐resolution computed tomography–confirmed ILD, pulmonary function, and therapy data, grouped into four time periods (≤2006, 2007–2011, 2012–2016, and ≥2017). We analyzed IST initiation, switching, discontinuation, and combination therapy. ILD progression was defined as a decline in the percentage of predicted forced vital capacity of 5% or greater or the percentage of predicted diffusing capacity of the lungs for carbon monoxide of 10% or greater over 12 ± 3 months. Results Among 1,409 patients, IST use at first evaluation increased significantly from 13.6% (≤2006) to 57.4% (≥2017) ( P < 0.001). Mycophenolate mofetil emerged as the most prescribed IST (7% to 57%) ( P < 0.001). Combination therapy rose from 17.9% to 26.9% ( P < 0.001), whereas ILD progression rates declined from 21.3% (2007–2011) to 12.1% (≥2017) ( P < 0.001). In the 2017 and later cohort, logistic regression showed shorter disease duration (odds ratio [OR] 0.991, 95% confidence interval [CI] 0.987–0.996; P < 0.001) and myositis (OR 9.9, 95% CI 1.94–51.76; P = 0.006) were associated with therapy initiation, whereas switching was higher in patients with a higher modified Rodnan skin score (OR 1.03, 95% CI 1.00–1.06; P = 0.035) and in patients with arthritis (OR 3.03, 95% CI 1.55–5.94; P = 0.001). Last, combination therapy was
A newsletter analisa uma meta-análise que indica benefícios significativos da metformina na redução da dor e melhora funcional em pacientes com osteoartrite de joelho. Outro destaque é a discussão sobre o mimetismo clínico entre a artrite reumatoide soronegativa e a doença por depósito de pirofosfato de cálcio (CPPD), especialmente em pacientes idosos. O conteúdo também revisa os principais avanços terapêuticos de 2025 em doenças como lúpus, esclerose sistêmica e IgG4-RD.
High-resolution, high-throughput single-cell omics has transformed our understanding of autoimmune disease pathogenesis. We synthesise recent single-cell omics advances across six autoimmune diseases-systemic sclerosis, systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, IgG4-related disease and rheumatoid arthritis. We further summarise translational progress in targeted therapies. We delineate core pathological networks shared across these conditions, highlight convergent mechanisms, and provide a mechanistic rationale for the clinical activity of agents such as tofacitinib and abatacept across multiple autoimmune settings. These insights support the feasibility of mechanism-informed, cross-disease targeting-deploying shared pathway interventions across distinct clinical entities. Finally, we discuss current technical and interpretative challenges and outline future directions for mechanistic discovery, target prioritisation and precision medicine.
Juvenile systemic sclerosis (jSSc) is a rare but serious rheumatic disease in children that significantly impacts growth and development. This study aimed to summarize the clinical characteristics and disease patterns of jSSc and to evaluate the treatment response over an 11-year period at our center. Twenty-one pediatric jSSc patients treated at our center from January 2015 to December 2025 were retrospectively analyzed. Classification was based on the 2013 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) systemic sclerosis classification criteria. Overall disease severity and multiorgan activity were assessed using the Juvenile Systemic Sclerosis Severity Score (J4s; range 0-40), while skin involvement was specifically evaluated using the modified Rodnan skin score (mRSS; range 0-51). The median follow-up duration was 2.3 years (range 0.5-7.2 years). Paired t-tests and Wilcoxon signed-rank tests were used to compare pre- and posttreatment parameters, with p < 0.05 considered statistically significant. Twenty-one patients were enrolled. Skin sclerosis was the most common symptom (100.0%). Antinuclear antibody (ANA) was positive in 16 cases (76.2%), with anti-single-stranded DNA (anti-ssDNA) antibody being the most common specific antibody (23.8%), followed by anti-PM-Scl antibody (19.0%). Glucocorticoids and methotrexate were commonly used as initial therapies. After a median treatment duration of 24 months, overall disease severity (J4s) significantly decreased (5.94 ± 1.66 vs 2.67 ± 2.22, p = 0.003), and skin involvement (mRSS) also improved significantly (10.0 ± 9.21 vs 7.42 ± 8.26, p = 0.008). Fourteen patients received biologic agents, with 11 using tocilizumab. During the follow-up, no deaths or serious adverse events occurred. jSSc is a rare and severe multiorgan disease with unique autoantibody profiles in Chinese children. The J4s and mRSS serve as objective assessment tools for evaluating
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.
Scar-associated macrophages (SAMs), defined by triggering receptor expressed on myeloid cells 2 (TREM2) and/or glycoprotein-NMB (GPNMB) expression, have been implicated in lung fibrosis. This study investigated the characteristics and functional roles of SAMs in lung tissues from patients with systemic sclerosis-interstitial lung disease (SSc-ILD) and healthy controls (HCs). SAM-related transcriptional profiles of lung tissues from patients with SSc-ILD and HCs were analyzed using single-cell RNA sequencing (scRNA-seq). Immunofluorescence staining of lung tissues was performed to detect CD68-positive SAMs expressing TREM2 or CCL2. Monocytes from patients with SSc-ILD and HCs were differentiated with granulocyte-macrophage colony-stimulating factor (GM-CSF) or M-CSF. The population of TREM2- and GPNMB-expressing cells was assessed by flow cytometry, and the levels of CCL2 and TGF-β1 in culture supernatants were measured in an ELISA. The fibrotic effects of macrophages on fibroblasts were examined in co-cultures. TREM2 inhibition was used to determine functional relevance. scRNA-seq revealed the expansion of TREM2 macrophages highly expressing SAM-associated genes in the lower lung lobes of SSc-ILD patients. Immunofluorescence showed increased numbers of CD68+TREM2+ and CD68+CCL2+ macrophages in SSc-ILD lung tissues compared to HCs. In GM-CSF-, but not M-CSF-induced CD14+CD16+ monocyte-derived macrophages from patients with SSc-ILD, the upregulated expression of TREM2, GPNMB, CCL2, and TGF-β1 recapitulated the transcriptional features of SAM. When these macrophages were co-cultured with fibroblasts, the production of collagen, α-SMA and TGF-β was enhanced. By contrast, TREM2 inhibition significantly reduced these responses, as determined at the bulk RNA-seq and protein levels. Our study identified a GM-CSF-TREM2-TGF-β1 axis driving monocytes-derived profibrotic macrophage-fibroblast crosstalk in SSc-ILD. It also showed that, in the lungs of SSc-ILD patients, CD14+CD16+ monocyte-derived SAMs drive fibrosis through a TREM2-mediated pathway, which may provide new therapeutic targets.
Rheumatic and musculoskeletal diseases (RMDs) confer an increased cardiovascular risk beyond traditional factors, with peripheral artery disease (PAD) being an important source of morbidity and disability in these patients. This review summarizes current evidence on PAD across RMDs, including rheumatoid arthritis, systemic lupus erythematosus, antiphospholipid syndrome, systemic sclerosis, polymyalgia rheumatica, psoriatic arthritis, and primary Sjögren's syndrome. Physiopathological mechanisms involved include persistent inflammation, immune dysregulation, and the presence of pathogenic autoantibodies. Protective humoral responses have also been linked to reduced CV risk and may serve as future biomarkers. Clinical studies reveal variable PAD prevalence across diseases but consistent high underdiagnosis. Optimal management requires aggressive CV risk control, including lipid-lowering, immunomodulatory, and biologic therapies. This review underscores PAD as a distinct and clinically relevant manifestation of systemic autoimmunity, calling for targeted screening and prevention strategies in rheumatic populations.
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.
Background Mixed connective tissue disease (MCTD) is a systemic autoimmune disease with overlapping features with systemic lupus erythematosus, systemic sclerosis, and inflammatory idiopathic myopathies, characterized by anti-U1-RNP antibodies. Although subclinical retinal microvascular changes have been described in other connective tissue diseases, such data are lacking in patients with MCTD. Methods We performed a cross-sectional exploratory pilot study including patients with a defined diagnosis of MCTD according to one of the sets of classification criteria and age- and sex-matched healthy controls (HC), with elderly individuals equally distributed. Data on disease duration, renal function (creatinine and eGFR), and complement levels (C3 and C4) were recorded. All participants underwent optical coherence tomography angiography (OCT-A) to evaluate retinal vessel density (VD) using parafoveal, perifoveal, and foveal scans, whole images, and foveal avascular zones (FAZs). Nailfold videocapillaroscopy (NVC) was performed in patients with MCTD on four fingers of both hands to assess microangiopathy patterns. Results Patients with MCTD (n = 20, mean age 60.6 ± 11.4 years, 85% females) showed a significant reduction in both superficial and deep retinal VD across all evaluated regions compared with 20 HC. In patients with MCTD, deep retinal VD was inversely correlated with disease duration (r = −0.6, P = 0.0003) and directly correlated with eGFR (r = 0.4, P = 0.05). In patients with MCTD, C3 levels were positively correlated with age (r = 0.4, P = 0.03) and superficial parafoveal VD (r = 0.5, P = 0.008). In MCTD, NVC abnormalities, including non-specific microangiopathy and scleroderma patterns, occurred in 60% (n = 12) of cases and did not correlated with OCT-A findings. Conclusion Patients with MCTD present subclinical retinal microvascular abnormalities detectable by OCT-A. Our hypothesis-generating study
Systemic autoimmune and chronic inflammatory rheumatic diseases predominantly affect childbearing women. These women are at greater risk for pregnancy complications stemming from both the underlying disease and the treatments required to manage it. This cross-sectional study aimed to assess the prevalence of effective contraceptive use across a wide range of diseases including systemic lupus, systemic sclerosis, Sharp syndrome, Sjögren’s disease, rheumatoid arthritis, and spondyloarthritis. We conducted a questionnaire-based study targeting women aged 18–45 years with any of the aforementioned diseases. The data were collected from July 2023 to July 2024. A standardized self-report questionnaire, specifically developed for this study, was used to assess gynecological follow-up and reproductive health. Additional clinical data were extracted from patients’ electronic medical records. Descriptive statistics were used to analyze contraception use across different risk groups, including those on teratogenic treatments and those at increased maternal or fetal obstetric risk. 143 patients were included; among those not trying to conceive, 63% used effective contraception. This rate is lower than the 72% reported for the general population in France in 2016. Among previously pregnant patients, 33% experienced an unplanned pregnancy, highlighting the impact of contraceptive failure. There was no difference between patients on teratogenic treatments, those with increased maternal or fetal obstetric risk, and other patients. This study emphasizes the urgent need for improved education and gynecological management of young women with rheumatic diseases in France. Specific educational programs and enhanced gynecological follow-ups are necessary to address this critical gap. This study was registered with ClinicalTrials.gov (NCT05961267), first posted on the 24th of July, 2023, and in the European database (ID-RCB 2023-A01207-38).
Case reports (CRs) are essential in physiotherapy, yet reporting remains heterogeneous and insufficiently standardised. The 2013 CAse REport (CARE) guideline improves transparency but lacks physiotherapy-specific detail. This study aimed to develop a consensus-driven extension of the CARE reporting guideline to support structured reporting of physiotherapy CRs, encompassing physiotherapy-specific assessments and interventions. An e-Delphi consensus process study following the ACcurate COnsensus Reporting Document (ACCORD) guidelines. Online. Forty-four international experts in physiotherapy practice, research and education, along with six core committee members. Experts objectively scored items for relevance (5-point Likert scale) and provided open-ended responses for each item of the drafts. Scores and responses were analysed to facilitate iterative refinement of the Physiotherapy CAse REport (PhyCARE) reporting guidelines. Consensus was predetermined at over 70% agreement. Round 1 had the majority of items achieving ≥70% agreement, except two items that did not meet the threshold were revised and replaced with an alternative. Five new items addressing physiotherapy-specific reporting needs were added, and 10 items were relocated. In round 2, all 35 items across 13 domains achieved 84%-100% agreement. The nomenclature of one domain was revised to 'Outcomes and Follow-up'. Following two e-Delphi rounds, consensus was achieved, and suggestions from online meeting, piloting led to item rephrasing, after which the PhyCARE guidelines were finalised. The PhyCARE guidelines have the potential to provide a physiotherapy-specific extension of CARE to support structured, transparent and reproducible reporting of physiotherapy CRs.
Antisynthetase syndrome (ASyS) is an idiopathic inflammatory myopathy characterized by interstitial lung disease (ILD), mechanic’s hands, fever, arthritis, and Raynaud’s phenomenon. Although several domestic and international reports have described the clinical manifestations of ASyS, regional differences in clinical characteristics, including skin involvement, remain poorly understood. This study aimed to compare the regional differences in clinical features of ASyS by comparing data of Japanese patients with ASyS with those of previously published cohorts. We conducted a retrospective chart review of 48 patients with ASyS at Yokohama City University Hospital between 2010 and 2024 and compared their data with those of previously published cohorts using univariate analysis. A literature review was performed using the PubMed database, with the search results limited to articles published between January 2010 and December 2024. The mean age at onset was 56.5 ± 14.0 years, with a male-to-female ratio of 13:35. The prevalence of anti-Jo1 antibody was 35%. ILD and muscle weakness were observed in 97% and 52% of the patients, respectively. The most frequent skin involvement was Gottron’s sign (73%), followed by mechanic’s hands (65%) and periungual erythema (40%). A literature review using the same ASyS diagnostic criteria revealed that Asian cohorts, including ours, tend to have higher rates of ILD complications and a lower prevalence of anti-Jo1 antibodies than European cohorts. Furthermore, in the comparison of clinical manifestations with other Japanese and Asian cohorts, the rates of Raynaud’s phenomenon, muscle weakness, and malignant complications were nearly identical, although slight differences were observed in skin manifestations. By contrast, the European cohort was characterized by a high frequency of Raynaud’s phenomenon (39%), muscle weakness (85%), and anti-Jo1 antibody positivity (83%); meanwhile, ILD and mechanic’s hands were observed
Antimitochondrial antibodies (AMA), the hallmark of primary biliary cholangitis (PBC), have been inconsistently reported and poorly characterized in systemic sclerosis (SSc). Although recently linked to subclinical dysmotility in a cohort enriched for gastrointestinal (GI) involvement, data on the prevalence and clinical relevance of AMA in real-life SSc cohorts remain limited. A retrospective cross-sectional study was conducted on consecutive SSc patients followed at a referral center for the disease. Patients were tested for serum AMA according to reference standards, including HEp-2 immunofluorescent screening and ELISA confirmation (anti-E2 pyruvate dehydrogenase). Patients’ features were compared between AMA-positive and -negative cases. Among 165 SSc patients (20% diffuse cutaneous disease, 33% interstitial lung disease, 7.3% pulmonary arterial hypertension; 51% positive for anticentromere antibodies, 29% anti-topoisomerase I, 12% anti-RNA polymerase III), 37 (22%) were AMA-positive. While strongly associated with PBC, AMA were not linked to significant differences in cutaneous, vascular, pulmonary, or myocardial involvement. However, AMA were associated with GI vascular involvement (OR 13.3, 95% CI 2.53–95.0; p = 0.002), including gastric antral vascular ectasia (OR 7.99, 95% CI 1.05–72.5; p = 0.045), independently from PBC or symptoms of SSc-GI involvement. These complications are clinically relevant, as they may lead to GI bleeding and refractory iron-deficiency anemia. In our cohort of SSc patients systematically screened for autoantibodies, we found a high prevalence of AMA and identified a novel putative association with GI vascular involvement, which warrants confirmation in independent studies.
To explore how appropriate different intervals between monitoring blood tests are considered in relation to the risk of clinically significant adverse drug reactions in adults prescribed conventional synthetic DMARDs (csDMARDs) for ≥1 year for systemic autoimmune rheumatic diseases (SARD). A RAND/UCLA Appropriateness Method consensus study was undertaken. Members of the BSR csDMARD guideline working group who manage adults with SARD participated. Experts rated the extent to which intervals between blood tests were appropriate using Likert-type scales with responses from 1 (totally inappropriate) to 9 (totally appropriate) for nine scenarios with 5-year predicted risk of discontinuing treatment due to abnormal monitoring blood tests from 5% to 25%. Median score and the number that voted 1-3 (inappropriate), 4-6 (unsure) and 7-9 (appropriate) were calculated for every interval in each scenario. Scenarios for which agreement could not be reached in the first round were recirculated, enclosing individual round 1 response and the panel median score. Consensus that an interval was appropriate for a scenario was reached where the median panel score was ≥7 and up to six experts rated 10% over 5 years, respectively. A threshold to aid risk-stratified monitoring during established csDMARD treatment was agreed for adults with SARD.
Rheumatic disease registries systematically collect real-world longitudinal data, improving patient care and research. Despite the high burden of rheumatic diseases, national registries are scarce in the Middle East. Rheumatology Research Center, with support from Iran’s Ministry of Health, launched Rheumatry in 2016 as the country’s first national rheumatic disease registry. To outline the design, governance, and data collection framework of Rheumatry. Rheumatry is a secure, web-based, multicenter registry led by Tehran University’s Rheumatology Research Center. It enrolls patients meeting standardized criteria for major rheumatic diseases (rheumatoid arthritis, Systemic lupus erythematosus, systemic sclerosis, ankylosing spondylitis, Takayasu arteritis, etc.) from over 26 centers nationwide. Comprehensive electronic case report forms (intake and follow-up) capture demographics, disease history, clinical features, laboratory and imaging results, standardized disease activity measures, patient-reported outcomes, and treatment data. As of September 2025, Rheumatry includes ~ 11,900 patients and 26,100 visits. Its multi-disease scope, inclusion of Takayasu arteritis, and alignment with international standards (ACR/EULAR criteria, MedDRA coding) are notable innovations. The registry supports systematic monitoring of disease courses, therapies, and outcomes, addressing a regional gap in real-world evidence. Rheumatry’s national-scale infrastructure provides detailed longitudinal data on diverse rheumatic diseases in Iran. By facilitating research, surveillance, and quality improvement, it bridges a critical information gap in the Middle Eastern context.
Abstract Objectives Systemic sclerosis (SSc)-associated interstitial lung disease (SSc-ILD) is the leading cause of death amongst SSc patients. However, profibrotic factors in SSc-ILD has not been systematically assessed and their working mechanisms remain unclear. Methods We performed an integrated (scRNA-seq) analysis of 17 normal and 17 SSc-ILD lung tissues, using CellChat and Monocle3. Single-cell ATAC sequencing (scATAC-seq) profiles were analyzed by Signac. We performed ELISA to detect specific ligand serum levels using specimens of 55 SSc patients with (n = 32) or without (n = 23) ILD. Bleomycin-induced SSc-associated animal models of pulmonary fibrosis (n = 5) were constructed and used for tissue-level validation using immunofluorescence and immunohistochemistry. Results Integrative scRNA-seq profiles from 17 healthy control and 17 SSc-ILD lung tissues showed a higher intercellular communication flow in SSc-ILD. SPP1/CCL18-positive macrophages and COL1A2 mesenchymal cells positive for MIF or MDK constitute the majority of intercellular communication in SSc-ILD. ELISA showed serum levels of SPP1, MIF, and MDK were increased in SSc-ILD. SPP1 from macrophages generated self-autocrine feedback for CD44-positive macrophages and paracrine activity for ITGB1-positive COL1A2 mesenchymal cells. MIF from COL1A2 mesenchymal cells and SPP1 from macrophages provided co-stimulatory signalling for CD74/CD44-positive macrophages. MDK-SDC2 pairs-mediated autocrine signal accomplished self-management of COL1A2 mesenchymal cells. Moreover, scATAC-seq analysis showed SSc-ILD had higher chromatin accessibility for SPP1 (promoter region, intron 4, and intron 7) and SDC2 (promoter region). Conclusion Ligand-receptor pairs, including SPP1-CD44/ITGB1, MIF-CD74, and MDK-SDC2, constitute a major component of intercellular communication in SSc-ILD. It provided a panoramic view of the pathogenesis of SSc-ILD in a new dimension.
Gastrointestinal (GI) involvement in systemic sclerosis (SSc) is common, with up to 87% of people affected. 1 Of all SSc manifestations, GI disease has the greatest impact on quality of life. 2
Background Interstitial Lung Disease (ILD) can occur in association with ANCA‐associated Vasculitis (AAV‐ILD) or as an isolated entity with positive ANCA (ANCA‐ILD). However, data on the epidemiology and outcomes of these conditions remain limited. Methods A European multicentre retrospective study encompassed patients with AAV‐ILD or ANCA‐ILD. Baseline and subsequent chest CT studies were centrally reviewed. Primary outcomes included forced vital capacity (FVC) decline, respiratory failure, and mortality. Results 162 patients (MPO‐ANCA 85%); 123 (76%) had AAV‐ILD and 39 (24%) ANCA‐ILD. At baseline, Usual Interstitial Pneumonia (UIP) was the most frequent radiologic pattern (57%), while half had a radiological fibrosis grade >10%. Kidney involvement was present in 73%, most commonly Berden focal class. UIP and Non‐specific interstitial pneumonia (NSIP) patterns showed greater annual FVC decline than other patterns (UIP: −1.99%, NSIP: −3.76%, [p=0.35] others: +0.36%). An adjusted mixed‐effects model indicated that rituximab was associated with mean FVC % improvement at 12 months (+6.02%; p=0.07). Radiologic progression occurred in ~50%, mainly in younger patients with higher fibrosis severity grade. Respiratory failure (19%) was associated with fibrosis severity (grade 4: HR 4.7; p=0.029) and baseline FVC% (HR 0.95; p=0.002). Over a median 4.2‐year follow‐up, 48% died. Age (HR 1.08; p=0.04) and baseline FVC% (HR 0.97; p=0.05) were independent predictors of mortality. Conclusion At baseline, higher fibrosis severity, UIP, and lower FVC% were associated with worse outcomes. Immunosuppressives, such as rituximab, may help preserve lung function. The need for early identification and individualized treatment in ILD associated with AAV or ANCA is underscored.
ABSTRACT Objectives Undifferentiated connective tissue disease (UCTD) represents a systemic autoimmune condition characterized by clinical and serological features suggestive of defined connective tissue diseases (CTDs), yet insufficient to fulfill existing classification criteria. Despite increasing interest, long-term outcomes—particularly progression to defined CTDs—remain incompletely understood. This study aimed to evaluate the clinical outcomes of a UCTD cohort followed for at least 5 years and to identify baseline clinical and serological factors associated with an increased risk of evolution to a defined CTD. Methods A total of 658 patients were screened for this retrospective cohort study. After applying predefined eligibility criteria, 504 patients who met established UCTD definitions were included. Baseline clinical, laboratory, and serological characteristics were analyzed. Two patient outcome groups were defined at 5-year follow-up: those who evolved to a defined CTD and those who remained stable. Given the limited number of cases evolving to defined CTDs, group comparisons were performed using Student’s t-test or Mann-Whitney U test rather than logistic regression. Autoantibodies were assessed using indirect immunofluorescence for ANA and validated immunoassays for anti-dsDNA, anti-Sm, anti-Ro/SS-A, anti-La/SS-B, anti-Scl-70, anti-centromere, anti-U1RNP, anti-Jo1, rheumatoid factor, anti-cyclic citrullinated peptide antibodies (ACPA), antiphospholipid antibodies (anti-β2 glycoprotein I IgM/IgG, anti-cardiolipin IgM/IgG), and lupus anticoagulant. Results After a mean follow-up of 82 months, 102 of the 504 UCTD patients (20.2%) developed a defined CTD (37 Sjögren’s disease (SjD), 35 systemic lupus erythematosus (SLE), 12 systemic sclerosis (SSc), 14 rheumatoid arthritis, and 4 mixed connective tissue disease) within a follow-up period of at least 5 years. The most common clinical manifestations of UCTD included arthralgias, sicca symptoms, photosensitivity, oral aphthae, and Raynaud’s phenomenon. Differentiation was significantly associated with features such as a Schirmer test <5 mm (p=0.007),
Antineutrophil cytoplasmic antibodies (ANCA) are a key biomarker for ANCA-associated vasculitis (AAV), particularly microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). Although indirect immunofluorescence (IIF) has traditionally been the reference technique, its diagnostic value in contemporary real-world practice remains uncertain. The aim of this study was to evaluate the diagnostic performance of IIF ANCA testing in routine clinical practice. We conducted a retrospective study of all patients with an ANCA request at a tertiary hospital over a four-year period. All IIF-positive sera were subsequently tested for anti-PR3 and anti-MPO antibodies by chemiluminescent immunoassay (CLIA). Clinical data, test indication and final diagnoses were retrieved from electronic medical records. We included 5,157 patients and IIF was positive in 653 (12.7%): perinuclear ANCA (P-ANCA) in 17.9%, cytoplasmic ANCA (C-ANCA) in 13.3% and atypical ANCA (A-ANCA) in 68.8%. CLIA was negative in 97.3% of A-ANCA. AAV was diagnosed in 47 patients, and 42 (89.4%) had positive IIF. For GPA and MPA, IIF showed a sensitivity of 93% and specificity of 88%, with a very high negative predictive value (NPV) (99.9%) but low positive predictive value (PPV) (6.1%). Specificity improved to 96.8% when restricted to typical patterns (C-ANCA or P-ANCA) and to 99.6% when combined with positive CLIA results >20 IU/ml. Almost all AAV cases were diagnosed in patients with high pre-test probability (such as renal disease, lung infiltrates, or peripheral neuropathies) and interstitial lung disease was the most frequent non-AAV diagnosis in IIF-positive patients. ANCA IIF retains good diagnostic efficiency and a very high NPV for GPA and MPA, but has low PPV, particularly when tested for nonspecific symptoms.
Ferroptosis, an iron-dependent cell death pathway driven by lipid peroxidation (LPO), is implicated in the pathogenesis of autoimmune diseases (AIDs). However, comprehensive clinical evidence establishing the association between specific LPO biomarkers and AIDs is lacking. To systematically evaluate the clinical evidence for elevated LPO in major AIDs through a meta-analysis, focusing on key biomarkers including malondialdehyde (MDA) and 8-isoprostaglandin F2α (8-isoPGF2α). We searched four databases for studies reporting serum, plasma, or urinary LPO levels in patients with AIDs and healthy controls. Standardized mean differences (SMDs) were pooled using a random-effects model. Across 175 studies (8227 patients; 6866 controls), serum/plasma MDA levels were significantly elevated in all ten investigated AIDs: Rheumatoid arthritis (RA) (SMD = 2.82), systemic sclerosis (SSc) (SMD = 2.08), graves' disease (GD) (SMD = 1.92), Behçet's disease (BD) (SMD = 1.90), Crohn's disease (CD) (SMD = 1.71), multiple sclerosis (MS) (SMD = 1.52), psoriasis (PsO) (SMD = 1.44), ulcerative colitis (UC) (SMD = 1.32), systemic lupus erythematosus (SLE) (SMD = 1.20) and type 1 diabetes (T1DM) (SMD = 1.12). Disease-specific elevations were found for serum/plasma 8-isoPGF2α and 4-hydroxynonenal in RA, urinary 8-isoPGF2α in SSc and T1DM, and serum/plasma oxidized low-density lipoprotein in T1DM. MDA was higher in active or severe subgroups, with significant between-subgroup differences in GD and PsO. This meta-analysis provides robust, large-scale clinical evidence that elevated lipid peroxidation is a common feature across diverse AIDs. These findings solidify the clinical relevance of ferroptosis, positioning LPO products as promising biomarkers and underscoring the therapeutic potential of targeting ferroptosis in autoimmune conditions.
Objectives To evaluate the relationship between type I interferon (IFN‐I) stimulated gene (ISG) expression, Still's disease, and the development of lung disease (LD) and drug‐associated immune reactions (DAIR) to IL‐1/IL‐6 inhibitors. Methods Whole blood ISG expression was quantified by NanoString array. ISG‐28 scores were calculated in consecutive patients with Still's or Still's‐like disease. Exome sequencing with family‐based variant prioritization identified candidate genes harboring rare candidate causative variants. Lists of candidate genes were subjected to functional enrichment analysis. Results Among 57 patients (32 children, 25 adults), 16 had elevated ISG‐28 scores. This group exhibited higher prevalence of LD (0.44 vs. 0.1, p=0.007) and DAIR (0.63 vs. 0.17, p=0.003), and lower IL‐6 inhibitor use (0 vs. 0.25, p=0.048) compared to others. No significant differences were found in the rates of macrophage activation syndrome, active disease, elevated IL‐18, or current IL‐1 inhibition. The combination of HLA‐DRB1*15 with high ISG‐28 scores associated with LD and DAIR with high specificity, while absence of both biomarkers had high negative predictive value. Candidate genes from high ISG‐28 individuals were enriched in interferon‐related pathways, including autophagy, IFN‐I production, toll‐like receptor signaling, macrophage activation, cytoskeletal organization and responses to stress. Conclusion High IFN‐I expression correlates with LD and DAIR in Still's disease, linked to rare genetic variation in immune pathways. Combining high ISG‐28 with HLA‐DRB1*15 significantly improves post‐hoc stratification of patients for these complications. If prospectively validated, these findings may guide molecular risk assessment and targeted therapies, including IFN‐I directed treatments in Still's disease with IFN‐I signature.
Abstract Objectives Mycophenolate mofetil (MMF) is routinely used in early diffuse cutaneous systemic sclerosis (dcSSc) but not in limited cutaneous (lc)SSc. This may miss an opportunity to slow disease progression. MINIMISE-Pilot tested feasibility of an open-label event-driven randomised trial of MMF versus no immunosuppression in lcSSc. Methods We tested feasibility of a trial evaluating impact of MMF on a novel event-driven composite endpoint. The MINIMISE endpoint measures time to worsening of lcSSc determined by progressive lung fibrosis, pulmonary hypertension, scleroderma renal crisis, heart failure, severe gut involvement, major digital vascular complications, or death. Pre-specified “Stop-Go” criteria were agreed. Subjects were stratified by anticentromere antibody (ACA) status. Results Recruitment was challenging. 53 subjects were screened and 43 randomised, 21 to MMF arm. Since recruitment was below 60 participants, MINIMISE-Pilot was terminated based upon the prespecified threshold for continuation. During the treatment period there were no clinical worsening clinical endpoints. Adherence to MMF was generally high, with 19 participants (95%) being 100% adherent at Week 1, decreasing to 9 participants (64%) at Week 24. Conclusion MINIMISE-Pilot achieved its goal as a feasibility trial leading to early termination of the study due to low recruitment. The rationale and concept for this study remain very strong. However, our findings suggest that a randomised prospective trial across 12 sites in UK with relatively short follow-up duration is not feasible. This will inform design of future studies testing benefit of MMF in lcSSc.