Eduardo Dourado

Objective: To better characterize the clinical phenotypes and heterogeneity of anti‐synthetase syndrome (ASyS), we performed unsupervised cluster analyses using clinical and serological data from the Classification Criteria for Anti‐Synthetase Syndrome (CLASS) project database. Methods: The CLASS database comprised 2,035 ASyS cases and 2,140 comparators with mimicking conditions, namely systemic autoimmune rheumatic diseases and/or interstitial lung disease (ILD), contributed by 103 centers worldwide. We applied multiple correspondence analysis followed by hierarchical clustering using 19 clinical and serological variables to classify ASyS and comparators in the entire CLASS cohort into distinct subgroups. We then repeated the cluster analysis in the ASyS cohort alone to identify phenotypic subgroups of ASyS. Results: Cluster analysis of the entire cohort identified three subgroups. Whereas Cluster 1 (n = 1,311) and Cluster 3 (n = 1,468) predominantly comprised ASyS and comparators, respectively, Cluster 2 (n = 1,105) included both groups. Interstitial pneumonia with autoimmune features (without anti‐synthetase autoantibodies) and systemic sclerosis were more prevalent in Cluster 2, whereas dermatomyositis and polymyositis were predominantly represented in Cluster 3. Cluster analysis of the ASyS cohort identified three distinct subgroups: Cluster 1 (anti‐Jo‐1‐positive, “full‐spectrum” ASyS with myositis, ILD, and arthritis; n = 1,034), Cluster 2 (ILD‐predominant; n = 581), and Cluster 3 (without ILD; n = 248). Conclusion: Cluster analyses identified ASyS as a distinct and heterogeneous clinical entity. Three distinct phenotypic clusters emerged among patients with ASyS, with ILD‐predominant cases representing the second largest subgroup, underscoring the need for classification criteria that adequately capture patients presenting with isolated ILD. image

Objectives: Anti-synthetase syndrome (ASyS) is a distinct entity within the myositis spectrum characterized by interstitial lung disease (ILD) which raises the concern of increased pulmonary vascular pressures. However, the prevalence of pulmonary hypertension (PH) in real-world ASyS populations remains unclear. We investigated the prevalence and impact of PH in ASyS. Methods: Data were obtained from a worldwide, physician-reported multicentre registry based on physician-diagnosed ASyS and/or a positive anti-synthetase antibody. Comparative analyses and multivariable logistic regression assessed the odds of PH in ASyS relative to other disease groups. Cox proportional hazards models evaluated associations with all-cause mortality. Results: A total of 1868 ASyS and 2043 controls from 103 centres were analysed. Prevalence of PH was 8.9% of ASyS, which was higher than in non-ASyS myositis (3%, P < 0.001), RA (4%, P = 0.009) and interstitial pneumonia with autoimmune features (IPAF 3%, P = 0.003), but not significantly different from SSc (13%, P = 0.07) or SLE (11%, P = 0.57). ASyS had higher odds of PH compared with non-ASyS myositis (OR 1.91) and IPAF (OR 3.72), but lower odds than SSc (OR 0.62) or SLE (OR 0.24), in multivariate models adjusted for age, sex, smoking and ILD. Five-year survival in ASyS was 94%, decreasing to 88.3% in those with PH (P = 0.001). PH remained associated with increased mortality in ASyS, independent of age, sex and ILD (HR 2.52, 95% CI 1.41–4.53). Conclusion: PH occurred in 8.9% of ASyS and was independently associated with increased mortality, highlighting the importance of PH evaluation in this population.

Background: Autoantibodies are central to the diagnosis and risk stratification of systemic sclerosis (SSc), but their prevalence and clinical associations may vary across populations. This study aimed to evaluate the prevalence and immuno-clinical associations of different autoantibodies in the Rheumatic Diseases Portuguese Register systemic sclerosis cohort. Methods: This was a multicentre observational registry-based study that used data from the Reuma.pt SSc module. Patients were divided according to autoantibody status, and associations between autoantibody expression and clinical data were assessed using appropriate statistical tests, with Bonferroni correction applied for multiple comparisons. Multivariable binary logistic regression was performed for clinically relevant outcomes, with adjustment for sex, age at diagnosis and disease duration. Results: A total of 1080 patients were included, 87.5% female, with a mean age at last evaluation of 60.2 ± 14.6 years and a mean disease duration of 12.4 ± 10.0 years. Limited cutaneous SSc was the most frequent clinical category (57.4%), followed by diffuse cutaneous SSc (17.7%), very early diagnosis of systemic sclerosis (VEDOSS; 12.3%), overlap syndromes (9.8%) and SSc sine scleroderma (2.8%). Antinuclear antibodies were present in 93.4% of patients. Anti-centromere antibodies (ACAs) were the most frequent SSc-specific autoantibodies (54.6%), followed by topoisomerase I antibodies (ATAs; 21.8%). ACA positivity was associated with limited cutaneous disease; older age at diagnosis; and lower frequency of interstitial lung disease (ILD), myositis and flexion contractures. ATA positivity was associated with diffuse cutaneous disease, male sex, higher modified Rodnan skin score (mRSS), digital ulcers, flexion contractures, oesophageal involvement and ILD. Among less frequent autoantibodies, anti-Pm/Scl antibodies were associated with myositis, joint involvement, calcinosis and ILD; anti-U1RNP antibodies with younger age, MCTD overlap, myositis and joint involvement; anti-RNA polymerase III antibodies (ARAs) with scleroderma renal crisis and higher mRSS; anti-U3RNP antibodies with diffuse cutaneous disease and renal involvement; and anti-Ku antibodies with overlap syndromes. Conclusions: In this large real-world SSc cohort, autoantibody status was strongly associated with distinct clinical phenotypes, confirming its value for disease stratification. While most established immuno-clinical associations were reproduced, some differences from international cohorts were observed, supporting the need for population-specific validation of autoantibody associations in SSc.

Objective: Adverse changes in body composition are increasingly being recognized in patients with rheumatoid arthritis (RA). This study aimed to explore the relationship between RA disease activity, disease impact, and functional disability with bioelectrical phase angle (PhA) and appendicular skeletal muscle mass index (ASMI). Methods: Patients with RA were recruited at a tertiary hospital in Portugal. The Disease Activity Score in 28 joints based on erythrocyte sedimentation rate and C-reactive protein (DAS28-ESR and DAS28-CRP, respectively) were used to assess disease activity. The impact of disease and functional status were evaluated using the Rheumatoid Arthritis Impact of Disease (RAID) questionnaire and the Health Assessment Questionnaire (HAQ), respectively. Body composition was measured by bioelectrical impedance analysis (BIA). PhA was stratified into tertiles, and ASMI was classified according to the European Working Group on Sarcopenia in Older People 2 criteria. Results: A total of 104 patients with RA were included (74% female; mean age 60.9 [SD 9.6] years). RAID scores were significantly lower in patients in the highest PhA tertile (PhA-T3) than in those in the lower PhA tertiles (PhA-T2 and PhA-T1, P = 0.001 and P < 0.001, respectively). HAQ scores were significantly lower in patients in the highest PhA tertile (PhA-T3) than in those in the lowest PhA tertile (PhA-T1, P < 0.001). Median DAS28-ESR and DAS28-CRP were lower among patients with higher PhA, but the difference did not reach statistical significance ( P = 0.07 and P = 0.16, respectively). No differences were found among the ASMI groups in DAS28-ESR ( P = 0.62), DAS28-CRP ( P = 0.97), RAID ( P = 0.30), or HAQ ( P = 0.51) scores. Conclusion: A lower PhA was associated with greater disease impact and greater significant functional disability in patients with RA.

Objectives: To identify clinical features distinguishing anti-synthetase syndrome (ASyS)-related ILD (ASyS-ILD) from non-ASyS ILD and to compare outcomes across ILD subgroups.Methods: We utilized an international, real-world physician-reported database to compare ASyS-ILD and ILD related to other causes. Comparative analysis was performed against the overall control group, and the five main control ILD disease subgroups. Logistic regression assessed associations with supplemental oxygen use and ILD-hospitalization, and Cox proportional hazards models evaluated associations with all-cause mortality. Results: Among 1,557 ASyS-ILD and 828 controls, ASyS-ILD patients were younger, had more acute onset, and had worse restrictive physiology. Nonspecific interstitial pneumonia (NSIP) was the most common radiological pattern across all groups. In ASyS-ILD, NSIP (55%) was followed by organizing pneumonia (OP, 19%), similar to ILD in dermatomyositis (DM) with and without MDA5 antibodies (NSIP 53% and 64%, OP 32% and 11%, respectively). NSIP remained common in rheumatoid arthritis (RA) and systemic sclerosis (SSc) ILD (39% and 59%) but was followed by usual interstitial pneumonia (36% and 14%). Compared with controls, ASyS-ILD had higher odds of hospitalization (OR 1.81, 95%CI 1.38-2.37). Mortality in ASyS-ILD was primarily pulmonary then cardiovascular, Five-year survival in ASyS-ILD was 94.7% which was comparable or higher than most control subgroups, except anti-MDA5-associated ILD (90.3%). ASyS-ILD had higher all-cause mortality (HR 1.66, 95%CI 1.03–2.66) than controls. Conclusions: ASyS-ILD is characterized by a younger, more acute, and symptomatic onset compared with other ILDs, and is associated with higher hospitalization rates and worse mortality, underscoring its overall more severe clinical course.

Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of systemic autoimmune rheumatic disorders in which chronic inflammation of skeletal muscle leads to muscle weakness. Many other organs, including the skin, heart, lungs, and joints, may be affected. Patients with IIM may be positive for myositis antibodies (MAs), including myositis-specific and/or associated antibodies. Although helpful for establishing the diagnosis of IIM in the appropriate clinical setting, the presence of MAs does not always predict the occurrence of connective tissue diseases. Additionally, commonly used techniques such as line blot are known to have high rates of false positivity, especially for rare MAs. The accuracy of MAs tests such as line blot may be improved by cross-checking their results with antinuclear antibody (ANA) patterns on HEp-2 indirect immunofluorescence (IIF). This study aims to examine the concordance between ANA IIF patterns and myositis-specific antibodies in a Portuguese cohort of patients with IIM. We will assess whether concordance between methods is associated with increased fulfillment of IIM classification criteria, greater disease severity, or distinct patterns of organ involvement among affected patients.

Objectives: We aimed to assess the safety and efficacy of ultrasound-guided needle muscle biopsy (UGNMB) using a 14G biopsy needle in obtaining adequate samples for histological analysis and establishing an inflammatory idiopathic myopathy (IIM) diagnosis in patients with suspected myositis. Methods: We included patients who were followed up at our Rheumatology Department with a suspected IIM diagnosis. UGNMBs were performed from January 2022 to April 2024. Ultrasound was used to select which muscle to biopsy, to guide the anaesthesia and the muscle sample retrieval using a 14G guillotine-type semiautomatic biopsy needle. Results: Forty-four biopsies were performed, half in female patients (n = 22). Nearly 90% (n = 40) of the samples allowed a thorough histologic evaluation. Almost one-third of the samples (n = 12) were compatible with myositis, 27.2% (n = 12) of the biopsies showed nonspecific muscle changes and the remaining revealed muscle tissue without pathological changes. More than half of the patients (30/44) had a histological result that matched the final clinical diagnosis. The UGNMB was generally well-tolerated, with an average Visual Analogical Scale (VAS) for pain of 3.8 out of 10 during the procedure. No moderate or severe adverse events were reported. Conclusion: Histological analysis was possible in most samples, suggesting that UGNMB is an effective way to collect muscle samples for IIM differential diagnosis. UGNMB also seems to be a safe method for collecting muscle samples.

Review; Authors: S.P. Silva, M. Pinto, D. Costa, A. Azevedo, E. Dourado

Objective: Anti‐synthetase syndrome (ASSD) is a rare systemic autoimmune rheumatic disease (SARD) with significant heterogeneity and no shared classification criteria. We aimed to identify clinical and serological features associated with ASSD that may be suitable for inclusion in the data‐driven classification criteria for ASSD.Methods: We used a large, international, multicenter “Classification Criteria for Anti‐synthetase Syndrome” (CLASS) project database, which includes both patients with ASSD and controls with mimicking conditions, namely, SARDs and/or interstitial lung disease (ILD). The local diagnoses of ASSD and controls were confirmed by project team members. We employed univariable logistic regression and multivariable Ridge regression to evaluate clinical and serological features associated with an ASSD diagnosis in a randomly selected subset of the cohort.Results: Our analysis included 948 patients with ASSD and 1,077 controls. Joint, muscle, lung, skin, and cardiac involvement were more prevalent in patients with ASSD than in controls. Specific variables associated with ASSD included arthritis, diffuse myalgia, muscle weakness, muscle enzyme elevation, ILD, mechanic's hands, secondary pulmonary hypertension due to ILD, Raynaud phenomenon, and unexplained fever. In terms of serological variables, Jo‐1 and non–Jo‐1 anti‐synthetase autoantibodies, antinuclear antibodies with cytoplasmic pattern, and anti‐Ro52 autoantibodies were associated with ASSD. In contrast, isolated arthralgia, dysphagia, electromyography/magnetic resonance imaging/muscle biopsy findings suggestive of myopathy, inflammatory rashes, myocarditis, and pulmonary arterial hypertension did not differentiate between patients with ASSD and controls or were inversely associated with ASSD.Conclusion: We identified key clinical and serological variables associated with ASSD, which will help clinicians and offer insights into the development of data‐driven classification criteria for ASSD. image