To describe and compare systemic sclerosis (SSc) phenotypes according to race/ethnicity. SSc patients enrolled in the Canadian Scleroderma Research Group cohort from 2004 to 2020 were included. Demographic, clinical and serological characteristics at baseline were collected using standardized questionnaires. Race/ethnicity was self-reported by participants, who were asked to identify with 1 (or more) of the following groups: White, Chinese, South Asian, Black, Filipino, Latin American, Southeast Asian, Arab, West Asian, Japanese, Korean, Indigenous (First Nations, Metis, Inuit) or none of the above. We compared clinical characteristics and serology, according to race/ethnicity. Of the 1727 CSRG participants, 80% indicated White race/ethnicity (n=1385), 5 % Indigenous (n=79), 3% Latin American (n=58), 1.6% Middle Eastern (n=27), 1.5% East/Southeast Asian (n=26), 1.2 % Black (n=21) and 0.8 % South Asian (n=12). Differences in demographic, clinical and serological characteristics according to race/ethnicity are highlighted in Table 1. White individuals were older at cohort entry and more frequently had limited SSc. Most SSc subjects were women, but men were affected in higher proportions among South Asians (39%) and East/Southeast Asians (23%). Although Raynaud’s phenomenon is almost universal in SSc, its prevalence was slightly lower among East/Southeast Asians (86%), who also had numerically lower frequency of digital ulcers (29%). Arthritis was relatively common among Latin Americans (55%), Blacks (47%) and possibly Indigenous individuals (39%) versus Whites (29%). Blacks also had higher frequency of diffuse SSc (67%), telangiectasias (79%) and myositis (40%), and the lowest mean pulmonary function test values. Indigenous individuals had higher prevalence of lower gastrointestinal involvement, including malabsorption (22%), bacterial overgrowth (15%) and need for hyperalimentation (9%). In regard to serological profiles, anti-centromere autoantibodies were positive in about one-third of SSc patients, but rare among Black individuals (6%). Anti-topoisomerase I autoantibodies were present in about one-third of Latin American, Black, East/Southeast Asian, Middle Eastern and South Asian patients, but in only 13% of White and Indigenous individuals. Finally, anti-RNA polymerase III autoantibodies were overrepresented among Indigenous individuals (30%). Table 1: Baseline demographic, clinical and serological characteristics of SSc individuals according to race/ethnicity In this Canadian cohort, race/ethnicity was associated with distinct SSc phenotypes. Some of these findings may be due to genetic factors, but some findings may be related to referral patterns or migration trends. Additional investigations are underway to better understand our findings. If validated, the results could help personalize care in SSc.

BACKGROUND:With numerous emerging treatments for systemic lupus erythematosus (SLE), it is imperative that clinical trials include diverse populations reflective of those with SLE, especially active disease. Epidemiological data from North America and Europe indicate that the prevalence of SLE is disproportionately higher among Black populations compared to White populations, relative to their distribution in the general population. The objectives of this study were to examine the racial composition of randomized controlled trials (RCTs) in SLE from 2014 to 2024, assessing whether these trials accurately represent the diversity of SLE populations. METHODS:A systematic review of the literature was conducted using EMBASE, PUBMED, Web of Science, and Cochrane CENTRAL from Jan 1, 2014 - May 14, 2024. RCTs of pharmaceutical interventions in SLE patients were included. Studies were excluded if they had less than 50 participants, were not in English, or did not report on race/ethnicity. Revman 5.4 and SPSS were used for statistical analysis. RESULTS:Of 2505 studies identified, 63 were included. The pooled proportion of women was 91%. Among studies reporting these categories, White participants represented 61% of trial participants, Black participants 14%, Asian participants 14%, and Indigenous (including Native American) participants 8%, whereas fewer than 1% were Pacific Islanders. Hispanic/Latino ethnicity, which was variably reported across studies and may overlap with racial categories, was reported in 37% of participants. CONCLUSION:Racial and ethnic minority groups appear under-represented in recent SLE RCTs, particularly Black participants. Interpretation of Hispanic/Latino representation is limited by inconsistent reporting of race and ethnicity across trials. Greater effort is needed to ensure that SLE research trials are generalizable to patients and equitable with respect to patient diversity.

Autoantibodies against NOR-90 are rare and have been associated with systemic sclerosis (SSc). This study seeks to identify the characteristics of SSc participants with anti-NOR-90 autoantibodies. An international (Canada, Australia, USA, Mexico) cohort of 2143 SSc participants was included. Sera were tested using a line immunoassay (Euroimmun, Lübeck, Germany). Clinical associations with anti-NOR-90 autoantibodies were investigated. Single-specificity anti-NOR-90-positive was defined as anti-NOR-90-positivity without other SSc-related autoantibodies, except for anti-Ro52/TRIM21. 115 (5

Objectives Chimeric antigen receptor T-cell (CAR-T) therapy is emerging as a novel approach for systemic sclerosis (SSc). We reviewed the current trial landscape—including study design, therapeutic targets, comparative arms—and integrated these findings with the most recent SSc case series. Methods On August 20, 2026, we searched ClinicalTrials.gov and ClinicalTrialsRegister.eu using “scleroderma” OR “systemic sclerosis” AND “CAR-T,” and screened references from published studies; identifying 29 actively recruiting trials; extracted prespecified data, including trial identifiers, targets, eligibility criteria, SSc participant details, interstitial lung disease (ILD) rules, product source, immunosuppression protocols, hospitalization requirements, comparators, sponsors, and study designs. Results Most targeted CD19: 27/29 trials (11 CD19-only; 16 multitarget constructs, ie, CD19 plus BCMA). One study each targeted CD20 or BCMA alone. Products were autologous in 20/29 and allogeneic (“off-the-shelf ”) in 9/29. Only 2 trials were randomized, and just 1 used an active comparator (rituximab). Mostly early diffuse cutaneous SSc (dcSSc) were eligible for inclusion. SSc enrollment was often within broader autoimmune “basket” trials; or SSc-specific studies (n=12). ILD eligibility criteria were inconsistently reported in trial registration: unspecified in 22/29, permitted in 5/29 (with limitations) and required in 1/29. Most protocols mandated immunosuppression washouts and lymphodepletion (Table 1). Three reports demonstrated feasibility and early clinical benefit in SSc. The BREAKFREE-1 update described a multicenter CD19 CAR-T with acceptable safety and encouraging signals in 5 SSc patients.[1] Another reported deep B-cell depletion and clinical responses in 2 patients with dcSSc.[2] Schett et al presented the largest series to date: 6 patients with dcSSc showed improvements in skin and lung disease with manageable safety (low-grade cytokine release, no major neurotoxicity).[3] Table 1. Main characteristics of the actively recruiting trials of CAR T-cell trials in systemic sclerosis Conclusion The SSc CAR-T landscape is promising but fragmented—dominated by early-phase, non-comparative designs with several targets and treatment regimens. Progress could be accelerated by: (1) harmonized eligibility and outcome measures across CD19, CD20, and BCMA programs; (2) fewer and larger multicenter trials; (3) inclusion of comparators or delayed-start designs; and (4) transparent reporting of subsets of SSc and SSc-ILD patients to learn whether it is “too late” for some patients to have optimal benefit. Early clinical signals support further development, but the high cost and risk of inequitable access demand parallel strategies for affordability and global access of CAR-T benefits. References [1.] Khanna D. Ann Rheum Dis 2025;84:841-2. [2.] Wang X. Cell 2024;187:4890-904.e9. [3.] Auth J. Lancet Rheumatol 2025;7:e83-93.

BACKGROUND:Rheumatological extraintestinal manifestations (EIMs) represent the most frequent complications of inflammatory bowel disease (IBD). Despite their clinical relevance, they remain heterogeneously defined and inconsistently assessed in both clinical practice and clinical trials. This narrative review aimed to summarize current evidence on the diagnostic assessment of IBD-associated rheumatological EIMs and to identify unmet needs for clinical evaluation and trial design. METHODS:A literature search was performed to identify studies evaluating the diagnosis and assessment of IBD-associated rheumatological EIMs. Data were extracted on diagnostic definitions, classification systems, outcome measures, and the use of patient-reported outcomes (PROs) across observational studies and randomized controlled trials. RESULTS:Substantial heterogeneity was observed in the diagnostic assessment of IBD-associated rheumatological EIMs, with inconsistent use of classification criteria and frequent reliance on nonstandardized clinical evaluation. No PRO instruments specifically developed or validated for IBD-associated rheumatological EIMs were identified. In randomized controlled trials, rheumatological EIMs were variably reported, with heterogeneous endpoints and limited structured assessment, particularly in phase 3 IBD trials. CONCLUSIONS:Evidence from this review reflects considerable methodological variability in the assessment of rheumatological EIMs in IBD. Standardized definitions, harmonized outcome measures, and the development of EIM-specific PROs are needed to support consistent endpoint selection and improve the evaluation of rheumatological outcomes in future clinical trials.

The global epidemiology, regional variation, sex- and ethnicity-based disparities, disease burden, and organ-specific involvement in systemic sclerosis were reviewed. A qualitative systematic search of PubMed/MEDLINE, EMBASE, SciELO, and the Cochrane Library was conducted following PRISMA 2020 guidelines. Forty-seven studies reporting incidence, prevalence, organ involvement, mortality, or quality of life were included. Global prevalence ranged from 0.9 to 37.9 per 100,000 and incidence from 0.05 to 4.1 per 100,000 person-years, with marked geographic heterogeneity across the globe. Women were predominantly affected (4-6:1), whereas men showed more severe disease and higher mortality. African-descent, Indigenous American, and some South Asian populations had higher frequencies of diffuse cutaneous systemic sclerosis, interstitial lung disease, and reduced survival. Pulmonary involvement accounted for most disease burden, with interstitial lung disease in 35-55% and pulmonary arterial hypertension in 6-12%. These findings highlight substantial epidemiologic heterogeneity and the need for early detection and standardized care in expert centers.

OBJECTIVES:This study aimed to determine whether the route of glucocorticoid (GC) administration in patients with early rheumatoid arthritis (ERA) is associated with the odds of persistent GC use or escalation to advanced therapies at 12 months. METHODS:Adults with newly diagnosed ERA (symptoms duration <1 year) enrolled in the Canadian Early Arthritis Cohort between 2007 and 2023 were included. Those with GC use 90 days prior to baseline, on advanced therapy by 3 months, or with <12 months of follow-up were excluded. Patients were stratified by GC use and route in the first 3 months and compared using analysis of variance or Wilcoxon tests. Adjusted multivariable logistic regression was used to calculate the odds ratios (OR). RESULTS:Among 2222 patients, median (SD) age was 55 (15) years, disease duration 5.5 (3.0) months, and the Clinical Disease Activity Index was 26 (14). During the first 3 months, 1661 patients (75%) received no GC, 421 (19%) oral, 121 (5%) parenteral (intra-articular and/or intramuscular), and 19 (1%) both oral and parenteral. Advanced therapies and GC use, respectively, at 12 months were 7% and 8% (no GC); 14% and 47% (oral); 14% and 26% (parenteral); 16% and 63% (both). The OR for GC use at 1 year was 9.8 (oral) and 4.1 (parenteral), compared with no GC (1.0). CONCLUSIONS:Patients receiving parenteral GC were half as likely to remain on GC at 12 months compared with those on oral GC. Rates of advanced therapy use were similar between groups. Parenteral GC administration may facilitate earlier discontinuation of steroids.

ABSTRACT Background Itch in systemic sclerosis (SSc) is thought to be most significant in early disease, but no longitudinal studies have examined itch course. We estimated itch presence and severity from SSc disease onset, accounting for participant age and time since onset at each assessment. Methods People with SSc from the multinational Scleroderma Patient-centred Intervention Network Cohort completed past-week itch severity assessments (0 to 10 numerical rating scale) at enrolment and longitudinally at 3-month intervals. To estimate itch probability (score > 0) and, if present, itch severity, we used two-stage mixed effects models with basis splines to address non-linearity. The primary predictor was age at each assessment, partitioned into age at non-Raynaud phenomenon symptom onset and time since onset. We estimated prevalence and severity for onset ages of 20, 30, 40, 50 and 60 years and, for each onset age, at 2 years, 3 years, 4 years, 5 years, 7 years, and 5-year intervals 10 years to 35 years post-onset. Findings We included 2173 participants with 19 733 itch assessments (mean [standard deviation] 9·1 [6·9] assessments). 1896 of 2173 (87·3%) participants were women. Mean age at enrolment was 54·7 (SD 12·7) years. 873 (40·2%) participants had diffuse cutaneous SSc. Predicted itch probability was between 35·0% (95% CI 31·8% to 38·5%) and 36·8% (95% CI 33·3% to 40·4%) at all onset age and disease duration combinations. Mean itch severity, when present, was moderate, between 4·1 (95% CI 4·1 to 4·1) and 4·4 (95% CI 4·3 to 4·4), for all age and duration combinations. Interpretation Itch prevalence and mean severity were stable across onset ages and over time within onset ages. Findings suggest that itch is common in SSc and not as closely related to disease duration as previously thought. Research is needed to elucidate itch pathophysiology and identify effective management strategies. Funding Funding for the study was provided by a Skin Investigation Network of Canada Team Development Award. Funding for the Scleroderma Patient-centred Intervention Network Cohort has been received from the Canadian Institutes of Health Research (TR3-119192; PJT-149073; PJT-148504; PJT-195879; PJT-203755); the Arthritis Society; the Lady Davis Institute for Medical Research of the Jewish General Hospital, Montréal, Québec, Canada; the Jewish General Hospital Foundation, Montréal, Québec, Canada; McGill University, Montréal, Québec, Canada Scleroderma Society of Ontario; Scleroderma Canada; Sclérodermie Québec; Scleroderma Manitoba; Scleroderma Atlantic; the Scleroderma Association of BC; Scleroderma SASK; Scleroderma Australia; Scleroderma New South Wales; Scleroderma Victoria; and the Scleroderma Foundation of California. RESEARCH IN CONTEXT Evidence before this study We searched PubMed using the terms “itch” or “pruritus” with “systemic sclerosis” or “scleroderma” on March 26, 2025, to identify previous studies that have evaluated the trajectory of itch prevalence or severity in systemic sclerosis (SSc) from the time of disease onset. We did not find any longitudinal studies. We identified 4 cross-sectional studies, and none found statistically significant associations between disease duration and itch. Three of the studies included between 56 and 126 participants. The fourth study included 959 participants and found that itch was experienced on most days in the last month based on a single dichotomous item among 46% of participants between 1 and 4·9 years since non-Raynaud phenomenon (non-RP) symptom onset and 41% for those 5 or more years since onset (not statistically significant). Added value of this study This was the first longitudinal study of itch prevalence and severity in SSc. We evaluated 2173 Scleroderma Patient-Centred Intervention Network participants from 7 countries who reported itch severity in the past week (0 to 10 numerical rating scale) at cohort enrolment and subsequently at 3-month intervals (19 733 total itch assessments). We simultaneously modelled probability of having any itch and, if present, itch severity. We accounted for both normal aging and SSc disease duration by including age of onset of non-RP symptoms and time since onset in our models. We found that itch prevalence and mean severity were stable across the course of the disease. Between 35% and 37% of participants reported itch (numerical rating scale score > 0) across all ages of onset and time since onset combinations. Mean itch severity, among participants with itch, was between 4·1 and 4·4 points, a moderate level, at all onset age and disease duration combinations. Findings were consistent for subgroups defined by participant country, sex, and diffuse versus limited cutaneous SSc. Implications of all the available evidence Itch is rarely researched in SSc, and itch assessment and management are typically not part of routine SSc care. It is commonly assumed that itch is most prominent, if present, in early disease. Our study showed that, contrary to this assumption, itch is present for many people with SSc across the course of the disease; itch prevalence and mean severity were stable across time regardless of age of SSc onset. Findings from our study underline the need for research on the pathogenesis of itch in SSc and the development and testing of treatments. Itch assessment and management should be part of routine SSc care.

Objectives Fibromyalgia (FM) symptoms are a common comorbidity in systemic lupus erythematosus (SLE), contributing to increased pain, fatigue, and insomnia. These symptoms can significantly impair physical and cognitive function, making it harder to perform daily activities, exercise, and tasks requiring concentration. This study examines the effect of FM symptoms on function and explores how various treatment approaches can moderate these effects through a multicenter cross-sectional analysis of SLE patients from 7 Canadian clinics. Methods Data on disease burden metrics (FM symptoms, pain areas, disease activity, and irreversible damage), medication use (antimalarials, corticosteroids, immunosuppressants, biologics and narcotics), and sociodemographic factors were collected. Linear mixed-effects models evaluated the effect of FM symptoms and other disease burden variables on 5 functional outcomes: fatigue severity (FSS), cognitive dysfunction (PDQ), disability (WHODAS), depression (BDI), and work role functioning (WRF). Moderation models were used to assess if SLE treatments ameliorated the effect of these variables on function, while correcting for multiple testing. Results The models established that a higher number of reported fibromyalgia symptoms was the strongest predictor of functional impairment, being significantly associated with increased fatigue (β = 1.06, p < 0.001), cognitive dysfunction (β = 1.21, p < 0.001), and higher disability (β = 0.68, p < 0.001), and depression scores (β = 0.73, p < 0.001). Conversely, irreversible damage scores were uniquely linked to worsened work role functioning (β = −4.41, p = 0.020). Building on these models, moderation analyses revealed that certain treatments lowered the effect of the disease burden metrics on various function metrics (Figure 1). Immunosuppressants moderated the impact of organ damage on disability from β = 2.62 to β = 0.45 (p = 0.022) and perceived deficits from 2.28 to −0.84 (p = 0.041). Corticosteroids attenuated the association between FM symptoms and cognitive dysfunction falling from β = 1.42 to β = 0.14 in users (p = .024). Figure 1. Simple Slopes of Effects of Immunosuppressants and Corticosteroids Conclusion This study demonstrates that the reported number of fibromyalgia symptoms is the dominant factor driving functional burden across nearly all measured domains in SLE, surpassing the impact of disease activity. Most significantly, we provide evidence that certain SLE treatments act as functional shields: corticosteroids protecting cognition from FM effects and immunosuppressants mitigating disability linked to damage. These moderation effects strongly support tailoring treatment not only to disease activity but also to the patient’s functional risk profile, moving clinical practice closer to truly personalized medicine. Supported by a CIORA grant

Diffuse cutaneous systemic sclerosis (dcSSc) is a life-limiting fibrotic disease. We and others have shown that dcSSc fibroblasts accumulate numerous somatic mutations associated with senescence-like features; however, the mechanism(s) enabling their survival remain unclear. Skin biopsies were obtained from lesional tissues from dcSSc (n=10), dcSSc treated with autologous hematopoietic stem cell transplantation (ASCT, n=8) or 7 age/sex-matched healthy controls. Primary dermal fibroblasts were generated from biopsies. Spatial RNA sequencing, immunoblotting, confocal microscopy, and functional assays were used to mechanistically delineate signaling pathways linking DNA-damage with fibroblast survival. dcSSc fibroblasts demonstrated increased pH2AX DNA double-strand-break foci yet remained apoptosis resistant. These cells displayed features of metabolic-stress remodeling, including mitochondrial hyperpolarization, increased reactive oxygen species production, and enhanced mitochondrial biogenesis. Spatial transcriptomics and subsequent biochemical analyses identified activation of a PERK/ATF4/FOXO1 axis, characterized by PERK phosphorylation, selective ATF4 translation, FOXO1 nuclear translocation, and induction of downstream antioxidant and metabolic programs. In contrast, fibroblasts from post-ASCT patients exhibited normalization of DNA-damage markers and mitochondrial parameters without ATF4/FOXO1 activation. Pharmacologic inhibition of either PERK or FOXO1 selectively restored mitochondrial-dependent apoptosis in dcSSc fibroblasts, demonstrating that this axis is required for their survival following extensive genomic injury. dcSSc fibroblasts persist despite substantial genomic injury by engaging a PERK/ATF4/FOXO1 metabolic-adaptation program that suppresses mitochondrial-dependent apoptosis. This survival axis is not present after ASCT. Targeting PERK or FOXO1 restores apoptosis selectively in dcSSc fibroblasts, highlighting its potential use as a therapeutic target for eliminating pathogenic senescence-like fibroblasts in dcSSc. Both ex-vivo skin and in-vitro primary dermal fibroblasts derived from dcSSc patients have a higher frequency of intrinsic DNA damage signals and senescence-associated features; yet they evade mitochondrial-dependent apoptosis. Pathogenic dcSSc fibroblasts rewire their metabolism, characterized by mitochondrial hyperpolarization and elevated ROS. Spatial transcriptomics and functional analyses reveal a PERK/ATF4/FOXO1 stress-adaptation axis that drives fibroblast survival in dcSSc. This maladaptive survival program characterized by increased genotoxic stress, and mitochondrial remodelling is absent in post-ASCT fibroblasts. Targeting PERK or FOXO1 selectively sensitizes dcSSc fibroblasts to apoptosis revealing a potential promising therapeutic strategy in dcSSc.

Objective Current guidelines recommend immunosuppressive treatment for diffuse cutaneous systemic sclerosis but are less clear on their use in limited cutaneous systemic sclerosis (lcSSc) in the absence of internal organ complications. We conducted an international survey to understand current immunosuppressive drug prescribing patterns in lcSSc.Methods An electronic REDCap survey was distributed to 756 general rheumatologists and 250 national and international SSc experts.Results A total of 139 participants (14%) responded to the survey (94% were rheumatologists); 58% of respondents reported at least sometimes using immunosuppressive drugs to treat cutaneous symptoms in lcSSc, whereas 42% rarely or never did. Conversely, only 21% reported at least sometimes prescribing immunosuppression to prevent future complications in lcSSc, whereas 79% rarely or never did. Over 70% of respondents indicated that they would likely treat lcSSc in the presence of tendon friction rubs, new areas of skin thickening, increasing modified Rodnan skin scores (mRSSs), or mRSSs of 15 and above. Close to half would likely prescribe immunosuppression in the presence of mRSS of 10 to 14, anti-topoisomerase I antibodies, or anti-RNA polymerase III antibodies. Interestingly, a majority of respondents would likely treat lcSSc in the presence of subclinical organ involvement, including subclinical myocardial, muscle, joint, and lung disease. The top first-line drugs of choice were mycophenolate mofetil (47%), methotrexate (28%), and hydroxychloroquine (20%).Conclusion This international survey highlights significant heterogeneity among rheumatologists in the use of immunosuppressive drugs in lcSSc. High-quality research is needed to guide and harmonize the approach to management in lcSSc.

Objectives Pain, fatigue, anxiety and depression are common in new RA and may predict worse outcomes. We compared the likelihood of biologics/JAKi use by 12 and 24 months by pain, fatigue, anxiety, and depression status at diagnosis and after 3 months of MTX. Methods We evaluated new RA patients in the Canadian Early Arthritis Cohort (CATCH) between 1/17-8/22 with active disease and on MTX. Participants underwent assessments and completed PROMIS-29 at 0 and 3 months. Anxiety, depression, fatigue, and pain interference were defined as PROMIS ≥55. Multivariable logistic regression and ROC curves at baseline and 3 months were adjusted for CDAI, age, sex, race, education, smoking, obesity, comorbidities, serology, and symptom duration. Results 255 adults had a mean (SD) age of 56(14), and were mostly women (69%), White (78%) with a CDAI of 30(14) at diagnosis. All started MTX monotherapy [55%] or with csDMARDs [45%]. At 3 months, mean CDAI improved substantially; 41% were classified as anxious (Table). Mean Pain, Fatigue, Anxiety and Depression scores were 8-15 points higher in anxious vs non-anxious patients. By 12 months, >2X as many patients who were anxious at 3 months were on advanced therapies (15% vs 7%); a similar trend was observed at 24 months (18% vs 10%). However, the proportion of patients on advanced therapies was similar by pain interference, fatigue, or depression status at 3 months. The optimal multivariable model for predicting advanced therapy use by 12 months included Anxiety status and CDAI at 3 months after adjustment for covariates (ROC=0.84). Patients who were anxious at 3 months had 5.1 the odds (95% CI 1.4, 18.2) of being on advanced therapy at 1 year, with a similar trend at 24 months (OR 3.0; 95% CI 1.1, 8.2). In contrast, Depression, Pain, and Fatigue status at 3 months was not associated with a greater likelihood of advanced therapy use by 12 and 24 months. Characteristics of new RA Patients by anxiety status at 3 months.* Conclusion In CATCH, 41% reported anxiety at 3 months even after a robust response to treatment. A novel finding is that Anxiety at 3 months (but not pain, fatigue, or depression) predicted worse CDAI, PROs and 3-5 times greater odds of advanced therapy use by 12 and 24 months. Anxious patients may be more likely to advocate for a treatment change; anxiety may also reflect a greater impact of social determinants of health. Better understanding of anxiety in early RA may help improve QOL and support treatment decision making.

OBJECTIVE:The objective is to describe and compare demographic, clinical, and serological characteristics of patients with systemic sclerosis (SSc) according to ethnic background. METHODS:Participants enrolled in the Canadian Scleroderma Research Group cohort who self-identified to a single ethnicity group were included. Baseline characteristics were compared using analysis of variance, chi-square, or Kruskal-Wallis rank sum test. Kaplan-Meier curves and Cox regression were used to estimate mortality. RESULTS:Of 1,477 eligible participants, 1,345 (91.1%) identified as White, 55 (3.7%) as Indigenous, 22 (1.5%) as East/Southeast Asian, 20 (1.4%) as Middle Eastern, 16 (1.1%) as Black, 12 (0.8%) as South Asian, and 7 (0.5%) as Latin American. White individuals had a lower prevalence of diffuse cutaneous SSc (33% vs 53%) and telangiectasias (44% vs 67%) compared with other ethnicities. Conversely, Black individuals had a higher prevalence of myositis (44% vs 10%), higher mean modified Rodnan skin score (18.4 vs 9.6), lower mean forced vital capacity (73.7% predicted vs 92.9% predicted) and DLco values (54.5% predicted vs 70.6% predicted), and the lowest survival probabilities at one (85%) and five years (57%). Indigenous individuals had the highest prevalence of anti-RNA polymerase III antibodies (34% vs 19%) and were more frequently affected by lower gastrointestinal manifestations. East/Southeast Asian individuals were the least frequently affected by Raynaud phenomenon (90%) and digital ulcers (29%). CONCLUSION:Ethnicity was associated with distinct SSc phenotypes. These differences provide prognostic information that can guide screening and management strategies, thus representing an opportunity to personalize care.

Objectives In the first phase of this study, 4 adapted definitions of difficult-to-treat rheumatoid arthritis (D2T-RA) were evaluated within the Ontario Best Practices Research Initiative (OBRI), differing by criteria for treatment failure, active or symptomatic disease, and clinician perception (Figure). These definitions showed heterogeneity in prevalence, with broader definitions capturing patients with higher disease activity and worse function. Building on those findings, this analysis examined baseline clinical and demographic characteristics associated with D2T-RA and assessed whether similar predictors emerged across the 4 definitions. Figure. Comparative framework and predictive performance of four adapted definitions of difficult-to-treat rheumatoid arthritis (D2T-RA) . The left panel outlines the criteria used in each definition, while the right panel displays receiver operating characteristic (ROC) curves from multivariable logistic regression models predicting D2T-RA status. Model discrimination was fair across definitions (AUC 0.66-0.71). Abbreviations: b/tsDMARD, biologic targeted synthetic DMARD; CDAI, Clinical Disease Activity Index; DAS28. Disease Activity Score-28; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; HAQ, Health Assessment Questionnaire; MD, physician; PT, patient. Methods Data were derived from the Ontario Best Practices Research Initiative (OBRI), a longitudinal, real-world registry of patients with rheumatoid arthritis (RA). Multivariable logistic regression analyses were conducted among participants with established RA who initiated their first advanced therapy (biologic or targeted synthetic DMARD) after enrollment. Candidate predictors were identified a priori based on existing literature encompassing demographic, clinical, serologic, and treatment-related variables. Separate regression models were developed for each of the 4 adapted definitions of D2T-RA. Results A total of 507 patients were included in the complete case analysis. The mean (SD) age was 56.9 (12.2) years, the mean disease duration was 7.6 (9.1) years, and 80.3% were female. The prevalence of difficult-to-treat RA (D2T-RA) ranged from 5.7% (Definition 4) to 14.4% (Definition 2). In multivariable models, female sex independently predicted D2T-RA under Definitions 2 (OR 2.46, 95% CI 1.10-5.49) and 3 (OR 3.42, 95% CI 1.11-10.5), and higher HAQ-pain scores were consistently associated with D2T-RA across inclusive definitions (OR 1.60-2.00, p < 0.05). Radiographic erosions were significant only under Definition 3 (OR 2.03, 95% CI 1.02-4.03). No predictors reached significance for the restrictive Definition 4 aside from borderline methotrexate use (p = 0.053). Disease duration, seropositivity, smoking, obesity, and baseline disease activity were not independently associated with D2T-RA. Model performance was fair across definitions (AUC 0.68-0.74) (Figure). Conclusion Female sex and higher pain-related functional impairment consistently predicted D2T-RA across the more inclusive definitions, suggesting that sex/gender considerations and pain perception are important factors to consider in treatment refractoriness. In contrast, restrictive definitions based solely on treatment count demonstrated limited discriminative value. These findings suggest that adapted D2T-RA definitions capture different facets of the disease spectrum, and their use should be guided by the specific clinical or research context—whether the goal is to identify persistent refractory inflammatory disease or to characterize the broader, multidimensional burden encountered in real-world practice.