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.

Objective To evaluate the clinical effectiveness of sodium glucose cotransporter 2 (SGLT2) inhibitors in reducing the risk of hospital admission for heart failure and mortality in a contemporary nationwide cohort of patients with heart failure with preserved ejection fraction (HFpEF).Design Nationwide cohort study (REFINE-HFpEF).Setting 170 veteran health medical centres across the US, 1 January 2014 to 31 December 2021.Participants 2177 patients with type 2 diabetes and HFpEF; 1129 patients were newly prescribed SGLT2 inhibitors and 1048 were newly prescribed dipeptidyl peptidase 4 (DPP4) inhibitors or sulfonylureas.Main outcome measures The primary outcome was a composite of all cause mortality and hospital admission for heart failure. Secondary outcomes included all cause mortality only and serial changes in body weight. Hazard ratios were derived from Cox proportional hazards models, incorporating inverse probability of treatment weighting based on propensity scores to account for confounding.Results From a validated cohort of 179 288 patients with type 2 diabetes and HFpEF, the study included 1129 new users of SGLT2 inhibitors (active treatment) and 1048 new users of DPP4 inhibitors or sulfonylureas (comparators). After a median follow-up of 2.63 years, 46.4% of the study population had at least one hospital admission for heart failure (n=1011) and the overall mortality rate was 45.9% (n=1000). Use of SGLT2 inhibitors was associated with a relative risk reduction in the primary composite outcome of 18% compared with the use of DPP4 inhibitors or sulfonylureas (hazard ratio 0.82, 95% confidence interval 0.70 to 0.96; P=0.01). The adjusted hazard ratio for all cause mortality only was 0.73 (0.60 to 0.89; P=0.002). Weight loss was similar in the two groups.Conclusions In this large, contemporary, nationwide cohort of patients with HFpEF, type 2 diabetes, and high event rates, starting SGLT2 inhibitors was associated with a significantly lower risk of hospital admission for heart failure and all cause mortality compared with starting treatment with DPP4 inhibitors or sulfonylureas.

Objectives Diffuse cutaneous Systemic Sclerosis (dcSSc) is a life-limiting autoimmune disease with minimal treatment options. Autologous hematopoietic stem cell transplantation (ASCT) is a potent disease-modifying therapy in dcSSc; however, its effects on fibroblasts are unknown. We recently showed that dermal fibroblasts (DFs in patients with dcSSc develop a cancer-like phenotype characterized by genomic instability and increased double-stranded DNA breaks (DSBs).[1] However, little is known about the mechanisms promoting DF survival following the accumulation of genomic mutations. We hypothesized that in dcSSc DF genomic instability results in the accumulation of genomic mutations; and that this results in the activation of Protein Kinase R-like ER Kinase (PERK) and transcription of forkhead box1 (FOXO1) promoting resistance-to-apoptosis and fibrosis (Figure 1). Methods We used whole exome sequencing (WES) to characterize the mutational frequencies and their associated signatures in dcSSc patients who did not undergo ASCT (dcSSc, N=35) and those who did (post-ASCT, N=9). We also generated DFs from dcSSc, post-AHSCT (or age/sex matched healthy controls (HC), (N=8-10 patients/group), and quantified the frequency of DSBs via γ-H2AX levels (immunoblot (IB)), and DSB nuclear foci (confocal microscopy). We measured the relative ROS levels, mitochondrial membrane potential, and phospho-PERK (active) in DFs to mechanistically link DSB with PERK activation using flow cytometry and/or IB, respectively. We also determined the downstream effects of PERK activation on mitochondria (eg, mitochondrial dynamics and biogenesis). Then, we measured FOXO1 activation via nuclear translocation, IB, and expression of its downstream mRNA target SOD2. Finally, mitochondrial-dependent resistance-to-apoptosis was determined at baseline, and following treatment with cyclophosphamide, a PERK or a FOXO1-inhibitor using TUNEL and cleaved caspase 9/3 levels (IB). Results dcSSc patients’ DFs had increased genomic instability and DSBs compared to patients treated with ASCT. dcSSc DFs had increased indicators associated with PERK activation (phospho-PERK, ROS, and mitochondrial membrane potential). This was associated with increased mitochondrial remodeling, mitochondrial biogenesis, and mitochondrial fusion. Importantly, FOXO1 was exclusively activated in dcSSc, but not HC or post-ASCT DFs. Inhibition of PERK or FOXO1 resulted in increased mitochondrial-dependent apoptosis. Conclusion Our study highlights a novel mechanism whereby genotoxic signals in dcSSc promote cell survival via a PERK/FOXO1-dependent axis and associated metabolic remodeling (Figure 1). It also provides mechanistic insights related to how changes to the mutational landscape reduce pro-fibrotic signals in DF after ASCT. Future studies targeting this dysregulated pathway may provide an additional rationale for exploring it therapeutically in patients with dcSSc. References [1.] Gniadecki R. J Autoimmun 2022;131:102847.

Objectives Diffuse cutaneous systemic sclerosis (dcSSc) is a life-limiting inflammatory disease characterized by progressive fibrosis, vasculopathy and immune dysfunction. Fibroblasts (FB) are the key drivers of fibrosis and adapt epigenetic changes that promote their activation, resistance to apoptosis, and release of pro-fibrotic mediators. Autologous stem cell transplantation (ASCT) is a disease-modifying therapy that improves fibrosis in some dcSSc patients - although its effects on restoring FB function(s) are unknown. We recently identified the cancer-associated glycan, polysialic acid (polySia), in skin sections from patients with dcSSc and polySia levels correlated with fibrosis which normalized post-ASCT.[1] We also showed that dermal sections from patients with dcSSc had increased genomic instability, double-stranded DNA breaks (DSB) and epigenetic activation of the transcription factor FOXO1. We hypothesized that FOXO1 may promote polySia expression to enhance fibrosis, and that targeting polySia may provide anti-fibrotic effects. Methods We measured polySia levels in sera from 22 patients with SSc using a specific polySia ELISA and correlated polySia levels with the severity of skin fibrosis using the modified Rodnan skin score (mRSS). We also used primary dermal FB from skin biopsies of healthy controls (HC, age/sex matched), less severe limited cutaneous SSc (lcSSc), dcSSc and post-ASCT patients (N=4-6/per group) and measured the frequency of DSBs, active (nuclear) FOXO1, and polySia levels using immunofluorescence/confocal microscopy and/or immunoblot (IB). We also quantified polySia, ST8SIA2 levels or pro-fibrotic markers (fibronectin and CTGF) using qRT-PCR and/or IB following FOXO1 pharmacological inhibition, ST8SIA2 knockdown via siRNA, or treatment with a polySia elongation inhibitor, 8-keto-Neu5Ac. Results Total polySia levels correlated with mRSS (p=0.007, rho=0.560) in SSc patients – highlighting its direct link with fibrosis in SSc. We also observed that FB from dcSSc had a 2-3-fold induction in polySia levels and ST8SIA2 expression compared to FB from lcSSc and age/sex matched HC (p=0.02). Importantly, post-ASCT FB had a substantial reduction in ST8SIA2 (p=0.04) and polySia levels. This was associated with increased DSBs and FOXO1 activation exclusively in dcSSc FB. Finally, FOXO1 inhibition, ST8SIA2 siRNA knockdown, or treatment with 8-keto-Neu5Ac resulted in a 1.9-fold reduction in pro-fibrotic markers and total polySia levels (Figure 1). Figure 1: A. Graphical abstract of proposed mechanism. In dcSSc fibroblasts, double-stranded DNA breaks activate the transcription factor FOXO1. Upon activation, FOXO1 upregulates the gene expression of the polySia synthetic enzyme ST8SIA2 , polySia, and fibrotic mediators such as CTGF and fibronectin, thereby promoting fibrotic remodelling and fibrosis in dcSSc. B. Confocal images showing polySia (green), cis-golgi marker GM130 (red), nucleus (DAPI, blue) in fibroblasts from HC, dcSSc and post-ASCT. C. Spearman correlation analysis comparing serum polySia to mRSS in SSc patients (n = 22). Conclusion Our study identifies a novel DSB/FOXO1/polySia pathway as a key driver of fibrosis in SSc. This axis may serve as a biomarker for disease progression and may be indicative of restoration of FB functions post-ASCT. We postulate that targeting the FOXO1/polySia pathway may provide a novel therapeutic approach in dcSSc. References [1.] Khan L. J Autoimmun 2023;140:103110.

Abstract Background VEXAS syndrome is a recently described X-linked somatic autoinflammatory syndrome which manifests with exaggerated hyperinflammation, an MDS-like syndrome, and probable immunodeficiency. Objective The objective of this study is to describe the clinical presentation and outcomes of patients with VEXAS syndrome with a focus on immunodeficiency and infectious complications. Methods We performed a retrospective case analysis of VEXAS patients seen in our center and a surrounding immunodeficiency and infectious complications. Results We identified five patients who were diagnosed with VEXAS syndrome between 2021 and 2023. All patients had autoinflammatory syndromes, UBA1 mutations, and characteristic vacuolization on bone marrow biopsy, while none met the criteria for MDS. Infectious complications were identified in all patients at the time of diagnosis. At presentation, patient 1 had Klebsiella pneumoniae bacteremia, patient 2 had disseminated nocardiosis, patient 3 had community acquired pneumonia (CAP), patient 4 had disseminated histoplasmosis, and patient 5 had CAP complicated by cavitary pulmonary lesions. Lymphocyte subset measurements revealed a reduced frequency of circulating effector T and B lymphocytes. All patients received corticosteroids and tocilizumab once infection was treated. Conclusion We identified severe infections in five patients associated with peripheral B and T cell depletion. UBA1-mutations may directly contribute to infection risk through monocyte dysfunction and lymphocyte depletion. Future research should aim to establish the utility of infection prophylaxis.

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.

Objective(S): To define the evolving role of serial transverse enteroplasty(STEP) in the surgical management of intestinal failure(IF) in patients with short bowel syndrome(SBS) especially among the adult population. Background: The current literature is lacking the rationale and long-term efficacy of STEP as a part of the multidisciplinary management of SBS-IF adult population. Methods: The study included a total of 64 total parenteral nutrition (TPN) dependent patients. The causes of SBS were wide-ranging with residual bowel length of 79+47 cm and plasma citrulline level of 22+12 umol/L. Partial or full colon was preserved in 56(88%) patients. STEP was primary in 32 patients and integrated with autologous gut reconstruction(AGR) in the remaining 32. Integrated STEP was technically feasible in 44% of the preoperative candidates. To assess the therapeutic benefits of integrated STEP, 32 of the contemporaneous AGR-only patients were statistically identified by propensity-score matching as control group. Results: With a mean follow-up of 35+24 months, the 64 study patients received a total of 81 STEP procedures. The 5-year disease-specific survival was 91% with a respective restored enteral autonomy (EA) rate of 80%. Compared to the matched control, integrated STEP significantly(P=0.02) enhanced the cumulative restoration of EA. The ASA comorbidity class IV was the only significant(P=0.05) survival risk factor. Preoperative TPN caloric requirements and total increment in bowel length were independent predictors of STEP-associated EA. Consequently, STEP was a significant predictor of restored EA among the overall SBS-IF patients. Conclusions: This study underscores the wide-applicability and long-term therapeutic efficacy of STEP among the SBS-patients including adults. Accordingly, the procedure should be increasingly utilized for all ages and promptly considered as an integral part of the SBS-IF management armamentarium.

Objectives Belimumab is an approved biologic therapy for active, autoantibody-positive SLE that has been shown to reduce disease activity, flare frequency, and glucocorticoid use, thereby preventing organ damage.[1] It is typically reserved for refractory disease but emerging evidence suggests earlier initiation of belimumab may lead to higher response rates, greater achievement of remission or low disease activity, and further reduction in glucocortoid use.[2] This cost-utility analysis evaluates the economic and health impacts of early vs delayed belimumab initiation for biologic-naïve adult patients with clinically active SLE, comparing direct medical costs and quality-adjusted life-years (QALYs). Methods A Markov model was developed to simulate disease progression over 5 years with monthly cycles from the U.S. payer perspective. Costs included drug acquisition, hospitalizations, outpatient care, and emergency visits, updated to 2024 USD. Transition probabilities, Euro-QoL-5D utility values, and healthcare resource utilization were derived from a targeted literature review. Patients began in a pre-treatment state and transitioned monthly between 4 health states: complete response (assessed by SLE Responder Index-4; SRI-4), partial response, non-response (did not meet SRI-4 and experienced a flare or treatment-emergent adverse event), and death. Patients in the early group had higher disease activity (3-point higher SLEDAI-2K) and higher glucocorticoid use (10mg/day more prednisone) at baseline relative to the delayed group. Early belimumab was defined as initiation within 2 years of diagnosis and delayed initiation followed failure of standard immunosuppressants. Results Early belimumab initiation provided an additional 0.09 QALYs at a cost savings of USD$8,639.48 per patient relative to delayed belimumab, yielding a favorable incremental cost-effectiveness ratio (ICER) of −USD$93,092.98/QALY, making it the dominant strategy. Sensitivity analyses identified utility values, flare rates, and SRI-4 response rates as key drivers (Figure 1). Early belimumab retained dominance across most parameter variations, though cost-effectiveness was attenuated in parameter extremes favoring delayed initiation. Conclusion Early initiation of belimumab in biologic-naïve adults with clinically active SLE is both clinically and economically advantageous, offering greater health benefits at a lower cost compared to delayed initiation. These findings support timely adoption of belimumab in appropriate patients and highlight the need to reform reimbursement policies that delay access. As mounting evidence across immune-mediated diseases supports early biologic intervention as disease-modifying, frameworks must evolve to recognize treatment timing as a critical driver of long-term outcomes.[3] This model highlights the potential of early belimumab to reduce morbidity, mitigate irreversible organ damage, and generate sustained value for patients and health systems. References [1.] Urowitz M. Arthritis Care Res (Hoboken) 2022;74:1822-8. [2.] Zhao Y. Rheumatology (Oxford) 2025;64:106-16. [3.] Mease P. ACR Open Rheumatol 2025;7:e70019.

Importance: Disease-modifying anti-rheumatic drugs (DMARDs) are the standard first-line therapy for psoriatic arthritis (PsA). Observational studies suggest earlier initiation is associated with superior achievement of minimal disease activity (MDA) and improved patient-reported outcomes, yet the long-term economic and health implications of treatment timing remain uncertain. We evaluated the cost-effectiveness of early versus delayed DMARD initiation in DMARD-naïve adults with PsA. Methods: This cost-utility analysis from a U.S. payer perspective was conducted using a state-transition (Markov) model with monthly cycles over a 15-year horizon and was informed by studies published from 2000 to 2025, identified through a targeted literature review. Adult DMARD-naïve PsA patients initiating conventional synthetic DMARDs (methotrexate), targeted synthetic DMARDs (tofacitinib or apremilast), or a biologic DMARD were modelled under two strategies: early initiation (≤1 year after diagnosis) and delayed initiation (>1 year). Patients transitioned among four health states: complete response (achieved sustained MDA), partial response (non-sustained MDA), non-response (did not meet MDA), and death. Primary outcomes included the incremental cost-effectiveness ratio (ICER) and incremental net monetary benefit (INMB). Uncertainty intervals (UIs) were derived from probabilistic sensitivity analyses. Findings: The simulated cohort included 1000 adults with a mean (SD) age of 53 (13) years at DMARD initiation. Early DMARD initiation provided an additional 0.56 (95% UI, 0.32 to 0.83) QALYs at an incremental cost of –USD$43,902.94 (95% UI, –USD$147,096.29 to USD$61,615.86) per patient relative to delayed initiation, yielding a favorable ICER of –USD$78,398.11/QALY. At a willing-to-pay threshold of USD$50,000/QALY, mean INMB was USD$71,902.94 (95% UI, –USD$36,663.51 to USD$176,658.91), with early initiation preferred in 90.6% simulations. Interpretation: Early DMARD initiation in DMARD-naive PsA adults was associated with improved long-term health outcomes at reduced costs. These findings support timely therapeutic intervention and reconsideration of reimbursement policies that may delay access to DMARDs.