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Abstract Background A consensus on digital ulcer (DU) definition in systemic sclerosis (SSc) has been recently reached (Suliman et al., J Scleroderma Relat Disord 2:115-20, 2017), while for their evaluation, classification and categorisation, it is still missing. The aims of this study were to identify a set of essential items for digital ulcer (DU) evaluation, to assess if the existing DU classification was useful and feasible in clinical practice and to investigate if the new categorisation was preferred to the simple distinction of DU in recurrent and not recurrent, in patients with systemic sclerosis (SSc). Methods DeSScipher is the largest European multicentre study on SSc. It consists of five observational trials (OTs), and one of them, OT1, is focused on DU management. The DeSScipher OT1 items on DU that reached ≥ 60% of completion rate were administered to EUSTAR (European Scleroderma Trials and Research group) centres via online survey. Questions about feasibility and usefulness of the existing DU classification (DU due to digital pitting scars, to loss of tissue, derived from calcinosis and gangrene) and newly proposed categorisation (episodic, recurrent and chronic) were also asked. Results A total of 84/148 (56.8%) EUSTAR centres completed the questionnaire. DeSScipher items scored by ≥ 70% of the participants as essential and feasible for DU evaluation were the number of DU defined as a loss of tissue (level of agreement 92%), recurrent DU (84%) and number of new DU (74%). For 65% of the centres, the proposed classification of DU was considered useful and feasible in clinical practice. Moreover, 80% of the centres preferred the categorisation of DU in episodic, recurrent and chronic to simple distinction in recurrent/not recurrent DU. Conclusions For clinical practice, EUSTAR centres identified only three essential items for DU evaluation and considered the proposed classification and categorisation as useful and feasible. The set of items needs to be validated while further implementation of DU classification and categorisation is warranted. Trial registration Observational trial on DU (OT1) is one of the five trials of the DeSScipher project (ClinicalTrials.gov; OT1 Identifier: NCT01836263, posted on April 19, 2013).

Systemic sclerosis is an autoimmune disorder which frequently affects the gastrointestinal tract. Anorectal dysfunction is common in systemic sclerosis and is manifested mainly by atrophy of internal anal sphincter. Faecal incontinence is the result of internal anal sphincter atrophy secondary to systemic sclerosis. In this study, we aimed to assess the internal anal sphincter in 17 patients with faecal incontinence and systemic sclerosis using anorectal manometry and endoanal ultrasound and compare them with an age and gender-matched control group without systemic sclerosis. Most patients have limited cutaneous systemic sclerosis. Majority of the patients with systemic sclerosis and faecal incontinence presented with symptoms of faecal leakage and urgency. Systemic sclerosis patients had low basal sphincter pressures. The mean thickness of internal anal sphincter in systemic sclerosis group was significantly lower than the control group (p < 0.001). Rectal sensation is preserved in systemic sclerosis. There was no difference in the mean thickness of the external anal sphincter between the two groups. To conclude internal anal sphincter is atrophic in systemic sclerosis resulting in decreased resting sphincter pressures and passive faecal leakage. Further investigations and studies are needed to determine the natural course of faecal incontinence in systemic sclerosis, associated risk factors and efficacy of therapeutic interventions., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2024.)

BACE1 is well-known for its role in the development of Alzheimer's disease. Recent publications, including our own, have demonstrated a role for this enzyme in other chronic diseases. The aim of this study was to investigate the role of BACE1 in the autoimmune disease systemic sclerosis (SSc). BACE1 protein levels were elevated in the skin of patients with SSc. Inhibition of BACE1 with small-molecule inhibitors or small interfering RNA blocked SSc and fibrotic stimuli-mediated fibroblast activation. Furthermore, we show that BACE1 regulation of dermal fibroblast activation is dependent on β-catenin and Notch signaling. The neurotropic factor brain-derived neurotrophic factor negatively regulates BACE1 expression and activity in dermal fibroblasts. Finally, sera from patients with SSc show higher β-amyloid and lower brain-derived neurotrophic factor levels than healthy controls. The ability of BACE1 to regulate SSc fibroblast activation reveals a therapeutic target in SSc. Several BACE1 inhibitors have been shown to be safe in clinical trials for Alzheimer's disease and could be repurposed to ameliorate fibrosis progression., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Raynaud's phenomenon (RP) is a symptom complex associated with digital vascular compromise. Our aim was to examine for clinically relevant differences between primary RP (PRP) and secondary RP (SRP) to connective tissue disease., Methods: We report cross-sectional results from the Patient Survey of experiences of Raynaud's Phenomenon (PASRAP), which aimed to explore the broad-ranging impact of RP. The survey was widely distributed online including via social medial. Participation was voluntary and responses were anonymous., Results: 1229 respondents completed PASRAP with self-reported RP: PRP 218 (17.7 %) and SRP 1011 (82.3 %) of which 903 (92.9 %) Systemic Sclerosis. The mean (SD) age was significantly lower in respondents with PRP (41.7 [11.8] vs 54.2 [12.4] years, P<0.0001). During attacks, more subjects with SRP reported cyanotic colour changes (92.2 % vs 86.5 %, P=0.0089). Patients with PRP experienced more pain (72.1 % vs 55.9 %, P<0.0001), numbness (80.3 % vs 69.4 %, P=0.0016), stinging/throbbing (93.4 % vs 80.8 %, P<0.0001), and tingling (84.0 % vs 77.5 %, P=0.0345). Only half of respondents' symptoms were adequately controlled by their current medication(s), more commonly in SRP (55.2 % vs 45.2 %, P=0.0084). There were important differences in the triggers, number, and seasonal variation of RP attacks., Conclusion: There are clinically relevant differences between PRP and SRP concerning the multifaceted lived patient experience of RP. Neurosensory symptoms are more common in PRP. Patients with SRP are older and present with more colour changes, overrepresented by cyanosis, and with less complete resolution of symptoms between attacks. These data provide novel insights for future RP clinical trial design., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Michael Hughes reports a relationship with Janssen Pharmaceuticals Inc, Certa Therapeutics that includes: board membership, funding grants, and speaking and lecture fees. John D Pauling reports a relationship with Boehringer Ingelheim, Astra Zenaca, Janssen, Sojournix Pharma, IsoMab and Permeatus Inc that includes: consulting or advisory and speaking and lecture fees. Francesco Del Galdo reports a relationship with Abbvie, AstraZeneca, Boehringer-Ingelheim, Capella Biosciences, Chemomab Therapeutics, Ergomed, GSK, Janssen, Mitsubishi-Tanabe that includes: consulting or advisory and funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Mycophenolate mofetil (MMF) is a mainstay for the treatment of systemic sclerosis (SSc). The occurrence and implications of MMF-related adverse events on drug retention rates in real life remain poorly defined. We aimed to determine the MMF retention rate and to investigate the causes and patterns of discontinuation, adverse events (AEs) and treatment options used after discontinuation., Methods: SSc patients who started MMF treatment underwent a retrospective longitudinal assessment for up to 5 years. We documented the incidence, predictors, and impacts of MMF treatment on gastrointestinal intolerance, infections, laboratory abnormalities, and cancer. Rescue strategies implemented after MMF discontinuation were recorded., Results: The 5-year MMF retention rate of 554 patients stood at 70.7% and 19.6% of them stopped MMF due to AEs. One out of every four patients experienced a dose reduction or discontinuation of MMF due to AEs, with gastrointestinal intolerance being the predominant cause. The 5-year cumulative incidence rates for gastrointestinal intolerance, cancer, severe infections, and laboratory toxicity leading to MMF discontinuation were 6.4%, 4.1%, 3.1%, and 2.1%, respectively. Lower respiratory tract was the most affected, with bacteria being the predominant causative agent. Intestinal and pulmonary circulation involvement were tied to elevated AE rates and MMF discontinuation. The most common approaches post-MMF cessation were "watch and wait" and switch to rituximab., Conclusions: MMF use in SSc appears to be limited by the occurrence of AEs, both in terms of persistence and dosing of the drug. Rescue options after MMF discontinuation are limited and many patients remain without immunosuppressant., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

This guideline was developed according to the British Society for Rheumatology Guidelines Protocol by a Guideline Development Group comprising healthcare professionals with expertise in SSc and people with lived experience, as well as patient organization representatives. It is an update of the previous 2015 SSc guideline. The recommendations were developed and agreed by the group and are underpinned by published evidence, assessed by systematic literature review and reinforced by collective expert opinion of the group. It considers all aspects of SSc including general management, treatment of organ-based complications, including cardiopulmonary, renal and gastrointestinal tract manifestations, as well as broader impact of disease. Whilst it is focused on adults with SSc we expect that the guideline will be relevant to people of all ages and expert input and review by paediatric rheumatologists and other relevant specialists considered where the guideline was, or may not be, applicable to young people with SSc and juvenile-onset disease. In addition to providing guidance on disease assessment and management the full guideline also considers service organization within the National Health Service and future approaches to audit of the guideline. The lay summary that accompanies this abstract can be found in Supplemental information 1., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Deubiquitylases (DUBs) play a pivotal role in cell signalling and are often regulated by homo- or hetero-interactions within protein complexes. The BRCC36 isopeptidase complex (BRISC) regulates inflammatory signalling by selectively cleaving K63-linked polyubiquitin chains on Type I interferon receptors (IFNAR1). BRCC36 is a Zn 2+ -dependent JAMM/MPN DUB, a challenging ubiquitin protease class for the design of selective inhibitors. We identified first-in-class DUB inhibitors that act as BRISC molecular glues (BLUEs). BLUEs inhibit DUB activity by stabilising a BRISC dimer consisting of 16 subunits. The BLUE-stabilised BRISC dimer is an autoinhibited conformation, whereby the active sites and interactions with the recruiting subunit SHMT2 are blocked. This unique mode of action leads to highly selective inhibitors for BRISC over related complexes with the same catalytic subunit, splice variants and other JAMM/MPN DUBs. Structure-guided inhibitor resistant mutants confirm BLUEs on-target activity in cells, and BLUE treatment results in reduced interferon-stimulated gene (ISG) expression in human peripheral blood mononuclear cells from Scleroderma patients, a disease linked with aberrant IFNAR1 activation. BLUEs represent a new class of molecules with potential utility in Type I interferon-mediated diseases and a template for designing selective inhibitors of large protein complexes by promoting protein-protein interactions instead of blocking them., Competing Interests: Competing interests E.Z., R.G., J.M.S., and F.S. are named co-inventors in a provisional patent application to use BRISC inhibitors as potential therapeutics. J.M.S. owns equity in Alliance Discovery, Inc and the Barer Institute, Inc, and consults for Syndeavor Therapeutics, Inc.

Background: Around the world, individuals are living longer, but an increased average lifespan does not always equate to an increased healthspan. With advancing age, the increased prevalence of ageing-related diseases can have a significant impact on health status, functional capacity, and quality of life. It is therefore vital to develop comprehensive classification and staging systems for ageing-related pathologies, diseases and syndromes. This will allow societies to better identify, quantify, understand, and meet the healthcare, workforce, wellbeing, and socioeconomic needs of ageing populations, while supporting the development and utilisation of interventions to prevent or to slow, halt or reverse the progression of ageing-related pathologies., Methods: The foundation for developing such classification and staging systems is to define the scope of what constitutes an ageing-related pathology, disease or syndrome. To this end, a consensus meeting was hosted by the International Consortium to Classify Ageing-Related Pathologies (ICCARP), on February 19 th , 2024, in Cardiff, UK, and was attended by 150 recognised experts. Discussions and voting were centred on provisional criteria that had been distributed prior to the meeting. The participants debated and voted on these. Each criterion required a consensus agreement of ≥70% for approval., Results: The accepted criteria for an ageing-related pathology, disease or syndrome were: Develops and/or progresses with increasing chronological age.Should be associated with, or contribute to, functional decline, or an increased susceptibility to functional decline.Evidenced by studies in humans., Conclusions: Criteria for an ageing-related pathology, disease or syndrome have been agreed by an international consortium of subject experts. These criteria will now be used by the ICCARP for the classification and ultimately staging of ageing-related pathologies, diseases and syndromes.

Background: Systemic sclerosis (SSc) is a heterogeneous disease, characterized by variable tissue and vascular fibrosis in the context of autoimmune activation. CCL24 (or Eotaxin2) has been shown to promote microangiopathic, proinflammatory, and profibrotic processes in preclinical models of SSc. Here, we study serum CCL24 levels in a real-life cohort of patients with SSc, to determine its distribution across disease features and its value in predicting disease progression and related mortality., Methods: Serum CCL24 was assessed in an observational cohort of consecutively enrolled patients with SSc. A high CCL24 cutoff was defined based on its distribution in a matched cohort of healthy controls. Disease progression and mortality were analyzed from the date of serum assessment., Results: Two-hundred thirteen consecutively enrolled patients with SSc were included in this analysis. Median disease duration was six years (interquartile range 3-14), 28.6% of patients presented with interstitial lung disease (ILD), 46.9% had digital ulcers, and 25.3% showed high CCL24 serum concentration. High-CCL24 patients were more frequently male and positive for anti-scl-70, with a diagnosis of ILD and synovitis (P < 0.05 for all). Notably, high-CCL24 patients had lower diffusion of carbon monoxide and higher prevalence of digital ulcers, telangiectasias, and calcinosis (P < 0.05 for all). In a longitudinal setting, high CCL24 was associated with greater lung function decline and with higher disease-related mortality., Conclusion: Serum CCL24 is a biomarker of disease severity across fibrotic and vascular disease manifestations. These data support the development of therapies targeting CCL24 as a novel comprehensive therapeutic target in SSc., (© 2024 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Purpose of Review: Identifying outcomes and clinical trial endpoints enabled the discovery of new inflammatory bowel disease (IBD) treatments. Herein, we describe efforts to advance the study of gastrointestinal (GI) manifestations in systemic sclerosis (SSc)., Recent Findings: Insights into the scope of the problem, as well as advancements in the measurement and treatment of SSc-GI, are underway. Proposed SSc esophageal endophenotypes are now defined, risk stratification methods are growing, and imaging and functional studies are now employed to guide therapeutic interventions. Additional progress is being made in characterizing the gut microbiome in patients with SSc. Research into the role of the immune response in the pathogenesis of SSc-GI disease is also ongoing, evolving simultaneously with the development of methods to facilitate data collection with real-time capture of diet, exercise, and medication data., Summary: Multidisciplinary teams are working to deepen our understanding of SSc-GI disease pathogenesis, to identify biomarkers for risk stratification and the assessment of disease activity, and to develop and validate outcomes and clinical trial endpoints to pave the way toward effective therapy for SSc-GI disease., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Systemic sclerosis (SSc) is a rare chronic multisystem autoimmune disease characterized by endothelial dysfunction, tissue hypoxia, and diffuse organ fibrosis. MRI provides a radiation free approach to noninvasively assess the key manifestations of SSc in multiple organs. The purpose of this review is to summarize recent advances in MRI techniques to provide diagnostic and prognostic information in patients with SSc., Recent Findings: MRI can probe processes that play a key role in the development of SSc-related complications, including neointima proliferation, fibrosis, and hypoxia. Feature tracking and parametric mapping MRI can detect cardiac involvement at the subclinical level. Contrast-free MRI angiography with Digital Artery Volume Index (DAVIX) assessment allow comprehensive assessment of hand involvement. T1 mapping and BOLD imaging can assess SSc effects on skeletal muscle, and lung MRI is becoming a key method for imaging of interstitial lung disease. As a new exciting application, the sodium content of the skin can be quantified by 23Na MRI reflective of glycosaminoglycan content., Summary: Recent advances in MRI provide a unique opportunity to study the key pathophysiologic processes and clinical manifestations of SSc in multiple organs noninvasively, which can pave the way for the development of effective therapies., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The gut microbiota is a complex ecosystem of microorganisms residing in the human gastrointestinal tract, playing a crucial role in various biological processes and overall health maintenance. Dysbiosis, an imbalance in the composition and function of the gut microbiota, is linked to systemic autoimmune diseases (SAD). Short-chain fatty acids (SCFAs), especially butyrate, produced by the gut microbiota through the fermentation of dietary fibers, play a significant role in immunomodulation and maintaining intestinal homeostasis. Butyrate is essential for colonocyte energy, anti-inflammatory responses, and maintaining intestinal barrier integrity. Studies show reduced butyrate-producing bacteria in SAD patients, suggesting that increasing butyrate levels could have therapeutic benefits. Butyrate's anti-inflammatory effects and its potential therapeutic role have been studied in rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, systemic sclerosis, and Behçet's disease. Despite promising in vitro and animal model results, human studies are limited, and the optimal strategies for modulating dysbiosis in SADs remain elusive. This review explores the current evidence on the immunoregulatory role of butyrate and its potential therapeutic effects in SAD.

Objectives: The type I interferon pathway is a promising target for treatment of patients with systemic sclerosis (SSc). Here, we describe the design of a multinational, randomised phase 3 study to Determine the effectiveness of the type I interferon receptor antibody, Anifrolumab, In SYstemic sclerosis (DAISY)., Methods: DAISY includes a 52-week double-blind, placebo-controlled treatment period, a 52-week open-label active treatment period, and a 12-week safety follow-up period. The patient population includes a planned 306 adults with limited or diffuse cutaneous active SSc who satisfied American College of Rheumatology/European Alliance of Associations for Rheumatology 2013 SSc criteria. Use of standard immunosuppressants, including mycophenolate mofetil, at a stable dose prior to randomisation is permitted in addition to weekly subcutaneous anifrolumab or placebo. Efficacy will be assessed at Week 52 via Revised-Composite Response Index in SSc (CRISS)-25 response (primary endpoint). Lung function and skin thickness will be assessed via change from baseline in forced vital capacity in patients with SSc-associated interstitial lung disease and modified Rodnan Skin Score, respectively (key secondary endpoints)., Conclusions: The DAISY trial will evaluate the efficacy and safety of anifrolumab as a first-in-class treatment option for patients with both limited and diffuse cutaneous SSc and will provide insight into the contributions of type I interferon to SSc pathogenesis. Revised-CRISS-25 can account for improvement and worsening in a broad set of validated clinical measures beyond lung function and skin thickness, including clinician- and patient-reported outcomes, capturing the heterogeneity of SSc.

Rationale: Interstitial lung disease (ILD) in systemic sclerosis (SSc) is a common complication that has varied progression rate and prognosis. Different progression definitions are available: include minimal clinically important worsening of forced vital capacity (FVC MCIW), EUSTAR (EUropean Scleroderma Trials and Research group) progression, OMERACT (Outcome Measures in Rheumatology Clinical Trials) progression, and Erice ILD working group progression. Pulmonary function and symptoms changes may act as specific confounding factors applying these definitions in SSc., Objective: To assess the concordance and prognostic value of four different definitions in SSc-ILD patients overall and specific clinical groups., Methods: Progression status in consecutive SSc-ILD patients was assessed over 24 months, 60-month disease-related mortality risk was compared between progressors and non-progressors using the four definitions., Results: Among 245 patients, 26 SSc-related deaths were reported. Mortality was linked to progression for FVC MCIW (HR 2.27, 95% CI 1.03-4.97), OMERACT (HR 2.90, 95% CI 1.28-6.57), and Erice definitions (HR 11.02, 95% CI 2.38-51.08). The association between progression and mortality was poor in patients with disease duration ≥3 years, mild functional impairment, and pulmonary artery systolic pressure (PASP)≥40 mmHg. Erice criteria appeared superior in patients with duration ≥3 years, limited cutaneous variant, and PASP<40 mmHg. OMERACT criteria performed better in diffuse cutaneous variant patients with severe functional impairment., Conclusions: The four evaluated definitions of progression in SSc-ILD are not interchangeable, resulting in up to a third of cases being classified differently based on the adopted criteria, and presenting different prognostic values, particularly within specific clinical groups.

Background: Hypothesizing that early treatment yields improved prognosis, we aimed to investigate how the timing of immunosuppressive treatment relates to interstitial lung disease (ILD) development and the course of pulmonary function in systemic sclerosis (SSc)., Methods: A cohort was created using data from the EUSTAR database and Nijmegen Systemic Sclerosis cohort, including adult patients who started their first immunosuppressive treatment (ie mycophenolate mofetil, methotrexate, cyclophosphamide, tocilizumab or rituximab) after SSc diagnosis, and no signs of ILD on high-resolution CT. ILD-free survival and the course of forced vital capacity % predicted (ppFVC) were assessed for up to 5 years follow-up comparing patients who started early (disease duration ≤ 3 years) vs late with immunosuppression., Results: 1052 patients met the eligibility criteria. The early treatment group (n = 547, 52%) showed a higher prevalence of male sex, diffuse cutaneous subtype (53.1% vs 36.5%), and anti-topoisomerase-I antibody (ATA, 51.1% vs 42.7%). Most patients were treated with methotrexate (60.1%), whereas only a few patients were treated with biologicals (1.7%). The incidence of ILD was 46.6% after mean (SD) 3.6(1.4) years; the hazards ratio for ILD in the early treatment group was 1.13 (95% CI: 0.93-1.38) after adjustment for confounders. PpFVC trajectories were comparable between groups., Conclusion: Our findings did not confirm a preventive role of early initiation of immunosuppressive therapy vs late initiation on ILD development. However, our findings should be interpreted with caution, considering the high inflammatory, ATA-positive enriched nature of the cohort, confounding by indication, and very few patients were treated with biologicals., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Inflammatory rheumatic diseases are different pathologic conditions associated with a deregulated immune response, codified along a spectrum of disorders, with autoinflammatory and autoimmune diseases as two-end phenotypes of this continuum. Despite pathogenic differences, inflammatory rheumatic diseases are commonly managed with a limited number of immunosuppressive drugs, sometimes with partial evidence or transferring physicians' knowledge in different patients. In addition, several randomized clinical trials, enrolling these patients, did not meet the primary pre-established outcomes and these findings could be linked to the underlying molecular diversities along the spectrum of inflammatory rheumatic disorders. In fact, the resulting patient heterogeneity may be driven by differences in underlying molecular pathology also resulting in variable responses to immunosuppressive drugs. Thus, the identification of different clinical subsets may possibly overcome the major obstacles that limit the development more effective therapeutic strategies for these patients with inflammatory rheumatic diseases. This clinical heterogeneity could require a diverse therapeutic management to improve patient outcomes and increase the frequency of clinical remission. Therefore, the importance of better patient stratification and characterization is increasingly pointed out according to the precision medicine principles, also suggesting a new approach for disease treatment. In fact, based on a better proposed patient profiling, clinicians could more appropriately balance the therapeutic management. On these bases, we synthetized and discussed the available literature about the patient profiling in regard to therapy in the context of inflammatory rheumatic diseases, mainly focusing on randomized clinical trials. We provided an overview of the importance of a better stratification and characterization of the clinical heterogeneity of patients with inflammatory rheumatic diseases identifying this point as crucial in improving the management of these patients., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest for this work., (Copyright © 2024. Published by Elsevier B.V.)

Background: The 2022 European Society of Cardiology/European Respiratory Society guidelines define pulmonary hypertension (PH) as a resting mean pulmonary artery pressure (mPAP) > 20 mm Hg at right heart catheterization (RHC). Previously, patients with an mPAP between 21 and 24 mm Hg were classified in a "gray zone" of unclear clinical significance., Research Question: What is the diagnostic performance of the main parameters used for PH screening in detecting patients with systemic sclerosis (SSc) with an mPAP of 21 to 24 mm Hg at RHC?, Study Design and Methods: Patients with SSc from the European Scleroderma Trials and Research (EUSTAR) database with available tricuspid annular plane systolic excursion (TAPSE), systolic PAP (sPAP), and mPAP data were included. Patients with mPAP 21 to 24 mm Hg and patients with mPAP ≤ 20 mm Hg were considered for the analysis. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated., Results: TAPSE/sPAP was lower in the group of patients with SSc with mPAP 21 to 24 mm Hg than in the non-PH group (0.58 [0.46-0.72] vs 0.69 [0.57-0.81] mm/mm Hg, respectively; P < .01). No difference was found in other parameters between the two groups. Diffusing capacity of the lungs for carbon monoxide < 80% of the predicted value had the highest sensitivity (88.9%) and NPV (80%), but the lowest specificity (18.2%) and PPV (30.8%) in detecting patients with SSc with mPAP 21 to 24 mm Hg. TAPSE/sPAP < 0.55 mm/mm Hg had the highest specificity (78.9%), PPV (50%), and accuracy (68.1%); its NPV was 75.4%, and its sensitivity was 45.1%., Interpretation: In this study, diffusing capacity of the lungs for carbon monoxide < 80% of the predicted value was the parameter with the highest sensitivity and NPV in detecting patients with SSc with mPAP 21 to 24 mm Hg. TAPSE/sPAP < 0.55 mm/mm Hg had the highest specificity, PPV, and accuracy and, therefore, can be a useful additional parameter to decrease the number of unnecessary RHCs., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: V. S. is senior clinical investigator of the Research Foundation—Flanders (Belgium): (FWO) (1.8.029.20N). This funding source had no role in the literature review and the synthesis and interpretation of the data; in the writing of the report; or in the decision to submit the paper for publication. C. B. received grants from Boehringer-Ingelheim, consulting fees from Janssen, honoraria for lectures from Novartis, and travel grants from Kyverna, which were not related to this project. E. Z. received speaking and lecture fees from Janssen and consulting fees from Janssen and GSK. F. I. received honoraria and speaking fees from AbbVie, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, and UCB outside this work. C. P. S. A. received consulting fees and support for attending meetings from Janssen-Cilag SAS, Boehringer Ingelheim Ltd and MSD. None declared (A. C., E. H., C. P., G. R., J. H., D. L., A. M., A. M. G., M.-E. T., S. O., M. V., F. D. G., E. R.)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

In SSc, dystrophic calcinosis is one of the major clinical manifestations, characterized by the deposition of insoluble calcific substances in tissues, predominantly in the chemical form of calcium hydroxyapatite. Furthermore, calcinosis might lead to compressive neuropathies and severe pain. Current evidence suggests that tissue ischemia and repeated trauma are implicated in the development of calcinosis; however, there are still too many unknown areas that need to be investigated. Detection of calcinosis is commonly performed using X-ray or ultrasound. Moreover, quantification of calcinosis with X-ray and dual-energy computed tomography might be useful for the assessment of disease burden and monitoring of the disease. Despite its prevalence and clinical outcomes, there are no approved disease-modifying treatments for calcinosis in SSc. Debulking or surgical intervention might be preferred for calcinosis complicated with infection, compressive symptoms, or relief of pain. Therefore, innovative investigations and tailored therapeutic approaches are urgently needed to lift the burden of calcinosis from the hands of SSc patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: The objectives were to explore rheumatologists' current clinical screening practices of pulmonary arterial hypertension in patients with systemic sclerosis in the United Kingdom and to identify barriers to screening and consider potential solutions., Methods: A survey of 31 questions was developed and included six sections: clinician demographics, the importance of screening, screening practices, barriers to screening, treatment and patient education. The survey was disseminated among rheumatologists working in the United Kingdom., Results: Forty-four rheumatologists working in the United Kingdom participated in the study, and the majority completed all the questions. Around one-third (37.0%) worked in specialised systemic sclerosis units (university or general hospitals (54.5% and 45.4%, respectively)). The majority recognised that systemic sclerosis-pulmonary arterial hypertension is a major cause of morbidity and mortality. Over half (60.0%) reported using the DETECT algorithm to screen for systemic sclerosis-pulmonary arterial hypertension, although other algorithms were also sometimes used. All of the respondents utilised transthoracic echocardiogram, and almost all (95.0%) performed pulmonary function tests for screening purposes. Various challenges and barriers were identified relating to systemic sclerosis-pulmonary arterial hypertension screening, with the difficulty in interpreting results from other hospitals and extended wait times for diagnostic tests being the most reported (76.0% and 74.0%, respectively). Most respondents agreed that access to key investigations (87.0%), ongoing clinician education (82.0%), multidisciplinary meetings (79.5%) and a better understanding of proposed screening algorithms (79.5%) could be potential solutions., Conclusion: Screening patients with systemic sclerosis for pulmonary arterial hypertension is crucial to improve survival, but variable practices exist among UK rheumatologists. Solutions include educating healthcare professionals on guidelines, sharing information between centres and integrating care services., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: M.P.A.-H.: none. Y.A.: speaking fees from Janssen outside the submitted work. I.A.: honoraria (speaker) fees, scientific board member for EchoRight and advisory board participant for ‘Pulmonary hypertension in the primary care setting’ for Janssen, outside the submitted work. M.H.B.: speaker fees from Boehringer Ingelheim, outside the submitted work. G.C.: consultancy and working groups’ fees from Janssen and MSD; honoraria from Inari and Janssen; grants from Janssen. F.D.G.: consulting fees and research support from Janssen, outside the submitted work. C.P.D.: consulting fees and research support from Janssen, outside the submitted work. D.K.: consultant: Amgen, AbbVie, BI, AZ, Merck, Horizon, Prometheus, Janssen, GSK; grants: Pfizer, BI and Horizon. D.G.K.: has received payment for participation in advisory boards, steering committees, speaker fees and support to attend educational meetings from Acceleron, Gossamer, GSK, Janssen, Ferrer, MSD and United Therapeutics; he has received grant funding from GSK and Janssen. His work is supported by a grant from the NIHR Biomedical research Centre Sheffield. J.D.P.: consultancy work for AstraZeneca, Boehringer Ingelheim, IsomAb, Janssen, Permeatus and Sojournix; speaker honoraria and educational support from Janssen. S.R.: consulting fees from Janssen, outside the submitted work. M.H.: speaking fees from Actelion, Eli Lilly, Janssen and Pfizer, outside the submitted work; research funding from Janssen; member of a data and safety monitoring board for Certa Therapeutics., (© The Author(s) 2024.)

Oral and dental manifestations of scleroderma are extremely common, yet they are often overlooked within rheumatology and poorly understood within dentistry. Previous research has indicated the need to understand the oral and dental experiences of people living with scleroderma and those involved in their care. This scoping review aims, for the first time, to comprehensively map what is known regarding the identification and management of oral and dental manifestations of scleroderma, how these are experienced by people living with scleroderma, and to explore key characteristics of barriers and enablers to good oral and dental care in scleroderma. A scoping review was conducted using six databases (Embase, PubMed, PsychINFO, ASSIA, Scopus and SSCI), according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses - extension for Scoping Review. Grey literature was also included. Studies were eligible for inclusion if the full text and abstract were available in English, published between 2002 and 2022, and focused on the concept of oral and dental care in adults with scleroderma, either relating to identification and management, enablers and barriers to best practice, or patient experiences and well-being. Qualitative research which seeks to understand patients' lived experiences was a notable gap in the literature. Similarly, there was a significant lack of focus on the oral and dental manifestations of scleroderma in rheumatology. Three key features were identified which would facilitate best practice in research and clinical contexts: the necessity of multidisciplinary care; the necessity of centralising patient experience; and the necessity of mitigating barriers to dental care. We conclude that increased awareness of scleroderma within dentistry and streamlining referral procedures between the disciplines of dentistry and rheumatology, to enable the early identification and management of scleroderma, are crucial., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2023.)

Background: To perform a detailed morphological analysis of the inorganic portion of two different clinical presentations of calcium-based deposits retrieved from subjects with SSc and identify a chemical dissolution of these deposits suitable for clinical use., Methods: Chemical analysis using Fourier Transform IR spectroscopy ('FTIR'), Raman microscopy, Powder X-Ray Diffraction ('PXRD'), and Transmission Electron Microscopy ('TEM') was undertaken of two distinct types of calcinosis deposits: paste and stone. Calcinosis sample titration with ethylenediaminetetraacetic acid ('EDTA') assessed the concentration at which the EDTA dissolved the calcinosis deposits in vitro., Results: FTIR spectra of the samples displayed peaks characteristic of hydroxyapatite, where signals attributable to the phosphate and carbonate ions were all identified. Polymorph characterization using Raman spectra were identical to a hydroxyapatite reference while the PXRD and electron diffraction patterns conclusively identified the mineral present as hydroxyapatite. TEM analysis showed differences of morphology between the samples. Rounded particles from stone samples were up to a few micron in size, while needle-like crystals from paste samples reached up to 0.5 µm in length. Calcium phosphate deposits were effectively dissolved with 3% aqueous solutions of EDTA, in vitro. Complete dissolution of both types of deposit was achieved in approximately 30 min using a molar ratio of EDTA/HAp of ≈ 300., Conclusions: Stone and paste calcium-based deposits both comprise hydroxyapatite, but the constituent crystals vary in size and morphology. Hydroxyapatite is the only crystalline polymorph present in the SSc-related calcinosis deposits. Hydroxyapatite can be dissolved in vitro using a dosage of EDTA considered safe for clinical application. Further research is required to establish the optimal medium to develop the medical product, determine the protocol for clinical application, and to assess the effectiveness of EDTA for local treatment of dystrophic calcinosis., (© 2024. The Author(s).)

Introduction: Digital ulcers (DUs) significantly impact on quality of life and function in patients with systemic sclerosis (SSc). The aim of our survey was to explore patients' perspectives and their unmet needs concerning SSc-DUs., Materials: SSc patients were invited through international patient associations and social media to participate in an online survey., Results: 358 responses were obtained from 34 countries: US (65.6%), UK (11.5%) and Canada (4.5%). Recurrent DUs are common: >10 DUs (46.1%), 5-10 DUs (21.5%), 1-5 DUs (28.5%), 1 DU (3.9%). Fingertip DUs were most frequent (84.9%), followed by those overlying the interphalangeal joints (50.8%). The impact of DUs in patients is broad, from broad-ranging emotional impacts to impact on activities of daily living, and personal relationships. Half (51.7%) of respondents reported that they received wound/ulcer care, most often provided by non-specialist wound care clinics (63.8%). There was significant variation in local (wound) DU care, in particular the use of debridement and pain management. DU-related education was only provided to one-third of patients. One-quarter (24.6%) were 'very satisfied' or 'satisfied' that the provided DU treatment(s) relieved their DU symptoms. Pain, limited hand function, and ulcer duration/chronicity were the main reasons for patients to consider changing DU treatment., Conclusions: Our data show that there is a large variation in DU treatment between countries. Patient access to specialist wound-care services is limited and only a small proportion of patients had their DU needs met. Moreover, patient education is often neglected. Evidence-based treatment pathways are urgently needed for DU management., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The alveolar epithelial-to-mesenchymal transition is the process of transformation of differentiated epithelial cells into mesenchymal-like cells through functional and morphological changes. A partial epithelial-to-mesenchymal transition process can indirectly contribute to lung fibrosis through a paracrine stimulation of the surrounding cells, while a finalized process could also directly enhance the pool of pulmonary fibroblasts and the extracellular matrix deposition. The direct demonstration of alveolar epithelial-to-mesenchymal transition in scleroderma-related interstitial lung disease is challenging due to technical pitfalls and the limited availability of lung tissue samples. Similarly, any inference on epithelial-to-mesenchymal transition occurrence driven from preclinical models should consider the limitations of cell cultures and animal models. Notwithstanding, while the occurrence or the relevance of this phenomenon in scleroderma-related interstitial lung disease have not been directly and conclusively demonstrated until now, pre-clinical and clinical evidence supports the potential role of epithelial-to-mesenchymal transition in the development and progression of lung fibrosis. Evidence consolidation on scleroderma-related interstitial lung disease epithelial-to-mesenchymal transition would pave the way for new therapeutic opportunities to prevent, slow or even reverse lung fibrosis, drawing lessons from current research lines in neoplastic epithelial-to-mesenchymal transition., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2023.)

Background and Objectives: In SSc, ILD is a major cause of morbidity and mortality. We aimed to investigate the performance of DLCO (diffusing capacity of lung carbon monoxide) and FVC (forced vital capacity) delta change (Δ) and baseline values in predicting the development of SSc-ILD., Methods: Longitudinal data of DLCO, FVC, and ILD on the HRCT of SSc patients from the EUSTAR database were evaluated at baseline (t 0 ) and after 12 (±4) (t 1 ) and 24 (±4) (t 2 ) months., Results: 474/17805 patients were eligible for the study (403 females); 46 (9.7%) developed ILD at t 2 . Positivity for anti-topoisomerase antibodies (117 patients) showed an association with ILD development at t 2 ( p = 0.0031). Neither the mean t 0 to t 1 change (Δ) of DLCO nor the mean t 0 to t 1 FVCΔ predicted the appearance of ILD at t 2 . Investigating the possible role of baseline DLCO and FVC values in predicting ILD appearance after 24 (±4) months, we observed a moderate predictive capability of t 0 DLCO < 80%, stronger than that of FVC < 80%., Conclusions: We suggest that an impaired baseline DLCO may be predictive of the appearance of ILD after 2 years of follow-up. This result advances the hypothesis that a reduction in gas exchange may be considered an early sign of lung involvement. However, further rigorous studies are warranted to understand the predictive role of DLCO evaluation in the course of SSc.

Objective: Our objective was to test the hypothesis, in a double-blind, placebo-controlled study that vipoglanstat, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) which decreases prostaglandin E2 (PGE2) and increases prostacyclin biosynthesis, improves RP., Methods: Patients with systemic sclerosis (SSc) and ≥7 RP attacks during the last screening week prior to a baseline visit were randomised to four weeks treatment with vipoglanstat 120 mg or placebo. A daily electronic diary captured RP attacks (duration and pain) and Raynaud's Condition Score, with change in RP attacks/week as primary end point. Cold challenge assessments were performed at baseline and end of treatment. Exploratory endpoints included patients' and physicians' global impression of change, Assessment of Scleroderma-associated Raynaud's Phenomenon questionnaire, mPGES-1 activity, and urinary excretion of arachidonic acid metabolites., Results: Sixty-nine subjects received vipoglanstat (n = 33) or placebo (n = 36). Mean weekly number of RP attacks (baseline; vipoglanstat 14.4[SD 6.7], placebo 18.2[12.6]) decreased by 3.4[95% CI -5.8;-1.0] and 4.2[-6.5;-2.0] attacks per week (p= 0.628) respectively. All patient reported outcomes improved, with no difference between the groups. Mean change in recovery of peripheral blood flow after cold challenge did not differ between the study groups. Vipoglanstat fully inhibited mPGES-1, resulting in 57% reduction of PGE2 and 50% increase of prostacyclin metabolites in urine. Vipoglanstat was safe and well tolerated., Conclusion: Although vipoglanstat was safe, and well tolerated in a dose achieving full inhibition of mPGES-1, it was ineffective in SSc-related RP. Further development and evaluation of vipoglanstat will therefore be in other diseases where mPGES-1 plays a pathogenetic role., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Hand involvement is an early manifestation of systemic sclerosis (SSc), culprit of diagnosis and classification, and recognised major driver of disability. Impairment of hand function burdens both limited and diffuse cutaneous subsets and therefore could be targeted as 'basket' endpoint in SSc. Nevertheless, its natural history in current standard of care is not well characterised, limiting the design of targeted trials. The aim of this study is to describe prevalence, natural history and clinical factors associated with hand function deterioration in a longitudinal, multicentre, observational SSc cohort., Methods: Hand function was captured through the validated Cochin Hand Function Scale in patients consecutively enrolled in a multicentre observational study and observed over 24 months. Minimal clinically important differences and patient acceptable symptom state were analysed as previously described., Results: Three hundred and ninety-six consecutive patients were enrolled from 10 centres; 201 with complete follow-up data were included in the analysis. Median (IQR) disease duration was 5 (2-11) years. One hundred and five (52.2%) patients reported clinically significant worsening. Accordingly, the proportion of patients reporting unacceptable hand function increased over 2 years from 27.8% to 35.8% (p<0.001). Least absolute shrinkage and selection operator analysis identified male gender, disease subset, Raynaud's Condition Score, tenosynovitis and pain, as some of the key factors associated with worsening hand involvement., Conclusions: Hand function deteriorates over time in more than 50% of SSc patients despite available therapies. The analysis of factors associated with hand function worsening supports the involvement of both inflammation, vascular and fibrotic processes in hand involvement, making it a hallmark clinical manifestation of SSc. Our data are poised to inform the design of intervention studies to target this major driver of disability in SSc., Competing Interests: Competing interests: Direct or indirect interests that might affect or be perceived to affect the conduct or reporting of this work. EDL: nothing to declare, VK; nothing to declare, SDD: nothing to declare, MW: nothing to declare, TB: nothing to declare, CPD: nothing to declare, EDS: nothing to declare, KD: nothing to declare, PW: nothing to declare, AH: nothing to declare, BS: nothing to declare, MN: nothing to declare, CM: nothing to declare, LG: nothing to declare, BAP: nothing to declare, FDG: nothing to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Systemic sclerosis (SSc), or scleroderma, is a rare, complex, systemic autoimmune disease of unknown aetiology, characterized by high morbidity and mortality often resulting from cardiopulmonary complications such as interstitial lung disease and pulmonary arterial hypertension. Despite substantial progress in unravelling the pathways involved in the pathogenesis of SSc and the increasing number of therapeutic targets tested in clinical trials, there is still no cure for this disease, although several proposed treatments might limit the involvement of specific organs, thereby slowing the natural history of the disease. A specific focus of recent research has been to address the plethora of unmet needs regarding the global management of SSc-related interstitial lung disease, including its pathogenesis, early diagnosis, risk stratification of patients, appropriate treatment regimens and monitoring of treatment response, as well as the definition of progression and predictors of progression and mortality. More refined stratification of patients on the basis of clinical features, molecular signatures, identification of subpopulations with distinct clinical trajectories and implementation of outcome measures for future clinical trials could also improve therapeutic management strategies, helping to avoid poor outcomes related to lung involvement., (© 2023. Springer Nature Limited.)

Objective: The outcome of patients with COVID-19 improved over the pandemic, including patients with systemic rheumatic diseases. However, data on patients with systemic sclerosis (SSc) are lacking. This study aimed to assess the outcome of patients with both SSc and COVID-19 over several waves., Methods: Patients with both SSc and COVID-19 who were registered in the European Scleroderma Trials and Research group (EUSTAR) were collected between April 2020 and April 2021. Patients were assigned to waves 1, 2, or 3 depending on the date of their COVID-19 diagnosis. Primary endpoints were death, intensive care unit stay, or ventilatory support (severe outcome). Subgroup analyses of patients who were hospitalized or died were conducted. General and SSc-specific characteristics and treatment were compared over the waves. Descriptive statistics and multivariate logistic regression were applied., Results: A total of 333 patients were included; 57 patients (17%) had a severe outcome, and 30 patients (9%) died. Compared to wave 1, significantly fewer patients with SSc suffered from severe COVID-19 in waves 2 and 3 (28.2% vs 9.8% and 12.7%; P < 0.001), fewer patients required hospitalization (46.7% vs 19.6% and 25.5%; P < 0.001) or ventilatory support (24.0% vs 8.7% and 10.9%; P = 0.001), and fewer patients died (15.7% vs 5.0% and 7.5%; P = 0.011). Patients were significantly younger, more often men, had less frequent arterial hypertension, and less SSc cardiac involvement over waves 1 to 3. Patients received significantly less medium to high doses of corticosteroids as they did SSc treatment., Conclusion: The outcome of patients with both SSc and COVID-19 improved significantly over time because of intrinsic and extrinsic factors., (© 2023 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: Juvenile systemic sclerosis (SSc) is an orphan disease, associated with high morbidity and mortality. New treatment strategies are much needed, but clearly defining appropriate outcomes is necessary if successful therapies are to be developed. Our objective here was to propose such outcomes., Methods: This proposal is the result of 4 face-to-face consensus meetings with a 27-member multidisciplinary team of pediatric rheumatologists, adult rheumatologists, dermatologists, pediatric cardiologists, pulmonologists, gastroenterologists, a statistician, and patients. Throughout the process, we reviewed the existing adult data in this field, the more limited pediatric literature for juvenile SSc outcomes, and data from 2 juvenile SSc patient cohorts to assist in making informed, data-driven decisions. The use of items for each domain as an outcome measure in an open label 12-month clinical trial of juvenile SSc was voted and agreed upon using a nominal group technique., Results: After voting, the domains agreed on were global disease activity, skin, Raynaud's phenomenon, digital ulcers, musculoskeletal, cardiac, pulmonary, renal, and gastrointestinal involvement, and quality of life. Fourteen outcome measures had 100% agreement, 1 item had 91% agreement, and 1 item had 86% agreement. The domains of biomarkers and growth/development were moved to the research agenda., Conclusion: We reached consensus on multiple domains and items that should be assessed in an open label, 12-month clinical juvenile SSc trial as well as a research agenda for future development., (© 2023 American College of Rheumatology.)

Introduction: Over the years several lines of evidence have implied a pathological involvement of autonomic nervous system (ANS) in systemic sclerosis (SSc). However, the relationship between autonomic dysfunction and SSc is not yet fully understood. The aims of this scoping review were to map the research done in this field and inform future research to investigate pathogenic hypotheses of ANS involvement., Methods: We performed a scoping review of publications collected through a literature search of MEDLINE and Web of Science databases, looking for dysautonomia in SSc. We included original data from papers that addressed ANS involvement in SSc regarding pathogenesis, clinical presentation and diagnostic tools., Results: 467 papers were identified, 109 studies were selected to be included in the present review, reporting data from a total of 2742 SSc patients. Cardiovascular system was the most extensively investigated, assessing heart rate variability with 24 h HolterECG or Ewing's autonomic tests. Important signs of dysautonomia were also found in digital vasculopathy, gastrointestinal system and SSc skin, assessed both with non-invasive techniques and histologically. Research hypotheses mainly regarding the relationship between sympathetic system - ischemia and the role of neurotrophins were then developed and discussed., Conclusion: We described the currently available evidence on pathogenesis, clinical presentation and diagnostic assessment of dysautonomia in SSc patients. A strong influence of ANS deregulation on SSc clearly emerges from the literature. Future research is warranted to clarify the mechanisms and timing of autonomic dysfunction in SSc., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2023. Published by Elsevier Inc.)

The identification of individuals with systemic sclerosis in an oligosymptomatic phase preceding the very early manifestations of the disease represents a challenge in the search for a new window of opportunity in systemic sclerosis. This phase could be identified in a clinical scenario as the pre-scleroderma phase, in which the disease would still be far from systemic sclerosis-related fibrotic or irreversible manifestations in skin or organs. In this Personal View, we discuss parameters and candidate definitions for a conceptual framework of pre-scleroderma, from the identification of populations at risk to autoantibodies and their potential functional activities. We discuss how this new paradigm of pre-scleroderma could represent a game-changing approach in the management of systemic sclerosis, allowing the treatment of patients at high risk of organ involvement or skin fibrosis before such events occur., Competing Interests: Declaration of interests FDG declares grants and contracts from AbbVie and Boehringer Ingelheim. CPD declares grants and contracts from GSK, Horizon, Servier, and Arxx Therapeutics; consulting fees from Boehringer Ingelheim, Roche, CSL Behring, Acceleron, Horizon, Arxx Therapeutics, Centessa, AstraZeneca, Lilly, and Novartis; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Boehringer Ingelheim and Janssen. DK declares grants and contracts from BMS, Bayer, and Pfizer; consulting fees from AbbVie, Genentech, GSK, Boehringer Ingelheim, AstraZeneca, Horizon, UCB, and Prometheus; and participation on a data safety monitoring board or advisory board for AbbVie. MK declares grants and contracts from Boehringer Ingelheim; consulting fees from Boehringer Ingelheim, AstraZeneca, and GSK; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Boehringer Ingelheim, Chugai, and Janssen; and participation on a data safety monitoring board or advisory board for Argenx. M-ET declares consulting fees from Boehringer Ingelheim, AbbVie, and UCB; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Lilly, AbbVie, and UCB; and support for attending meetings and travel from Novartis and AbbVie. MMC declared payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Boehringer Ingelheim, Biogen, and Lilly. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Vascular fibrosis is a key manifestation of systemic sclerosis that leads to the narrowing of small and medium arteries, causing vascular clinical manifestations including digital ulcers and pulmonary arterial hypertension. We investigated the potential of the MRI-based Digital Artery Volume Index (DAVIX) as a surrogate outcome measure of vascular fibrosis by using it to quantify and predict the burden of digital ulcer disease in patients with systemic sclerosis., Methods: Two independent cohorts of patients participating in the prospective observational study STRIKE were consecutively enrolled from the Scleroderma Clinic of the Leeds Teaching Hospitals Trust, Leeds, UK. Eligible patients were aged 18 years or older and fulfilled the very early diagnosis of systemic sclerosis (VEDOSS) or the 2013 American College of Rheumatology (ACR)-European Alliance of Associations for Rheumatology (EULAR) systemic sclerosis classification criteria. DAVIX was calculated as the percentage mean of the ratio of digital artery volume to finger volume in the four fingers of the dominant hand. Data were collected at baseline and 12-month follow-up, and the primary outcome was the presence of digital ulcers at 12-month follow-up., Findings: Between Feb 7, 2018, and April 11, 2022, we included 85 patients in the exploratory cohort and 150 in the validation cohort. In the exploratory cohort, the mean age was 54·5 years (SD 11·6), 75 (88%) of 85 patients were women, ten (12%) were men, and 69 (82%) were White. In the validation cohort, the mean age was 53·5 years (SD 13·8), 136 (91%) of 150 patients were women, 14 (9%) were men, and 127 (85%) were White. In the exploratory cohort, DAVIX was significantly lower in patients with previous or active digital ulcers (0·34% [IQR 0·16-0·69]) than in those without digital ulcer disease (0·65% [0·42-0·88]; p=0·015); this finding was substantiated in the validation cohort (0·43% [0·20-0·73] vs 0·73% [0·53-0·97]; p<0·0001). Patients who developed new digital ulcers during 12-month follow-up had a lower DAVIX (0·23% [0·10-0·66]) than those who did not (0·65% [0·45-0·91]; p=0·0039). DAVIX was negatively correlated with disease duration (r=-0·415; p<0·0001), the ratio of forced vital capacity to the diffusing capacity of the lungs for carbon monoxide (r=-0·334; p=0·0091), nailfold capillaroscopy pattern (r=-0·447; p<0·0001), and baseline modified Rodnan skin score (r=-0·305; p=0·014) and was positively correlated with the diffusing capacity of carbon monoxide (r=0·368; p=0·0041). DAVIX was negatively correlated with change in score on the Scleroderma Health Assessment Questionnaire-Disability Index (r=-0·308; p=0·024), Visual Analogue Scale (VAS) Raynaud's (r=-0·271; p=0·044), and VAS digital ulcers (r=-0·291; p=0·044)., Interpretation: DAVIX is a promising surrogate outcome measure of digital ulcer disease in patients with systemic sclerosis. The ability of DAVIX to non-invasively predict future digital ulcers and worsening of patient-reported outcomes could aid patient enrichment and stratification in clinical trials. Clinically, DAVIX could offer insights into the assessment of vascular activity. The sensitivity of DAVIX to change over time and with treatment will establish its value as an imaging outcome measure of vascular disease., Funding: National Institute for Health Research Biomedical Research Centre and University of Leeds Industry Engagement Accelerator Fund., Competing Interests: Declaration of interests MH reports speaking fees from Actelion Pharmaceuticals, Eli Lilly, and Pfizer, outside of the submitted work and he is a member of a data and safety monitoring board for Certa Therapeutics. OK and JD are employees and shareholders of Image Analysis Group and co-developers of DAVIX. OK reports speaking fees from Takeda Pharmaceuticals and is on scientific advisory boards for Werfen and MiMedx. FDG reports consulting fees from Argenx, Arxx Therapeutics, AstraZeneca, Ergomed, GSK, Image Analysis Group, Janssen Pharmaceuticals, and Novartis and research support from AbbVie, AstraZeneca, Boehringer-Ingelheim, Capella Biosciences, Chemomab Therapeutics, and Mitsubishi Tanabe Pharma. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Although the painful and disabling features of early diffuse cutaneous SSc (dcSSc) have an inflammatory basis and could respond to corticosteroids, corticosteroids are a risk factor for scleroderma renal crisis. Whether or not they should be prescribed is therefore highly contentious. Our aim was to examine safety and efficacy of moderate-dose prednisolone in early dcSSc., Methods: PRedSS set out as a Phase II, multicentre, double-blind randomized controlled trial, converted to open-label during the Covid-19 pandemic. Patients were randomized to receive either prednisolone (∼0.3 mg/kg) or matching placebo (or no treatment during open-label) for 6 months. Co-primary endpoints were the HAQ Disability Index (HAQ-DI) and modified Rodnan skin score (mRSS) at 3 months. Over 20 secondary endpoints included patient reported outcome measures reflecting pain, itch, fatigue, anxiety and depression, and helplessness. Target recruitment was 72 patients., Results: Thirty-five patients were randomized (17 prednisolone, 18 placebo/control). The adjusted mean difference between treatment groups at 3 months in HAQ-DI score was -0.10 (97.5% CI: -0.29, 0.10), P = 0.254, and in mRSS -3.90 (97.5% CI: -8.83, 1.03), P = 0.070, both favouring prednisolone but not significantly. Patients in the prednisolone group experienced significantly less pain (P = 0.027), anxiety (P = 0.018) and helplessness (P = 0.040) than control patients at 3 months. There were no renal crises, but sample size was small., Conclusion: PRedSS was terminated early primarily due to the Covid-19 pandemic, and so was underpowered. Therefore, interpretation must be cautious and results considered inconclusive, indicating the need for a further randomized trial., Trial Registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT03708718., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Interstitial lung disease (ILD) is a significant cause of disability and mortality in systemic sclerosis (SSc), where lung fibrosis stems from the interaction of cells within the epithelial, endothelial, interstitial, and immune cell compartments. Extracellular vesicles (EVs) are particles released by cells capable of transferring functionally active molecules, playing a crucial role in intercellular communication. This scoping review aims to identify and map existing evidence about the role of EVs as biomarkers or pathophysiological actors in SSc-ILD. It also retrospectively assesses the compliance of published articles with the current reporting guidelines established by the International Society of Extracellular Vesicles (ISEV)., Methods: This scoping review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. The searches were conducted up until 31 May 2023, with no restrictions on the starting year., Results: Out of 778 publications identified and screened, 9 references were selected. The eligible studies collectively involved a total of 539 SSc patients, with 220 patients presenting with ILD, as demonstrated by high-resolution computed tomography. The studies largely focused on the quantitative assessment of EVs through flow cytometry, primarily concerning larger EVs. The studies primarily focused on the association of EV features with vascular complications, with fibrotic pulmonary involvement typically explored as a secondary finding. The evaluated patients' clinical characteristics were significantly heterogeneous across the studies as well as the association of EV features with the evidence of ILD but none of them longitudinally investigated the relationships with SSc-ILD prognosis. Adherence of these exploratory studies to ISEV reporting guidelines in terms of EV nomenclature, reporting of pre-analytic variables, and qualitative verification of EV separation products was incomplete., Conclusions: The evidence concerning the clinical association of EV features is limited and conflicting. The interpretation of available data is substantially biased due to patient selection tailored for vascular complications, heterogeneity of separation methodology, and a lack of validation procedures., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Importance: Systemic sclerosis (SSc) sine scleroderma (ssSSc) is a subset of SSc defined by the absence of skin fibrosis. Little is known about the natural history and skin manifestations among patients with ssSSc., Objective: To characterize the clinical phenotype of patients with ssSSc compared with patients with limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) within the EUSTAR database., Design, Setting, and Participants: This longitudinal observational cohort study based on the international EUSTAR database included all patients fulfilling the classification criteria for SSc assessed by the modified Rodnan Skin score (mRSS) at inclusion and with at least 1 follow-up visit; ssSSc was defined by the absence of skin fibrosis (mRSS = 0 and no sclerodactyly) at all available visits. Data extraction was performed in November 2020, and data analysis was performed from April 2021 to April 2023., Main Outcomes and Measures: Main outcomes were survival and skin manifestations (onset of skin fibrosis, digital ulcers, telangiectasias, puffy fingers)., Results: Among the 4263 patients fulfilling the inclusion criteria, 376 (8.8%) were classified as having ssSSc (mean [SD] age, 55.3 [13.9] years; 345 [91.8%] were female). At last available visit, in comparison with 708 patients with lcSSc and 708 patients with dcSSc with the same disease duration, patients with ssSSc had a lower prevalence of previous or current digital ulcers (28.2% vs 53.1% in lcSSc; P < .001; and 68.3% in dcSSc; P < .001) and puffy fingers (63.8% vs 82.4% in lcSSc; P < .001; and 87.6% in dcSSc; P < .001). By contrast, the prevalence of interstitial lung disease was similar in ssSSc and lcSSc (49.8% and 57.1%; P = .03) but significantly higher in dcSSc (75.0%; P < .001). Skin telangiectasias were associated with diastolic dysfunction in patients with ssSSc (odds ratio, 4.778; 95% CI, 2.060-11.081; P < .001). The only independent factor for the onset of skin fibrosis in ssSSc was the positivity for anti-Scl-70 antibodies (odds ratio, 3.078; 95% CI, 1.227-7.725; P = .02). Survival rate was higher in patients with ssSSc (92.4%) compared with lcSSc (69.4%; P = .06) and dcSSc (55.5%; P < .001) after up to 15 years of follow-up., Conclusions and Relevance: Systemic sclerosis sine scleroderma should not be neglected considering the high prevalence of interstitial lung disease (>40%) and SSc renal crisis (almost 3%). Patients with ssSSc had a higher survival than other subsets. Dermatologists should be aware that cutaneous findings in this subgroup may be associated with internal organ dysfunction. In particular, skin telangiectasias in ssSSc were associated with diastolic heart dysfunction.

Objective: The aim of the study was to evaluate the association between the tricuspid annular plane systolic excursion (TAPSE)/systolic pulmonary artery pressure (sPAP) ratio and estimated glomerular filtration rate (eGFR) and their association with mortality in the European Scleroderma Trials and Research (EUSTAR) cohort., Methods: Patients with systemic sclerosis (SSc) from the EUSTAR database with TAPSE, sPAP, and parameters required to calculate eGFR were included. Logistic regression and Cox regression analysis were performed to evaluate TAPSE/sPAP as a risk factor for chronic kidney disease (CKD) and overall survival., Results: A total of 2,370 patients with SSc were included; 284 (12%) patients had CKD stage 3a-5. TAPSE/sPAP (odds ratio [OR] 0.479; 95% CI 0.310-0.743; P < 0.001), arterial hypertension (OR 3.118; 95% CI 2.173-4.475; P < 0.001), diastolic dysfunction (OR 1.670; 95% CI 1.148-2.428; P < 0.01), and N-terminal pro-B-type natriuretic peptide (OR 1.165; 95% CI 1.041-1.304; P < 0.01) were associated with CKD stage 3a-5. TAPSE/sPAP ≤0.32 mm/mm Hg (hazard ratio [HR] 3.589; 95% CI 2.236-5.761; P < 0.001), eGFR <60 mL/min per 1.73 m 2 (HR 2.818; 95% CI 1.777-4.468; P < 0.001), and age (HR 1.782; 95% CI 1.348-2.356; P < 0.001) were the most significant predictive factors for all-cause mortality. A total of 276 patients with SSc had pulmonary hypertension (PH) confirmed by right heart catheterization, with 69 (25%) having CKD stage 3a-5. No difference was found in eGFR between patients with PH with reduced or normal cardiac index., Conclusion: Reduced TAPSE/sPAP ratio is independently associated with CKD. TAPSE/sPAP ratio ≤0.32 mm/mm Hg and eGFR <60 mL/min per 1.73 m 2 are prognostic factors for all-cause mortality. In patients with SSc with PH, eGFR is independent by reduced cardiac output., (© 2023 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Skin ultrasound has shown promising results in the evaluation of skin involvement in patients with systemic sclerosis, as substantiated by a recent systematic literature review from the World Scleroderma Foundation Skin Ultrasound Working Group. In this Viewpoint, we will discuss the role of ultrasound in evaluating skin involvement in patients with systemic sclerosis, particularly the possibility of using this technique to detect an early subclinical skin involvement from the very early phase, suggesting its possible use in both diagnosis and disease follow-up. To detect subclinical skin involvement, it is essential to understand the difference between the skin of patients with systemic sclerosis and that of healthy controls, including defining exactly which structures are affected by the disease and which are spared. The potential of this non-invasive technique might suggest its future role in both clinical practice and clinical trials, possibly replacing invasive and painful procedures such as skin biopsies and promoting patient retention in clinical trials., Competing Interests: Declaration of interests MH reports speaking fees from Actelion pharmaceuticals, Eli Lilly, Janssen, and Pfizer, outside of the submitted work; reports research funding from Janssen; and is a member of a data and safety monitoring board for Certa Therapeutics. YA reports grants from Alpine ImmunoSciences; consulting fees from Horizon, AstraZeneca, Boehringer Ingelheim, Janssen, Prometheus, Medsenic, Galderma, and AbbVie. CPD reports consulting fees from Arxx Therapeutics, Roche, Janssen, GlaxoSmithKline, Bayer, Sanofi, Galapagos, Boehringer Ingelheim, CSL Behring, AstraZeneca, and Acceleron. FDG reports consulting fees and research support from AbbVie, AstraZeneca, Boehringer Ingelheim, Chemomab, Janssen, and MitsubishiTanabe. DK reports grants from Bristol Myers Squibb, Horizon Therapeutics, and Pfizer; consulting fees from AstraZeneca, Boehinger Ingelheim, Bristol Myers Squibb, Chemomab, CSL Behring, Horizon Therapeutics, Janssen, Prometheus, Sanofi, Talaris, and Bauch Health. MMC reports participation on a data safety monitoring board or advisory board for Biogen, Gesynta, Chemomab, and Galapagos. All other authors report no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This guideline will provide a practical roadmap for management of SSc that builds upon the previous treatment guideline to incorporate advances in evidence-based treatment and increased knowledge about assessment, classification and management. General approaches to management as well as treatment of specific complications will be covered, including lung, cardiac, renal and gastrointestinal tract disease, as well as RP, digital vasculopathy, skin manifestations, calcinosis and impact on quality of life. It will include guidance related to emerging approved therapies for interstitial lung disease and account for National Health Service England prescribing policies and national guidance relevant to SSc. The guideline will be developed using the methods and processes outlined in Creating Clinical Guidelines: Our Protocol. This development process to produce guidance, advice and recommendations for practice has National Institute for Health and Care Excellence accreditation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: CD248 is a glycoprotein, highly expressed on pericytes and fibroblasts (FBs), that is implicated in the fibrotic process. During angiogenesis, CD248 can promote vessel regression, binding multimerin-2 (MMRN-2). Thus, we investigated the expression of MMRN-2 in systemic sclerosis (SSc)-skin and of CD248 in isolated SSc-FBs. The anti-angiogenic property of CD248+ SSc-FBs was evaluated by co-culturing these cells with healthy control endothelial cells (HC-ECs). The apoptotic effect of CD248 on HC-ECs was evaluated. Finally, the ability of CD248 to prevent activation of VEGF receptor 2 (VEGFR2) was assessed., Methods: By IF, MMRN-2 was investigated in SSc-skin and CD248 in SSc FBs. The anti-angiogenic property of CD248+ SSc-FBs was evaluated by HC-ECs/SSc-FBs co-cultures. Lentiviral-induced CD248 short-hairpin RNA delivery was employed for loss-of-function studies in SSc-FBs. HC-ECs were cultured in the presence of CD248 to assess apoptosis by IF and VEGFR2 phosphorylation by western blot., Results: MMRN-2 expression was increased in skin SSc-ECs, whereas CD248 expression was increased in SSc-FBs. Functionally, CD248+-SSc-FBs suppressed angiogenesis in the organotypic model, as assessed by the reduction in total tube length of HC-ECs. This anti-angiogenetic behaviour was reversed by CD248 silencing. Furthermore, the presence of CD248 promoted the apoptosis of HC-ECs. Finally, CD248 prevented activation of VEGFR2 by reducing its phosphorylation after VEGF stimulation., Conclusion: CD248 was anti-angiogenic in vitro due to a reduction in tube formation and to induction of apoptosis of ECs. Increased expression of CD248 in SSc could contribute to the microvascular rarefaction observed at the tissue level in SSc. Our results suggest a pathogenic role for CD248-MMRN-2 in SSc., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Subclinical systemic sclerosis (SSc) primary heart involvement is commonly described. Whether these findings progress over time is not clear. The study aimed to investigate cardiovascular magnetic resonance (CMR) interval change of subclinical SSc primary heart involvement., Methods: Patients with SSc with no cardiovascular disease underwent two CMR scans that included T1 mapping and quantitative stress perfusion. The CMR change (mean difference) and association between CMR measures and clinical phenotype were assessed. The study had a prospective design., Results: Thirty-one patients with SSc participated, with a median (interquartile range) follow-up of 33 (17-37) months (10 [32%] in the diffuse subset, 16 [52%] with interstitial lung disease [ILD], and 11 [29%] who were Scl-70+). Four of thirty-one patients had focal late gadolinium enhancement (LGE) at visit 1; one of four had an increase in LGE scar mass between visits. Two patients showed new focal LGE at visit 2. No change in other CMR indices was noted. The three patients with SSc with increased or new LGE at visit 2 had diffuse cutaneous SSc with ILD, and two were Scl-70+. A reduction in forced vital capacity and total lung capacity was associated with a reduction in left ventricular ejection fraction (ρ = 0.413, P = 0.021; ρ = 0.335, P = 0.07) and myocardial perfusion reserve (MPR) (ρ = 0.543, P = 0.007; ρ = 0.627, P = 0.002). An increase in the N-terminal pro-brain natriuretic peptide level was associated with a reduction in MPR (ρ = -0.448, P = 0.042). Patients on disease-modifying antirheumatic drugs (DMARDs) had an increase in native T1 (mean [SD] 1208 [65] vs. 1265 [56] milliseconds, P = 0.008). No other clinically meaningful CMR change in patients receiving DMARDs or vasodilators was noted., Conclusion: Serial CMR detects interval subclinical SSc primary heart involvement progression; however, this study suggests abnormalities remain largely stable with follow-up., (© 2023 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: The cytokine oncostatin M (OSM) is implicated in the pathology of SSc. Inhibiting OSM signalling using GSK2330811 (an anti-OSM monoclonal antibody) in patients with SSc has the potential to slow or stop the disease process., Methods: This multicentre, randomized, double-blind, placebo-controlled study enrolled participants ≥18 years of age with active dcSSc. Participants were randomized 3:1 (GSK2330811:placebo) in one of two sequential cohorts to receive GSK2330811 (cohort 1: 100 mg; cohort 2: 300 mg) or placebo s.c. every other week for 12 weeks. The primary endpoint was safety; blood and skin biopsy samples were collected to explore mechanistic effects on inflammation and fibrosis. Clinical efficacy was an exploratory endpoint., Results: Thirty-five participants were randomized to placebo (n = 8), GSK2330811 100 mg (n = 3) or GSK2330811 300 mg (n = 24). Proof of mechanism, measured by coordinate effects on biomarkers of inflammation or fibrosis, was not demonstrated following GSK2330811 treatment. There were no meaningful differences between GSK2330811 and placebo for any efficacy endpoints. The safety and tolerability of GSK2330811 were not favourable in the 300 mg group, with on-target, dose-dependent adverse events related to decreases in haemoglobin and platelet count that were not observed in the 100 mg or placebo groups., Conclusion: Despite a robust and novel experimental medicine approach and evidence of target engagement, anticipated SSc-related biologic effects of GSK2330811 were not different from placebo and safety was unfavourable, suggesting OSM inhibition may not be a useful therapeutic strategy in SSc., Trial Registration Number: ClinicalTrials.gov, NCT03041025; EudraCT, 2016-003417-95., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Driven by increased prevalence of type 2 diabetes and ageing populations, wounds affect millions of people each year, but monitoring and treatment remain limited. Glucocorticoid (stress hormones) activation by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) also impairs healing. We recently reported that 11β-HSD1 inhibition with oral AZD4017 improves acute wound healing by manual 2D optical coherence tomography (OCT), although this method is subjective and labour-intensive., Objectives: Here, we aimed to develop an automated method of 3D OCT for rapid identification and quantification of multiple wound morphologies., Methods: We analysed 204 3D OCT scans of 3 mm punch biopsies representing 24 480 2D wound image frames. A u-net method was used for image segmentation into 4 key wound morphologies: early granulation tissue, late granulation tissue, neo-epidermis, and blood clot. U-net training was conducted with 0.2% of available frames, with a mini-batch accuracy of 86%. The trained model was applied to compare segment area (per frame) and volume (per scan) at days 2 and 7 post-wounding and in AZD4017 compared to placebo., Results: Automated OCT distinguished wound tissue morphologies, quantifying their volumetric transition during healing, and correlating with corresponding manual measurements. Further, AZD4017 improved epidermal re-epithelialisation (by manual OCT) with a corresponding trend towards increased neo-epidermis volume (by automated OCT)., Conclusion: Machine learning and OCT can quantify wound healing for automated, non-invasive monitoring in real-time. This sensitive and reproducible new approach offers a step-change in wound healing research, paving the way for further development in chronic wounds., Competing Interests: The authors state no competing financial interests. The content of this article was expressly written by the authors listed. No ghostwriters were used to write this article., (© 2022 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Objective: Diffuse cutaneous systemic sclerosis (SSc) is a highly heterogeneous disease. A provisionally approved Composite Response Index in diffuse cutaneous SSc (CRISS) was developed as a 1-year outcome measure for clinical trials. Our goal was to further validate the CRISS by examining agreement between CRISS definitions for improved/non-improved with physicians' evaluation of disease., Methods: Patient profiles from a large observational cohort were created for 50 random diffuse cutaneous SSc patients of <5 years disease duration with improved CRISS scores after 1 year and 50 with non-improved CRISS scores. Profiles described disease features used during the initial CRISS development at baseline and at 1 year. Each profile was independently rated by 3 expert physicians. Majority opinion determined whether a patient was improved or not improved, and kappa agreement with the CRISS cutoff of 0.6 was calculated., Results: Patients had mean ± SD disease duration of 2.2 ± 1.3 years. There was substantial agreement between the physician majority opinion about each case and the CRISS (κ = 0.76 [95% confidence interval (95% CI) 0.64-0.88]). The agreement between each individual physician opinion and the CRISS was also substantial (κ = 0.70 [95% CI 0.62-0.78]). All CRISS non-improvers were also rated as non-improved by physician majority; however, 12 CRISS improvers were rated as non-improved by physicians., Conclusion: There was substantial agreement between the dichotomous CRISS rating and physician assessment of diffuse cutaneous SSc patients after 1 year. This supports the use of a CRISS cutoff at 0.6 for improvement versus non-improvement, although the CRISS tended to rate more patients as improved than did physicians., (© 2021 American College of Rheumatology.)