Objectives:To evaluate contemporary global treatment of diffuse cutaneous systemic sclerosis (dcSSc) skin by SSc specialists. Methods:An anonymous survey was distributed via the Scleroderma Clinical Trials Consortium, European Scleroderma Trials and Research Group (EUSTAR), and Collaborative National Quality and Efficacy Registry (CONQUER) distribution lists between June and September 2025. The survey comprised four sections: Demographics, Treatment of dcSSc Skin, Impact of Recent Guidelines, and Clinical Trials. Results:Responses included 103 physicians (93 completed): 43% North America, 31% Europe, 15% South America and 12% elsewhere. The majority practice within an SSc centre (80%) and participate in clinical trials (84%). Mycophenolate mofetil (MMF) was preferred first-line treatment (71%) for dcSSc without ILD, rising to 92% for dcSSc with mild/non-progressive ILD. For active skin involvement despite MMF, trial referral was preferred as next step irrespective of ILD (59% without ILD and 58% with ILD). Treatment preferences have evolved, with 40% increasing MMF use and 47% decreasing methotrexate use, over the previous 2-3 years. Biologic use has increased, with 56% and 37% reporting increasing rituximab and tocilizumab use, respectively. For dcSSc without ILD, 85% have prescribed rituximab, and 65% have prescribed tocilizumab. Biologic availability has impacted trial enrolment (73% agreement). Treatment decision-making for dcSSc skin involvement has been materially influenced by recent BSR and/or EULAR guidelines (43% agreement). Conclusion:MMF is preferred first-line for dcSSc. In the absence of compelling scientific justification for combination or step-up immunomodulatory approaches, trial referral is currently the preferred next treatment option. Biologic use is increasing, which impacts trial enrolment.

Interstitial lung disease (ILD) affects up to half of individuals with systemic sclerosis (SSc), within which it is a major cause of disease-related morbidity and a leading cause of mortality. Forced vital capacity (FVC) has been endorsed as a primary outcome measure for randomised controlled trials (RCT) assessing the efficacy of novel treatments for SSc-ILD. The FVC is considered a suitable surrogate biomarker, although does not directly capture information on how patients ‘feel’ and ‘function’, which regulators consider essential for marketing authorisation. Only patient-reported outcome (PRO) instruments can provide this insight. This review aims to systematically examine the inclusion, validity and performance of respiratory-specific PRO instruments used in SSc-ILD RCTs, using the COnsensus based Standards for the selection of health Measurement INstruments (COSMIN) framework and regulatory guidance.Our search identified 10 respiratory-specific PRO instruments used in SSc-ILD RCTs. Of these, 4 are single-item instruments and 2 were developed with any ILD patient input. Seventeen studies assessing the measurement properties of respiratory-specific PRO instruments within an SSc-ILD population were identified, with varying methodologies.The findings of this review highlight the lack of consensus for the use of respiratory-specific PRO instrument use in SSc-ILD RCTs. Identified instruments have unproven content validity within this population and limited evidence for other measurement properties, primarily derived from post hoc analyses of RCT data or cross-sectional studies. Future work should prioritise assessing the content validity and measurement properties of existing ILD specific instruments according to COSMIN guidance.

The Scleroderma Clinical Trials Consortium (SCTC) is committed to advancing the understanding and treatment of systemic sclerosis (SSc). This review focuses on the development and validation of various outcome instruments by the SCTC, which are crucial for evaluating the effectiveness of interventions in clinical trials and observational studies. Key instruments discussed include the Assessment of Systemic Sclerosis-Associated RAynaud's Phenomenon Questionnaire, the SCTC Radiologic Scoring System for calcinosis, the Mawdsley Questionnaire for calcinosis, the University of California Los Angeles SCTC Gastrointestinal Tract Instrument (GIT) 2.0, the SCTC Activity Index and the SCTC Damage Index. Additionally, the SCTC and World Scleroderma Foundation (WSF) Skin Scoring Certification is highlighted as an important resource for researchers. Each instrument's purpose, description and validation process are examined, underscoring their pivotal role in advancing SSc research and improving patient outcomes.

Objectives:Associations between Raynaud's phenomenon (RP) and body mass index (BMI), fibromyalgia syndrome (FMS) and migraine have been reported but their influence on the lived experience of RP is unknown. Design:Cross-sectional electronic survey. Setting:A social media-based awareness campaign organised by Scleroderma & Raynaud's UK. Participants:4141 respondents with RP, including 3279 with primary RP (PRP), 476 with systemic sclerosis-related RP (SSc-RP) and 386 with other systemic autoimmune rheumatic disease-related RP (SARD-RP). Interventions:Not applicable. Main outcome measures:RP symptom characteristics (colour change patterns, pain, numbness, tingling and thumb involvement) and their associations with BMI, FMS and migraine. Results:In PRP, low BMI correlated with higher prevalence of cyanosis (55.1% vs 41.2%), hyperaemia (48.2% vs 41.3%), triphasic change (30.4% vs 23.0%) and thumb involvement (36.0% vs 27.0%) compared with high BMI. In PRP, concomitant FMS was associated with higher prevalence of pain (77.7% vs 57.4%), cyanosis (53.8% vs 45.4%), tingling (72.6% vs 62.8%) and thumb involvement (46.2% vs 27.2%) compared with those without FMS. Higher prevalence of pain was reported by FMS respondents with SSc-RP (82.8% vs 69.9%) and SARD-RP (84.1% and 70.9%, respectively). In PRP, migraine was associated with higher prevalence of cyanosis (50.0% vs 44.9%), hyperaemia (50.3% vs 43.7%), pain (69.0% vs 56.2%) and thumb involvement (33.4% vs 27.1%). Migraine was associated with higher prevalence of hyperaemia and pain in SARD-RP. Conclusion:BMI, FMS and migraine influence the lived experience of RP, particularly in PRP. FMS is associated with a greater pain burden, whereas low BMI and migraine are associated with prominent vasospastic features. These aetiopathogenic drivers influence RP symptomatology, with implications for management.

Abstract Background/Aims Organ damage remains an important predictor of morbidity and mortality in systemic lupus erythematosus (SLE). The Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) is the only validated clinician completed tool for measuring this. Routinely collected electronic health records (EHR) provide a data source about unselected patients. Optimising the SDI for use in this setting provides the chance for studying SLE damage in a larger, more representative context than traditional hospital cohorts. This study aimed to (1) develop an electronic adaptation of the SDI (eSDI) suitable for use within an EHR dataset, the UK Clinical Practice Research Datalink (CPRD), and (2) examine preliminary associations between damage and mortality. Methods A retrospective cohort study was conducted using CPRD GOLD (study period 1990-2020). Adults (≥18 years) with SLE were selected using our previously published algorithm. Damage items were operationalised from SDI definitions using diagnostic, procedural, and medication codes. Associations between individual and overall damage (eSDI > 0) and mortality were tested using univariate and multivariable logistic regression adjusting for age, sex, smoking, ethnicity, and baseline comorbidities. Odds ratios (OR) with 95% confidence intervals (CI) were reported. Results 8,363 SLE patients were included (87.5% female, mean age 46.7 ± 16 years); 1,004 deaths occurred during follow-up. Overall, 42.3% developed damage (eSDI > 0). The most frequent items were osteoporosis (10.4%), malignancy (8.4%), and cataract (7.4%), with musculoskeletal, ocular, and cardiovascular the most affected domains. Most damage items were associated with increased mortality on univariate analysis. The highest odds were seen for malignancy (OR 6.26, 95% CI 5.27-7.42), pulmonary fibrosis (OR 4.89, 95% CI 3.15-7.48), and significant tissue loss (OR 6.82, 95% CI 2.95-15.60). The presence of any damage (eSDI > 0) was strongly associated with mortality (adjusted OR 4.46, 95% CI 3.57-5.57, p < 0.001) in the multivariable model. Age at diagnosis (OR 1.06, 95% CI 1.05-1.07), male sex (OR 1.40, 95% CI 1.08-1.80), and smoking (OR 1.62, 95% CI 1.29-2.03) were independent predictors of death. Conclusion Assessment of SLE-related organ damage using EHR data is feasible. Damage was common and independently associated with a fourfold increase in the odds of mortality, even after adjustment for demographic and comorbidities. EHR datasets therefore provides a viable and important opportunity for further study of SLE damage in the ‘real world’ setting; further work interrogating the associations between damage and survival as well as patterns of damage will be valuable. Disclosure J. Ellis: None. N. McHugh: None. J.D. Pauling: Honoraria; JDP has undertaken consultancy work and/or received speaker honoraria from Janssen, Astra Zeneca, Boehringer Ingelheim, IsoMab, Sojournix Pharma and Permeatus Inc. I. Bruce: Consultancies; INB has received consulting fees from AstraZeneca, Eli Lilly, GSK, Takeda, UCB and Dragonfly Therapeutics. Honoraria; INB was a speaker for AstraZeneca, Janssen, GSK and UCB. Grants/research support; INB has received grant support from GSK, Janssen and Astra Zeneca. S. Gor: None. J.H. Humphreys: None. H. Vaughan-Williams: None. E. Korendowych: None. S. Skeoch: None. A. McGrogan: None.

Objectives:Cardiovascular events (CVEs) and malignancy are important non-disease-related causes of mortality in SSc. We evaluated secondary care utilisation and impact of deprivation on comorbidity patterns in SSc in England. Methods:We analysed secondary care service utilisation in SSc using Hospital Episode Statistics for England for 2024. Cases were linked to Index of Multiple Deprivation deciles. Myocardial infarction (MI), lung cancer, breast cancer, melanoma rates and short-term all-cause mortality were explored, alongside comparisons with SLE and RA. Results:In 2024, ≈6000 people with SSc (84.6% female, 70.8% between 51 and 80 years of age, 73.3% White ethnicity) accessed secondary healthcare in England. Older SSc patients were overrepresented in less-deprived postcodes (P < 0.001). MI, lung cancer, breast cancer and melanoma were more common in SSc compared with unmatched estimates in the general population. Lung cancer was more frequent among less-deprived patients (P < 0.001). The all-cause mortality attrition rate was ≈3% in SSc over 3 months (30.8% with lung cancer and >60% with melanoma). Rates of breast cancer were higher in SSc compared with SLE (P = 0.014) and RA (P = 0.012). There was a higher rate of lung cancer in SSc compared with SLE (P < 0.001). Melanoma rates were similar across diseases (≈0.2%). Conclusion:Secondary care utilisation in SSc suggests less deprived SSc patients are older. All-cause mortality is higher in SSc patients receiving cancer care. Cancer occurrence is higher in SSc compared with SLE and RA. Our findings might support healthcare services planning and cancer screening for SSc in England.

INTRODUCTION:Assessment of disease activity in juvenile systemic sclerosis (jSSc) is essential for clinical care and trial readiness, yet no validated pediatric activity measures exist. Adult systemic sclerosis activity tools, including the Scleroderma Clinical Trials Consortium Activity Index, revised CRISS, and revised EUSTAR, provide conceptual frameworks but require adaptation for developmental, physiologic, and feasibility considerations for children. At the 17th Hamburg Symposium on JSSc, an international multidisciplinary panel reviewed adult indices, evaluated corresponding variables in the jSSc Inception Cohort and the NRCOS registry, and conducted a structured Delphi process to define organ-specific indicators of clinically meaningful activity in jSSc. AREAS COVERED:Across skin, pulmonary, cardiac, vascular, musculoskeletal, gastrointestinal, renal, and global domains, the panel reached broad and often unanimous consensus on variables reflecting active, potentially reversible disease. Key endorsed measures included mRSS progression, new ILD on HRCT, ≥10% declines in FVC or DLCO, new cardiac abnormalities, active digital ulcers, synovitis, myositis, nutritional decline, and physician global assessment. Patient-reported outcomes were strongly supported across domains. EXPERT OPINION:These consensus-derived indicators provide the first comprehensive pediatric-specific foundation for defining disease activity in jSSc and represent a critical step toward developing and validating a unified pediatric activity index suitable for future clinical trials.

Objectives:SLE, the exemplar autoimmune multisystem disease, is still burdened by excess morbidity and mortality. Damage is a key mediator of this. Studies of damage in outside-of-hospital cohorts are lacking, limiting understanding of real-world patient outcomes. The objectives were thus to design an instrument for measurement of SLE organ damage (eSDI) usable within a UK electronic primary care healthcare database [Clinical Practice Research Datalink (CPRD)] and describe the accrual of damage and mortality associations in an SLE cohort. Methods:A cohort of SLE individuals, including incident and prevalent cases, was identified in the CPRD. Organ damage item definitions were made usable for the electronic registry setting. Prevalence of damage in the overall cohort was described using descriptive statistics. Associations with mortality and damage (expressed in two ways, SDI > 0 ever, or modelled as a continuous cumulative variable) were examined using multivariable logistic regression, Kaplan-Meier analysis and extended Cox proportional hazards analysis in the incident SLE population. Results:We identified 8363 SLE patients in total, of whom the eSDI measured damage in 3537 (42.3%). The most common items were osteoporosis (10.39%), malignancy (8.4%) and cataract (7.4%). Damage across all organ systems was associated with an increased odds of death (e.g. malignancy [odds ratio 6.33 (95% CI 5.34, 7.49)]. Development of damage (eSDI >0 or as a numerical damage score) was significantly associated with an increased hazard of mortality. Conclusion:The use of an adapted eSDI for community electronic health records is feasible and enables widening of the study of damage and its morbidity and mortality consequences to primary care populations. This is more likely to reflect the real-world accumulation and outcomes of damage over time in SLE.

Objectives:To describe a novel radiographic phenotype of systemic autoimmune rheumatic disease-associated interstitial lung disease (SARD-ILD) observed within a regional specialist multidisciplinary (MDT) service. Methods:This was a retrospective case series of patients with SARD-ILD complicated by radiographic pulmonary cystic destruction. Cases were identified through review of MDT records from the North Bristol SARD-ILD service. Cases with MDT reported 'cystic changes' were identified and clinico-radio-pathological features reviewed. Results:Five cases of SSc-associated ILD (SSc-ILD) and two cases of antisynthetase syndrome-associated ILD (ASyS-ILD) with cystic changes were identified among a total of 108 SARD-ILD patients. All seven cases presented with radiological patterns of cellular non-specific interstitial pneumonia (NSIP). The median age at diagnosis with SARD was 33 years and six cases had ILD identified within 6 months of SARD diagnosis. The cohort was ethnically diverse, with one ex-smoker. Microcystic destructive changes appeared and progressed within areas of ground glass despite standard-of-care immunomodulation. Changes are radiographically and histologically distinct from traction bronchiolectasis, honeycombing and smoking-related lung disease. Histological specimens were available for two cases confirming fibrotic NSIP, with one including affected tissue demonstrating intimal thickening of the pulmonary vasculature. Over a median follow-up of 49 months, all cases remain alive and transplant free; five fulfilled criteria for progressive disease and six required ambulatory oxygen. Conclusions:This represents the first western cohort describing microcystic destructive pulmonary changes in SSc-ILD and the first report in ASyS-ILD. Systematic case identification is required to determine demographic associations and prognostic implications.

Abstract Background/Aims Autoantibodies are valuable diagnostic and prognostic biomarkers in the systemic autoimmune/inflammatory disease systemic sclerosis (SSc) and associate with specific clinical phenotypes. Juvenile-onset SSc (JSSc) is very rare and studies investigating autoantibody profiles in children affected are sparse. This study aimed to assess autoantibody profiles and associated clinical presentations in JSSc patients. Methods 28 JSSc patients recruited to PAtient STratification & Individualised trEatment: Systemic sclerosis (PASTIES) study were analysed by Radio-IP, unidentifiable bands were characterised by mass spectrometry and associated clinical information described. Statistical analysis was performed using R version 4.5.1. Results Autoantibodies were detected in 25/28 (89%) of JSSc patients (Table 1). Anti-U1 positivity (n = 9) associated with overlap SSc (89% vs 37%, p = 0.016), lower risk for gastrointestinal (GI) involvement (11% vs 79%, p = 0.0012), fewer abnormal nailfold capillaroscopy results (56% vs 95%, p = 0.02), and arthritis (67% vs 16%, p = 0.01). Anti-PM-Scl (n = 5) associated with overlap disease (100% vs 44%, p = 0.04), interstitial lung disease (ILD) (80% vs 13%, p = 0.007) and diarrhoea (40.0% vs 0%, p = 0.02). Anti-Scl-70 (n = 5) was exclusively found in diffuse cutaneous SSc (dcSSc) cases (100% vs 17%, p = 0.001) and associated with more digital ulcers (40% v 0%, p = 0.04). Anti-U3 positivity (n = 5) associated with African American ethnicity (40% vs 0%, p = 0.027). Five patients had unknown bands on Radio-IP, identified as Regulator-of-chromosome-condensation-1 (RCC1) (n = 1) found in isolation, Argonaute1-4 (n = 2) co-occurring with anti-U1, and SNF2-Related-Chromatin-Remodelling-ATPase-5 (SMARCA5) (n = 2) co-occurring with anti-U3 and anti-PM-Scl. Conclusion We did not detect anti-centromere autoantibodies, and anti-U1 were the most common autoantibodies identified in this cohort, which links to the comparably high frequency of overlap disease in juvenile-onset disease. This study confirms association between autoantibody specificity and SSc subtype, particularly between anti-Scl-70 and dcSSc, and anti-U1/PM-Scl and overlap SSc. Autoantibodies targeting RCC1 and SMARCA5 were identified in JSSc for the first time. Anti-RCC1 has previously been identified in adult-onset SSc. Anti-AGO2/Su has previously been identified in several rheumatic diseases and is not associated with a particular disease subtype. Antibodies targeting SMARCA5, a component of the ISWI chromatin-remodelling complex, have not been reported before. Results confirm the importance of autoantibodies in JSSc and their use in guiding organ specific screening. Disclosure F.K. McMorrow: None. H. Lu: None. J. Fitzgerald: None. J.D. Pauling: Consultancies; John D Pauling has undertaken consultancy work, educational support and/or received speaker honoraria from Astra Zenaca, Boehringer Ingelheim, John & Johnson, IsoMab and CSL Vifor.. C. Hedrich: None. C.E. Pain: None. K.S. Torok: None. S.L. Tansley: None. S. Maltby: None. M. Elfadil: None.

Systemic sclerosis (SSc) is a vascular disease. Immune-mediated endothelial injury leading to vasculopathy characterised by a progressive obliterative microangiopathy is a key aetiopathogenic driver of SSc. This typically manifests clinically as Raynaud's phenomenon (RP), which occurs in virtually all individuals with SSc and digital ulcers (DU), which develop in around half of patients at some stage in the disease course. The term RP encompasses a constellation of clinical features associated with digital vasospasm, typically in response to cold exposure. People with SSc-DU typically report more severe RP symptoms but it is an over-simplification to suggest that DU are simply a consequence of profound RP. The level of ischaemic tissue injury required to cause DU requires more protracted tissue hypoxia and there is a large body of work linking SSc-DU disease with progression of the obliterative microangiopathy and irreversible capillary loss typical of established SSc. The present chapter shall discuss the burden, aetiopathogenesis, assessment and management of SSc-RP and SSc-DU. We shall highlight practical considerations for the assessment and management of these digital vascular complications in routine clinical practice. The complexity of SSc-related digital vasculopathy is illustrated through examples from the clinic setting. The management of these complications shall focus on recently published clinical guidelines, highlighting nuances of management and the therapeutic rationale underpinning the use of unlicensed therapies for which the evidence base is sometimes scant.

OBJECTIVES:Telangiectasia are common in SSc. We explored the relationship between the site and quantity of telangiectasia with disease characteristics in SSc, and the agreement between patient- and physician-reported quantification of telangiectasia. METHODS:A retrospective analysis of a large, cross-sectional international SSc-related vasculopathy study was undertaken, including clinician and patient assessments of telangiectasia counts (0, 1-6, 7-15 or >15) in the face, forearms and hands. Relationships between telangiectasia count at each site, demographics and clinical features including calcinosis, digital ulceration (DU) and pulmonary arterial hypertension (PAH) were examined using proportional odds logistic regression. A binary logistic regression model examined the value of telangiectasia counts on the accuracy of identifying co-existent PAH. Concordance between clinician- and patient-reported telangiectasia counts at each anatomical site was tested. RESULTS:Higher telangiectasia counts over the face and hands were associated with higher prevalence of calcinosis, DU and PAH in univariate analysis (P < 0.001-0.003). In multivariate analysis, the presence of PAH, DU and calcinosis were associated with higher facial telangiectasia (P < 0.05). The logistic regression model for the detection of PAH was enhanced with inclusion of telangiectasia count and site (area under the precision recall curve 0.824-0.875). Strength of agreement between clinician- and patient-reported telangiectasia counts were moderate for face and forearms (kappa 0.648 and 0.605 respectively, P < 0.001) and relatively weaker for hands (kappa 0.584, P < 0.001). CONCLUSION:The number of telangiectasia might be considered a complementary biomarker to the presence of vascular complications of SSc including PAH, DU and calcinosis. The anatomical regions and level of instruction provided for patient-reported count of telangiectasia need further optimization to be considered reliable and feasible. In addition, future work should consider correlations with nailfold capillaroscopic patterns.

OBJECTIVES:Mycophenolate mofetil (MMF) is routinely used in early diffuse cutaneous systemic sclerosis (dcSSc) but not in limited cutaneous (lc)SSc. This may miss an opportunity to slow disease progression. MINIMISE-Pilot tested the feasibility of an open-label event-driven randomised trial of MMF vs no immunosuppression in lcSSc. METHODS:We tested the feasibility of a trial evaluating the impact of MMF on a novel event-driven composite endpoint. The MINIMISE endpoint measures time to worsening of lcSSc determined by progressive lung fibrosis, pulmonary hypertension, scleroderma renal crisis, heart failure, severe gut involvement, major digital vascular complications or death. Prespecified 'Stop-Go' criteria were agreed. Subjects were stratified by ACA status. RESULTS:Recruitment was challenging. A total of 53 subjects were screened and 43 were randomised, 21 to the MMF arm. Since recruitment was <60 participants, MINIMISE-Pilot was terminated based upon the prespecified threshold for continuation. During the treatment period there were no clinical worsening endpoints. Adherence to MMF was generally high, with 19 participants (95%) being 100% adherent at week 1, decreasing to 9 participants (64%) at week 24. CONCLUSION:MINIMISE-Pilot achieved its goal as a feasibility trial, leading to early termination of the study due to low recruitment. The rationale and concept for this study remain very strong. However, our findings suggest that a randomised prospective trial across 12 sites in the UK with relatively short follow-up duration is not feasible. This will inform the design of future studies testing the benefit of MMF in lcSSc. TRIAL REGISTRATION:Eudract (https://eudract.ema.europa.eu/) 2019-004139-21.

Giant cell arteritis is the most common vasculitis in those over 50 years old with a peak incidence between 70 and 80. Symptoms include a new-onset headache, scalp tenderness, jaw/tongue claudication, and visual symptoms, which can be sight-threatening. We report a case of an 82-year-old lady who presented with typical symptoms of giant cell arteritis and bilateral halo sign on an ultrasound scan. Despite initial steroid treatment she deteriorated and developed neurological symptoms including mononeuritis multiplex. Following further investigations, it was found that she was suffering from granulomatosis with polyangiitis and treatment was adjusted accordingly with additional immunomodulating treatment preventing further progression of symptoms. This case highlights how granulomatosis with polyangiitis can mimic giant cell arteritis and should be considered in refractory cases.

BACKGROUND:The OMERACT Scleroderma Vascular Disease Working Group sought to identify essential core outcome domains for inclusion in clinical trials focusing on Raynaud's phenomenon (RP) and/or digital ulcers (DUs) related to systemic sclerosis (SSc). METHODS:Candidate domains identified from previous qualitative work and systematic literature reviews were included in separate Delphi exercises for SSc-RP and SSc-DUs. Patients with SSc and other participants (clinicians with experience in treating patients with SSc and/or conducting clinical trials) were invited to participate through international patient advocacy groups and clinical networks. Core domains were defined as the domains reaching group consensus agreement (≥ 70% ratings of 'critical' in both patient and other participant groups) after three rounds of the Delphi. RESULTS:The 3-round Delphi exercises were completed by 78 patients and 116 others from 39 countries for SSc-RP, and by 26 patients and 99 others from 36 countries for SSc-DUs. For SSc-RP, nine domains reached consensus agreement as critically important: three domains in the Pathophysiological Manifestations core area and six in the Life Impact core area. For SSc-DUs, 16 domains reached consensus: five domains in the Pathophysiological Manifestations core area, seven in the Life Impact core area, and four in the Resource Use area. CONCLUSION:Patients with SSc and clinicians identified core domains for use in clinical trials in SSc-associated RP and DUs, with several Life Impact domains common to both vascular manifestations of disease. These results will inform development of a final Core Domain Set for use in clinical trials.

Objectives Physician global assessments (PhyGAs) are commonly performed in randomized controlled trials (RCTs) in SSc. However, there is no single PhyGA applied across RCTs. We performed an exploratory qualitative study to explore perceptions of the PhyGA, its role in RCTs and how physicians perform their own assessment.Methods Participants with expertise in the clinical assessment and, or actively involved in research on SSc were invited to participate. Participants were asked to define disease constructs of activity, damage, severity, and overall health, and to describe how they perform a PhyGA and their perception of what a PhyGA should assess. Interview transcripts were analysed using deductive and inductive thematic analysis.Results Eighteen rheumatologists and one patient research partner were interviewed. Four major themes were identified: (i) physician uncertainty; (ii) variation in the conduct of a PhyGA; (iii) physician efforts to improve PhyGA consistency; (iv) utility of a PhyGA. Most participants felt a PhyGA should assess changeable aspects of SSc, commonly conceived of as disease activity. There was considerable uncertainty about the optimal method for assessing disease activity. Participants were uncertain about their own methods of performing a PhyGA, and variability in the application of the instrument was identified. Despite these limitations, physicians generally agreed that the PhyGA is useful and can assess unquantifiable aspects of SSc.Conclusion We identified significant heterogeneity in the approach to PhyGAs in SSc. This variation was considered a limitation of the PhyGA. Overall, a PhyGA was viewed as a useful instrument that can aid the assessment of treatment response in RCTs.

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 SSc and ≥7 RP attacks during the last screening week prior to a baseline visit were randomized to 4 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 the primary end point. Cold challenge assessments were performed at baseline and end of treatment. Exploratory end points 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). The mean weekly number of RP attacks [baseline; vipoglanstat 14.4 (S.D. 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. The mean change in recovery of peripheral blood flow after the 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 the 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. TRIAL REGISTRATION:ClinicalTrials.gov, https://www.clinicaltrials.gov, NCT0474420.

Immune-mediated vascular endothelial injury is considered one of the earliest pathological features in systemic sclerosis and is thought to occur simultaneously within a broad range of organs, although typically clinically manifesting only as Raynaud's phenomenon in the early stages. Overt vascular systemic sclerosis manifestations include Raynaud's phenomenon, abnormal nailfold capillary morphology, digital ulcers, pulmonary arterial hypertension, cardiovascular disease (primary and coronary), telangiectasia, renal crisis, and gastric antral vascular ectasia. Tissue ischaemia might also contribute to aberrant tissue remodelling, resulting in calcinosis and fibrosis. Recognition of the substantial inter-relationship between these vascular complications is growing; examples of vascular treatment interventions targeting digital vasculopathy having off-target vascular benefits in other organs have been reported. In general, treatment of life-threatening vascular complications, such as pulmonary arterial hypertension, is not commenced until classifiable organ disease has occurred; however, the identification of robust prognostic biomarkers might allow such complications to be averted with preventative disease modification. In this Personal View, we describe the inter-relationship between vascular features of systemic sclerosis. We consider how these features might be exploited to establish a unified vascular conceptual framework that can inform the development of both predictive composite indices to guide preventative intervention, and a unified vascular composite endpoint model that can effectively capture clinically meaningful disease modification in future clinical trials of vasoactive treatments in systemic sclerosis.