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Objectives: The 2022 European Society of Cardiology and European Respiratory Society (ESC/ERS) Guidelines for pulmonary arterial hypertension (PAH) recommend risk stratification to optimize management. However, the performance of generic PAH risk stratification tools in patients with systemic sclerosis (SSc)-associated PAH remains unclear. Our objective was to identify the most accurate approach for risk stratification at SSc-PAH diagnosis., Methods: In this multicentre, international cohort study from the European Scleroderma Trials and Research (EUSTAR) group database, we screened eleven risk stratification tools upon SSc-PAH diagnosis. We compared the performance of the three top-ranked tools to predict mortality with the ESC/ERS three-strata model, the currently recommended tool for baseline risk assessment. We also assessed the impact of incorporating SSc-specific characteristics into the tools. Kaplan-Meier analyses and Cox regression with area under the ROC curve (AUC) were conducted., Results: The ESC/ERS three-strata model had a lower ability to predict mortality than the ESC/ERS four-strata model, "SPAHR updated", and "REVEAL Lite 2". The ESC/ERS four-strata model divided "intermediate-risk" patients into two groups with significantly different long-term survival rates and is the easiest applicable tool. Incorporating SSc-specific characteristics did not significantly improve the predictive ability of any model, but a low DLCO was an independent predictor of mortality., Conclusion: Considering its ability to predict mortality, risk segregation capabilities, and clinical applicability, this study provides a rationale for using the simplified ESC/ERS four-strata model at SSc-PAH diagnosis as an alternative to the comprehensive ESC/ERS three-strata model. We propose considering DLCO as an individual prognostic marker in SSc-PAH., (© The Author(s) 2025. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: Gastroesophageal reflux disease (GERD) is frequent in systemic sclerosis (SSc) and could predict progression of interstitial lung disease (ILD). We aimed to analyse (1) the prevalence of GERD among SSc-ILD patients, (2) its association with disease characteristics and (3) predictive factors for ILD progression in SSc-ILD patients with GERD., Methods: SSc patients from the EUSTAR database with ILD were included. GERD was labeled as present if reflux/dysphagia was reported at the baseline visit or before. Disease characteristics of patients with and without GERD were compared at baseline. ILD progression was defined as relative FVC decline ≥10% or relative FVC decline between 5-9% in association with relative DLCO decline of ≥ 15% over 12±3 months of follow-up. Prognostic factors for ILD progression, overall survival and progression-free survival in SSc-ILD patients with GERD were tested by multivariable Cox regression., Results: 5462 SSc-ILD patients were included, 4400 (80.6%) had GERD. Patients with GERD presented more frequently with diffuse cutaneous SSc (OR: 1.44 [1.22-1.69], p < 0.001) and more severe lung involvement with lower FVC (85.8±22.1 vs 90.2±20.1, p < 0.001), lower DLCO (60.8±19.7 vs 65.3±20.6, p < 0.001) and worse performance at the 6-minute walking test. Female sex (HR: 1.39 [1.07-1.80], p = 0.012) and older age (HR: 1.02 [1.01-1.03], p < 0.001) independently predicted ILD progression in SSc-ILD patients with GERD., Conclusion: SSc-ILD patients with GERD appear to suffer from a more severe SSc disease. In this population, female sex may be considered as risk factor for ILD progression., (© The Author(s) 2025. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: Systemic sclerosis (SSc)-interstitial lung disease (ILD) is one of the leading causes of mortality in SSc. Data from randomised controlled trials (RCTs) supports rituximab and tocilizumab monotherapy but there is limited data regarding their use for those who fail standard immunomodulatory therapies., Methods: SSc patients treated with rituximab or tocilizumab were retrospectively identified in a single centre cohort. Linear mixed effect models were used to analyse before and after treatment lung function trajectory and identify patient characteristics associated with treatment response., Results: 127 patients were included for analysis. 51 of 94 (51.4%) and 13 of 33 (39.4%) of the rituximab and tocilizumab cohorts respectively were receiving concurrent mycophenolate mofetil. Pre-treatment decline in absolute change %FVC/year and %DLCO/year respectively, was similar in both cohorts (-3.2% and -4.0% rituximab and -3.2% and -3.6% tocilizumab). Both treatments resulted in lung function stabilisation (%FVC/year and %DLCO/year: 1.2% and +0.2% rituximab cohort, 1.0% and 1.0% tocilizumab cohort). Anti-topoisomerase antibody (ATA) positive patients had a significant response on %FVC/year to tocilizumab compared with ATA negative patients. Gender had a significant impact on %FVC/year response to rituximab, with males responding to a greater degree than females. Age, ILD extent and skin subset had no impact on treatment response., Conclusion: Combination rituximab or tocilizumab with background immunosuppressive therapy is associated with stabilisation in lung function trajectory among those who remain refractory to standard immunosuppressives. Specific patient characteristics have an impact on lung function response. Improved FVC response among ATA patients receiving tocilizumab validate data from RCTs., (© The Author(s) 2025. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: The Very Early Diagnosis of Systemic Sclerosis (VEDOSS) EUSTAR study showed that, despite not showing any clinical sign of disease, patients with Raynaud's and antinuclear antibodies and/or capillaroscopy abnormalities often progress to systemic sclerosis (SSc) within 5 years. We aimed to determine whether VEDOSS biosamples show biological SSc activity pre-clinically., Methods: Skin biopsies were histologically analysed. Dermal fibroblasts analysed by RT-qPCR and gel contraction assays. Sera were assayed by Luminex (CXCL10) or ELISA (ELF score). Healthy controls (HC) and SSc biosamples were used for controls., Results: Overall, 114 consecutive VEDOSS patients were enrolled, of which 36 consented to have skin biopsies. Skin biopsies showed a variable but overall increased collagen staining and skin thickness, increased perivascular infiltrate of CD45 positive cells and CXCL10 expression. In vitro, VEDOSS dermal fibroblasts showed increased profibrotic gene expression and contractibility compared with HC. Increased serological CXCL10 (mean [SD]; 75.90 [107.80] vs HC 39.90 [26.27] pg/ml, p = 0.02) and ELF score was evident in VEDOSS compared with HC (8.19 [0.78] vs 8.55 [0.79], p = 0.04). In longitudinal analysis of a median of 27.5 (IQR 44.5) months, 14.9% of VEDOSS patients progressed to SSc. Baseline CXCL10 serum concentration was significantly higher in the VEDOSS patients that progressed (2-fold increase, p = 0.0071) and correlated with ELF score (R = 0.3096, p = 0.0065)., Conclusions: Despite not fulfilling classification criteria, VEDOSS patients show SSc-linked fibrosis and immunity dysregulation both within the tissue and sera, supporting a biological diagnosis of disease and a window of opportunity to detect the biological pathways amenable for preventive intervention., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To examine disease and target engagement biomarkers in the RISE-SSc trial of riociguat in early diffuse cutaneous systemic sclerosis and their potential to predict the response to treatment., Methods: Patients were randomized to riociguat (n = 60) or placebo (n = 61) for 52 weeks. Skin biopsies and plasma/serum samples were obtained at baseline and week 14. Plasma cyclic guanosine monophosphate (cGMP) was assessed using radio-immunoassay. α-Smooth muscle actin (αSMA) and skin thickness were determined by immunohistochemistry, mRNA markers of fibrosis by qRT-PCR in skin biopsies, and serum CXC motif chemokine ligand 4 (CXCL-4) and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) by enzyme-linked immunosorbent assay., Results: By week 14, cGMP increased by 94 (78)% with riociguat and 10 (39)% with placebo (P < 0.001, riociguat vs placebo). Serum sPECAM-1 and CXCL-4 decreased with riociguat vs placebo (P = 0.004 and P = 0.008, respectively). There were no differences in skin collagen markers between the two groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies was associated with a larger reduction of modified Rodnan skin score from baseline at week 52 with riociguat vs placebo (interaction P-values 0.004 and 0.02, respectively)., Conclusion: Plasma cGMP increased with riociguat, suggesting engagement with the nitric oxide-soluble guanylate cyclase-cGMP pathway. Riociguat was associated with a significant reduction in sPECAM-1 (an angiogenic biomarker) vs placebo. Elevated sPECAM-1 and the presence of αSMA-positive skin cells may help to identify patients who could benefit from riociguat in terms of skin fibrosis., Trial Registration: Clinicaltrials.gov, NCT02283762., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

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.)

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.)

Objectives: Interstitial lung disease (ILD) is the most common cause of death in patients with systemic sclerosis (SSc), although disease behavior is highly heterogeneous. While a usual interstitial pneumonia (UIP) pattern is associated with worse survival in other ILDs, its significance in SSc-ILD is unclear. We sought to assess the prognostic utility of a deep-learning HRCT algorithm of UIP probability in SSc-ILD., Methods: Patients with SSc-ILD were included if HRCT images, concomitant lung function tests, and follow-up data were available. We used the Systematic Objective Fibrotic Imaging analysis Algorithm (SOFIA), a convolution neural network algorithm which provides probabilities of a UIP pattern on HRCT images. These were converted into the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED)-based UIP probability categories. Decline in lung function was assessed by mixed-effect model analysis and relationship with survival by Cox proportional hazards analysis., Results: 522 patients were included in the study. 19.5% were classified as UIP not in the differential, 53.5% as low probability of UIP, 25.7% as intermediate probability of UIP, and 1.3% as high probability of UIP. A higher likelihood of UIP probability expressed as PIOPED categories was associated with worse baseline FVC, as well as with decline in FVC (p= 0.008), and worse 15-year survival (p= 0.001), both independently of age, gender, ethnicity, smoking history, and baseline FVC or Goh et al. staging system., Conclusion: A higher probability of a SOFIA-determined UIP pattern is associated with more advanced ILD, disease progression, and worse survival, suggesting that it may be a useful prognostic marker in SSc-ILD., (© 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.)

Objectives: The aim of this study was to validate the Patient self-Assessment of Skin Thickness in Upper Limb questionnaire (PASTUL) in systemic sclerosis (SSc) and assess impact of skin involvement on health-related quality of life (HRQoL)., Methods: Participants were included in four UK centres. PASTUL specifies a grading of skin at 8 sites corresponding to the modified Rodnan Skin Score (mRSS). Construct validity was assessed by comparing PASTUL scores with mRSS. HRQoL was evaluated with EQ5D5L and Leeds SSc HRQoL questionnaires. Additionally, correlation between PASTUL and Scleroderma Skin Patient reported Outcome (SSPRO) was explored. Follow-up was 12 months., Results: In total, 196 participants were included, mean age was 56.4 years (SD 13.9), 80.6% female (n = 158), mean disease duration 11.9 years (SD 9.9), 110 (56.1%) had limited cutaneous (lcSSc) and 81 (41.3%) diffuse cutaneous SSc (dcSSc). PASTUL and upper limb mRSS were well correlated at baseline, 6 and 12 months (ICC = 0.67, 0.78 and 0.62, p< 0.001). Test-retest reliability was good (ICC = 0.83, p< 0.001). There was a stronger correlation between PASTUL and upper limb mRSS in dcSSc compared with lcSSc (0.69 vs 0.51, p< 0.001). In participants with early disease (< 4 years) PASTUL was moderately correlated with HRQoL (r = 0.53, p< 0.001), correlations were weaker in the whole group. Mean time to do the PASTUL self-assessment was 5.0 min (SD 3.7)., Conclusion: PASTUL is a feasible outcome tool that adds to assessments as SSPRO. Skin thickening is correlated with HRQoL, particularly in early disease., (© 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.)

Objectives: Measures of right heart size and function are prognostic in systemic sclerosis-associated pulmonary hypertension (SSc-PH), but the importance of myocardial tissue characterisation remains unclear. We aimed to investigate the predictive potential and interaction of cardiovascular magnetic resonance (CMR) myocardial tissue characterisation and right heart size and function in SSc-PH., Methods: A retrospective, single-centre, observational study of 148 SSc-PH patients confirmed by right heart catheterization who underwent clinically indicated CMR including native myocardial T1 and T2 mapping from 2016 to 2023 was performed., Results: Sixty-six (45%) patients died during follow-up (median 3.5 years, range 0.1-7.3). Patients who died were older (65 vs 60 years, P = 0.035) with more dilated (P < 0.001), hypertrophied (P = 0.013) and impaired (P < 0.001) right ventricles, more dilated right atria (P = 0.043) and higher native myocardial T1 (P < 0.001).After adjustment for age, indexed right ventricular end-systolic volume (RVESVi, P = 0.0023) and native T1 (P = 0.0024) were independent predictors of all-cause mortality. Both RVESVi and native T1 remained independently predictive after adjusting for age and PH subtype (RVESVi P < 0.001, T1 P = 0.0056). Optimal prognostic thresholds for RVESVi and native T1 were ≤38 mL/m2 and ≤1119 ms, respectively (P < 0.001). Patients with RVESVi ≤ 38 mL/m2 and native T1 ≤ 1119 ms had significantly better outcomes than all other combinations (P < 0.001). Furthermore, patients with RVESVi > 38mL/m2 and native T1 ≤ 1119 ms had significantly better survival than patients with RVESVi > 38mL/m2 and native T1 > 1119ms (P = 0.017)., Conclusion: We identified prognostically relevant CMR metrics and thresholds for patients with SSc-PH. Assessing myocardial tissue characterisation alongside right ventricular function confers added value in SSc-PH and may represent an additional treatment target., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: Assessment of construct validity and reliability of a novel patient-reported outcome (PRO) instrument for assessing the severity and impact of RP in SSc., Methods: An international multicentre study validation study of the 27-item Assessment of Systemic Sclerosis-Associated Raynaud's Phenomenon (ASRAP) and 10-item short-form (ASRAP-SF) questionnaires. The relationship between ASRAP questionnaires and demographics, clinical phenotype and legacy instruments for assessing SSc-RP severity, disability and pain was assessed. Repeatability was evaluated at 1 week. Anchor-based statements of health status facilitated assessment of ASRAP thresholds of meaning., Results: A total of 420 SSc subjects were enrolled. There was good correlation between ASRAP (and ASRAP-SF) with RP visual analogue scale (VAS) and Scleroderma Health Assessment Questionnaire RP VAS (rho range 0.648-0.727, P < 0.001). Correlation with diary-based assessment of SSc-RP attack frequency and duration was lower (rho range 0.258-0.504, P < 0.001). ASRAP questionnaires had good correlation with instruments for assessing disability, hand function, pain and global health assessment (rho range 0.427-0.575, P < 0.001). Significantly higher ASRAP scores were identified in smokers, patients with active digital ulceration (DU), previous history of DU and calcinosis (P < 0.05 for all comparisons). There was excellent repeatability at 1 week among patients with stable SSc-RP symptoms (intra-class coefficients of 0.891 and 0.848, P < 0.001). Patient-acceptable symptom state thresholds for ASRAP and ASRAP-SF were 45.34 and 45.77, respectively. A preliminary Minimally Important Clinical Difference threshold of 4.17 (95% CI 0.53, 7.81, P = 0.029) was estimated., Conclusion: ASRAP and ASRAP-SF questionnaires are valid and reliable novel PRO instruments for assessing the severity and impact of SSc-RP., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To investigate the course of interstitial lung disease (ILD) and the effects of nintedanib in patients with limited cutaneous systemic sclerosis (lcSSc)., Methods: In the SENSCIS trial, patients with SSc-ILD were randomized to receive nintedanib or placebo. Patients who completed the SENSCIS trial were eligible to enter SENSCIS-ON, in which all patients received open-label nintedanib., Results: Among 277 patients with lcSSc treated in the SENSCIS trial, the rate (s.e.) of decline in forced vital capacity (FVC; ml/year) over 52 weeks was -74.5 (19.2) in the placebo group and -49.1 (19.8) in the nintedanib group (difference: 25.3 [95% CI -28.9, 79.6]). Among 249 patients with data at week 52, mean (s.e.) change in FVC at week 52 was -86.4 (21.1) ml in the placebo group and -39.1 (22.2) ml in the nintedanib group. Among 183 patients with lcSSc who participated in SENSCIS-ON and had data at week 52, mean (s.e.) change in FVC from baseline to week 52 of SENSCIS-ON was -41.5 (24.0) ml in patients who took placebo in the SENSCIS trial and initiated nintedanib in SENSCIS-ON and -45.1 (19.1) ml in patients who took nintedanib in the SENSCIS trial and continued it in SENSCIS-ON., Conclusion: Patients with lcSSc may develop progressive fibrosing ILD. By targeting pulmonary fibrosis, nintedanib slows decline in lung function in patients with lcSSc and ILD., Trial Registration: ClinicalTrials.gov (https://clinicaltrials.gov), NCT02597933 and NCT03313180., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: To explore prognostic and predictive markers of SSc-associated interstitial lung disease (SSc-ILD) outcomes in a phase 3 trial (focuSSced) and prognostic markers in a real-world cohort (SMART)., Methods: The focuSSced SSc-ILD subgroup included 68 of 106 placebo-treated and 68 of 104 tocilizumab-treated patients. The SMART cohort included 505 patients with SSc-ILD. Linear mixed-effect models were used to identify factors associated with change in forced vital capacity (FVC). Kaplan-Meier estimation and Cox regression were used for time-to-event analyses., Results: In placebo-treated focuSSced patients, sex was a significant prognostic factor for FVC decline; males had increased risk for absolute decline ≥10% in percent-predicted FVC (ppFVC) and 0.22% faster weekly FVC decline than females (P = 0.0001). FVC was 9.8% lower in patients with CRP >6 mg/ml vs those with CRP ≤6 mg/ml (P = 0.0059). Tocilizumab reduced the risk for ≥10% decline in ppFVC in patients who were male, had earlier disease (<2 years duration), had IL-6 levels <10 pg/ml, or had anti-topoisomerase antibodies (ATA). In the SMART cohort, prognostic factors for ppFVC <70% were male sex, ATA, and low baseline FVC. Males had 3.3% lower FVC 1 year after disease onset (P < 0.001) and 0.6% faster yearly decline (P = 0.03) than females., Conclusion: Prognostic markers in SSc-ILD were similar between focuSSced and SMART. Male sex and inflammatory markers were associated with lower FVC but IL-6 ≥10 pg/ml was not predictive of response to tocilizumab., Trial Registration: ClinicalTrials.gov: NCT02453256., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

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.)

Objective: To evaluate the evidence concerning systemic pharmacological treatments for SSc digital ulcers (DUs) to inform the development of evidence-based treatment guidelines., Methods: A systematic literature review of seven databases was performed to identify all original research studies of adult patients with SSc DUs. Randomized controlled trials (RCTs) and prospective longitudinal observational studies (OBSs) were eligible for inclusion. Data were extracted, applying the patient, intervention, comparison, outcome framework, and risk of bias (RoB) was assessed. Due to study heterogeneity, narrative summaries were used to present data., Results: Forty-seven studies that evaluated the treatment efficacy or safety of pharmacological therapies were identified among 4250 references. Data from 18 RCTs of 1927 patients and 29 OBSs of 661 patients, at various RoB (total 2588 patients) showed that i.v. iloprost, phosphodiesterase-5 inhibitors and atorvastatin are effective for the treatment of active DUs. Bosentan reduced the rate of future DUs in two RCTs (moderate RoB) and eight OBSs at low to high RoB. Two small studies (moderate RoB) indicate that Janus kinase inhibitors may be effective for the treatment of active DUs, otherwise there are no data to support the use of immunosuppression or anti-platelet agents in the management of DUs., Conclusion: There are several systemic treatments, across four medication classes, that are effective therapies for the management of SSc DUs. However, a lack of robust data means it is not possible to define the optimal treatment regimen for SSc DUs. The relatively low quality of evidence available has highlighted further areas of research need., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

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.)

Objectives: Men with SSc have a more severe clinical phenotype and reduced survival compared with women. No previous psychosocial studies have focused solely on men with SSc. This study aimed to explore experiences, coping strategies and support preferences of men with SSc., Material and Methods: An international qualitative research study comprising seven focus groups (three USA, four UK) of 25 men with SSc. Transcripts were analysed using reflexive thematic analysis., Results: Three overarching themes and one underpinning theme were identified. In 'impact of SSc on masculinity', the men described an 'impact on roles and activities', reported 'sex, intimacy, and erectile dysfunction' as a salient issue that may be overlooked by clinicians, and experienced challenges to 'masculine self-image'. 'Dealing with SSc' meant 'always being prepared', 'becoming an expert' and 'balancing priorities' in responsibilities, activities and symptom management. In 'support for living with SSc' men were selective in '(Not) talking about SSc', would '(reluctantly) accept help' and described 'preferences for support'. Underpinning these experiences was 'facing an uncertain future' with some participants preferring not to focus on an unpredictable future, and others worrying about disease progression., Conclusion: These novel data suggest SSc impacts male patients' masculine identity and roles, and although they will accept practical help, they may mask the full emotional impact. Sex and intimacy are important overlooked issues with erectile dysfunction often not discussed at diagnosis. Further research should develop a self-management intervention for men with rheumatic diseases with a combination of disease-specific and common core components., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To assess associations between the extent of fibrotic interstitial lung disease (ILD) and forced vital capacity (FVC) at baseline and change in FVC over 52 weeks in patients with systemic sclerosis-associated ILD (SSc-ILD) in the SENSCIS trial., Material and Methods: We used generalized additive models, which involve few assumptions and allow for interaction between non-linear effects, to assess associations between the extent of fibrotic ILD on high-resolution computed tomography (HRCT), and the interplay of extent of fibrotic ILD on HRCT and FVC % predicted, at baseline and FVC decline over 52 weeks., Results: In the placebo group (n = 288), there was weak evidence of a modest association between a greater extent of fibrotic ILD at baseline and a greater decline in FVC % predicted at week 52 [r: -0.09 (95% CI -0.2, 0.03)]. Higher values of both the extent of fibrotic ILD and FVC % predicted at baseline tended to be associated with greater decline in FVC % predicted at week 52. In the nintedanib group (n = 288), there was no evidence of an association between the extent of fibrotic ILD at baseline and decline in FVC % predicted at week 52 [r: 0.01 (95% CI: -0.11, 0.12)] or between the interplay of extent of fibrotic ILD and FVC % predicted at baseline and decline in FVC % predicted at week 52., Conclusions: Data from the SENSCIS trial suggest that patients with SSc-ILD are at risk of ILD progression and benefit from nintedanib largely irrespective of their extent of fibrotic ILD at baseline., Study Registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02597933., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD)., Methods: A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification., Results: Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration., Conclusions: Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT., (© 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.)

SSc is a multiphase autoimmune disease with a well-known triad of clinical manifestations including vasculopathy, inflammation and fibrosis. Although a plethora of drugs has been suggested as potential candidates to halt SSc progression, nothing has proven clinically efficient. In SSc, both innate and adaptive immune systems are abnormally activated fuelling fibrosis of the skin and other vital organs. Macrophages have been implicated in the pathogenesis of SSc and are thought to be a major source of immune dysregulation. Due to their plasticity, macrophages can initiate and sustain chronic inflammation when classically activated while, simultaneously or parallelly, when alternatively activated they are also capable of secreting fibrotic factors. Here, we briefly explain the polarization process of macrophages. Subsequently, we link the activation of macrophages and monocytes to the molecular pathology of SSc, and illustrate the interplay between macrophages and fibroblasts. Finally, we present recent/near-future clinical trials and discuss novel targets related to macrophages/monocytes activation in SSc., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: Four intrinsic molecular subsets (inflammatory, fibroproliferative, limited, normal-like) have previously been identified in SSc and are characterized by unique gene expression signatures and pathways. The intrinsic subsets have been linked to improvement with specific therapies. Here, we investigated associations between baseline demographics and intrinsic molecular subsets in a meta-analysis of published datasets., Methods: Publicly available gene expression data from skin biopsies of 311 SSc patients measured by DNA microarray were classified into the intrinsic molecular subsets. RNA-sequencing data from 84 participants from the ASSET trial were used as a validation cohort. Baseline clinical demographics and intrinsic molecular subsets were tested for statistically significant associations., Results: Males were more likely to be classified in the fibroproliferative subset (P = 0.0046). SSc patients who identified as African American/Black were 2.5 times more likely to be classified as fibroproliferative compared with White/Caucasian patients (P = 0.0378). ASSET participants sera positive for anti-RNA pol I and RNA pol III autoantibodies were enriched in the inflammatory subset (P = 5.8 × 10-5, P = 9.3 × 10-5, respectively), while anti-Scl-70 was enriched in the fibroproliferative subset. Mean modified Rodnan Skin Score (mRSS) was statistically higher in the inflammatory and fibroproliferative subsets compared with normal-like (P = 0.0027). The average disease duration for inflammatory subset was less than fibroproliferative and normal-like intrinsic subsets (P = 8.8 × 10-4)., Conclusions: We identified multiple statistically significant differences in baseline demographics between the intrinsic subsets that may represent underlying features of disease pathogenesis (e.g. chronological stages of fibrosis) and have implications for treatments that are more likely to work in certain SSc populations., (© 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.)

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.)

Objective: The aim of these analyses was to investigate the rate of decline in forced vital capacity (FVC) in patients with SSc-associated interstitial lung disease (SSc-ILD) with and without cough or dyspnoea in the SENSCIS trial., Methods: Patients in the SENSCIS trial were randomized to receive nintedanib or placebo. Subgroups with and without cough or dyspnoea at baseline were defined by responses to the St George's Respiratory Questionnaire., Results: At baseline, 114/575 patients (19.8%) did not have cough and 172/574 patients (30.0%) did not have dyspnoea. In the placebo group, the rate of FVC decline over 52 weeks was similar in patients with and without cough (-95.6 and -83.4 mL/year, respectively) or dyspnoea (-95.8 and -87.7 mL/year, respectively). The effect of nintedanib vs placebo on reducing the rate of FVC decline was numerically more pronounced in patients without than with cough [difference: 74.4 (95% CI -11.1, 159.8) vs 31.5 (-11.1, 74.1)] and without than with dyspnoea [79.8 (9.8, 149.7) vs 25.7 (-19.9, 71.3)], but interaction P-values did not indicate heterogeneity in the treatment effect between these subgroups (P = 0.38 and P = 0.20, respectively)., Conclusion: In the placebo group of the SENSCIS trial, the rate of FVC decline was similar irrespective of the presence of cough or dyspnoea at baseline. The effect of nintedanib on reducing the rate of FVC decline was numerically more pronounced in patients without than with cough or dyspnoea at baseline, but no statistically significant heterogeneity was observed between the subgroups., Trial Registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02597933., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: Nailfold videocapillaroscopy (NVC) plays a well-established role in differentiating primary from secondary RP due to SSc. However, the association of NVC with novel severe organ involvement/progression in SSc has never been evaluated in a multicentre, multinational study, which we now perform for the first time., Methods: Follow-up data from 334 SSc patients [265 women; 18 limited SSc (lSSc)/203 lcSSc/113 dcSSc] registered between November 2008 and January 2016 by seven tertiary centres in the EUSTAR-database, were analysed. Novel severe organ involvement/progression was defined as new/progressive involvement of the peripheral vasculature, lungs, heart, skin, gastrointestinal tract, kidneys, musculoskeletal system, or death, at the 12- or 24-month follow-up. NVC images at enrolment were quantitatively and qualitatively evaluated according to the standardized definitions of the EULAR Study Group on Microcirculation in Rheumatic Diseases. Uni- and multivariable logistic regression modelling (ULR, MLR) was performed., Results: Of the 334 included SSc patients, 257 (76.9%) developed novel overall severe organ involvement/progression. Following MLR, normal capillary density was associated with less-frequent novel overall severe organ involvement/progression [odds ratio (OR) = 0.77, P &lt; 0.001] and novel peripheral vascular involvement (OR = 0.79, P = 0.043); microhaemorrhages were associated with less novel pulmonary hypertension (OR = 0.47, P = 0.029); and a 'severe' (active/late) NVC pattern was associated with novel overall severe organ involvement/progression (OR = 2.14, P = 0.002) and skin progression (OR = 1.70, P = 0.049)., Conclusions: Our results suggest that NVC may be a promising biomarker in SSc, certainly warranting further investigation. Despite the participation of tertiary centres, which follow their patients in a standardized way, we were underpowered to detect associations with infrequent severe organ involvement/progression., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: The aim of this study was to explore outcomes in a cohort of dcSSc patients fulfilling eligibility criteria for stem cell transplantation (SCT) studies but receiving standard immunosuppression., Methods: From a large single-centre dcSSc cohort (n = 636), patients were identified using the published SCT trials' inclusion criteria. Patients meeting the trials' exclusion criteria were excluded., Results: Of the 227 eligible patients, 214 met the inclusion criteria for ASTIS (Autologous Stem Cell Transplantation International Scleroderma), 82 for SCOT (Scleroderma: Cyclophosphamide Or Transplantation) and 185 for the UPSIDE (UPfront autologous haematopoietic Stem cell transplantation vs Immunosuppressive medication in early DiffusE cutaneous systemic sclerosis) trial, and 66 were excluded based on age >65 years, low diffusing capacity of the lungs for carbon monoxide (DLco), pulmonary hypertension or creatinine clearance <40 ml/min. The mean follow-up time was 12 years (s.d. 7). Among the eligible patients, 103 (45.4%) died. Survival was 96% at 2 years, 88% at 5 years, 73% at 10 years and 43% at 20 years. Compared with this 'SCT-eligible' cohort, those patients who would have been excluded from SCT trials had a worse long-term survival (97% at 2 years, 77% at 5 years, 52% at 10 years and 15% at 20 years, log rank P < 0.001). Excluded patients also had a significantly worse long-term event-free survival. Hazard of death was higher in patients with higher age at onset [hazard ratio (HR) 1.05, P < 0.001], higher ESR at baseline (HR 1.01, P = 0.025) and males (HR 2.12, P = 0.008)., Conclusion: SCT inclusion criteria identify patients with poor outcome despite current best practice treatment. Patients meeting the inclusion criteria for SCT but who would have been excluded from the trials because of age, pulmonary hypertension, poor kidney function or DLco <40% had worse outcomes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: The aim of this study was to identify the main CT features that may help in distinguishing a progression of interstitial lung disease (ILD) secondary to SSc from COVID-19 pneumonia., Methods: This multicentric study included 22 international readers grouped into a radiologist group (RADs) and a non-radiologist group (nRADs). A total of 99 patients, 52 with COVID-19 and 47 with SSc-ILD, were included in the study., Results: Fibrosis inside focal ground-glass opacities (GGOs) in the upper lobes; fibrosis in the lower lobe GGOs; reticulations in lower lobes (especially if bilateral and symmetrical or associated with signs of fibrosis) were the CT features most frequently associated with SSc-ILD. The CT features most frequently associated with COVID- 19 pneumonia were: consolidation (CONS) in the lower lobes, CONS with peripheral (both central/peripheral or patchy distributions), anterior and posterior CONS and rounded-shaped GGOs in the lower lobes. After multivariate analysis, the presence of CONs in the lower lobes (P < 0.0001) and signs of fibrosis in GGOs in the lower lobes (P < 0.0001) remained independently associated with COVID-19 pneumonia and SSc-ILD, respectively. A predictive score was created that was positively associated with COVID-19 diagnosis (96.1% sensitivity and 83.3% specificity)., Conclusion: CT diagnosis differentiating between COVID-19 pneumonia and SSc-ILD is possible through a combination of the proposed score and radiologic expertise. The presence of consolidation in the lower lobes may suggest COVID-19 pneumonia, while the presence of fibrosis inside GGOs may indicate SSc-ILD., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To assess the prevalence and burden of SSc-related gastrointestinal dysfunction (SSc-GI) and to evaluate associations with demographic, clinical and serological characteristics., Methods: Patients completed the UCLA SCTC GIT 2.0 questionnaire for SSc-GI disease to assess the burden of GI disease across multiple functional and psychological domains. Questionnaire scores were assessed using non-parametric and quantile regression analyses., Results: Our cohort included 526 patients with SSc, with a typical distribution of disease-associated autoantibodies (ACA, ARA, ATA, PM-Scl, U1RNP, U3RNP). We demonstrated associations between hallmark antibodies and the domain-specific burden of GI disease. In particular, ACA, ARA and ENA-negative demonstrated increased SSc-GI disease burden, while PM-Scl conferred relative protection. In a distributional analysis, associations with autoantibodies were particularly marked in those with the highest burden of GI disease., Conclusion: There is a significant burden of SSc-GI disease in patients with SSc; reflux and bloating symptoms are most prominent. SSc hallmark antibodies may predict increased risk of SSc-GI disease, in particular ACA and ARA, while PM-Scl may be protective., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In patients with SSc, the coexistence of ANCA-associated vasculitis (SSc-AAV) has been reported to be associated with a severe disease course, including significant pulmonary and renal involvement. The presence of ANCA is not uncommon in patients with SSc, and therefore clinicians must maintain a high index of clinical suspicion about SSc-AAV. p-ANCA and anti-myeloperoxidase antibodies are the most common antibodies observed. Patients typically present with clinical features of microscopic polyangiitis or renal-limited vasculitis. There are multiple areas of potential interaction in the pathogenesis of SSc and AAV, which can exacerbate/compound vascular disease. In addition, similar patterns of major internal organ involvement (e.g. lung and kidneys) are seen in both conditions. We highlight a diagnostic approach to SSc-AAV and the paucity of data to inform management. As such, SSc-AAV is typically treated as per isolated AAV, which can potentially be hazardous in patients with SSc (e.g. due to the association between high-dose steroid and scleroderma renal crisis). We propose that this rare clinical entity warrants rigorous investigation, including definition of a therapeutic strategy to ameliorate the potentially devastating combination of pathologies in SSc-AAV., (© The Author(s) 2021. 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: To evaluate clinical associations of anti-PM/Scl antibodies in patients with SSc in a multicentre international cohort, with particular focus on unresolved issues, including scleroderma renal crisis (RC), malignancies, and functional outcome of interstitial lung disease (ILD)., Methods: (1) Analysis of SSc patients from the EUSTAR database: 144 anti-PM/Scl+ without SSc-specific autoantibodies were compared with 7202 anti-PM/Scl-, and then to 155 anti-Pm/Scl+ with SSc-specific antibodies. (2) Case-control study: additional data were collected for 165 anti-PM/Scl+ SSc patients (85 from the EUSTAR registry) and compared with 257 anti-PM/Scl- SSc controls, matched for sex, cutaneous subset, disease duration and age at SSc onset., Results: Patients with isolated anti-PM/Scl+, as compared with anti-Pm/Scl-, had higher frequency of muscle involvement, ILD, calcinosis and cutaneous signs of DM, but similar frequency of SRC and malignancies (either synchronous with SSc onset or not). The presence of muscle involvement was associated with a more severe disease phenotype. Although very frequent, ILD had a better functional outcome in cases than in controls. In patients with both anti-PM/Scl and SSc-specific antibodies, a higher frequency of typical SSc features than in those with isolated anti-PM/Scl was observed., Conclusion: The analysis of the largest series of anti-PM/Scl+ SSc patients so far reported helps to delineate a specific clinical subset with muscle involvement, cutaneous DM, calcinosis and ILD characterized by a good functional outcome. SRC and malignancies do not seem to be part of this syndrome., (© The Author(s) 2021. 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: To investigate the association between proton pump inhibitor (PPI) use and the presence and severity of calcinosis in SSc., Methods: We analysed data from two SSc cohorts from a single centre. Cohort 1 included 199 patients reviewed over 10 years, for whom retrospective data on PPI use and calcinosis were available. Cohort 2 was recruited prospectively and included 215 consecutive patients, who underwent clinical assessment. Outcomes of interest were presence of current calcinosis (CC) or calcinosis at any time (CAT)., Results: The cohort 1 data analysis showed that among patients on standard dose PPI 20% had calcinosis, while in those on high doses of PPI calcinosis was present in 39% (P = 0.003). Analysis of the data from cohort 2 confirmed these findings, demonstrating that the odds of CAT increased significantly with longer PPI exposure [odds ratio (OR) 1.04, 95% CI: 1.02, 1.06; P < 0.001], longer disease duration (OR 1.08, 95% CI: 1.05, 1.12; P < 0.001) and greater age (OR 1.03, CI: 1.01, 1.05; P = 0.010). Multivariable logistic regression showed that higher exposure to PPI remained a significant predictor of calcinosis, with PPI exposure >10 years increasing the risk of CAT >6-fold, compared with no PPI (OR 6.37, 95% CI: 1.92, 21.17; P = 0.003) after adjusting for disease duration and antibodies., Conclusion: We confirm a significant association between high PPI exposure with severity of calcinosis in SSc. Given the clinical impact of calcinosis and reflux in SSc, PPI exposure as a potentially modifiable risk factor for calcinosis requires further evaluation., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Cytokines released by infiltrating T cells may promote mechanisms leading to fibrosis in scleroderma. The aim of this study was to investigate the role of the Th2 cytokine IL-31, and its receptor IL-31RA, in scleroderma skin and lung fibrosis., Methods: IL-31 was measured by ELISA of plasma, and by immunochemistry of fibrotic skin and lung tissue of scleroderma patients. The receptor, IL-31RA, was assayed by qPCR of tissue resident cells. Next-generation sequencing was used to profile the responses of normal skin fibroblasts to IL-31. In wild-type Balb/c mice, IL-31 was administered by subcutaneous mini pump, with or without additional TGFβ, and the fibrotic reaction measured by histology and ELISA of plasma., Results: IL-31 was present at high levels in plasma and fibrotic skin and lung lesions in a subset of scleroderma patients, and the receptor overexpressed by downstream cells relevant to the disease process, including skin and lung fibroblasts, through loss of epigenetic regulation by miR326. In skin fibroblasts, IL-31 induced next generation sequencing profiles associated with cellular growth and proliferation, anaerobic metabolism and mineralization, and negatively associated with angiogenesis and vascular repair, as well as promoting phenotype changes including migration and collagen protein release via pSTAT3, resembling the activation state in the disease. In mice, IL-31 induced skin and lung fibrosis. No synergy was seen with TGFβ, which supressed IL-31RA., Conclusion: IL-31/IL-31RA is confirmed as a candidate pro-fibrotic pathway, which may contribute to skin and lung fibrosis in a subset of scleroderma patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations., Methods: SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses., Results: The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP. AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001]., Conclusion: Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

SSc is a rare CTD that affects multiple organ systems, resulting in substantial morbidity and mortality. Evidence of interstitial lung disease (ILD) is seen in ∼80% of patients with SSc. Currently there is no approved disease-modifying treatment for ILD and few effective treatment options are available. CYC is included in treatment guidelines, but it has limited efficacy and is associated with toxicity. MMF is becoming the most commonly used medication in clinical practice in North America and the UK, but its use is not universal. Newer agents targeting the pathogenic mechanisms underlying SSc-ILD, including fibrotic and inflammatory pathways, lymphocytes, cell-cell and cell-extracellular membrane interactions, hold promise for better treatment outcomes, including improved lung function, patient-related outcomes and quality of life. Here we review ongoing trials of established and novel agents that are currently recruiting patients with SSc-ILD., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: To validate enhanced liver fibrosis (ELF) test and its components-amino-terminal propeptide of procollagen type III (PIIINP), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and HA-as biomarkers of fibrosis in SSc in an independent, international, multicentre cohort., Methods: Two hundred and fifty-four SSc patients from six Rheumatology Centres were included. Sera were collected and stored according to EUSTAR biobanking recommendations and analysed through automated high throughput diagnostics. Statistical analysis was performed with SPSS software., Results: Two hundred and forty-seven SSc patients (mean age 55.7 ± 13.9 years, 202 F) were analysed. ELF score, TIMP-1 and PIIINP levels were higher in males (P = 0.0197, P = 0.0107, P = 0.0108 respectively) and in dcSSc (P = 0.001, P = 0.0008, P < 0.0001 respectively). ELF score and the single markers significantly correlated with modified Rodnan skin score (r = 0.37, P < 0.0001), disease activity and severity (P < 0.0001 for all markers, except for HA P = 0.0001) and inversely with forced vital capacity, (FVC) % (TIMP-1, r = -0.21, P = 0.0012; PIIINP, r = -0.26, P = 0.0001), TLC% (ELF score, r = -0.20, P = 0.0036; TIMP-1, r = -0.32, P < 0.0001; PIIINP, r = -0.28, P < 0.0001), diffusion capacity of the lung for carbon monoxide (DLCO) % (P < 0.0001 for all markers, except for HA P = 0.0115). Multivariate analysis indicated that age (P < 0.001), modified Rodnan skin score (P < 0.001) and DLCO% (P = 0.005) were independently associated with ELF score., Conclusion: Between the first and this validation studies, the value of the ELF score as independent marker of skin and lung involvement in SSc is confirmed in 457 patients. A longitudinal study is on-going to identify an SSc specific algorithm with predictive value for skin and lung progression.

Objective: To gain insight into clinical practice regarding referral, early diagnosis and other aspects of the management of patients with dcSSc in Europe and the USA., Methods: Semi-structured interviews were conducted with 84 rheumatologists (or internal medicine physicians) and 40 dermatologists in different countries (the UK, France, Germany, Italy, Spain and the USA). Physicians were asked to identify key steps in the patient pathway relating to patient presentation, diagnosis and referral, in addition to other treatment and follow-up processes., Results: The interviewed physicians reported that late presentation with dcSSc was common, with some patients presenting to primary care physicians after symptoms had persisted for up to 1 year. Awareness of dcSSc is reported to vary widely among primary care physicians. Final diagnosis, generally following guideline-based recommendations, was by rheumatologists in most cases (or internal medicine physicians in France) and they remained responsible for global patient management, with lesser involvement in diagnosis and management by dermatologists. Specialist centres were not well defined and did not exist in all countries., Conclusion: Patients and primary healthcare providers can be unaware of the symptoms of dcSSc, therefore presentation and referral to specialist care are often late. Thus, improved awareness among patients and primary care physicians is necessary to facilitate earlier referral and diagnosis. Once referred, more consistent use of the modified Rodnan skin score at diagnosis and follow-up may help to monitor disease progression. Furthermore, establishing specialist centres may help to promote such changes and improve patient care.

Objectives: Our aim was to describe the burden of early dcSSc in terms of disability, fatigue and pain in the European Scleroderma Observational Study cohort, and to explore associated clinical features., Methods: Patients completed questionnaires at study entry, 12 and 24 months, including the HAQ disability index (HAQ-DI), the Cochin Hand Function Scale (CHFS), the Functional Assessment of Chronic Illness Therapy-fatigue and the Short Form 36 (SF36). Associates examined included the modified Rodnan skin score (mRSS), current digital ulcers and internal organ involvement. Correlations between 12-month changes were also examined., Results: The 326 patients recruited (median disease duration 11.9 months) displayed high levels of disability [mean (s.d.) HAQ-DI 1.1 (0.83)], with 'grip' and 'activity' being most affected. Of the 18 activities assessed in the CHFS, those involving fine finger movements were most affected. High HAQ-DI and CHFS scores were both associated with high mRSS (ρ = 0.34, P < 0.0001 and ρ = 0.35, P < 0.0001, respectively). HAQ-DI was higher in patients with digital ulcers (P = 0.004), pulmonary fibrosis (P = 0.005), cardiac (P = 0.005) and muscle involvement (P = 0.002). As anticipated, HAQ-DI, CHFS, the Functional Assessment of Chronic Illness Therapy and SF36 scores were all highly correlated, in particular the HAQ-DI with the CHFS (ρ = 0.84, P < 0.0001). Worsening HAQ-DI over 12 months was strongly associated with increasing mRSS (ρ = 0.40, P < 0.0001), decreasing hand function (ρ = 0.57, P < 0.0001) and increasing fatigue (ρ = -0.53, P < 0.0001)., Conclusion: The European Scleroderma Observational Study highlights the burden of disability in early dcSSc, with high levels of disability and fatigue, associating with the degree of skin thickening (mRSS). Impaired hand function is a major contributor to overall disability., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Objectives: Patient acceptable symptom state (PASS) as an absolute state of well-being has shown promise as an outcome measure in many rheumatologic conditions. We aimed to assess whether PASS may be effective in active diffuse cutaneous SSc differentiating active from placebo., Methods: Data from the phase 2 Safety and Efficacy of Subcutaneous Tocilizumab in Adults with Systemic Sclerosis (faSScinate) trial were used, which compared tocilizumab (TCZ) vs placebo over 48 weeks followed by an open-label TCZ period to 96 weeks. Three different types of PASS questions were evaluated at weeks 8, 24, 48 and 96, including if a current state would be acceptable over time as a yes vs no response and Likert scales about how acceptable a current state is if remaining over time. Additional outcomes assessed included modified Rodnan skin score, HAQ disability index (HAQ-DI), physician and patient global assessments on a visual analogue scale, CRP and ESR., Results: The placebo group consisted of 44 patients and the TCZ group had 43 patients. At baseline, 33% achieved a PASS for all three PASS questions, with the proportion increasing to 69, 71 and 78%, respectively, at 96 weeks. Changes in PASS scores showed a moderately negative correlation with HAQ-DI and patient and physician global assessments visual analogue scales, which indicates expected improvements as PASS improved. The PASS question, 'Considering all of the ways your scleroderma has affected you, how acceptable would you rate your level of symptoms?' showed significant correlations with patient-reported outcomes and differentiating placebo vs TCZ at 48 weeks (P = 0.023)., Conclusion: PASS may be used as a patient-centred outcome in SSc, especially as a 7-point Likert scale. Further validation is required to determine the utility as an outcome measure in trials and clinical practice., (© The Author 2017. 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: IVIG is known to confer significant benefit in rheumatologic conditions, including inflammatory myopathy. This study aimed to assess the efficacy of IVIG across different aspects of internal organ involvement in refractory active SSc, particularly the gastrointestinal (GI) system., Methods: SSc patients with overlap polymyositis who remained active and unresponsive to conventional disease-modifying agents and who subsequently received IVIG were identified. GI symptoms were assessed using validated questionnaires. The Medical Research Council Sum Score for muscle strength and modified Rodnan skin score (mRSS) were assessed. Serial measurements were undertaken at baseline prior to the first IVIG treatment and post-treatment in the most recent assessment., Results: Fifteen SSc patients were consecutively recruited into this observational study. The mean duration of IVIG treatment was 2.3 years, with treatment frequency ranging from every 6 weeks to 4 months. Compared with baseline, there was a significant reduction in gastro-oesophageal reflux frequency and intensity mean scores (P = 0.006 and P = 0.013, respectively). Significant improvement in the Gastrointestinal Tract (GIT) 2.0 score from a baseline mean score of 1.07 (s.d. 0.67) to 0.60 (0.46) (P = 0.002) was observed. There was regression in the markers of muscle disease with a reduction in the mean (s.d.) Medical Research Council sum score and the median creatine kinase level (P = 0.001 and P = 0.025, respectively). Significant amelioration of the mean basal modified Rodnan skin score from 21.5 (s.d. 13.8) to 10 (10.6) (P = 0.005) was observed., Conclusion: IVIG may be a helpful adjunctive therapy in the amelioration of some key clinical aspects in refractory SSc. Sustained benefit from IVIG suggests a specific immunomodulatory effect on those with established SSc GI complications., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

SSc is a multiorgan disease with significant morbidity that is associated with poor health-related quality of life. Treatment of this condition is often organ based and non-curative. However, there are newer, potentially disease-modifying therapies available to treat certain aspects of the disease. This review focuses on old and new therapies in the management of SSc in clinical practice., (© The Author 2014. 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: Digital vasculopathy (comprising RP, digital ulceration and critical digital ischaemia) is responsible for much of the pain and disability experienced by patients with SSc. However, there is a limited evidence base to guide clinicians in the management of SSc-related digital vasculopathy. Our aim was to produce recommendations that would be helpful for clinicians, especially for those managing patients outside specialist centres., Methods: The UK Scleroderma Study Group set up several working groups to develop a number of consensus best practice pathways for the management of SSc-specific complications, including digital vasculopathy., Results: This overview presents the background and best practice consensus pathways for SSc-related RP, digital ulceration and critical ischaemia. Examples of drug therapies, including doses, are suggested in order to inform prescribing practice., Conclusion: A number of treatment algorithms are provided that are intended to provide the clinician with accessible reference tools for use in daily management., (© The Author 2015. 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: The aim of this study was to assess the prognostic value of systolic pulmonary artery pressure (sPAP) estimated by echocardiography in the multinational European League Against Rheumatism Scleroderma Trial and Research (EUSTAR) cohort., Methods: Data for patients with echocardiography documented between 1 January 2005 and 31 December 2011 were extracted from the EUSTAR database. Stepwise forward multivariable statistical Cox pulmonary hypertension analysis was used to examine the independent effect on survival of selected variables., Results: Based on our selection criteria, 1476 patients were included in the analysis; 87% of patients were female, with a mean age of 56.3 years (s.d. 13.5) and 31% had diffuse SSc. The mean duration of follow-up was 2.0 years (s.d. 1.2, median 1.9). Taking index sPAP of <30 mmHg as reference, the hazard ratio (HR) for death was 1.67 (95% CI 0.92, 2.96) if the index sPAP was between 30 and 36 mmHg, 2.37 (95% CI 1.14, 4.93) for sPAP between 36 and 40 mmHg, 3.72 (95% CI 1.61, 8.60) for sPAP between 40 and 50 mmHg and 9.75 (95% CI 4.98, 19.09) if sPAP was >50 mmHg. In a multivariable Cox model, sPAP and the diffusing capacity for carbon monoxide (DLCO) were independently associated with the risk of death [HR 1.833 (95% CI 1.035, 3.247) and HR 0.973 (95% CI 0.955, 0.991), respectively]. sPAP was an independent risk factor for death with a HR of 3.02 (95% CI 1.91, 4.78) for sPAP ≥36 mmHg., Conclusion: An estimated sPAP >36 mmHg at baseline echocardiography was significantly and independently associated with reduced survival, regardless of the presence of pulmonary hypertension based on right heart catheterization., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: SSc is clinically and aetiopathogenically heterogeneous. Consensus standards for more uniform trial design and selection of outcome measures are needed. The objective of this study was to develop evidence-based points to consider (PTCs) for future clinical trials in SSc., Methods: Thirteen international SSc experts experienced in SSc clinical trial design were invited to participate. One researcher with experience in systematic literature review and three trainees were also included. A systematic review using PubMed and the Cochrane Central Register of Controlled Trials was conducted and PTCs when designing clinical trials in SSc were developed. As part of that development we conducted an Internet-based Delphi exercise regarding the main points to be made in the consensus statement. Consensus was defined as achieving a median score of ≥7 of 9., Results: By consensus, the experts decided to develop PTCs for each individual organ system. The current document provides a unifying outline on PTCs regarding general trial design, inclusion/exclusion criteria and analysis. Consensus was achieved regarding all the main points of the PTCs., Conclusion: Using European League Against Rheumatism suggestions for PTCs, a general outline for PTCs for controlled clinical trials in SSc was developed. Specific outlines for individual organ systems are to be published separately. This general outline should lead to more uniform and higher-quality trials and clearly delineate areas where further research is needed., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: To define the clinical, serological, histological and immunogenetic features of patients with scleroderma and ANCA-associated vasculitis (AAV)., Methods: We examined a clinical database of 2,200 patients with either limited or diffuse cutaneous systemic sclerosis (SSc). Patients with a confirmed diagnosis of vasculitis who were ANCA positive with either MPO or PR3 reactivity had their clinical features, serology, histology and HLA haplotypes examined in detail., Results: From this SSc cohort, 35 patients (1.6%) had evidence of vasculitis, and the SSc autoantibody profiles in this group were comparable to those previously published from the whole cohort. Of these 35 patients, 8 (0.4% of whole SSc cohort) had either anti-MPO or anti-PR3 antibodies and two further patients were ANCA positive without defined specificities. Of the eight ANCA-positive patients, seven had limited cutaneous SSc and anti-MPO antibodies and only one had anti-PR3 antibodies, associated with diffuse cutaneous SSc. Two ANCA-positive patients had anti-U3RNP antibodies, usually associated with overlap disease. None of the patients had granulomatous disease. The majority had glomerulonephritis, renal arteritis and pulmonary fibrosis. There were several shared HLA haplotypes from the DP and DQ loci in these overlap patients., Conclusion: SSc in overlap with ANCA-associated vasculitis is rare, and clinical features are more mixed than when either of these two conditions occurs separately. From our database, U3RNP antibodies may be more associated with overlap AAV than the other scleroderma-specific antibodies.