OBJECTIVE:This study aims to identify factors associated with patient global assessment (PtGA) and physician global assessment (PhGA) and discordance between them in systemic sclerosis (SSc). METHODS:Data from adults with early SSc (<5 years) from the Collaborative National Quality and Efficacy Registry were included. PtGA and PhGA (0-10 scale), clinical evaluations, and patient-reported outcomes (PROs) were collected every six months. Multivariable mixed-effects linear regression identified factors associated with PtGA and PhGA using (1) clinical variables and (2) clinical variables plus PROs. Relative weight analysis (RWA) determined the relative importance of each variable. Discordance (≥2 points between PtGA and PhGA) was assessed using multinomial mixed-effects logistic regression. RESULTS:Among 956 patients (83% women, 33% limited disease), mean PtGA and PhGA at enrollment were 4.2 (SD 2.6) and 3.4 (SD 2.0), respectively (P < 0.001). RWA of clinical variables identified modified Rodnan skin score (mRSS) and New York Heart Association (NYHA) functional class as most influential for both global assessments. After including PROs, PtGA was most influenced by measures of pain, skin symptoms, and physical function. Discordance occurred in 53% of patients (35% PtGA worse, 18% PhGA worse). Worse PtGA was associated with higher overall pain and discomfort. Worse PhGA was associated with higher mRSS, worse NYHA class, higher pain interference, and lower diffusing capacity of the lung. CONCLUSION:Discordance between PtGA and PhGA occurs commonly, highlighting the need for comprehensive symptom management and measurement of disease burden in this complex disease. In SSc, differences in PtGA and PhGA reflect dissimilar weighting of data elements.

Objective Anti-RNA-polymerase-III (ARA) and anti-topoisomerase-I (ATA) autoantibodies are associated with diffuse cutaneous SSc (dcSSc). ARA is associated with rapidly progressive skin thickening, scleroderma renal crisis (SRC), and gastric antral vascular ectasia, while ATA is associated with severe interstitial lung disease (ILD). However, these associations were derived from heterogenous SSc cohorts. As SSc is now often diagnosed earlier, we aimed to ascertain whether these relationships hold true in early dcSSc and to examine autoantibody associations with organ involvement in early dcSSc. Methods The Prospective Registry of Early Systemic Sclerosis (PRESS) includes adults with dcSSc ≤2 years from the first non-Raynaud’s phenomenon symptom who met 2013 ACR/EULAR classification criteria for SSc. Participants were enrolled at 12 U.S. academic centers and evaluated every 6 months. Those with dual-positivity were excluded. Differences across autoantibody groups were assessed using appropriate parametric and nonparametric tests. Results Of 303 enrolled, 233 participants were included (108 ARA+, 68 ATA+, 57 double-negative). Mean age was 51 years; 68% were female. Mean disease duration was 1.2 years. ATA+ participants had lower baseline FVC% predicted (76.0% vs 86.0% ARA+, p=0.0011) and higher prevalence of ILD (69.6% vs 44.3% ARA+, p=0.0029). ARA+ participants had higher baseline mRSS (25.0 vs 17.9 ATA+, p<0.0001) and higher prevalence of SRC (14.4% vs 0.0% ATA+, p=0.0024). Only the double-negative group had improvement in FVC% predicted over time (+1.39% per year, p=0.03). Conclusions Autoantibody-specific differences in organ involvement were evident early. The double-negative group uniquely showed improvement in lung function over time.

OBJECTIVES:Vasculopathy and fibrosis are central to the pathogenesis of systemic sclerosis (SSc) and their genetic underpinnings are largely unknown. Here, we sought to examine the aetiology of severe vascular phenotypes and poorer outcomes in African American (AA) patients with SSc. METHODS:The study focuses on AA patients with SSc who have more severe vascular phenotypes and poorer outcomes and combines genetics, single-cell RNA sequencing, functional assays, and a mouse model to explore the role of NOTCH4 in SSc vasculopathy and the potential for NOTCH4-directed therapies. RESULTS:Gene-based testing identified NOTCH4 association at an exome-wide significance with SSc (P = 1.6 × 10-7) and patients with severe vascular disease (P = 3.5 × 10-7). The risk haplotype defined by the missense (c.2824C>T) and promoter (c.-117G>A) variants was enriched in AAs with SSc (11%) vs controls, and the population attributable risk due to this haplotype in AAs with SSc was 2.6%, which was 52-fold higher than in European Americans. The SSc-associated NOTCH4 variants increased NOTCH4 expression and signalling, leading to decreased angiogenesis and increased endothelial-to-mesenchymal transition (EndoMT). Nailfold capillary abnormalities, decreased angiogenesis, and fibrosis of the vascular lumen are commonly seen in SSc. Genetic, chemical, antibody, or Food and Drug Administration-approved drug inhibition of NOTCH4 signalling rescued angiogenesis and returned EndoMT to baseline. CONCLUSIONS:NOTCH4 variants are associated with SSc pathogenesis and vasculopathy, partly explaining the increased prevalence of SSc in AAs. The study highlights the need for further research and clinical trials in the inhibition of the NOTCH4 pathway as a strategy to treat the vascular and fibrotic manifestations of SSc.

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.

OBJECTIVES:To determine the efficacy, safety and pharmacodynamics of belumosudil in patients with diffuse cutaneous systemic sclerosis (dcSSc) treated with background immunosuppressive therapies. METHODS:Eligible patients were randomised 1:1:1 to receive belumosudil 200 mg once daily (QD) or twice daily (BID), or placebo for 28 weeks (double-blind period). After unblinding, the patients who received belumosudil continued the same dose, whereas the patients who received placebo were re-randomised for one of the belumosudil doses for 24 weeks (open-label extension). RESULTS:Thirty-five and 31 patients were treated in the double-blind and open-label periods, respectively. The study was terminated prematurely, and target enrolment was not met. The primary end point, of CRISS score ≥0.60 at week 24, did not exhibit an efficacy signal in the belumosudil vs placebo groups [odds ratio: 1.06 (0.19-5.82; P = 0.9472) for the QD, and 0.39 (0.07-2.35; P = 0.3078) for the BID group]. Belumosudil was well tolerated and exhibited similar safety profiles in both double-blind and open-label periods. Tissue-based RNA sequencing analysis revealed FOXP3 upregulation and STAT3, IL23A and TGF-β downregulation in patients with CRISS score ≥0.60, which supported the mechanism of action of belumosudil. In blood and tissue samples, trends of decreased fibrosis biomarker levels were seen in the belumosudil-treated group vs placebo. CONCLUSION:Efficacy signal for belumosudil could not be detected. Signalling pathway modulation analysis supported the mechanism of action of belumosudil. A trend for decreased fibrosis-related biomarkers was observed in the belumosudil-treated group. TRIAL REGISTRATION:ClinicalTrials.gov, https://clinicaltrials.gov, NCT03919799.

Background:Systemic sclerosis (scleroderma) is associated with functional disability and poor quality of life. Patient-reported outcome measures provide valuable insights into patients' experiences, symptoms, and perceptions of their health. The Health Assessment Questionnaire-Disability Index (HAQ-DI) and the Scleroderma Health Assessment Questionnaire (S-HAQ) are widely used patient-reported outcome measures in scleroderma research and clinical care. However, there is lack of data to (a) ensure and document patients with systemic sclerosis understand the concepts contained in these measure and (b) demonstrate face, item, and content validity for these items and measures. Methods:We conducted cognitive debriefing of the S-HAQ in patients with diffuse cutaneous systemc sclerosis (dcSSc). The S-HAQ includes the HAQ-DI, a 20-item questionnaire that assesses functional ability for performing day-to-day activities, four systemic sclerosis-specific items that assess scleroderma symptoms, and one item on overall scleroderma-related limitations. Results:The total sample of patients with dcSSc (N = 20) had a mean age of 57.6 years and average disease duration of 3.4 years. For the HAQ-DI, the participants understood the concepts and the items were clear. In addition, majority (60%-100%) of participants reported using aids and devices to perform activities of daily living and/or utilizing assistance from another person. The systemic sclerosis-specific items of the S-HAQ were relevant to participants but required revisions to item wording and response options, including a change from the visual analog scales to numerical rating scales. Conclusion:The HAQ-DI and S-HAQ systemic sclerosis-specific items demonstrated content and item validity, respectively. Several minor modifications were made to the S-HAQ instructions, item wording, and rating scales.

OBJECTIVE:Scleroderma renal crisis (SRC) is historically described to occur within the first five years of systemic sclerosis (SSc) diagnosis. However, it has been observed to occur beyond five years. In this analysis, we aim to describe the prevalence, clinical features, and outcomes of late-onset SRC and compare them with early-onset SRC. METHODS:This retrospective observational study included patients diagnosed with SRC between 1995 and 2018 at three university-affiliated hospitals. Late-onset SRC was defined as SRC occurring five years after SSc diagnosis. After obtaining institutional review board approval, data including demographics, SRC onset, clinical characteristics, laboratory data, and outcomes were extracted. Continuous data were expressed as mean/median and categorical data as frequencies/percentages. Differences were analyzed via Pearson's chi-square test. RESULTS:A total of 223 patients with SRC were identified, with 169 (75.8%) classified as early onset and 54 (24.2%) as late onset. The late-onset group had a mean SRC onset of 12.2 years after SSc diagnosis. Male predominance was observed in the late-onset compared with the early-onset group (59% vs 9%). Steroid exposure was more common in late vs early group (56% vs 29%). There was no evidence of difference in autoantibodies profile and outcomes between early- and late-onset groups. CONCLUSION:Late-onset SRC was seen in up to 25% of patients with SRC, with a mean of 12 years after SSc diagnosis. Our findings reveal comparable clinical characteristics and outcomes between early- and late-onset SRC, underlying the importance of recognizing SRC regardless of disease duration to optimize outcomes.

OBJECTIVE:Raynaud phenomenon (RP) is often the initial clinical manifestation of systemic sclerosis (SSc), but some patients develop other manifestations first. To help elucidate the diversity of SSc presentation in its early stages, we describe the initial clinical manifestations and antinuclear antibody (ANA) profiles of patients in two early SSc cohorts. METHODS:All patient data in the Genetics vs Environment in Scleroderma Outcomes Study (GENISOS) and Collaborative National Quality and Efficacy Registry (CONQUER) cohorts were reviewed. Both studies enrolled patients within five years of the first non-RP symptom. RESULTS:In GENISOS and CONQUER, respectively, 194 (44.2%) of 439 and 292 (31.1%) of 938 patients had a non-RP initial symptom, most commonly puffy fingers/hands. Black patients had a non-RP symptom before RP more commonly than patients in other race and ethnicity categories. Non-RP first patients were more likely than RP first patients to have diffuse cutaneous involvement and joint contractures at enrollment and had a higher prevalence of RNA polymerase III antibody positivity. CONCLUSION:In two large US cohorts, >30% of patients began to manifest SSc with puffy fingers/hands or other symptoms, without the "warning sign" of RP as their initial symptom. These patients presented with more severe skin and musculoskeletal disease on average, highlighting the importance of early recognition. The most common autoantibody associated with this presentation was RNA polymerase III. These results should be considered in efforts to recognize SSc in its earliest stages. Puffy fingers/hands, even in the absence of RP, should prompt consideration of early SSc and testing for ANA and SSc-associated autoantibodies, including RNA polymerase III.

BACKGROUND:Type I interferon (IFN) pathway activation has been associated with severe systemic sclerosis. We aimed to examine the association of serum IFN scores with disease activity and outcomes in two cohorts of patients with diffuse cutaneous systemic sclerosis. METHODS:In this retrospective cohort study, we included adult (aged >18 years) patients with diffuse cutaneous systemic sclerosis enrolled in the US Prospective Registry of Early Systemic Sclerosis (PRESS; incident cohort) or in the UK observational cohort (Stratification for Risk of Progression in Scleroderma [STRIKE]; prevalent cohort) registries and healthy controls (volunteers). Sera were analysed by Myriad-Rules Based Medicine's Luminex xMAP Technology Multiplex Assay (Austin, TX, USA), and IFN scores were generated using concentrations of CCL2, CCL8, CCL19, CXCL9, CXCL10, and CXCL11. Patients were classified as IFN-high (vs IFN-low) when mean sum of the natural logarithm of the six chemokines was greater than (or within) two standard deviations of healthy controls. The main outcome measures were the baseline and the minimal clinically important differences for modified Rodnan Skin Score, forced vital capacity (FVC), diffusing capacity for carbon monoxide (DLCO), and Health Assessment Questionnaire-Disability Index at 12 months. A person with lived experience of systemic sclerosis was involved in writing the report. FINDINGS:Patients with diffuse cutaneous systemic sclerosis in the PRESS incident cohort were recruited between April 1, 2012, and Jan 1, 2019, and healthy controls and patients in the STRIKE prevalent cohort were recruited between Dec 1, 2014, and Dec 1, 2018. IFN scores were generated for 110 patients in the incident cohort (mean age 50·2 years [SD 15·0], 76 [69%] women and 34 [31%] men, 87 [79%] White) and 72 patients in the prevalent cohort (mean age 51·7 years [SD 10·9], 50 [69%] women and 22 [31%] men, 64 [89%] White), and 32 healthy controls (mean age 47·0 years [SD 12·4]; 19 [59%] women and 13 [41%] men; 24 [75%] White). 50 (45%) of 110 patients in the incident cohort and 27 (38%) of 72 patients in the prevalent cohort were classified as IFN-high. In the incident cohort, patients classified as IFN-high had worse baseline disease compared with patients classified as IFN-low, as assessed by mean predicted FVC (72·0% [SD 18·9] vs 85·3% [18·5]; p=0·0028), DLCO (56·8% [SD 21·6] vs 76·6% [25·3]; p=0·0008), and median Health Assessment Questionnaire-Disability Index (1·4 [IQR 0·8-2·0] vs 0·8 [0·4-1·5]; p=0·0033). Differences in FVC and DLCO persisted at last follow-up (median 34 months [IQR 19·8- 54·0] for FVC and median 34 months [IQR 22·5- 54·0] for DLCO). In the prevalent cohort, patients classified as IFN-high had a shorter median disease duration (2·2 years [IQR 0·7-8·2] vs 5·0 years [1·9-10·0]; p=0·035) compared to those classified as IFN-low, and worse 12-month lung outcomes independent of baseline FVC or immunosuppression (5% relative worsening of FVC in nine [39%] of 23 patients with IFN-high vs seven [17%] of 41 patients with IFN-low; p=0·051). Moreover, cumulative 5-year mortality was 24·9% (95% CI 14·9-39·7) for IFN-high versus 8·6% (3·6-19·9) for IFN-low (p=0·052). INTERPRETATION:Serum IFN score assessment for patients with diffuse cutaneous systemic sclerosis could identify patients with high disease activity who are more likely to have worse 12-month prognosis and overall survival. FUNDING:National Scleroderma Foundation, National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases Rheumatic Disease Research Core Centers, National Institute of Health Research Leeds Biomedical Research Centre, and Kennedy Trust for Rheumatology Research.

OBJECTIVE:We aimed to evaluate the psychometric properties of the Scleroderma Skin Questionnaire (SSQ), a novel patient-reported outcome (PRO) to assess systemic sclerosis (SSc)-related skin symptoms. METHODS:Participants were recruited from the SSc Collaborative National Quality and Efficacy Registry (CONQUER). Internal consistency was determined using Cronbach α and McDonald ω total (ωt). The correlation of the SSQ was assessed with the modified Rodnan skin score (mRSS), physician global assessment (PGA), Scleroderma Health Assessment Questionnaire, 29-item Patient-Reported Outcomes Measurement Information System (PROMIS-29), and patient global assessment to assess criterion, convergent, and divergent validity. Correlations were also assessed between patients' self-reported recall of skin changes over the past 6 months ("SSQ 6-Month") and 6-month change in mRSS. RESULTS:The SSQ was administered to 799 adults (mean age 52.7; 83% female) enrolled in CONQUER. Cronbach α was 0.90 and ωt was 0.92, indicating high internal consistency. The SSQ was moderately correlated with mRSS (r 0.56), with stronger correlations in diffuse (r 0.54) vs limited cutaneous subtypes (r 0.24; all P < 0.05). The SSQ was also moderately-to-strongly correlated with PROMIS-29 physical function (r -0.50) and pain interference subscales (r 0.61), strongly with Health Assessment Questionnaire score (r 0.63) and severity subscale (r 0.62), and moderately with PGA SSc activity score (r 0.48; all P < 0.05). SSQ 6-Month correlated weakly with the 6-month change in mRSS (r 0.26; P < 0.05). CONCLUSION:SSQ demonstrated high reliability and moderate correlation with mRSS and legacy PROs. This study provides initial support for SSQ, but not SSQ 6-Month, to assess skin symptoms in patients with SSc.