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Objective: Accurate measurement of disease activity in systemic sclerosis (SSc) remains a significant clinical challenge. The Scleroderma Clinical Trials Consortium (SCTC) convened an Activity Index (AI) Working Group (WG) to develop a novel measure of disease activity (SCTC‐AI). Methods: Using consensus methodology, we developed a conceptual definition of disease activity. Literature review and expert consensus generated provisional SCTC‐AI items, which were reduced by Delphi survey. Provisional items were weighted against a combined endpoint of morbidity and mortality, using time‐dependent Cox proportional hazards regression analysis of the Australian Scleroderma Cohort Study (ASCS) (n = 1,254). External validation of the SCTC‐AI was performed using data collected from 1,103 Canadian Scleroderma Research Group Study participants. Results: Disease activity in SSc was defined using consensus methodology as "aspects of disease that are reversible, or can be arrested, with time and, or effective therapy." One‐hundred and forty‐one provisional SCTC‐AI items were generated and reduced using three rounds of Delphi survey and statistical reduction and weighting, against mortality and quality of life measures, yielding a final 24‐item index with a maximum possible score of 140. Survival analysis in an external cohort showed a graded relationship between disease activity scores and survival (P < 0.01). Conclusion: We present a novel instrument to quantify the burden of disease activity in SSc. We have employed a rigorous consensus‐based process in combination with data‐driven methods to develop an instrument that has face, content, and criterion validity. Further work is required to fully validate and confirm the construct and discriminative validity of the SCTC‐AI. [ABSTRACT FROM AUTHOR]

Objective: Facilitated self‐management interventions have the potential to enhance resilience and well‐being. We examined whether resilience is a mediator of improving physical and psychological symptoms for people with systemic sclerosis (SSc) who participated in a 12‐week online peer‐led symptom management intervention. Methods: We conducted a secondary data analysis from a randomized control trial comparing a peer health‐coached intervention to a waitlist control. Participants completed the Connor‐Davidson Resilience Scale, the Functional Assessment of Chronic Illness Therapy‐Fatigue scale, and the Patient Reported Outcomes Measurement Information System measures of pain interference and depressive symptoms at the baseline and at weeks 6 and 12. Linear mixed effect regression models were used to assess the effect of intervention on changes in resilience. Causal mediation analyses were conducted to examine whether changes in resilience at week 12 mediated intervention effects on changes in fatigue, pain interference, and depressive symptoms at week 12. Results: One hundred and seventy‐three eligible participants were enrolled. Participants in the intervention group reported improvements in resilience (P < 0.001). These changes in resilience mediated the intervention effects on fatigue with indirect effect of −1.41 (95% confidence interval [CI] −2.41 to −0.41), pain interference of −0.86 (95% CI −1.65 to −0.08), and depressive symptoms of −1.99 (95% CI −3.16 to −0.81). Conclusion: For participants in the intervention who had positive improvements in their physical and psychological symptoms, increased resilience was a mechanism for these improvements. These findings support the importance of addressing resilience to improve symptoms in similar SSc interventions. [ABSTRACT FROM AUTHOR]

Objective: We provide evidence‐based recommendations regarding the treatment of interstitial lung disease (ILD) in adults with systemic autoimmune rheumatic diseases (SARDs). Methods: We developed clinically relevant population, intervention, comparator, and outcomes questions. A systematic literature review was then performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A panel of clinicians and patients reached consensus on the direction and strength of the recommendations. Results: Thirty‐five recommendations were generated (including two strong recommendations) for first‐line SARD‐ILD treatment, treatment of SARD‐ILD progression despite first‐line ILD therapy, and treatment of rapidly progressive ILD. The strong recommendations were against using glucocorticoids in systemic sclerosis–ILD as a first‐line ILD therapy and after ILD progression. Otherwise, glucocorticoids are conditionally recommended for first‐line ILD treatment in all other SARDs. Conclusion: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the treatment of ILD in people with SARDs. [ABSTRACT FROM AUTHOR]

Objective: We provide evidence‐based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease. Methods: We developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation. Results: Fifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high‐resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6‐minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs. Conclusion: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs. [ABSTRACT FROM AUTHOR]

Objective: Patient engagement is critical to clinical practice guideline (CPG) development. This work presents our approach to ascertaining patients' values and preferences to inform the American College of Rheumatology guidelines for screening, monitoring, and treatment of interstitial lung disease (ILD) in people with systemic autoimmune rheumatic diseases (SARDs). Methods: We conducted a cross‐sectional qualitative study of a purposefully sampled Patient Panel using a modified content analytic approach. The study team reviewed text transcripts from the Patient Panel discussion to identify themes and develop a clustered thematic schema. Results: Twenty‐one patients (75% women) participated, with a mean age of 53 years (range 33–73). Patients had one or more SARDs: systemic sclerosis (38%), Sjögren disease (38%), idiopathic inflammatory myopathy (33%), rheumatoid arthritis (24%), and mixed connective tissue disease (10%). We identified 10 themes in 4 thematic clusters: communication, screening and monitoring, treatment goals, and treatment adverse effects. Patients prioritized recognizing ILD symptoms, importance of ILD screening and close monitoring, goals of survival and improving quality of life, and willingness to accept treatment risks provided that there is close communication with providers. Patient representatives shared patients' priorities and insight at the Voting Panel meeting, influencing multiple guideline recommendations. Conclusion: Patient engagement fosters a holistic approach to CPG development, leading to recommendations aiming for the best clinical outcomes while prioritizing outcomes important for patients. The patient‐identified themes played a critical role in ILD guideline development and provide core elements for shared decision‐making as clinicians make management and therapeutic decisions with patients with SARD‐associated ILD. [ABSTRACT FROM AUTHOR]

Objective: The evidence‐based DETECT pulmonary arterial hypertension (PAH) algorithm is frequently used in patients with systemic sclerosis (SSc) to help clinicians screen for PAH by using noninvasive data to recommend patient referral to echocardiography and, if applicable, for a diagnostic right‐sided heart catheterization. However, the hemodynamic definition of PAH was recently updated in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines. The performance of DETECT PAH in identifying patients with a high risk of PAH according to this new definition was assessed. Methods: In this post hoc analysis of DETECT, which comprised 466 patients with SSc, the performance of the DETECT PAH algorithm in identifying patients with a high risk of PAH as defined in the 2022 ESC/ERS guidelines (mean pulmonary arterial pressure [mPAP] >20 mm Hg, pulmonary capillary wedge pressure [PCWP] ≤15 mm Hg, and pulmonary vascular resistance >2 Wood units) was assessed using summary statistics and was descriptively compared to the known performance of DETECT PAH as defined in 2014, when it was developed (mPAP ≥25 mm Hg and PCWP ≤15 mm Hg). Results: The sensitivity of DETECT PAH in identifying patients with a high risk of PAH according to the 2022 ESC/ERS definition was lower (88.2%) compared to the 2014 definition (95.8%). Specificity improved from 47.8% to 50.8%. Conclusion: The performance of the DETECT algorithm to screen for PAH in patients with SSc is maintained when PAH is defined according to the 2022 ESC/ERS hemodynamic definition, indicating that DETECT remains applicable to screen for PAH in patients with SSc. [ABSTRACT FROM AUTHOR]

Objective: Supported self‐management interventions for individuals with systemic sclerosis (SSc) are needed. We examined the effects of a 12‐week resilience‐building energy management program (called RENEW) for fatigue and other patient‐reported outcomes. Methods: Participants, who had physician‐diagnosed SSc, moderate to severe fatigue, and were ≥18 years old, were randomly assigned to RENEW or waitlist control in a 2:1 ratio. The RENEW intervention included an educational website/application plus nine virtual peer‐led health coaching sessions. The primary outcome was change in the Functional Assessment of Chronic Illness Therapy‐Fatigue scale. Secondary outcomes were change in Patient Reported Outcomes Measurement Information System measures of pain interference and depressive symptoms and Connor‐Davidson Resilience Scale. Outcomes were assessed at baseline, 6 weeks, and 12 weeks. Multiple imputation was conducted; linear mixed models were used to assess group differences. A three‐way interaction with group, time, and SSc duration was examined in each model. Results: Among 173 participants (mean ± SD age 54.5 ± 11.7 years; 93% female, 85% White), 47% had diffuse cutaneous SSc; 57% were ≤5 years from diagnosis. At 12 weeks, compared to controls, RENEW participants had a clinically meaningful fatigue improvement (β = −4.7; 95% confidence interval −6.7 to −2.7; P < 0.001) and improvement in all secondary outcomes. Among RENEW participants, individuals with shorter disease duration had greater improvements in fatigue at 12 weeks. Conclusion: An mHealth supported self‐management intervention improved fatigue and other outcomes, particularly in newly diagnosed patients. This program may be broadly scalable for SSc symptom management. [ABSTRACT FROM AUTHOR]

Objective: To describe the health care resource use (HCRU) and costs of patients with systemic sclerosis (SSc) prior to and after diagnosis. Methods: This retrospective study used a claims data set (Merative MarketScan; 2015‐2019). Eligible patients with SSc were identified by diagnosis codes and required at least 24 months of enrollment without an SSc diagnosis before their first SSc claim and at least 12 months of enrollment thereafter. Total HCRU and costs were reported for three intervals: 2 years and 1 year before and 1 year after index diagnosis. A general population cohort without SSc was matched 1:1 to the SSC cohort on age and sex for comparison. Results: Eligibility criteria identified 902 patients with SSc (mean age: 54 years old; 85% female). Mean per‐member per year costs increased each year from $22,383 to $29,708 to $47,095, 2 years before, 1 year before, and 1 year after index diagnosis versus $10,232 to $9656 to $9714 in the general population cohort. Outpatient settings represented the largest proportion of cost 1 year after SSc diagnosis ($16,392), followed by prescription drugs ($10,692), physician office ($10,523), and inpatient ($9448) settings. Conclusion: Patients with SSC accrued greater costs and required more services than a general population cohort. These elevated expenditures and HCRU were observed at least 2 years before an SSc diagnosis and increased over time, reflecting both the progressive, multisystem nature of SSc and potential challenges in diagnosis. These findings suggest that SSc poses a substantial burden on the US health care system and highlights the need for early diagnosis and effective therapies. [ABSTRACT FROM AUTHOR]

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

Objective: Systemic sclerosis (SSc) is a multifactorial autoimmune fibrotic disorder involving complex rewiring of cell‐intrinsic and cell‐extrinsic signaling coexpression networks involving a range of cell types. However, the rewired circuits as well as corresponding cell–cell interactions remain poorly understood. To address this, we used a predictive machine learning framework to analyze single‐cell RNA‐sequencing data from 24 SSc patients across the severity spectrum as quantified by the modified Rodnan skin score (MRSS). Methods: We used a least absolute shrinkage and selection operator (LASSO)–based predictive machine learning approach on the single‐cell RNA‐sequencing data set to identify predictive biomarkers of SSc severity, both across and within cell types. The use of L1 regularization helps prevent overfitting on high‐dimensional data. Correlation network analyses were coupled to the LASSO model to identify cell‐intrinsic and cell‐extrinsic co‐correlates of the identified biomarkers of SSc severity. Results: We found that the uncovered cell type–specific predictive biomarkers of MRSS included previously implicated genes in fibroblast and myeloid cell subsets (e.g., SFPR2+ fibroblasts and monocytes), as well as novel gene biomarkers of MRSS, especially in keratinocytes. Correlation network analyses revealed novel cross‐talk between immune pathways and implicated keratinocytes in addition to fibroblast and myeloid cells as key cell types involved in SSc pathogenesis. We then validated the uncovered association of key gene expression and protein markers in keratinocytes, KRT6A and S100A8, with SSc skin disease severity. Conclusion: Our global systems analyses reveal previously uncharacterized cell‐intrinsic and cell‐extrinsic signaling coexpression networks underlying SSc severity that involve keratinocytes, myeloid cells, and fibroblasts. [ABSTRACT FROM AUTHOR]

Objective: This phase 3 study was undertaken to investigate the efficacy and safety of lenabasum, a cannabinoid type 2 receptor agonist, in patients with diffuse cutaneous systemic sclerosis (dcSSc). Methods: A multinational double‐blind study was conducted in 365 dcSSc patients who were randomized and dosed 1:1:1 with lenabasum 20 mg, lenabasum 5 mg, or placebo, each twice daily and added to background treatments, including immunosuppressive therapies (IST). Results: The primary end point, the American College of Rheumatology combined response index in dcSSc (CRISS) at week 52 for lenabasum 20 mg twice a day versus placebo, was not met, with CRISS score of 0.888 versus 0.887 (P = 0.4972, using mixed models repeated measures [MMRM]). The change in the modified Rodnan skin thickness score (MRSS) at week 52 for lenabasum 20 mg twice a day versus placebo was −6.7 versus −8.1 (P = 0.1183, using MMRM). Prespecified analyses showed higher CRISS scores, greater improvement in MRSS, and lower decline in forced vital capacity in patients on background mycophenolate and those who were taking IST for ≤1 year. No deaths or excess in serious or severe adverse events related to lenabasum were observed. Conclusion: A benefit of lenabasum in dcSSc was not demonstrated. Most patients were treated with background IST, and treatment with mycophenolate mofetil in particular was associated with better outcomes. These findings support the use of IST in the treatment of dcSSc and highlight the challenge of demonstrating a treatment effect when investigational treatment is added to standard of care IST. These findings have relevance to trial design in SSc, as well as to clinical care. [ABSTRACT FROM AUTHOR]

Objective: We undertook this study to explore the efficacy, safety, and tolerability of ziritaxestat, a selective autotaxin inhibitor, in patients with early diffuse cutaneous systemic sclerosis (dcSSc). Methods: NOVESA was a 24‐week, multicenter, phase IIa, double‐blind, placebo‐controlled study. Adults with dcSSc were randomized to oral ziritaxestat 600 mg once daily or matching placebo. The primary efficacy end point was change from baseline in modified Rodnan skin score (MRSS) at week 24. Secondary end points assessed safety and tolerability; other end points included assessment of skin and blood biomarkers. Patients in NOVESA could enter a 104‐week open‐label extension (OLE). Results: Patients were randomized to ziritaxestat (n = 21) or placebo (n = 12). Reduction in MRSS was significantly greater in the ziritaxestat group versus the placebo group (–8.9 versus –6.0 units, respectively; P = 0.0411). Placebo patients switching to ziritaxestat in the OLE showed similar reductions in MRSS to those observed for ziritaxestat patients in the parent study. Ziritaxestat was well tolerated; the most frequent treatment‐related treatment‐emergent adverse events were headache and diarrhea. Circulating lysophosphatidic acid (LPA) C18:2 was significantly reduced, demonstrating ziritaxestat target engagement, and levels of fibrosis biomarkers were reduced in the blood. No differentially expressed genes were identified in skin biopsies. Significant changes in 109 genes were identified in blood samples. Conclusion: Ziritaxestat resulted in significantly greater reduction in MRSS at week 24 than placebo; no new safety signals emerged. Biomarker analysis suggests ziritaxestat may reduce fibrosis. Modulation of the autotaxin/LPA pathway could improve skin involvement in patients with dcSSc. A plain language summary is provided in the Supplementary Material, available on the Arthritis & Rheumatology website at https://onlinelibrary.wiley.com/doi/10.1002/art.42477. [ABSTRACT FROM AUTHOR]

Objective: To develop, refine, and score a novel patient‐reported outcome instrument to assess the severity and impact of Raynaud's phenomenon (RP) in systemic sclerosis (SSc). Methods: The Assessment of Systemic Sclerosis–Associated Raynaud's Phenomenon (ASRAP) questionnaire items were developed with patient insight partner support and grounded in the lived patient experience of SSc‐RP. ASRAP items underwent formal qualitative assessment and linguistic testing. An international multicenter study was undertaken to field test the preliminary ASRAP questionnaire. Results: A preliminary 37‐item ASRAP questionnaire was supplemented with 2 additional items following expert review to enhance content coverage before undergoing formal linguistic testing to optimize readability. Patient cognitive debriefing interviews were undertaken to enhance comprehension, ambiguity, cognitive difficulty, relevance, and content coverage of both the ASRAP items and instructions. We enrolled 420 SSc patients from scleroderma centers in the UK and US over 2 consecutive winters. Factor analysis with item response theory was undertaken to remove redundant and poorly fitting items. The retained 27‐item long‐form ASRAP questionnaire was calibrated and scored using the graded response model. A fixed 10‐item short‐form ASRAP questionnaire was developed using computerized adaptive testing simulations. Conclusion: The ASRAP questionnaire has been developed with extensive SSc patient input, with items grounded in the lived experience of SSc‐RP to ensure strong content validity, with a focus on how patients feel and function. An advanced psychometric approach with expert input has removed redundant and/or poorly fitting items without eroding content validity. Long‐ and short‐form ASRAP questionnaires have been calibrated and scored to permit formal validation. [ABSTRACT FROM AUTHOR]

Objective: Perceived cognitive dysfunction is prevalent in patients with systemic sclerosis (SSc) but not well understood. This study aimed to examine potential factors associated with perceived cognitive function and to investigate the contributions of perceived cognitive function and symptoms to functional measures. Methods: A cross‐sectional survey was conducted among patients with SSc (n = 106). Participants were mainly female (84%) and White (82%). Perceived cognitive function, symptoms, and functional measures were assessed with Patient‐Reported Outcomes Measurement Information System (PROMIS) measures. A multivariable regression was conducted to identify factors associated with perceived cognition. Hierarchical linear regressions examined the unique contributions of perceived cognitive function and symptoms to social participation and physical function. Results: Fifty‐nine (56%) patients with SSc perceived mild‐to‐severe cognitive dysfunction. Being on work disability and having more fatigue were both significantly associated with perceived cognitive dysfunction. When examining the contributions of cognition and other symptoms to functional measures, self‐reported cognition became nonsignificant after fatigue and pain were entered into the regression model. Conclusion: Being on work disability and having more fatigue were most highly associated with perceived cognitive dysfunction in patients with SSc. Unlike fatigue and pain, perceived cognitive function was not independently associated with functional measures. Nonetheless, future research should disentangle cognitive function and other symptoms, as well as their effects on daily activities, in SSc. [ABSTRACT FROM AUTHOR]

Global assessments of disease by both patients and physicians are widely used in clinical studies of systemic sclerosis (SSc). They are commonly secondary end points in randomized controlled trials (RCTs) and are considered important items in composite measures of treatment response. A comprehensive literature review was conducted of the formats, wording, and clinimetric properties of the patient global assessment of disease status (PtGA) and physician global assessment of disease status (PhGA) used in RCTs of SSc. Marked heterogeneity was found in the wording and measurement scales of the global assessments applied in RCTs. These instruments were not developed using rigorous methodology and have not been fully validated. There is a pressing need for standardization and validation of patient and physician global assessment tools in SSc to enable universal application of these measures across RCTs in SSc. [ABSTRACT FROM AUTHOR]

Objective: Systemic sclerosis (SSc) patients are classified according to degree of skin fibrosis (limited and diffuse cutaneous [lc and dc]) and serum autoantibodies. We undertook the present multicenter study to determine whether intrinsic subset (IS) classification based upon skin gene expression yields additional valuable clinical information. Methods: SSc patients and healthy participants (HPs) were classified into Normal‐like, Limited, Fibroproliferative, and Inflammatory ISs using a previously trained classifier. Clinical data were obtained (serum autoantibodies, pulmonary function testing, modified Rodnan skin thickness scores [mRSS], and high‐resolution chest computed tomography [HRCT]). Statistical analyses were performed to compare patients classified by IS, traditional cutaneous classification, and serum autoantibodies. Results: A total of 223 participants (165 SSc [115 dcSSc and 50 lcSSc] and 58 HPs) were classified. Inflammatory IS patients had higher mRSS (22.1 ± 9.9; P < 0.001) than other ISs and dcSSc patients (19.4 ± 9.4; P = 0.05) despite similar disease duration (median [interquartile range] months 14.9 [19.9] vs. 18.4 [31.6]; P = 0.48). In multivariable modeling, no significant association between mRSS and RNA polymerase III (P = 0.07) or anti–topoisomerase I (Scl‐70) (P = 0.09) was found. Radiographic interstitial lung disease (ILD) was more prevalent in Fibroproliferative IS compared with other ISs (91%; P = 0.04) with similar prevalence between lcSSc and dcSSc (67% vs. 76%; P = 0.73). Positive Scl‐70 antibody was the strongest ILD predictor (P < 0.001). Interestingly, all lcSSc/Fibroproliferative patients demonstrated radiographic ILD. Conclusions: Classification by IS identifies patients with distinct clinical phenotypes versus traditional cutaneous or autoantibody classification. IS classification identifies subgroups of SSc patients with more radiographic ILD (Fibroproliferative), higher mRSS (Inflammatory), and milder phenotype (Normal‐like) and may provide additional clinically useful information to current SSc classification systems. [ABSTRACT FROM AUTHOR]

Objective: Patients with diffuse cutaneous systemic sclerosis (dcSSc) display a complex clinical phenotype. Transcriptional profiling of whole blood or tissue from patients are affected by changes in cellular composition that drive gene expression and an inability to detect minority cell populations. We undertook this study to focus on the 2 main subtypes of circulating monocytes, classical monocytes (CMs) and nonclassical monocytes (NCMs) as a biomarker of SSc disease severity. Methods: SSc patients were recruited from the Prospective Registry for Early Systemic Sclerosis. Clinical data were collected, as well as peripheral blood for isolation of CMs and NCMs. Age‐, sex‐, and race‐matched healthy volunteers were recruited as controls. Bulk macrophages were isolated from the skin in a separate cohort. All samples were assayed by RNA sequencing (RNA‐seq). Results: We used an unbiased approach to cluster patients into 3 groups (groups A–C) based on the transcriptional signatures of CMs relative to controls. Each group maintained their characteristic transcriptional signature in NCMs. Genes up‐regulated in group C demonstrated the highest expression compared to the other groups in SSc skin macrophages, relative to controls. Patients from groups B and C exhibited worse lung function than group A, although there was no difference in SSc skin disease at baseline, relative to controls. We validated our approach by applying our group classifications to published bulk monocyte RNA‐seq data from SSc patients, and we found that patients without skin disease were most likely to be classified as group A. Conclusion: We are the first to show that transcriptional signatures of CMs and NCMs can be used to unbiasedly stratify SSc patients and correlate with disease activity outcome measures. [ABSTRACT FROM AUTHOR]

Objective: To better understand the symptoms and impacts of Raynaud phenomenon (RP) in patients with systemic sclerosis (SSc) and to evaluate the content validity and usability of a new electronic patient‐reported outcome (PRO) measure for RP: the Raynaud Diary. Methods: The Raynaud Diary was developed as a daily eDiary for assessing the number and duration of symptomatic Raynaud attacks; worst pain, numbness, tingling, and discomfort in the fingers; and overall disease severity, captured using the Raynaud's Condition Score. The Raynaud Diary was debriefed in two waves of qualitative interviews with adults with self‐reported RP secondary to SSc. All interviews included open‐ended questions about participants' experiences of RP. Results: Participants (N = 39) had a mean age of 55.1 years, and 87% were female. Frequently reported RP symptoms were color change (reported by all participants), numbness (90%), tingling (82%), pain (77%), and discomfort (72%). Common attack triggers included temperature‐related factors and stress. Participants reported being unable to be outside or do outdoor activities and had problems gripping objects. All participants demonstrated understanding of the Raynaud Diary instructions. Most participants indicated that they would be able to use the Raynaud Diary to record the worst severity of individual RP symptoms in the previous 24 hours. Conclusion: Patients with RP secondary to SSc bear a heavy symptom burden. The Raynaud Diary is a content valid PRO measure that captures the most frequent symptoms of RP in patients with SSc. [ABSTRACT FROM AUTHOR]

Objective: Among individuals with systemic sclerosis (SSc) randomized to cyclophosphamide (CYC) (n = 34) or hematopoietic stem cell transplantation (HSCT) (n = 33), we examined longitudinal trends of clinical, pulmonary function, and quality of life measures while accounting for the influence of early failures on treatment comparisons. Methods: Assuming that data were missing at random, mixed‐effects regression models were used to estimate longitudinal trends for clinical measures when comparing treatment groups. Results were compared to observed means and to longitudinal trends estimated from shared parameter models, assuming that data were missing not at random. Longitudinal trends for SSc intrinsic molecular subsets defined by baseline gene expression signatures (normal‐like, inflammatory, and fibroproliferative signatures) were also studied. Results: Available observed means for pulmonary function tests appeared to improve over time in both arms. However, after accounting for participant loss, forced vital capacity in HSCT recipients increased by 0.77 percentage points/year but worsened by –3.70/year for CYC (P = 0.004). Similar results were found for diffusing capacity for carbon monoxide and quality of life indicators. Results for both analytic models were consistent. HSCT recipients in the inflammatory (n = 20) and fibroproliferative (n = 20) subsets had superior long‐term trends compared to CYC for pulmonary and quality of life measures. HSCT was also superior for modified Rodnan skin thickness scores in the fibroproliferative subset. For the normal‐like subset (n = 22), superiority of HSCT was less apparent. Conclusion: Longitudinal trends estimated from 2 statistical models affirm the efficacy of HSCT over CYC in severe SSc. Failure to account for early loss of participants may distort estimated clinical trends over the long term. [ABSTRACT FROM AUTHOR]

Objective: Hand dysfunction is common in systemic sclerosis (SSc). We undertook this study to evaluate the capacity of autologous adipose‐derived regenerative cells (ADRCs) to improve hand function in SSc patients. Methods: The Scleroderma Treatment with Celution Processed Adipose Derived Regenerative Cells Trial was a prospective, randomized, double‐blind trial of ADRCs, in which ADRCs were obtained from patients with SSc by small‐volume adipose tissue harvest, and the fingers of each patient were injected with ADRCs. The primary end point was change in hand function at 24 and 48 weeks, assessed using the Cochin Hand Function Scale (CHFS). One of the secondary end points included the change in Health Assessment Questionnaire disability index (HAQ DI) at 48 weeks. Separate prespecified analyses were performed for patients with diffuse cutaneous SSc (dcSSc) and those with limited cutaneous SSc (lcSSc). Results: Eighty‐eight patients were randomized to receive ADRCs (n = 48 [32 patients with dcSSc and 16 with lcSSc]) or placebo (n = 40 [19 patients with dcSSc and 21 with lcSSc]). Change in hand function according to CHFS score was numerically higher for the ADRC group compared to the placebo group but did not achieve statistical significance (mean ± SD improvement in the CHFS score at 48 weeks 11.0 ± 12.5 versus 8.9 ± 10.5; P = 0.299). For patients with dcSSc, the between‐group difference in the CHFS at 48 weeks was 6.3 points (nominal P = 0.069). For the secondary end point, the dcSSc group exhibited a between‐group difference of 0.17 points in the HAQ DI (nominal P = 0.044) at 48 weeks. Of the ADRC‐treated patients with dcSSc, 52% reported improvement greater than the minimum clinically important difference for both CHFS and HAQ DI compared to 16% in the placebo group (nominal P = 0.016). Small‐volume adipose tissue harvest and ADRC treatment were well tolerated. Conclusion: While the primary end point of this trial was not achieved, efficacy trends were observed in patients with dcSSc. Adipose tissue harvest and ADRC injection were demonstrated to be feasible. Further clinical trials of this intervention in the setting of dcSSc are warranted. [ABSTRACT FROM AUTHOR]

Objective: Although a high‐resolution computed tomography (HRCT) scan of the chest is the gold standard test for the detection of interstitial lung disease (ILD), there is no consensus among rheumatologists regarding the use of HRCT to screen for ILD in their patients with systemic sclerosis (SSc). The aims of this study were to describe the HRCT ordering practices at SSc centers in the United States and to determine which patient characteristics are associated with HRCT performance. Methods: We performed a prospective cohort study of patients with SSc enrolled in the US‐based Collaborative National Quality and Efficacy Registry (CONQUER). We performed univariate logistic regression followed by multivariable logistic regression to determine which patient characteristics were associated with HRCT performance. Results: Of the 356 patients with SSc enrolled in CONQUER, 286 (80.3%) underwent HRCT at some point during their disease course. On multivariable analyses, missing total lung capacity percent predicted (odds ratio [OR] 3.26, 95% confidence interval [CI]: 1.53‐7.41, P = 0.007) was positively associated with ever having undergone HRCT, whereas a positive anti‐centromere antibody (OR 0.27, 95% CI: 0.12‐0.61, P = 0.008) and missing forced vital capacity percent predicted (OR 0.29, 95% CI: 0.10‐0.80, P = 0.005) were negatively associated with ever having undergone HRCT. There was a trend toward a positive association between crackles on pulmonary exam and ever having undergone HRCT (OR 2.28, 95% CI: 0.97‐6.05, P = 0.058), although this relationship did not reach statistical significance. Conclusion: The majority of patients with SSc enrolled in CONQUER underwent HRCT. A positive anti‐centromere antibody was the key clinical variable inversely associated with performance of HRCT. [ABSTRACT FROM AUTHOR]

Objective: Using data from the SENSCIS trial, these analyses were undertaken to assess the effects of nintedanib versus placebo in subgroups of patients with systemic sclerosis–associated interstitial lung disease (SSc‐ILD), based on characteristics previously identified as being associated with the progression of SSc‐ILD. Methods: Patients with SSc‐ILD were randomized to receive either nintedanib or placebo, stratified by anti–topoisomerase I antibody (ATA) status. We assessed the rate of decline in forced vital capacity (FVC) (expressed in ml/year) over 52 weeks in subgroups based on baseline ATA status, modified Rodnan skin thickness score (MRSS) (<18 versus ≥18), and SSc subtype (limited cutaneous SSc [lcSSc] versus diffuse cutaneous SSc [dcSSc]). Results: At baseline, 60.8% of 576 patients who received treatment with either nintedanib or placebo were positive for ATA, 51.9% had dcSSc, and 77.5% of 574 patients with MRSS data available had an MRSS of <18. The effect of nintedanib versus placebo on reducing the rate of decline in FVC (ml/year) was numerically more pronounced in ATA‐negative patients compared to ATA‐positive patients (adjusted difference in the rate of FVC decline, 57.2 ml/year [95% confidence interval (95% CI) –3.5, 118.0] versus 29.9 ml/year [95% CI –19.1, 78.8]), in patients with a baseline MRSS ≥18 compared to those with a baseline MRSS of <18 (adjusted difference in the rate of FVC decline, 88.7 ml/year [95% CI 7.7, 169.8] versus 26.4 ml/year [95% CI –16.8, 69.6]), and in patients with dcSSc compared to those with lcSSc (adjusted difference in the rate of FVC decline, 56.6 ml/year [95% CI 3.2, 110.0] versus 25.3 ml/year [95% CI –28.9, 79.6]). However, all exploratory interaction P values were nonsignificant (all P > 0.05), indicating that there was no heterogeneity in the effect of nintedanib versus placebo between these subgroups of patients. Conclusion: In patients with SSc‐ILD, reduction in the annual rate of decline in FVC among patients receiving nintedanib compared to those receiving placebo was not found to be heterogenous across subgroups based on ATA status, MRSS, or SSc subtype. Video Abstract [ABSTRACT FROM AUTHOR]

Objective: In this study, we sought a comprehensive understanding of myeloid cell types driving fibrosis in diffuse cutaneous systemic sclerosis (dcSSc) skin. Methods: We analyzed the transcriptomes of 2,465 myeloid cells from skin biopsy specimens from 12 dcSSc patients and 10 healthy control subjects using single‐cell RNA sequencing. Monocyte‐derived dendritic cells (mo‐DCs) were assessed using immunohistochemical staining and immunofluorescence analyses targeting ficolin‐1 (FCN‐1). Results: A t‐distributed stochastic neighbor embedding analysis of single‐cell transcriptome data revealed 12 myeloid cell clusters, 9 of which paralleled previously described healthy control macrophage/DC clusters, and 3 of which were dcSSc‐specific myeloid cell clusters. One SSc‐associated macrophage cluster, highly expressing Fcγ receptor IIIA, was suggested on pseudotime analysis to be derived from normal CCR1+ and MARCO+ macrophages. A second SSc‐associated myeloid population highly expressed monocyte markers FCN‐1, epiregulin, S100A8, and S100A9, but was closely related to type 2 conventional DCs on pseudotime analysis and identified as mo‐DCs. Mo‐DCs were associated with more severe skin disease. Proliferating macrophages and plasmacytoid DCs were detected almost exclusively in dcSSc skin, the latter clustering with B cells and apparently derived from lymphoid progenitors. Conclusion: Transcriptional signatures in these and other myeloid populations indicate innate immune system activation, possibly through Toll‐like receptors and highly up‐regulated chemokines. However, the appearance and activation of myeloid cells varies between patients, indicating potential differences in the underlying pathogenesis and/or temporal disease activity in dcSSc. [ABSTRACT FROM AUTHOR]

Aim: Interstitial lung disease (ILD) is the leading cause of disease‐related death in systemic sclerosis (SSc). Here, we assess baseline characteristics of SSc subjects with and without restrictive lung disease (RLD) in a multi‐center, US‐based registry. Methods: SSc patients within 5 years of disease onset were enrolled in the Collaborative National Quality and Efficacy Registry (CONQUER), a multi‐center US‐based registry of SSc study participants (age ≥ 18 years) enrolled at 13 expert centers. All subjects met 2013 American College of Rheumatology / European League Against Rheumatism criteria. Subjects with a pulmonary function test (PFT) at baseline before April 1, 2020 were included. High‐resolution computed tomography scan of the chest was not available to characterize ILD for all subjects. RLD was defined as forced vital capacity (FVC) <80% or total lung capacity (TLC) <80% predicted. Results: There were 160 (45%) SSc subjects characterized as having RLD. There was no significant difference in age, gender or disease duration. RLD subjects had a mean disease duration from date of first non‐Raynaud's symptom of 2.6 years and a mean FVC% predicted of 67% at baseline. In multivariable analysis, non‐White race, higher physician global health assessment and modified Medical Research Council (mMRC) dyspnea scores, were independently associated with RLD. In the subgroup of RLD subjects with ILD, ILD had a negative correlation with RNA polymerase III antibody. Conclusion: CONQUER is the largest, multi‐center, prospective cohort of early SSc patients in the US. Non‐White race was independently associated with RLD. In addition, 45% of CONQUER subjects already had RLD, highlighting the importance of screening for SSc‐ILD at initial diagnosis. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc; scleroderma) has the highest individual mortality of all rheumatic diseases, and interstitial lung disease (ILD) is among the leading causes of SSc‐related death. Two drugs are now approved by the US Food and Drug Administration (FDA) and indicated for slowing the rate of decline in pulmonary function in patients with SSc‐associated ILD (SSc‐ILD): nintedanib (a tyrosine kinase inhibitor) and tocilizumab (the first biologic agent targeting the interleukin‐6 pathway in SSc). In addition, 2 generic drugs with cytotoxic and immunoregulatory activity, mycophenolate mofetil and cyclophosphamide, have shown comparable efficacy in a phase II trial but are not FDA‐approved for SSc‐ILD. In light of the heterogeneity of the disease, the optimal therapeutic strategy for the management of SSc‐ILD is still to be determined. The objectives of this review are 2‐fold: 1) review the body of research focused on the diagnosis and treatment of SSc‐ILD; and 2) propose a practical approach for diagnosis, stratification, management, and therapeutic decision‐making in this clinical context. This review presents a practical classification of SSc patients in terms of disease severity (subclinical versus clinical ILD) and associated risk of progression (low versus high risk). The pharmacologic and nonpharmacologic options for first‐ and second‐line therapy, as well as potential combination approaches, are discussed in light of the recent approval of tocilizumab for SSc‐ILD. [ABSTRACT FROM AUTHOR]

Objective: To systematically review evidence of rehabilitation interventions for improving outcomes in systemic sclerosis (SSc) and to evaluate evidence quality. Methods: Several electronic databases were searched to identify studies in which rehabilitation professionals delivered, supervised, or participated in interventions for individuals with SSc. Randomized controlled trials (RCTs) or non‐randomized trials, one‐arm trials, and prospective quasi‐experimental studies with interventions were included if they had ≥10 participants. Quality appraisal was conducted by 2 independent raters using the Physiotherapy Evidence Database (PEDro) Scale. Results: A total of 16 good or excellent quality studies (15 RCTs, 1 prospective quasi‐experimental study) were included. Most rehabilitation interventions focused on hands/upper extremities, followed by multicomponent, orofacial, and directed self‐management. Sample sizes varied between 20–267 participants (median 38). In 50% of studies, participants in intervention groups significantly improved compared to controls. Most studies demonstrated within‐group improvements in intervention groups. Interventions varied in content, delivery, length, and dose and outcome measures collected. Conclusion: Existing evidence provides some support for rehabilitation in SSc, such as interventions that focus on hand and upper extremity outcomes or are multicomponent, although there is high study heterogeneity. The evidence base would benefit from interventions testing similar replicable components, use of common outcome measures, and incorporation of delivery modes that enable larger sample sizes. There are challenges in recruiting participants due to the rarity of SSc and high disease burden, as participants' involvement in rehabilitation studies requires active participation over time. Intervention studies designed to reduce participation barriers may facilitate translation of effective interventions into practice. [ABSTRACT FROM AUTHOR]

Objective: To explore patient priorities and ranking of factors influencing patient decision-making concerning treatment escalation in the management of Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc).Methods: Patients with SSc were invited to participate in an online survey disseminated through patient-led organizations and social media platforms.Results: Responses from 747 individuals with self-reported SSc-RP were evaluable with broad international representation. The mean ± SD age (54.7 ± 12.1 years), clinical phenotype, and disease subsets distribution (limited cutaneous SSc [402 of 747, 53.8%], diffuse cutaneous SSc [260 of 747, 34.8%], and overlap disease [85 of 747, 11.4%]) were consistent with expected demographic information. Around one-half (56.3%) of patients reported that their SSc-RP symptoms were adequately controlled. The 5 highest ranked factors (of 13) that would prompt treatment escalation for SSc-RP were as follows: 1) inability to use the fingers properly; 2) emergence of new digital ulcer on ≥1 fingers; 3) worsening pain or discomfort from RP; 4) more severe attacks; and 5) if it may help with internal problems. Despite symptoms not being adequately controlled, 47.1% were concerned about potential treatment side effects and were more likely to accept mild (~20-40%) versus severe (2%) side effects. Patients were open to different management strategies for uncontrolled RP that included adding new treatment in combination with existing treatment (52.8%), drug substitution (40.9%), increasing the current dose (28.8%), or focusing on nonpharmacologic approaches (29.7%).Conclusion: We have identified the relative importance of different factors influencing patient preferences for treatment decision-making regarding SSc-RP. Side-effect profiles influence acceptability of drug treatments, and many patients report a preference for nonpharmacologic management of SSc-RP. [ABSTRACT FROM AUTHOR]

Objective: Pulmonary arterial hypertension (PAH) is one of the leading causes of mortality in systemic sclerosis (SSc). This study was undertaken to assess predictive accuracies of the DETECT algorithm and the 2015 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines in SSc patients who underwent right‐sided heart catheterization (RHC) for pulmonary hypertension (PH) evaluation. Methods: Patients with SSc who had diagnostic RHC, had no PH or had PAH, and had available data on variables to allow application of the DETECT and 2015 ESC/ERS guidelines were included for analysis. PH classification was based on hemodynamics using the 2018 revised criteria and extent of lung fibrosis shown on high‐resolution computed tomography. Sensitivity and predictive accuracies of the DETECT algorithm and 2015 ESC/ERS guidelines were calculated, including analysis of subjects with a diffusing capacity for carbon monoxide (DLco) of ≥60% predicted. Results: Sixty‐eight patients with SSc had RHC, of whom 58 had no PH and 10 had PAH. The mean age was 60.0 years, and 58.8% had limited cutaneous SSc. The DETECT algorithm had a sensitivity of 1.00 (95% confidence interval [95% CI] 0.69–1.00) and a negative predictive value (NPV) of 1.00 (95% CI 0.80–1.00), whereas the 2015 ESC/ERS guidelines had a sensitivity of 0.80 (95% CI 0.44–0.97) and an NPV of 0.94 (95% CI 0.81–0.99). In patients with a DLco of ≥60% (n = 27), the DETECT algorithm had a sensitivity of 1.00 (95% CI 0.29–1.00) and an NPV of 1.00 (95% CI 0.59–1.00), whereas the 2015 ESC/ERS guidelines had a sensitivity of 0.67 (95% CI 0.09–0.99) and an NPV of 0.94 (95% CI 0.71–1.00). Conclusion: The DETECT algorithm has high sensitivity and NPV for diagnosis of PAH, including among individuals with a DLco of ≥60%. [ABSTRACT FROM AUTHOR]

Objective: Pegloticase is used for the treatment of severe gout, but its use is limited by immunogenicity. This study was undertaken to evaluate whether mycophenolate mofetil (MMF) prolongs the efficacy of pegloticase. Methods: Participants were randomized 3:1 to receive 1,000 mg MMF twice daily or placebo for 14 weeks, starting 2 weeks before receiving pegloticase and continuing while receiving intravenous pegloticase 8 mg biweekly for 12 weeks. Participants then received pegloticase alone from week 12 to week 24. The primary end points were the proportion of patients who sustained a serum urate level of ≤6 mg/dl at 12 weeks and the rate of adverse events (AEs). Secondary end points included 24‐week durability of serum urate level ≤6 mg/dl. Fisher's exact test and Wilcoxon's 2‐sample test were used for analyses, along with Kaplan‐Meier estimates and log rank tests. Results: A total of 32 participants received ≥1 dose of pegloticase. Participants were predominantly men (88%), with a mean age of 55.2 years, mean gout duration of 13.4 years, and mean baseline serum urate level of 9.2 mg/dl. At 12 weeks, a serum urate level of ≤6 mg/dl was achieved in 19 (86%) of 22 participants in the MMF arm compared to 4 (40%) of 10 in the placebo arm (P = 0.01). At week 24, the serum urate level was ≤6 mg/dl in 68% of MMF‐treated patients versus 30% of placebo‐treated patients (P = 0.06), and rates of AEs were similar between groups, with more infusion reactions occurring in the placebo arm (30% versus 0%). Conclusion: Our findings indicate that MMF therapy with pegloticase is well tolerated and shows a clinically meaningful improvement in targeted serum urate level of ≤6 mg/dl at 12 and 24 weeks. This study suggests an innovative approach to pegloticase therapy in gout. [ABSTRACT FROM AUTHOR]

Objective: Systemic sclerosis (SSc) is characterized by widespread fibrosis and vascular complications. This study was undertaken to examine the chromatin landscape and transcription factor footprints in SSc, using an assay for genome‐wide chromatin accessibility. Methods: Dermal endothelial cells (ECs) and fibroblasts were isolated from healthy controls and patients with diffuse cutaneous SSc (dcSSc). Assay for transposase‐accessible chromatin with sequencing (ATAC‐seq) was performed to assess genome‐wide chromatin accessibility at a read depth of ~150 million reads per sample. Transcription factor footprinting and motif binding analysis were performed, followed by functional experiments. Results: Chromatin accessibility was significantly reduced in dcSSc patients compared to healthy controls. Differentially accessible chromatin loci were enriched in pathways and gene ontologies involved in the nervous system, cell membrane projections and cilia motility, nuclear and steroid receptors, and nitric oxide. In addition, chromatin binding of transcription factors SNAI2, ETV2, and ELF1 was significantly increased in dcSSc ECs, while recruitment of RUNX1 and RUNX2 was enriched in dcSSc fibroblasts. We found significant down‐regulation of the neuronal gene NRXN1 and up‐regulation of SNAI2 and ETV2 in dcSSc ECs. In dcSSc fibroblasts, down‐regulation of the neuronal gene ENTPD1 and up‐regulation of RUNX2 were confirmed. Further functional analysis revealed that ETV2 and NRXN1 dysregulation affected angiogenesis in ECs, while ENTPD1 enhanced profibrotic properties in dcSSc fibroblasts. Conclusion: Our data identify the chromatin blueprint of dcSSc, and suggest that neuronal‐related characteristics of SSc ECs and fibroblasts could be a culprit for dysregulated angiogenesis and enhanced fibrosis. Targeting the key pathways and transcription factors identified might present novel therapeutic approaches in SSc. [ABSTRACT FROM AUTHOR]

Objective: Tocilizumab (TCZ) has demonstrated lung function preservation in 2 randomized controlled trials in early systemic sclerosis (SSc). This effect has yet to be characterized in terms of radiographically evident quantitative lung involvement. We undertook this study to assess the impact of TCZ on lung function preservation in a post hoc analysis, stratifying treatment arms according to the degree of lung involvement. Methods: The focuSSced trial was a phase III randomized placebo‐controlled trial of TCZ in patients with SSc and progressive skin disease. Participants underwent baseline and serial spirometry along with high‐resolution chest computed tomography at baseline and at week 48. Quantitative interstitial lung disease (QILD) and fibrosis scores were assessed by computer software. We classified QILD into the following categories of lung involvement: mild (>5–10%), moderate (>10–20%), and severe (>20%). Results: Of 210 participants recruited for the trial, 136 patients (65%) had ILD. The majority of these patients (77%) had moderate‐to‐severe involvement (defined as >10% lung involvement). The TCZ arm demonstrated preservation of forced vital capacity percent predicted (FVC%) over 48 weeks (least squares mean change in FVC% = −0.1) compared to placebo (−6.3%). For mild, moderate, and severe QILD, the mean ± SD change in FVC% in the TCZ arm at 48 weeks were −4.1 ± 2.5% (n = 11), 0.7 ± 1.9% (n =19), and 2.1 ± 1.6% (n = 26), respectively, and in the placebo group were −10.0 ± 2.6% (n = 11), −5.7 ± 1.6% (n = 26), and −6.7 ± 2.0% (n = 16), respectively. Similar treatment‐related preservation findings were seen independent of fibrosis severity. Conclusion: TCZ in early SSc–associated ILD with progressive skin disease stabilized FVC% over 48 weeks, independent of the extent of radiographically evident QILD. [ABSTRACT FROM AUTHOR]

Objective: Response to immunosuppression is highly variable in systemic sclerosis (SSc)–related interstitial lung disease (ILD). This study was undertaken to determine whether a composite serum interferon (IFN)–inducible protein score exhibits predictive significance for the response to immunosuppression in SSc‐ILD. Methods: Serum samples collected in the Scleroderma Lung Study II, a randomized controlled trial of mycophenolate mofetil (MMF) versus cyclophosphamide (CYC), were examined. Results were validated in an independent observational cohort receiving active treatment. A composite score of 6 IFN‐inducible proteins IFNγ‐inducible 10‐kd protein, monokine induced by IFNγ, monocyte chemotactic protein 2, β2‐microglobulin, tumor necrosis factor receptor type II, and macrophage inflammatory protein 3β) was calculated, and its predictive significance for longitudinal forced vital capacity percent predicted measurements was evaluated. Results: Higher baseline IFN‐inducible protein score predicted better response over 3 to 12 months in the MMF arm (point estimate = 0.41, P = 0.001) and CYC arm (point estimate = 0.91, P = 0.009). In contrast, higher baseline C‐reactive protein (CRP) levels were predictive of a worse ILD course in both treatment arms. The predictive significance of the IFN‐inducible protein score and CRP levels remained after adjustment for baseline demographic and clinical predictors. During the second year of treatment, in which patients in the CYC arm were switched to placebo, a higher IFN‐inducible protein score at 12 months showed a trend toward predicting a worse ILD course (point estimate = −0.61, P = 0.068), while it remained predictive of better response to active immunosuppression in the MMF arm (point estimate = 0.28, P = 0.029). The predictive significance of baseline IFN‐inducible protein score was replicated in the independent cohort (rs = 0.43, P = 0.028). Conclusion: A higher IFN‐inducible protein score in SSc‐ILD is predictive of better response to immunosuppression and could potentially be used to identify patients who may derive the most benefit from MMF or CYC. [ABSTRACT FROM AUTHOR]

Objective: Data on the magnitude of benefit of modern therapies for pulmonary arterial hypertension (PAH) in connective tissue disease (CTD)–associated PAH are limited. In this study, we performed meta‐analyses of randomized, controlled trials (RCTs) and registries to quantify the benefit of these modern therapies in patients with CTD‐PAH. Methods: The PubMed and Embase databases were searched for articles reporting data from RCTs or registries published between January 1, 2000 and November 25, 2019. Eligibility criteria included multicenter studies with ≥30 CTD‐PAH patients. For an RCT to be included, the trial had to evaluate an approved PAH therapy, and long‐term risks of clinical morbidity and mortality or 6‐minute walk distance had to be reported. For a registry to be included, survival rates had to be reported. Random‐effects models were used to pool the data. Results: Eleven RCTs (total of 4,329 patients; 1,267 with CTD‐PAH) and 19 registries (total of 9,739 patients; 4,008 with CTD‐PAH) were included. Investigational therapy resulted in a 36% reduction in the risk of clinical morbidity/mortality events both in the overall PAH population (hazard ratio [HR] 0.64, 95% confidence interval [95% CI] 0.54, 0.75; P < 0.001) and in CTD‐PAH patients (HR 0.64, 95% CI 0.51, 0.81; P < 0.001) as compared to control subjects. The survival rate was lower in CTD‐PAH patients compared to all PAH patients (survival rate 62%, 95% CI 57, 67% versus 72%, 95% CI 69, 75% at 3 years). The survival rate in CTD‐PAH patients treated primarily after 2010 was higher than that in CTD‐PAH patients treated before 2010 (survival rate 73%, 95% CI 62, 81% versus 65%, 95% CI 59, 71% at 3 years). Conclusion: Modern therapy provides a similar reduction in morbidity/mortality risk in patients with CTD‐PAH when compared to the PAH population overall. Risk of death is higher in CTD‐PAH patients than in those with PAH overall, but survival has improved in the last 10 years, which may be related to increased screening and/or new treatment approaches. Early detection of PAH in patients with CTD and up‐front intensive treatment are warranted. [ABSTRACT FROM AUTHOR]

Objective: Intravenous iloprost improves Raynaud's phenomenon (RP) and promotes healing of digital ulcers in systemic sclerosis (SSc; scleroderma). Despite a short half‐life, its clinical efficacy lasts weeks. Endothelial adherens junctions, which are formed by VE‐cadherin clustering between endothelial cells (ECs), regulate endothelial properties including barrier function, endothelial‐to‐mesenchymal transition (EndoMT), and angiogenesis. We undertook this study to investigate the hypothesis that junctional disruption contributes to vascular dysfunction in SSc, and that the protective effect of iloprost is mediated by strengthening of those junctions. Methods: Dermal ECs from SSc patients and healthy controls were isolated. The effect of iloprost on ECs was examined using immunofluorescence, permeability assays, Matrigel tube formation, and quantitative polymerase chain reaction. Results: Adherens junctions in SSc were disrupted compared to normal ECs, as indicated by reduced levels of VE‐cadherin and increased permeability in SSc ECs (P < 0.05). Iloprost increased VE‐cadherin clustering at junctions and restored junctional levels of VE‐cadherin in SSc ECs (mean ± SD 37.3 ± 4.3 fluorescence units) compared to normal ECs (mean ± SD 29.7 ± 3.4 fluorescence units; P < 0.05), after 2 hours of iloprost incubation. In addition, iloprost reduced permeability of monolayers, increased tubulogenesis, and blocked EndoMT in both normal and SSc ECs (n ≥ 3; P < 0.05). The effects in normal ECs were inhibited by a function‐blocking antibody that prevents junctional clustering of VE‐cadherin. Conclusion: Our data suggest that the long‐lasting effects of iloprost reflect its ability to stabilize adherens junctions, resulting in increased tubulogenesis and barrier function and reduced EndoMT. These findings provide a mechanistic basis for the use of iloprost in treating SSc patients with RP and digital ulcers. [ABSTRACT FROM AUTHOR]

Objective: Fatigue is consistently ranked as one of the most problematic symptoms of systemic sclerosis (SSc), but the impact of fatigue on daily life is not well characterized. The purpose of this study was to examine the contribution of fatigue to deficits in social participation, functioning, and quality of life. Methods: Baseline data from a sample undertaking a clinical trial were utilized (n = 267). Fatigue, pain interference, depressive symptoms, physical function, and social participation were assessed by measures from the Patient‐Reported Outcomes Measurement Information System. Hierarchical linear regressions were performed to determine the unique contribution of fatigue to social participation, physical function, and quality of life above and beyond the effects of demographic and clinical variables, pain interference, and depressive symptoms. Results: The sample was predominantly female (91%), with an average age of 53.7 years, average disease duration of 9 years, and a mean fatigue T score of 58.7. Of all outcomes, fatigue was most strongly associated with deficits in social participation, explaining 48% of the variance beyond demographic and clinical factors, which is similar to the amount of variance contributed by pain interference and depressive symptoms combined (49%). Fatigue also accounted for significant amounts of variance in physical function and quality of life (R2 = 0.27 and 0.33, respectively) above and beyond the effects of demographic and clinical factors. Conclusion: Fatigue is an important clinical problem in SSc and is strongly associated with decreased participation in social roles and activities. Rehabilitation interventions that focus on fatigue management may be necessary to maximize participation. [ABSTRACT FROM AUTHOR]

Objective: To evaluate short‐ and long‐term outcomes of African American (AA) participants of Scleroderma Lung Studies (SLS) I and II. Methods: SLS I randomized 158 participants with systemic sclerosis‐interstitial lung disease (SSc‐ILD) to 1 year of oral cyclophosphamide (CYC) versus placebo. SLS II randomized 142 participants with SSc‐ILD to 1 year of oral CYC followed by 1 year of placebo versus 2 years of mycophenolate (MMF). Joint models compared the course of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) between AA and non‐AA, and Cox proportional hazard models assessed long‐term morbidity and mortality outcomes. Results: In SLS I, there was no difference in the course of the FVC or DLCO between AA and non‐AA in either treatment arm. In SLS II, AA had an improved course of the FVC compared with non‐AA in the CYC arm; in the MMF arm, there was no difference in FVC course. There was no difference in DLCO course in either arm. Time to death and respiratory failure were similar for AA and non‐AA in SLS I. There was a trend for improved survival and time to respiratory failure in AA compared with non‐AA in SLS II. AA race was not independently associated with mortality in the SLS I or II in the Cox models. Conclusion: Data from two randomized controlled trials demonstrated that AA patients with SSc‐ILD have similar morbidity and mortality outcomes compared with non‐AA patients. These findings contrast with the racial disparities described in prior observational studies and warrant further investigation. [ABSTRACT FROM AUTHOR]

Objective: Interstitial lung disease (ILD) is the leading cause of death in patients with systemic sclerosis (SSc). Although pulmonary function tests (PFTs) are commonly used to screen for ILD in patients with SSc, studies have shown that they lack sensitivity for the detection of ILD in general SSc cohorts. This study was undertaken to assess the performance characteristics of PFTs for the detection of ILD in patients with early diffuse cutaneous SSc (dcSSc), a population at high risk for the development of ILD. Methods: We performed a retrospective cohort study of patients enrolled in the Prospective Registry of Early Systemic Sclerosis at 11 sites in the US between April 2012 and January 2019. Patients were included if they underwent spirometry and high‐resolution computed tomography (HRCT) of the chest. We calculated the performance characteristics of PFTs for the detection of ILD on HRCT. Results: The study included 212 patients, 54% of whom had radiographic ILD. For the detection of ILD on HRCT imaging, a forced vital capacity (FVC) <80% predicted had a sensitivity of 63%. The combination of FVC <80% predicted or diffusing capacity for carbon monoxide (DLco) <80% predicted improved the sensitivity to 85%. An FVC <80% predicted had a negative predictive value (NPV) of 61%, while the combination of FVC <80% predicted or DLco <80% predicted had an NPV of 70%. Conclusion: PFTs alone are an inadequate screening tool for the diagnosis of ILD in patients with early dcSSc. HRCT should be part of the ILD screening algorithm in patients with dcSSc. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is an autoimmune rheumatic disease with heterogeneous clinical manifestations and a variable course in which the severity of the pathology dictates the disease prognosis and course. Among autoimmune rheumatic diseases, SSc has the highest mortality rate among all rheumatic diseases, though there are exciting new therapeutic targets that appear to halt the progression of SSc manifestations such as skin or lung fibrosis. In selected patients, high‐intensity regimens with autologous stem cell transplantation can favorably modify the course. In what was once thought to be an untreatable disease, targeted therapies have now changed the outlook of SSc to a treatable disorder. Herein, we discuss the targeted therapies modifying the outlook on selected organ involvement and creating opportunities for future treatment. We also present a framework for defining low disease activity in SSc. [ABSTRACT FROM AUTHOR]

Objective: To provide guidance for the management of gout, including indications for and optimal use of urate‐lowering therapy (ULT), treatment of gout flares, and lifestyle and other medication recommendations. Methods: Fifty‐seven population, intervention, comparator, and outcomes questions were developed, followed by a systematic literature review, including network meta‐analyses with ratings of the available evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and patient input. A group consensus process was used to compose the final recommendations and grade their strength as strong or conditional. Results: Forty‐two recommendations (including 16 strong recommendations) were generated. Strong recommendations included initiation of ULT for all patients with tophaceous gout, radiographic damage due to gout, or frequent gout flares; allopurinol as the preferred first‐line ULT, including for those with moderate‐to‐severe chronic kidney disease (CKD; stage >3); using a low starting dose of allopurinol (≤100 mg/day, and lower in CKD) or febuxostat (<40 mg/day); and a treat‐to‐target management strategy with ULT dose titration guided by serial serum urate (SU) measurements, with an SU target of <6 mg/dl. When initiating ULT, concomitant antiinflammatory prophylaxis therapy for a duration of at least 3–6 months was strongly recommended. For management of gout flares, colchicine, nonsteroidal antiinflammatory drugs, or glucocorticoids (oral, intraarticular, or intramuscular) were strongly recommended. Conclusion: Using GRADE methodology and informed by a consensus process based on evidence from the current literature and patient preferences, this guideline provides direction for clinicians and patients making decisions on the management of gout. [ABSTRACT FROM AUTHOR]

Objective: Our objective was to determine if treatment with cyclophosphamide (CYC) and mycophenolate mofetil (MMF) improves patient‐reported outcomes (PROs) among patients with systemic sclerosis‐related interstitial lung disease (SSc‐ILD). Methods: This study examined PROs in patients with SSc‐ILD (N = 142) who participated in the Scleroderma Lung Study II, a randomized controlled trial comparing MMF for 2 years with oral CYC for 1 year followed by 1 year of a placebo. Joint models were created to evaluate the course of PROs over 2 years. The difference in PRO scores from baseline to 24 months was measured, and the percentage of patients meeting the minimum clinically important difference (MCID) was calculated. Correlations between PROs and SSc‐ILD disease severity measures were also examined. Results: Treatment with CYC and MMF led to improvements in several PROs with no between‐treatment differences. Scores for the Transitional Dyspnea Index (TDI) and St. George's Respiratory Questionnaire (SGRQ) improved significantly over 2 years, and 29%/24% and 28%/25% of participants in the CYC/MMF groups met or exceeded the MCID estimates for TDI and SGRQ, respectively. At baseline, the forced vital capacity (FVC) percentage predicted (FVC%‐predicted) did not correlate with the Baseline Dyspnea Index or SGRQ. However, improvements in the FVC%‐predicted were weakly associated with improvements in dyspnea (assessed by the TDI) and SGRQ scores. Conclusion: Treatment with CYC and MMF improved overall health‐related quality of life in patients with SSc‐ILD. The relationship between PRO measures and the FVC was relatively weak, suggesting that PROs provide complementary information about treatment efficacy not captured by changes in the FVC alone in this patient population. [ABSTRACT FROM AUTHOR]

Objective: Digital ulcers (DUs) are a major cause of disease-related morbidity and are a difficult-to-treat vascular complication of systemic sclerosis (SSc). Demonstrating treatment efficacy has traditionally focused on clinician assessment of DUs alone. No existing patient-reported outcome (PRO) instrument captures the multifaceted impact of SSc-DU. We report the findings of a multicenter qualitative research study exploring the patient experience of SSc-DU.Methods: Patient focus groups were conducted across 3 scleroderma units, following a topic guide devised by SSc patients, experts, and experienced qualitative researchers. A purposive sampling framework ensured that the experiences of a diverse group of patients were captured. Focus groups were audio recorded, and information was transcribed, anonymized, and analyzed using inductive thematic analysis. We continued focus groups until thematic saturation was achieved.Results: Twenty-nine SSc patients with a history of DU disease participated in 4 focus groups across the UK (Bath, Manchester, and London). Five major interrelated themes (and subthemes) were identified that encompass the patient experience of SSc-DU: disabling pain and hypersensitivity; deep and broad-ranging emotional impact; impairment of physical and social activity; factors aggravating occurrence, duration, and impact; and mitigating, managing, and adapting.Conclusion: The patient experience of SSc-DU is multifaceted and comprises a complex interplay of experiences associated with significant pain and morbidity. Patient experiences of SSc-DU are not captured using existing SSc-DU outcomes. Our findings will inform the development of a novel PRO instrument to assess the severity and impact of SSc-DU for use in future SSc-DU clinical trials. [ABSTRACT FROM AUTHOR]

Objective: To examine changes in the extent of specific patterns of interstitial lung disease (ILD) as they transition from one pattern to another in response to immunosuppressive therapy in systemic sclerosis–related ILD (SSc‐ILD). Methods: We evaluated changes in the quantitative extent of specific lung patterns of ILD using volumetric high‐resolution computed tomography (HRCT) scans obtained at baseline and after 2 years of therapy in patients treated with either cyclophosphamide (CYC) for 1 year or mycophenolate mofetil (MMF) for 2 years in Scleroderma Lung Study II. ILD patterns included lung fibrosis, ground glass, honeycombing, and normal lung. Net change was calculated as the difference in the probability of change from one ILD pattern to another. Wilcoxon's signed rank test was used to compare the changes. Results: Forty‐seven and 50 patients had baseline and follow‐up scans in the CYC and MMF groups, respectively. Mean net improvements reflecting favorable changes from one ILD pattern to another in the whole lung in the CYC and MMF groups, respectively, were as follows: from lung fibrosis to a normal lung pattern, 21% and 19%; from a ground‐glass pattern to a normal lung pattern, 30% and 28%; and from lung fibrosis to a ground‐glass pattern, 5% and 0.5%. The mean overall improvement in transitioning from a ground‐glass pattern or lung fibrosis to a normal lung pattern was significant for both treatments (all P < 0.001). Conclusion: Significantly favorable transitions from both ground‐glass and lung fibrosis ILD patterns to a normal lung pattern were observed in patients undergoing immunosuppressive treatment for SSc‐ILD, suggesting the usefulness of examining these transitions for insights into the underlying pathobiology of treatment response. [ABSTRACT FROM AUTHOR]

Objective: T cells play a key role in the pathogenesis of early systemic sclerosis. This study was undertaken to assess the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc). Methods: In this 12‐month, randomized, double‐blind, placebo‐controlled trial, participants were randomized 1:1 to receive either subcutaneous abatacept 125 mg or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at 6 months for worsening disease. The coprimary end points were change in the modified Rodnan skin thickness score (MRSS) compared to baseline and safety over 12 months. Differences in longitudinal outcomes were assessed according to treatment using linear mixed models, with outcomes censored after initiation of escape therapy. Skin tissue obtained from participants at baseline was classified into intrinsic gene expression subsets. Results: Among 88 participants, the adjusted mean change in the MRSS at 12 months was −6.24 units for those receiving abatacept and −4.49 units for those receiving placebo, with an adjusted mean treatment difference of −1.75 units (P = 0.28). Outcomes for 2 secondary measures (Health Assessment Questionnaire disability index and a composite measure) were clinically and statistically significantly better with abatacept. The proportion of subjects in whom escape therapy was needed was higher in the placebo group relative to the abatacept group (36% versus 16%). In the inflammatory and normal‐like skin gene expression subsets, decline in the MRSS over 12 months was clinically and significantly greater in the abatacept group versus the placebo group (P < 0.001 and P = 0.03, respectively). In the abatacept group, adverse events occurred in 35 participants versus 40 participants in the placebo group, including 2 deaths and 1 death, respectively. Conclusion: In this phase II trial, abatacept was well‐tolerated, but change in the MRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed evidence in support of abatacept. These data should be confirmed in a phase III trial. [ABSTRACT FROM AUTHOR]

The article looks at the relationship between pneumoproteins Krebs von den Lungen (KL-6) and CCL18 and the progression and severity of interstitial lung disease (ILD) in systemic sclerosis (SSc). According to the article, data and plasma samples from participants (ages 18-75) enrolled in the Scleroderma Lung Study (SLS) were analyzed. Baseline levels of lung glycoproteins as predictors for the progression of ILD were also considered.

Objective: To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). Methods: This international initiative had four phases. 1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta‐regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort, and a patient survey. 2) Criteria reduction by Delphi and nominal group technique exercises. 3) Criteria definition and weighting based on criterion performance and on results of a multi‐criteria decision analysis. 4) Refinement of weights and threshold scores in a new derivation cohort of 1,001 subjects and validation compared with previous criteria in a new validation cohort of 1,270 subjects. Results: The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in 7 clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and 3 immunologic (antiphospholipid antibodies, complement proteins, SLE‐specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria. Conclusion: These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered, and weighted criteria reflects current thinking about SLE and provides an improved foundation for SLE research. Video Abstract [ABSTRACT FROM AUTHOR]

Objective: We previously identified CYR61 as a histone deacetylase 5 (HDAC‐5)–repressed gene in systemic sclerosis (SSc; scleroderma) endothelial cells (ECs). When overexpressed, cysteine‐rich angiogenic inducer 61 (CYR‐61) promoted angiogenesis in SSc ECs. This study was undertaken to examine the role of CYR‐61 in fibrosis and determine the mechanisms involved in CYR‐61–mediated angiogenesis in SSc. Methods: Dermal ECs and fibroblasts were isolated from biopsy specimens from healthy subjects and patients with SSc. CYR‐61 level was determined by quantitative polymerase chain reaction, Western blotting, and enzyme‐linked immunosorbent assay. CYR‐61 was overexpressed using a CYR61 vector or knocked down using small interfering RNA, and functional and mechanistic studies were then conducted in fibroblasts and ECs. Results: Lower CYR61 messenger RNA levels were observed in dermal fibroblasts and ECs from SSc patients than in those from healthy controls. In SSc fibroblasts, overexpression of CYR‐61 led to significant reduction in the expression of profibrotic genes, including COL1A1 (P = 0.002) and ACTA2 (P = 0.04), and an increase in the expression of matrix‐degrading genes, including MMP1 (P = 0.002) and MMP3 (P =0.004), and proangiogenic VEGF (P = 0.03). The antifibrotic effect of CYR‐61 was further demonstrated by delay in wound healing, inhibition of gel contraction, inactivation of the transforming growth factor β pathway, and early superoxide production associated with senescence in SSc fibroblasts. In SSc ECs, overexpression of CYR‐61 led to increased production of vascular endothelial cell growth factor. The proangiogenic effects of CYR‐61 were mediated by signaling through αvβ3 receptors and downstream activation of AMP‐activated protein kinase, AKT, and the endothelial cell nitric oxide synthase/nitric oxide pathway system. Conclusion: CYR‐61, which is epigenetically regulated by HDAC‐5, is a potent antifibrotic and proangiogenic mediator in SSc. Therapeutic intervention to promote CYR‐61 activity or increase CYR‐61 levels might be of benefit in SSc. [ABSTRACT FROM AUTHOR]

Objective: Systemic sclerosis (SSc) is associated with interstitial lung disease (ILD) and pulmonary hypertension (PH). This study was undertaken to determine the prevalence, characteristics, treatment, and outcomes of PH in a cohort of patients with SSc‐associated ILD. Methods: Patients with SSc‐associated ILD on high‐resolution computed tomography (HRCT) were included in a prospective observational cohort. Patients were screened for PH based on a standardized screening algorithm and underwent right‐sided heart catheterization (RHC) if indicated. PH classification was based on hemodynamic findings and the extent of ILD on HRCT. Summary statistics and survival using the Kaplan‐Meier method were calculated. Results: Of the 93 patients with SSc‐associated ILD included in the study, 76% were women and 65.6% had diffuse cutaneous SSc. The mean age was 54.9 years, and the mean SSc disease duration was 8 years. Twenty‐nine patients (31.2%) had RHC‐proven PH; of those 29 patients, 24.1% had PAH, 55.2% had World Health Organization (WHO) Group III PH, 34.5% had WHO Group III PH with pulmonary vascular resistance >3.0 Wood units, 48.3% had a PH diagnosis within 7 years of SSc onset, 82.8% received therapy for ILD, and 82.8% received therapy for PAH. The survival rate 3 years after SSc‐associated ILD diagnosis for all patients was 97%. The survival rate 3 years after PH diagnosis for those with SSc‐associated ILD and PH was 91%. Conclusion: In a large cohort of patients with SSc‐associated ILD, a significant proportion of patients had coexisting PH, which often occurs early after SSc diagnosis. Most patients were treated with ILD and PAH therapies, and survival was good. Patients with SSc‐associated ILD should be evaluated for coexisting PH. [ABSTRACT FROM AUTHOR]

Objective: To generate a core set of items to develop classification criteria for scleroderma renal crisis (SRC) using consensus methodology. Methods: An international, multidisciplinary panel of experts was invited to participate in a 3‐round Delphi exercise developed using a survey based on items identified by a scoping review. In round 1, participants were asked to identify omissions and clarify ambiguities regarding the items in the survey. In round 2, participants were asked to rate the validity and feasibility of the items using Likert‐type scales ranging from 1 to 9 (where 1 = very invalid/unfeasible, 5 = uncertain, and 9 = very valid/feasible). In round 3, participants reviewed the results and comments from round 2 and were asked to provide final ratings. Items rated as highly valid and feasible (median scores ≥7 for each) in round 3 were selected as the provisional core set of items. A consensus meeting using a nominal group technique was conducted to further reduce the core set of items. Results: Ninety‐nine experts from 16 countries participated in the Delphi exercise. Of the 31 items in the survey, consensus was achieved on 13, in the categories hypertension, renal insufficiency, proteinuria, and hemolysis. Eleven experts took part in the nominal group technique discussion, where consensus was achieved in 5 domains: blood pressure, acute kidney injury, microangiopathic hemolytic anemia, target organ dysfunction, and renal histopathology. Conclusion: A core set of items that characterize SRC was identified using consensus methodology. This core set will be used in future data‐driven phases of this project to develop classification criteria for SRC. [ABSTRACT FROM AUTHOR]

Aim: The modified Rodnan skin score (mRSS) is a validated outcome measure for skin thickness in systemic sclerosis (SSc). Training has been shown to reduce variability in the measurement of mRSS. Our objective was to assess the inter‐ and intra‐observer variability of mRSS scoring using the proposed recommendations for training by the Scleroderma Clinical Trials Consortium (SCTC) and World Scleroderma Foundation (WSF). Method: Fifty‐two trainees and eight adult SSc patients participated in the SSc skin scoring workshop that was conducted in two sessions by four teachers. Each session, attended by 26 trainees, had a teaching and evaluation phase. The teaching phase comprised of: (a) lecture on mRSS scoring; (b) video demonstration of mRSS scoring; and (c) live demonstration of mRSS on one SSc patient. In the evaluation phase, each trainee independently assessed the mRSS in four SSc patients. For intra‐observer reliability, 14 trainees re‐assessed the mRSS of two SSc patients whom they had previously examined. We computed the inter‐ and intra‐observer variability using a linear mixed model. Results: For the evaluation phase, 34 (65.4%) trainees were within five units of the established teachers' score in 3 out of 4 patients. Overall, the whole group had acceptable inter‐observer variability (intra‐class correlation coefficient [ICC] = 0.71, mean = 8.64 and within‐patient standard deviation [SD] = 4.25). The intra‐observer ICC was 0.85 and within‐patient SD was 2.73. Conclusion: There was good inter‐observer and excellent intra‐observer reliability. This is the first study examining the training of assessors using the SCTC/WSF recommendations and our results support the importance of standardized training for skin scoring. [ABSTRACT FROM AUTHOR]