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To investigate whether obstetric complications prior to systemic sclerosis (SSc) diagnosis are more common in SSc patients compared to the general obstetric population.A case-control study was performed at Kaiser Permanente Northern California to compare prior obstetric complications in adult women who later developed SSc (cases) with women from the general obstetric population who did not develop SSc (controls; matched 10:1 by age and year of delivery) from 2007 to 2016. Exposures included past hypertensive disorders of pregnancy (preeclampsia, eclampsia, gestational hypertension), premature rupture of membranes (PROM), intrauterine growth restriction (IUGR), maternal infections, neonatal intensive care unit (NICU) admission, and preterm birth. Fischer's exact tests were used to compare categorical variables. Conditional logistic regression models estimated the odds ratio (OR), and corresponding 95% confidence intervals (95% CIs) for the outcome SSc.Seventeen SSc cases and 170 non-SSc controls were identified, with median maternal age at delivery 34 years (range 23-46 years) and median time from delivery to SSc diagnosis 2 years (range 0.2-7.3 years). Women with SSc were more likely to be Hispanic and Black. Prior obstetric complications appeared higher in women with an eventual SSc diagnosis compared to controls (70.6% versus 50%), including hypertensive disorders (17.7% versus 9.4%), PROM (11.8% versus 4.1%), IUGR (5.9% versus 1.8%), maternal infection (29.4% versus 14.1%), NICU admissions (23.5% versus 7.7%), and preterm delivery (29.4% versus 21.8%). Women with SSc had a higher odds of delivering infants requiring NICU admission (OR 4.7 [95% CI 1.2-18.8]).Women who eventually develop SSc had trends toward more complicated pregnancy histories before overt diagnosis.

Background Systemic sclerosis (scleroderma; SSc) is a rare autoimmune connective tissue disease. We completed an initial feasibility trial of an online self-administered version of the Scleroderma Patient-centered Intervention Network Self-Management (SPIN-SELF) Program using the cohort multiple randomized controlled trial (RCT) design. Due to low intervention offer uptake, we will conduct a new feasibility trial with progression to full-scale trial, using a two-arm parallel, partially nested RCT design. The SPIN-SELF Program has also been revised to include facilitator-led videoconference group sessions in addition to online material. We will test the group-based intervention delivery format, then evaluate the effect of the SPIN-SELF Program on disease management self-efficacy (primary) and patient activation, social appearance anxiety, and functional health outcomes (secondary). Methods This study is a feasibility trial with progression to full-scale RCT, pending meeting pre-defined criteria, of the SPIN-SELF Program. Participants will be recruited from the ongoing SPIN Cohort (http://www.spinsclero.com/en/cohort) and via social media and partner patient organizations. Eligible participants must have SSc and low to moderate disease management self-efficacy (Self-Efficacy for Managing Chronic Disease (SEMCD) Scale score ≤ 7.0). Participants will be randomized (1:1 allocation) to the group-based SPIN-SELF Program or usual care for 3 months. The primary outcome in the full-scale trial will be disease management self-efficacy based on SEMCD Scale scores at 3 months post-randomization. Secondary outcomes include SEMCD scores 6 months post-randomization plus patient activation, social appearance anxiety, and functional health outcomes at 3 and 6 months post-randomization. We will include 40 participants to assess feasibility. At the end of the feasibility portion, stoppage criteria will be used to determine if the trial procedures or SPIN-SELF Program need important modifications, thereby requiring a re-set for the full-scale trial. Otherwise, the full-scale RCT will proceed, and outcome data from the feasibility portion will be utilized in the full-scale trial. In the full-scale RCT, 524 participants will be recruited. Discussion The SPIN-SELF Program may improve disease management self-efficacy, patient activation, social appearance anxiety, and functional health outcomes in people with SSc. SPIN works with partner patient organizations around the world to disseminate its programs free-of-charge. Trial registration ClinicalTrials.govNCT04246528. Registered on 27 January 2020

Objectives We evaluated the safety and efficacy of oral treprostinil in preventing progression of SSc-associated calcinosis. Methods This prospective open-label study enrolled 12 SSc patients meeting 2013 ACR/EULAR classification criteria with confirmed clinical and radiographic evidence of one or more calcinosis deposit in the hands. Patients received oral treprostinil for 1 year. Primary endpoints were safety/tolerability and percentage of patients without radiographic progression of calcinosis at 1 year ( Results Twelve female patients were enrolled, half with diffuse cutaneous disease; median age was 55 years (range 35–68 years). Five patients completed the study. Seven patients withdrew due to intolerable adverse effects (n = 3), intercurrent unrelated illness (n = 2, cirrhosis, cancer), progressive SSc (n = 1) and personal reasons (n = 1). Most patients developed headaches and gastrointestinal adverse effects. Four of 11 (36%) patients with 1-year follow-up hand radiographs experienced progression of calcinosis. Of five who completed treatment, calcinosis was stable in four (80%) with progression in one. Based on SF-36 Physical and Mental Component and Domain scores, transition question and SF-6D utility score, all patients who finished the trial reported overall improvement or no change compared with baseline. Conclusion Oral treprostinil was poorly tolerated in SSc patients with calcinosis. Of five patients who completed treatment, most (80%) had documented stability of calcinosis on hand radiographs at 1 year. ClinicalTrials.gov identifier NCT02663895.

OBJECTIVE Interstitial lung disease (ILD) is a frequent complication of systemic sclerosis (SSc), and ILD screening, characterization, and monitoring are important for therapeutic decision-making and prognostication. Lung ultrasonography (US) is a potential alternative imaging modality for ILD detection. In this study, our objective was to develop and test a novel lung US examination technique and interpretation criteria for detecting SSc-ILD. METHODS Lung US acquisition was performed by collecting short US movies at 14 lung positions. Lung US interpretation criteria for SSc-ILD detection focused on visualized pleural changes. To assess the performance of our methodology for SSc-ILD detection, we prospectively enrolled SSc patients with high-resolution computed tomography (HRCT) imaging within 3 months of lung US. Lung US examinations were scored independently by 2 blinded readers (1 ultrasonographer and 1 nonultrasonographer). The sensitivity and specificity for SSc-ILD detection were assessed, and agreement was measured with Cohen's kappa statistic. RESULTS To test the performance of our lung US acquisition technique and interpretation criteria, 20 SSc patients were evaluated by lung US (278 lung zones) and HRCT. HRCT confirmed ILD in 9 patients (45%). Lung US was positive for SSc-ILD in 11 patients (55%) with a sensitivity of 100% and specificity of 82% versus HRCT, with perfect agreement between the 2 readers (κ = 1). Analysis by individual lung zones found excellent agreement between readers, with 93.8% concordance and κ = 0.82. CONCLUSION We developed a novel lung US examination technique and interpretation criteria that are highly sensitive and specific for SSc-ILD detection in an SSc cohort, affording perfect agreement between ultrasonographer and nonultrasonographer readers.

OBJECTIVE To investigate the ability of ultrasound (US) compared to radiographs to detect calcinosis in hands/wrists of patients with systemic sclerosis (SSc), and to assess US markers of pathologic perfusion. METHODS Patients with SSc were evaluated for calcinosis in the hands/wrists by radiograph and US. The presence or absence of calcinosis was recorded by patient, hand, and anatomic zone; sensitivity and specificity for calcinosis detection by US versus radiographs was determined. Bilateral US vascular measurements of ulnar artery occlusion (UAO) and finger pulp blood flow (FPBF) were obtained. For each hand, associations between markers of pathologic blood flow (UAO, FPBF, and a composite severity score of UAO and FPBF) and the presence of calcinosis were assessed using generalized estimating equations. RESULTS Of 43 patients with SSc (19 diffuse, 24 limited), 39.5% had calcinosis on radiographs compared to 30.2% on US. Sensitivity and specificity for US, respectively, were 61% and 95% by zone, 78% and 98% by hand, and 76% and 100% by patient. UAO was seen in 30% and 28% of left and right hands, respectively; FPBF was absent in ≥1 digit of the left and right hands in 49% and 44%, respectively. UAO was associated with radiograph-identified calcinosis by hand (odds ratio [OR] 8.08 [95% confidence interval (95% CI) 2.45-26.60], P < 0.001), whereas FPBF and the composite severity score were not significant. UAO was associated with calcinosis even in the absence of digital ulcers (OR 33.00 [95% CI 3.39-321.09], P = 0.003). CONCLUSION US was sensitive and highly specific in detecting calcinosis in SSc. UAO was strongly associated with radiograph-identified calcinosis.

Rationale: Systemic sclerosis (SSc)–pulmonary arterial hypertension (PAH) is one of the most prevalent and deadly forms of PAH. B cells may contribute to SSc pathogenesis. Objectives: We investigated the safety and efficacy of B-cell depletion for SSc-PAH. Methods: In an NIH-sponsored, multicenter, double-blinded, randomized, placebo-controlled, proof-of-concept trial, 57 patients with SSc-PAH on stable-dose standard medical therapy received two infusions of 1,000 mg rituximab or placebo administered 2 weeks apart. The primary outcome measure was the change in 6-minute-walk distance (6MWD) at 24 weeks. Secondary endpoints included safety and invasive hemodynamics. We applied a machine learning approach to predict drug responsiveness. Measurements and Main Results: We randomized 57 subjects from 2010 to 2018. In the primary analysis, using data through Week 24, the adjusted mean change in 6MWD at 24 weeks favored the treatment arm but did not reach statistical significance (23.6 ± 11.1 m vs. 0.5 ± 9.7 m; P = 0.12). Although a negative study, when data through Week 48 were also considered, the estimated change in 6MWD at Week 24 was 25.5 ± 8.8 m for rituximab and 0.4 ± 7.4 m for placebo (P = 0.03). Rituximab treatment appeared to be safe and well tolerated. Low levels of RF (rheumatoid factor), IL-12, and IL-17 were sensitive and specific as favorable predictors of a rituximab response as measured by an improved 6MWD (receiver operating characteristic area under the curve, 0.88–0.95). Conclusions: B-cell depletion therapy is a potentially effective and safe adjuvant treatment for SSc-PAH. Future studies in these patients can confirm whether the identified biomarkers predict rituximab responsiveness. Clinical trial registered with www.clinicaltrails.gov (NCT 01086540).

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.

Calcinosis is dystrophic calcification of the soft tissue which can lead to painful and debilitating disease. It is commonly seen in patients with systemic sclerosis (SSc). Imaging can assist in diagnosis, quantification of disease, and better pathophysiologic understanding of calcinosis. Traditionally, X-rays have been the most frequently used imaging modality for diagnosis; however, advances in ultrasound (US), computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging (MRI) have led to greater ability to characterize these lesions and surrounding structures. This narrative review aims to describe the use of imaging for calcinosis in patients with SSc. Key Points • Imaging is useful in the diagnosis of calcinosis, assessment of disease severity, and disease monitoring. • X-ray is commonly used and offers high sensitivity and specificity, but both ultrasound and CT-scans are alternatives when greater anatomic detail is sought regarding surrounding structures. • Investigational imaging modalities include dual energy CT-scans, cinematic rendering CT-scans, and PET- CT scans. • Conventional MRI scans have less sensitivity and specificity for detection of calcinosis.

Objective Interstitial lung disease (ILD) is a major cause of morbidity and mortality in connective tissue diseases (CTDs). We aimed to assess the effect of rituximab ± mycophenolate mofetil (MMF) compared with MMF on pulmonary function and prednisone dosage in patients with CTD-related ILD (CTD-ILD). Methods This retrospective study included 83 patients from Stanford and Centre Hospitalier de l'Universite de Montreal. Fifteen patients received rituximab ± MMF (rituximab group), and 68 patients received MMF only (control group). Results Median ILD duration at the start of treatment was longer in the rituximab group at 47 months (range: 4-170) versus 6.5 months (range: 0-164) in controls. Forced vital capacity (FVC) decreased by 3.0% (range: 11%-21%) after treatment in the rituximab group, whereas it increased by 2.0% (range: 14%-25%) in the control group (p = 0.025). Diffusing capacity of carbon monoxide (DLCO) decreased by 3.0% (range: 10%-12%) after treatment in the rituximab group, whereas it increased by 4.5% (range: 30%-36%) in the control group (p = 0.046). Mixed model analysis controlling for ILD duration, baseline DLCO, systemic sclerosis, pulmonary hypertension, and prednisone use showed no significant difference in FVC or DLCO between groups at 6 months or 1 year. The average daily prednisone dose score decreased after treatment in the rituximab group, whereas it remained unchanged in the control group (p = 0.017). Conclusion Rituximab ± MMF did not significantly change pulmonary function compared with MMF alone, but it did result in a relative decrease in average daily prednisone dose in a population with recalcitrant CTD-ILD.

The objective of this analysis is to examine whether the severity of systemic sclerosis (SSc)-hand involvement influences patient-reported outcome measure (PROM) completion rate in a US cohort of early disease. Participants included SSc patients with less than 5 years disease duration consented and enrolled in the Collaborative, National, Quality, and Efficacy Registry (CONQUER) between June 2018 and December 2019. Participants' socio-demographics, hand clinical features (severe modified Rodnan skin score, presence of small joint contractures, acro-osteolysis, calcinosis, and digital ulcers), and completion rates of seven PROMs including a Resource Use Questionnaire were analyzed. Cohort characteristics and baseline PROM completion were evaluated. Multivariable logistic regression assessed the relationship between hand limitations and PROM incompletion at several time points using generalized estimating equations. At the time of data lock, 339 CONQUER subjects had a total of 600 visits available for analysis. Calcinosis (odds ratio [OR] 6.35, confidence interval [CI] 2.41-16.73 and acro-osteolysis OR 3.88 (1.57-9.55) were significantly associated with incomplete PROM. The Resource Use Questionnaire was the PROM most commonly not completed. Increasing age was correlated with resource use questionnaire incompletion rate. Acro-osteolysis and calcinosis were associated with lower PROM completion rates in a US SSc cohort, independent of the length of the questionnaires or the modality of administration (electronic or paper). Resource Use Questionnaires are important for understanding the economic impact and burden of chronic disease; however, in this study, it had lower completion rates than PROMs devoted to clinical variables. Key points •Multiple strategies are needed to ensure optimal completion of PROM in longitudinal cohort studies. Even if patients request electronic surveys, we have found it is important to follow up incomplete surveys with paper forms provided at the time of a clinical visit. •The Resource Utilization Questionnaire was lengthy and prone to non-completion in the younger population. •Acro-osteolysis and calcinosis were associated with reduced PROM completion rates.

Systemic sclerosis (systemic scleroderma) is characterized by a heterogeneous range of clinical manifestations. Systemic sclerosis is classified into limited cutaneous systemic sclerosis and diffuse cutaneous systemic sclerosis subgroups based on the extent of skin involvement. Randomized controlled trials in scleroderma have mainly focused on diffuse cutaneous systemic sclerosis partly because the measurement of skin involvement, critical for evaluating a therapeutic intervention, is more dynamic in this subset. Nonetheless, limited cutaneous systemic sclerosis, the most common cutaneous subset (about two-third), is also associated with significant morbidity and detrimental impact on health-related quality of life. The lack of interventional studies in limited cutaneous systemic sclerosis is partly due to a lack of relevant outcome measures to evaluate this subgroup. Combining several clinically meaningful outcomes selected specifically for limited cutaneous systemic sclerosis may improve representativeness in clinical trials and responsiveness of outcomes measured in randomized controlled trials. A composite index dedicated to limited cutaneous systemic sclerosis combining such relevant outcomes could advance clinical trial development for limited cutaneous systemic sclerosis by providing the opportunity to test and select among candidate drugs that could act as disease-modifying treatments for this neglected subgroup of systemic sclerosis. This proposed index would include items selected by expert physicians and patients with limited cutaneous systemic sclerosis across domains grounded in the lived experience of limited cutaneous systemic sclerosis. This article reviews the reasons behind the relative neglect of limited cutaneous systemic sclerosis, discusses the current state of outcome measures for limited cutaneous systemic sclerosis, identifies challenges, and proposes a roadmap for a combined limited cutaneous systemic sclerosis-specific treatment response index.

Objective Calcinosis is a debilitating complication of systemic sclerosis (SSc) with no effective treatments. We sought to identify clinical correlations and to characterize complications and disability associated with calcinosis in a multi-center, international cohort of SSc patients. Methods We established a cohort of 568 consecutive SSc patients who fulfill 2013 revised ACR/EULAR criteria at 10 centers within North America, Australia, and Mexico. Calcinosis was defined as subcutaneous calcium deposition by imaging and/or physical examination, or a clear history of extruded calcium. All patients completed the Scleroderma Health Assessment Questionnaire Disability Index and Cochin Hand Functional Scale. Results 215 (38%) patients had calcinosis. In multivariable analysis, disease duration (OR=1.24, p = 0.029), digital ischemia (OR=1.8, p = 0.002) and Acro-osteolysis (OR=2.97, p = 0.008) were significantly associated with calcinosis. In the subset of patients with bone densitometry (n = 68), patients with calcinosis had significantly lower median T-scores than patients without (-2.2 vs. -1.7, p = 0.004). The most common location of calcinosis lesions was the hands (70%), particularly the thumbs (19%) with decreasing frequency moving to the fifth fingers (8%). The most common complications were tenderness (29% of patients) and spontaneous extrusion of calcinosis through the skin (20%), while infection was rare (2%). Disability and hand function were worse in patients with calcinosis, particularly if locations in addition to the fingers/thumbs were involved. Conclusions We confirmed a strong association between calcinosis and digital ischemia. Calcinosis in SSc patients most commonly affects the hands and is associated with a high burden of disability and hand dysfunction.

Summary Digital ulcers are a serious, recurrent complication in patients with systemic sclerosis. They are often slow to heal and exquisitely painful. Local wound care, such as debridement of the wound bed, is an essential component in the management of digital ulcers in systemic sclerosis. However, digital ulcer debridement is not a standard of care, and there is substantial international variation in the use of this approach. In this Viewpoint, we discuss the assessment of the wound bed and different methods of debridement using the model of tissue management, infection and inflammation, moisture control, and wound edge or epidermal advancement, known as TIME. We highlight the challenges in standard practice and the need for research into local wound care for this type of ulceration, before suggesting a potential roadmap to develop a standardised approach to support ulcer debridement in systemic sclerosis. Debridement might be the missing component in optimising the management of digital ulcers and we propose that the approach should be rigorously investigated as a standard of care in this common complication of systemic sclerosis.

OBJECTIVE The objective of this study is to evaluate racial/ethnic differences in disease manifestations and survival in a US cohort of patients with systemic sclerosis (SSc), with a focus on Asian patients. METHODS A retrospective cohort study was conducted among Kaiser Permanente Northern California adults with an incident SSc diagnosis by a rheumatologist from 2007 to 2016, confirmed by a chart review to fulfill 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria. Self-reported race/ethnicity was categorized as non-Hispanic white, Asian, Hispanic, and black. Disease manifestations and survival were compared, using white patients as the reference. RESULTS A total of 609 patients with incident SSc were identified: 89% were women, and 81% had limited cutaneous SSc, with a mean age at diagnosis of 55.4 ± 14.8 years. The racial/ethnic distribution was 51% non-Hispanic white (n = 310), 25% Hispanic (n = 154), 16% Asian (n = 96), and 8% black (n = 49). Compared with white patients, black patients had a greater prevalence of diffuse disease (14.5% vs. 44.9%; P < 0.001), and Asians had higher rates of anti-U1-RNP antibodies (32.1% vs. 11.9%; P = 0.005). Nine-year overall survival rates following SSc diagnosis were lower in Asian (52.3%), black (52.2%), and Hispanic patients (68.2%) compared with white patients (75.8%). Pulmonary hypertension and infections were the leading causes of death in Asian patients. Asian race was associated with higher mortality on univariable (hazard ratio [HR] 1.83 [95% confidence interval (CI) 1.08-2.99]; P = 0.020) and multivariable analyses (HR 1.80 [95% CI 0.99-3.16]; P = 0.047) when adjusting for age, sex, body mass index, cutaneous subtype, smoking status, interstitial lung disease, pulmonary hypertension, renal crisis, and malabsorption syndrome. CONCLUSION Asian patients with SSc in this US cohort had increased mortality compared with white patients. These patients warrant close monitoring for disease progression.

Introduction: Systemic sclerosis (SSc) is an autoimmune connective tissue disease that is characterized by excessive collagen deposition, vascular dysfunction, and fibrosis of cutaneous and visceral organs. Current therapeutic options are limited and provide only modest benefit.Areas covered: This review summarizes investigational agents in recent Phase I and II clinical trials evaluated for the treatment of SSc with a focus on skin in patients with early diffuse disease and interstitial lung disease. We performed a search on Pubmed and https://clinicaltrials.gov with keywords systemic sclerosis, Phase I clinical trial, and Phase II clinical trial to identify relevant studies from 2015 to 2019.Expert opinion: Therapeutic interventions in SSc should be guided by the level of disease activity and the degree of organ involvement. While most novel agents have failed to meet the primary endpoints of reducing skin thickening as measured by the modified Rodnan skin score, some have shown promise in improving the Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis (CRISS), reducing lung function decline, or improving patient-reported outcomes. However, most of the current evidence is based on small or open-label clinical trials. Well-designed, large, randomized, Phase III clinical trials are necessary to define the roles of investigational agents in treating SSc.

Raynaud phenomenon is a symptom complex caused by impaired digital perfusion and can occur as a primary phenomenon or secondary to a wide range of underlying causes. Raynaud phenomenon occurs in virtually all patients with systemic sclerosis (SSc) and is often the earliest clinical manifestation to occur. Careful assessment is required in patients with Raynaud phenomenon to avoid missing secondary causes such as SSc. Digital ulcers are a painful and disabling visible manifestation of digital vascular injury in patients with SSc. Progress has been made in the classification and assessment of digital ulcers and in understanding ulcer pathogenesis, and there are a wide range of treatments available to both prevent and heal digital ulcers, some of which are also used in Raynaud phenomenon management. In this Review, the assessment of patients with Raynaud phenomenon is discussed, including ‘red flags’ that are suggestive of SSc. The pathogenesis, classification and assessment of SSc-associated digital ulcers are also covered, alongside an overview of management approaches for SSc-associated Raynaud phenomenon and digital ulcers. Finally, unmet needs are discussed and the concept of a unified vascular phenotype in which therapies that affect the vasculature to support disease modification strategies is introduced.

Summary Background Abatacept was well tolerated by patients with early diffuse cutaneous systemic sclerosis in a phase 2, double-blind randomised trial, with potential efficacy at 12 months. We report here the results of an open-label extension for 6 months. Methods Patients (aged ≥18 years) with diffuse cutaneous systemic sclerosis of less than 3 years' duration from their first non-Raynaud's symptom were enrolled into the ASSET trial (A Study of Subcutaneous Abatacept to Treat Diffuse Cutaneous Systemic Sclerosis), which is a double-blind trial at 22 sites in Canada, the UK, and the USA. After completion of 12 months of treatment with either abatacept or placebo, patients received a further 6 months of abatacept (125 mg subcutaneous every week) in an open-label extension. The primary endpoint of the double-blind trial was modified Rodnan Skin Score (mRSS) at 12 months, which was reassessed at 18 months in the open-label extension. The primary analysis included all participants who completed the double-blind trial and received at least one dose of open-label treatment (modified intention to treat). This trial is registered with ClinicalTrials.gov , NCT02161406 . Findings Between Sept 22, 2014, and March 15, 2017, 88 participants were randomly allocated in the double-blind trial either abatacept (n=44) or placebo (44); 32 patients from each treatment group completed the 6-month open-label extension. Among patients assigned abatacept, a mean improvement from baseline in mRSS was noted at 12 months (−6·6 [SD 6·4]), with further improvement seen during the open-label extension period (−9·8 [8·1] at month 18). Participants assigned placebo had a mean improvement from baseline in mRSS at 12 months (−3·7 [SD 7·6]), with a further improvement at month 18 (−6·3 [9·3]). Infections during the open-label extension phase occurred in nine patients in the placebo–abatacept group (12 adverse events, one serious adverse event) and in 11 patients in the abatacept–abatacept group (14 adverse events, one serious adverse event). Two deaths occurred during the 12-month double-blind period in the abatacept group, which were related to scleroderma renal crisis; no deaths were recorded during the open-label extension. Interpretation During the 6-month open-label extension, no new safety signals for abatacept were identified in the treatment of diffuse cutaneous systemic sclerosis. Clinically meaningful improvements in mRSS and other outcome measures were observed in both the abatacept and placebo groups when patients transitioned to open-label treatment. These data support further studies of abatacept in diffuse cutaneous systemic sclerosis. Funding Bristol-Myers Squibb and National Institutes of Health.

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)

Calcinosis cutis is the deposition of insoluble calcium in the skin and subcutaneous tissues. It is a manifestation of several autoimmune connective tissue diseases, most frequently with systemic sclerosis and juvenile dermatomyositis, followed by adult dermatomyositis. Autoimmune connective tissue disease–associated calcinosis is of the dystrophic subtype, which occurs at sites of damaged tissue in the setting of normal serum calcium and phosphate levels. In juvenile dermatomyositis, calcinosis is considered a marker of ongoing disease activity and possibly inadequate treatment, while in adult dermatomyositis, it is a hallmark of skin damage due to chronic rather than active disease. Calcinosis is associated with long disease duration in systemic sclerosis and dermatomyositis, anti-polymyositis/sclerosis autoantibodies in systemic sclerosis and NXP-2 and melanoma differentiation-associated gene 5 in dermatomyositis. Calcinosis in systemic sclerosis occurs most frequently in the hands, particularly the fingers, whereas in dermatomyositis, it affects mainly the trunk and extremities. The primary mineral component of calcinosis is hydroxyapatite in systemic sclerosis and carbonate apatite in dermatomyositis. Calcinosis in dermatomyositis and systemic sclerosis share some pathogenic mechanisms, but vascular hypoxia seems to play a more important role in systemic sclerosis, whereas the release of calcium from mitochondria in muscle cells damaged by myopathy may be a primary mechanism contributing to dermatomyositis-related calcinosis. Multiple treatment strategies for dermatomyositis and systemic sclerosis-related calcinosis have been used with variable results. Early aggressive treatment of underlying myositis in patients with dermatomyositis may improve long-term outcomes of calcinosis. A better understanding of the pathogenesis of calcinosis is needed to improve treatment options.

Objective To evaluate the prevalence and clinical associations of ultrasound (US) findings of inflammatory arthritis and joint and soft tissue pathology in patients with systemic sclerosis (SSc). Methods The hands and wrists of 43 SSc patients and 35 age-balanced controls were evaluated by clinical exam and musculoskeletal US. Synovial and tenosynovial pathology were assessed using semi-quantitative Gray Scale (GS) and Power Doppler (PD) scoring. US evaluation for osteophytes, erosions, ulnar artery occlusion, and median nerve cross-sectional areas was performed. Tender joints (TJ), swollen joints (SJ), modified Rodnan skin score (mRSS), digital ulcers, contractures, and calcinosis were evaluated. Concordance between US and physical exam findings at each joint region were assessed, and associations between their severity were analyzed. Results TJs and SJs were present in 44.2% and 62.8% of SSc patients, respectively. Inflammatory arthritis, defined as having both GS>0 and PD>0, was observed in 18.6% of SSc patients and no controls. There was a high concordance by joint region between GS synovial hypertrophy and osteophytes (κ=0.88) as well as TJs (κ=0.72). SSc patients had more osteophytes compared to controls (48.8% vs 22.9%, p = 0.018) as well as higher osteophyte severity (p = 0.033). Conclusions Despite a high percentage of tender and swollen joints, less than 20% of SSc patients met criteria for inflammatory arthritis on US. The high concordance of osteophytes with GS synovial hypertrophy and tender joints suggest that osteophytosis may be a significant contributor to joint pain in SSc patients.

The Collaborative National Quality and Efficacy Registry (CONQUER) for Scleroderma is a multicenter US-based longitudinal study of patients with systemic sclerosis (SSc) within 5 years of first non-Raynaud’s symptom. The data collection methodology incorporates successful models from other SSc registries. The cohort is designed to provide linked bio-specimen and clinical outcomes data on a longitudinal cohort of SSc patients for validation of hypothesis-driven research and to provide a platform for studying patient-reported outcomes in scleroderma. The CONQUER registry was developed using the guidelines of the International Society for Biological Repositories, and was an iterative process between physicians with an expertise in SSc, patient stakeholders, and information technology experts. Enrollment commenced in June 2018. During the first 6 months of the CONQUER Scleroderma study, 151 SSc patients with less than 5 years of disease duration (from first non-Raynaud’s symptom) have been recruited. The mean age is 51 ± 14 years, 83% are female, and 60% of patients have diffuse disease. Survey completion rates are above 88% for all patient-reported outcome surveys. Bio-specimen collection rates are over 97%, and disease severity score completion rates are over 98%. Pulmonary function test data is available on 91% of patients, and echocardiography is available 80%. The CONQUER scleroderma study provides a unique and growing resource for studying scleroderma in a longitudinal, US-based population. • The Collaborative National Quality and Efficacy Registry (CONQUER) for Scleroderma is a multicenter US-based longitudinal study of patients with systemic sclerosis (SSc) within 5 years of first non-Raynaud’s symptom. • The CONQUER scleroderma study provides a unique and growing resource for studying scleroderma in a longitudinal, US-based population. • CONQUER is innovative in its design in that it is focused on prospective collection of paired clinical and patient outcome data with bio-specimens.

Periarterial sympathectomy and arterial bypass are microsurgical techniques which the literature suggests can provide improvement in digital pain and ulceration in patients with systemic sclerosis who have persistent symptoms despite medication management. This review summarizes the relevant anatomy, medical therapies, operative techniques, and surgical outcomes and complications associated with the management of the vascular manifestations of systemic sclerosis in the hand. Multidisciplinary collaboration between dermatology, rheumatology, and hand surgery can facilitate optimal medical and surgical management for systemic sclerosis patients.

The development of treatments for systemic sclerosis has historically been hampered by the clinical heterogeneity of the disease and limited understanding of its pathogenesis. Encouragingly, advances including the identification of important molecular targets and improvements in clinical trial design have now greatly increased the number of investigative therapies.

Systemic sclerosis (SSc; scleroderma) is a poorly understood autoimmune rheumatic disease that primarily affects women. The clinical hallmark is hardening of the skin, but internal organ dysfunction is the leading cause of death. Diagnosis and treatment are complicated by heterogeneity within the disease including variable lethality, fibrosis severity, serum autoantibody production, and internal organ involvement. Important gaps remain in our knowledge of the exact molecular and cellular pathways underlying distinct SSc subtypes. Herein, we identify genome-wide chromatin accessibility profiles of peripheral CD4+ T cells to distinguish and better understand the observed heterogeneity in SSc patients. We identify a link between serum anticentromere autoantibody (ACA) subtype and elevated levels of T helper 2 (Th2) cells and increased chromatin access at gene loci encoding fibrosis-driving Th2 cytokines IL4, IL13, and IL4 receptor. Biological sex followed by autoantibody subtype are the predominant variables associated with differences in CD4+ T cell epigenomic profiles, while mycophenolate mofetil treatment appeared to have no effect. These results suggest new mechanistic basis and therapeutic strategies to address SSc, especially the ACA+ subtype that is associated with pulmonary arterial hypertension.

Summary Background Pain is an important and detrimental feature of systemic sclerosis but is often overlooked or deprioritised in research and clinical care. Raynaud's phenomenon, arthritis, and cutaneous ulcers are among the commonly reported disease manifestations of systemic sclerosis that could be associated with pain. We aimed to assess levels of pain intensity and interference and to evaluate disease factors associated with pain intensity and interference. Methods In this multicentre cross-sectional study, participants from the Scleroderma Patient-centered Intervention Network cohort who completed pain intensity and interference measures (Patient Reported Outcomes Information System-29 profile, version 2·0) as part of baseline assessments were included. Patients were recruited from 46 centres in Australia, Canada, France, Mexico, Spain, the UK, and the USA between April 15, 2014, and Jan 7, 2020. Eligible patients included those aged 18 years or older who met the criteria for systemic sclerosis devised by the American College of Rheumatology and the European League Against Rheumatism. Associations of pain intensity and pain interference with systemic sclerosis-related variables and overlap syndromes, controlling for sociodemographic variables, were assessed with multiple linear regression. Continuous independent variables were standardised. Findings Among 2157 participants with systemic sclerosis (268 [12%] males and 1889 [88%] females), 1870 (87%) reported mild, moderate, or severe pain (defined as ≥1 on a 0 to 10 scale), and 815 (38%) reported moderate or severe pain (defined as ≥5). Moreover, 757 (35%) participants reported moderate or severe pain interference. Greater pain intensity was independently associated with female sex (0·58 points [95% CI 0·26–0·90]), non-White race or ethnicity (0·50 points [0·21–0·79]), fewer years in formal education (0·30 points per SD [0·19–0·41]), country (reference: USA; Canada: 0·29 points [0·01–0·57] and UK: 0·58 points [0·21–0·95]), greater body-mass index (0·35 points per SD [0·24–0·45]); joint contractures (0·67 points [0·39–0·94]), digital ulcers (0·33 points [0·10–0·55]), gastrointestinal involvement (0·66 points [0·33–0·98]), skin involvement (measured using modified Rodnan skin score; 0·22 points per SD [0·10–0·35]), rheumatoid arthritis (0·96 points [0·50–1·43]), and Sjogren's syndrome (0·42 points [0·01–0·83]). Pain interference results were similar. Interpretation Pain is common among people with systemic sclerosis. Controlling for sociodemographic variables, greater pain was associated with multiple systemic sclerosis-related manifestations, including joint contractures, digital ulcers, gastrointestinal involvement, skin involvement, and the presence of overlap syndromes. Health-care providers should work with patients to address pain, including identifying and addressing systemic sclerosis manifestations associated with their pain, and supporting behavioural approaches to minimise impact on function and quality of life. Funding Canadian Institutes of Health Research, Arthritis Society, The Lady Davis Institute for Medical Research of the Jewish General Hospital, Jewish General Hospital Foundation, McGill University, Scleroderma Society of Ontario, Scleroderma Canada, Sclerodermie Quebec, Scleroderma Manitoba, Scleroderma Atlantic, Scleroderma Association of BC, Scleroderma SASK, Scleroderma Australia, Scleroderma New South Wales, Scleroderma Victoria, and Scleroderma Queensland.

Objectives To identify clinical factors associated with cancer risk in the idiopathic inflammatory myopathies (IIMs) and to systematically review the existing evidence related to cancer screening. Methods A systematic literature search was carried out on Medline, Embase and Scopus. Cancer risk within the IIM population (i.e. not compared with the general population) was expressed as risk ratios (RR) for binary variables and weighted mean differences (WMD) for continuous variables. Evidence relating to cancer screening practices in the IIMs were synthesized via narrative review. Results Sixty-nine studies were included in the meta-analysis. DM subtype (RR 2.21), older age (WMD 11.19), male sex (RR 1.53), dysphagia (RR 2.09), cutaneous ulceration (RR 2.73) and anti-transcriptional intermediary factor-1 gamma positivity (RR 4.66) were identified as being associated with significantly increased risk of cancer. PM (RR 0.49) and clinically amyopathic DM (RR 0.44) subtypes, Raynaud’s phenomenon (RR 0.61), interstitial lung disease (RR 0.49), very high serum creatine kinase (WMD −1189.96) or lactate dehydrogenase (WMD −336.52) levels, and anti-Jo1 (RR 0.45) or anti-EJ (RR 0.17) positivity were identified as being associated with significantly reduced risk of cancer. Nine studies relating to IIM-specific cancer screening were included. CT scanning of the thorax, abdomen and pelvis appeared to be effective in identifying underlying asymptomatic cancers. Conclusion Cancer risk factors should be evaluated in patients with IIM for risk stratification. Screening evidence is limited but CT scanning could be useful. Prospective studies and consensus guidelines are needed to establish cancer screening strategies in IIM patients.

Systemic sclerosis (SSc) is a disease at the intersection of autoimmunity and fibrosis. However, the epigenetic regulation and the contributions of diverse cell types to SSc remain unclear. Here we survey, using ATAC-seq, the active DNA regulatory elements of eight types of primary cells in normal skin from healthy controls, as well as clinically affected and unaffected skin from SSc patients. We find that accessible DNA elements in skin-resident dendritic cells (DCs) exhibit the highest enrichment of SSc-associated single-nucleotide polymorphisms (SNPs) and predict the degrees of skin fibrosis in patients. DCs also have the greatest disease-associated changes in chromatin accessibility and the strongest alteration of cell–cell interactions in SSc lesions. Lastly, data from an independent cohort of patients with SSc confirm a significant increase of DCs in lesioned skin. Thus, the DCs epigenome links inherited susceptibility and clinically apparent fibrosis in SSc skin, and can be an important driver of SSc pathogenesis., Systemic sclerosis (SSc) is a disease with manifestation in the skin and immune etiology, but the pathogenic immune cell types remain unidentified. Here the authors use ATAC-seq to profile chromatin landscapes of skin samples from patients with SSc to implicate skin dendritic cells for having the strongest disease-associated epigenetic changes.

Background CTD-PAH has historically represented a PAH subtype with poor prognosis. New therapies, as well as combination therapy approaches targeting multiple pathways have been approved for PAH based on RCTs. CTD-PAH patients comprise a subgroup of the RCT populations and efficacy analyses are based on subgroup analyses which can be less reliable than the overall analysis. We conducted a meta-analysis of RCTs of approved PAH therapies to evaluate outcomes of patients with CTD-PAH. Purpose To use meta-analysis to determine response to treatment in patients with CTD-PAH. Methods The PubMed and EMBASE databases were searched for English-only articles published between January 1, 2000 and November 25, 2019. Inclusion criteria were multicenter RCTs that enrolled adults with WHO group 1 pulmonary hypertension (PAH); enrollment in 2000 or later; long-term clinical morbidity and/or mortality event or 6-minute walk distance (6MWD) as an efficacy endpoint reported for ≥30 patients with CTD-PAH; and evaluation of a US Food and Drug Administration-approved PAH therapy. The primary outcomes were treatment effect as measured by the study time to first morbidity or morality event and change in 6MWD from baseline to between 3–6 months, per the data provided in each article. Results from individual studies were combined using a random-effects model for overall study population (PAH patients) and the subgroup of CTD-PAH patients. Results Ten RCTs (N=4329 PAH patients; n=1263 (29%) with CTD-PAH) met inclusion criteria and were included in the meta-analysis. At baseline, PAH patients had a mean age of 50 years, approximately 78% were female, and approximately 58% had functional class III or IV disease. These characteristics were balanced between treatment and control groups. Baseline 6MWD was 356 m for the overall population and 337 m for patients with CTD-PAH. Five RCTs (N=3172; n=941 with CTD-PAH [30%]) reported hazard ratios (HRs) for time to a morbidity or mortality event by drug treatment and PAH etiology: overall population HR=0.63 (95% confidence interval [CI], 0.56–0.72; P Conclusions The improvement in 6MWD in patients with CTD-PAH is smaller than in those with other types of PAH, perhaps reflecting comorbidities and CTD-induced mobility constraints, independent of their cardiopulmonary capacity. Data from long term clinical morbidity/mortality endpoint studies in this large group of patients with CTD-PAH demonstrate that these patients derive significant benefit from currently available PAH therapies which, in many patients, comprised the addition of a drug targeting a second or third pathway involved in the pathophysiology of PAH. Treatment effect on morbidity/mortality Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Actelion Pharmaceuticals US, Inc.

Introduction No studies have examined factors associated with fear in any group of people vulnerable during COVID-19 due to pre-existing medical conditions. Objective To investigate factors associated with fear of consequences of COVID-19 among people living with a pre-existing medical condition, the autoimmune disease systemic sclerosis (SSc; scleroderma), including country. Methods Pre-COVID-19 data from the Scleroderma Patient-centered Intervention Network (SPIN) Cohort were linked to COVID-19 data collected in April 2020. Multivariable linear regression was used to assess factors associated with continuous scores of the 10-item COVID-19 Fears Questionnaire for Chronic Medical Conditions, controlling for pre-COVID-19 anxiety symptoms. Results Compared to France (N = 156), COVID-19 Fear scores among participants from the United Kingdom (N = 50) were 0.12 SD (95% CI 0.03 to 0.21) higher; scores for Canada (N = 97) and the United States (N = 128) were higher, but not statistically significant. Greater interference of breathing problems was associated with higher fears due to COVID-19 (Standardized regression coefficient = 0.12, 95% CI 0.01 to 0.23). Participants with higher financial resources adequacy scores had lower COVID-19 Fear scores (Standardized coefficient = −0.18, 95% CI −0.28 to −0.09). Conclusions Fears due to COVID-19 were associated with clinical and functional vulnerabilities in this chronically ill population. This suggests that interventions may benefit from addressing specific clinical issues that apply to specific populations. Financial resources, health policies and political influences may also be important. The needs of people living with chronic illness during a pandemic may differ depending on the social and political context in which they live., Highlights • People with chronic diseases may experience high levels of fear due to COVID-19. • We examined factors associated with fears due to COVID-19 in an at-risk population. • We used the validated COVID-19 Fears Questionnaire for Chronic Medical Conditions. • Fears due to COVID-19 among people with SSc differed substantially by country. • Interference of breathing problems and financial adequacy were related to fears.

On behalf of the authors, we appreciate the interest from Mittal and Sharma in the Phase 2 study results of lenabasum for the treatment of diffuse cutaneous systemic sclerosis (dcSSc) [1]. The small sample size and specified set of efficacy analyses done in this study preclude separate subset analyses of the course of interstitial lung disease, pulmonary artery hypertension, gastrointestinal involvement, or all efficacy analyses by disease duration or background immunosuppressant use, over 16 weeks.

Background and objective In the SENSCIS trial in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) (mL/year) over 52 weeks by 44% in comparison with placebo, with manageable adverse events in most patients. We analyzed the efficacy and safety of nintedanib in patients of Asian race. Methods Patients with SSc-ILD were randomized to receive nintedanib or placebo. The outcomes over 52 weeks were analyzed in Asian versus non-Asian patients. Results Of the 288 patients in each treatment group, 62 (21.5%) in the nintedanib group and 81 (28.1%) in the placebo group were Asian; 90.2% of the Asian patients were enrolled in Asian countries. In the placebo group, the rate of FVC decline over 52 weeks was consistent between Asian and non-Asian patients (−99.9 and −90.6 mL/year, respectively). The effect of nintedanib on reducing the rate of FVC decline over 52 weeks was consistent between Asian (difference, 44.3 mL/year [95% CI: −32.8, 121.4]) and non-Asian patients (difference, 39.0 mL/year [95% CI: −5.1, 83.1]) (treatment-by-time-by-subgroup interaction, p = 0.91). Diarrhea was the most frequent adverse event and was reported in similar proportions of Asian and non-Asian patients in the nintedanib group (80.6% and 74.3%, respectively) and placebo group (28.4% and 32.9%, respectively). Conclusions In patients with SSc-ILD, nintedanib had a consistent benefit on slowing the progression of SSc-ILD in Asian and non-Asian patients, with a similar adverse event profile. Trial registration ClinicalTrials.gov NCT02597933 .

BackgroundPeripheral blood leucocyte telomere length (PBL-TL) is associated with outcomes in patients with idiopathic pulmonary fibrosis. Whether PBL-TL is associated with progression of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is unknown.MethodsA retrospective observational cohort study was performed using prospectively collected data from 213 patients with SSc followed at the University of California San Francisco (UCSF) Scleroderma Center. PBL-TL was measured by quantitative PCR of DNA isolated from peripheral blood. Associations between PBL-TL and pulmonary function test trends in patients with SSc-ILD were assessed by longitudinal analysis using Generalised Linear Mixed Models. Findings were validated in a cohort of 61 patients with SSc-ILD enrolled in the Stanford University Scleroderma Center database.ResultsPatients with UCSF SSc with ILD were found to have shorter PBL-TL compared with those without ILD (6554±671 base pairs (bp) vs 6782±698 bp, p=0.01). Shorter PBL-TL was associated with the presence of ILD (adjusted OR 2.1 per 1000 bp TL decrease, 95% CI [1.25 to 3.70], p=0.006). PBL-TL was shorter in patients with SSc-ILD lacking SSc-specific autoantibodies compared with seropositive subjects (6237±647 bp vs 6651±653 bp, p=0.004). Shorter PBL-TL was associated with increased risk for lung function deterioration with an average of 67 mL greater loss in per year for every 1000 bp decrease in PBL-TL in the combined SSc-ILD cohorts (longitudinal analysis, adjusted model: 95% CI −104 mL to −33 mL, pConclusionsThese findings suggest that telomere dysfunction may be associated with SSc-ILD progression and that PBL-TL measurement may be useful for stratifying risk for SSc-ILD progression.

Background. Few therapies specifically address the chronic airway inflammation in cystic fibrosis (CF) that contributes to progressive destruction of lung tissue and loss of lung function. Lenabasum is a cannabinoid type 2 receptor (CB2) agonist that resolves inflammation in a number of in vitro and in vivo models. Methods. A Phase 2 double-blind, randomized, placebo-controlled study assessed the safety and tolerability of lenabasum in adults with CF. Subjects with FEV1% (ppFEV1) ≥40% predicted were randomized to lenabasum 1 or 5 mg or placebo once daily (QD) (Weeks 1–4), then 20 mg QD, 20 mg twice daily (BID) or placebo (Weeks 5–12), with follow-up at Week 16. Pulmonary exacerbations (PEx) were recorded and biomarkers of blood and lung inflammation were measured. Results. Of 89 subjects randomized, 51 lenabasum and 23 placebo-only subjects completed the study. No deaths or serious or severe adverse events (AE) were considered related to lenabasum. Most AEs were mild/moderate, and the most common were PEx, hemoptysis, dry mouth, and upper respiratory infection. Three lenabasum and one placebo-only subjects discontinued the study for a treatment related AE. New PEx were treated with intravenous antibiotics in 4.0% of lenabasum-treated vs. 11.4% of placebo-treated subjects, during Weeks 1–4 and 5.2% compared to 13.0% during Weeks 5–12 (p Conclusions. The safety findings of lenabasum, coupled with biomarker data, support further testing in a larger study with a longer duration.

OBJECTIVE: Gastric Antral Vascular Ectasia (GAVE) is a vascular manifestation of systemic sclerosis (SSc) that can lead to iron deficiency anemia or acute gastrointestinal (GI) bleeding. We aimed to identify clinical features associated with GAVE. METHODS: We performed a cohort study of SSc patients who were seen at Stanford between 2004 and 2018 and had undergone esophagogastroduodenoscopy (EGD). We compared the clinical features of those with and without GAVE, and multivariable logistic regression was performed to identify clinical correlates with GAVE. RESULTS: A total of 225 patients with SSc who underwent EGD were included in this study and 19 (8.4%) had GAVE. Those with GAVE were more likely to have scleroderma renal crisis (SRC) (21% vs 3%; p

Background Systemic sclerosis (SSc), or scleroderma, is a rare disease that often results in significant disruptions to activities of daily living and can negatively affect physical and psychological well-being. Because there is no known cure, SSc treatment focuses on reducing symptoms and disability and improving health-related quality of life (HRQoL). Self-management programs are known to increase self-efficacy for disease management in many chronic diseases. The Scleroderma Patient-centered Intervention Network (SPIN) developed a Web-based self-management program (SPIN self-management; SPIN-SELF) to increase self-efficacy for disease management and to improve HRQoL for patients with SSc. Objective The proposed study aims to assess the feasibility of conducting a full-scale randomized controlled trial (RCT) of the SPIN-SELF program by evaluating the trial implementation processes, required resources and management, scientific aspects, and participant acceptability and usage of the SPIN-SELF program. Methods The SPIN-SELF feasibility trial will be conducted via the SPIN Cohort. The SPIN Cohort was developed as a framework for embedded pragmatic trials using the cohort multiple RCT design. In total, 40 English-speaking SPIN Cohort participants with low disease management self-efficacy (Self-Efficacy for Managing Chronic Disease Scale score ≤7), who have indicated interest in using a Web-based self-management program, will be randomized with a 3:2 ratio into the SPIN-SELF program or usual care for 3 months. Feasibility outcomes include trial implementation processes, required resources and management, scientific aspects, and patient acceptability and usage of the SPIN-SELF program. Results Enrollment of the 40 participants occurred between July 5, 2019, and July 27, 2019. By November 25, 2019, data collection of trial outcomes was completed. Data analysis is underway, and results are expected to be published in 2020. Conclusions The SPIN-SELF program is a self-help tool that may improve disease-management self-efficacy and improve HRQoL in patients with SSc. The SPIN-SELF feasibility trial will ensure that trial methodology is robust, feasible, and consistent with trial participant expectations. The results will guide adjustments that need to be implemented before undertaking a full-scale RCT of the SPIN-SELF program. International Registered Report Identifier (IRRID) DERR1-10.2196/16799

Cytokines and other secreted soluble proteins are routinely assayed as fluorescence intensities on the Luminex (Luminex, Austin, TX) platform. As with any immunoassay, a portion of the measured Ab binding can be nonspecific. Use of spiked-in microbead controls (e.g., AssayChex Process, Control Panel; Radix Biosolutions, Georgetown, TX) can determine the level of nonspecific binding on a per specimen basis. A statistical approach for correction of this assay’s nonspecific binding artifact was first described in earlier work. The current paper describes a novel utility written in the R language (https://www.r-project.org), that refines correction for nonspecific binding in three important ways: 1) via local polynomial regression, the utility allows for curvature in relationships between soluble protein median fluorescence intensities and nonspecific binding median fluorescence intensities; 2) to stabilize correction, the fit of the nonlinear regression function is obtained via repeated cross-validation; and 3) the utility addresses possible bias due to technical error in measured nonspecific binding. The utility first logarithm transforms and then removes plate/batch/lot artifacts from median fluorescence intensities prior to correction for nonspecific binding, even when plates/batches/lots are unbalanced with respect to experimental factors of interest. Continuous (e.g., age) and categorical (e.g., diagnosis) covariates are accommodated in plate/batch/lot artifact correction. We present application of the utility to a panel of 62 cytokines in a sample of human patients diagnosed with systemic sclerosis and to an experiment that examined multiple lots of a human 51-cytokine panel. The R script for our new utility is publicly available for download from the web.

Objective Contagious disease outbreaks and related restrictions can lead to negative psychological outcomes, particularly in vulnerable populations at risk due to pre-existing medical conditions. No randomised controlled trials (RCTs) have tested interventions to reduce mental health consequences of contagious disease outbreaks. The primary objective of the Scleroderma Patient-centered Intervention Network COVID-19 Home-isolation Activities Together (SPIN-CHAT) Trial is to evaluate the effect of a videoconference-based program on symptoms of anxiety. Secondary objectives include evaluating effects on symptoms of depression, stress, loneliness, boredom, physical activity, and social interaction. Methods The SPIN-CHAT Trial is a pragmatic RCT that will be conducted using the SPIN-COVID-19 Cohort, a sub-cohort of the SPIN Cohort. Eligible participants will be SPIN-COVID-19 Cohort participants without a positive COVID-19 test, with at least mild anxiety (PROMIS Anxiety 4a v1.0 T-score ≥ 55), not working from home, and not receiving current counselling or psychotherapy. We will randomly assign 162 participants to intervention groups of 7 to 10 participants each or waitlist control. We will use a partially nested RCT design to reflect dependence between individuals in training groups but not in the waitlist control. The SPIN-CHAT Program includes activity engagement, education on strategies to support mental health, and mutual participant support. Intervention participants will receive the 4-week (3 sessions per week) SPIN-CHAT Program via videoconference. The primary outcome is PROMIS Anxiety 4a score immediately post-intervention. Ethics and dissemination The SPIN-CHAT Trial will test whether a brief videoconference-based intervention will improve mental health outcomes among at-risk individuals during contagious disease outbreak., Highlights • No RCTs have tested mental health interventions in contagious disease outbreaks. • People with scleroderma face fear and isolation during COVID-19. • SPIN-CHAT is designed to improve mental health in SSc patients during COVID-19. • SPIN-CHAT provides 12 group sessions over 4 weeks. • The SPIN-CHAT trial will randomize 162 participants to intervention or waitlist.

Background:High-resolution computed tomography (HRCT) is the gold standard diagnostic test for Interstitial lung disease (ILD), a significant cause of morbidity and mortality in systemic sclerosis (SSc). Different algorithms have been proposed for the screening of SSc-ILD, including the use of pulmonary function tests (Forced Vital Capacity - FVC, Lung Diffusion of Carbone Monoxyde - DLCO). A prior survey reported that 50-66% of general rheumatologists and SSc experts ordered HRCT for ILD screening in newly diagnosed SSc patients (1).Objectives:Given the recent availability of on-label treatment for SSc-ILD (2), the publication of consensus recommendations for the identification of SSc-ILD (3) and recent awareness programs for the use of HRCT to detect SSc-ILD, we aimed to re-evaluate the use of HRCT for screening, re-screening and follow-up of SSc-ILD.Methods:An invitation was sent to the European Scleroderma Trials and Research (EUSTAR) and Scleroderma Clinical Trials Consortium (SCTC) members, also advertised through social media. Answers were recorded between Nov 25th and Dec 31st 2020. Questions were asked on the use of chest HRCT at baseline, the re-screening of patients with a negative baseline HRCT and the follow-up of HRCT positive SSc-ILD patients. When HRCT was not routinely requested, additional details were collected about the parameters guiding its use. The results of the survey were tested for association with geographical origin, medical specialty, working environment, SSc referral institute and scientific group membership of the responders, using Chi-squared test.Results:205/630 (32.5%) physicians replied to the survey. Participants were widely distributed in terms of geographical origin (130 Europe, 23 Asia, 23 North America, 31 other continents), medical specialty (156 rheumatology, 21 internal medicine, 14 clinical immunology, 14 other), working environment (176 University Hospital, 12 community hospital, 17 other), SSc dedicated clinic (179 referral and 26 non-referral) and scientific group membership (98 EUSTAR, 42 SCTC, 42 EUSTAR and SCTC, 23 not declared).At SSc diagnosis, 95.7% of responders would perform HRCT: 66.7% as routine screening for ILD (67,4% of SSc referral and 62% for non-referral physicians) and 29% for diagnostic purposes (among the latter, if crackles on auscultation – 92.5%, FVCDuring follow-up, 78.8% of responders would repeat an HRCT in baseline negative cases: 20.3% as a yearly routine screening and 64.5% for diagnostic aims (decision on the latter group was more frequently driven by FVC±DLCO relative decline indicative of ILD progression– 90.6%, new onset or worsening of dyspnoea at rest/exercise – 80.5/86.6%, new onset or worsening of lung crackles on auscultation – 82.6%).Finally, 94.5% of responders would repeat a chest HRCT after SSc-ILD diagnosis: 36.8% as a yearly routine and 56.7% according to clinical evaluation (driven by new FVC±DLCO relative decline based ILD progression – 90.8%, new onset or worsening of dyspnoea at rest/exercise – 83.2/81.7%; 5.2% to evaluate treatment effects). We found no difference in the distribution of answers among groups.Conclusion:The use of baseline HRCT for the screening of SSc-ILD has slightly increased in non-referral and remained stable in referral centers compared to previous surveys, indicating that the implementation of guidelines might be successful and awareness programs should be continued. In addition, we provide new data on use of HRCT in re-screening and follow-up. The development of validated algorithms to further support the appropriate application of HRCT at follow-up is highly needed.References:[1]Bernstein EJ et al. Arthritis Rheumatol. 2018 Jun;70(6):971-972.[2]Distler O et al. N Engl J Med. 2019 Jun 27;380(26):2518-2528.[3]Hoffmann-Vold AM et al. The Lancet Rheumatology, Volume 2, Issue 2, e71 - e83.Disclosure of Interests:Cosimo Bruni Speakers bureau: Actelion, Consultant of: Eli Lilly, Grant/research support from: Foundation for Research in Rheumatology (FOREUM), Gruppo Italiano Lotta alla Sclerodermia (GILS), Fondazione Italiana per la Ricerca sull’Artrite (FIRA), New Horizon Fellowship, European Sclerodermia Trial and Reserach (EUSTAR) Group., Lorinda Chung Consultant of: Boehringer Ingelheim, Eicos, Mitsubishi Tanabe, Reata., Anna-Maria Hoffmann-Vold Consultant of: Actelion, ARXX therapeutics, Bayer, Boehringer-Ingelheim, Medscape, MSD, Lilly, Roche, Shervin Assassi Speakers bureau: Integrity Continuing Education, Consultant of: Boehringer Ingelheim, Novartis, and Corbus, Armando Gabrielli: None declared, Dinesh Khanna Consultant of: Acceleron, Actelion, Abbvie, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, Corbus, Gilead, Galapagos, Genentech/Roche, GSK, Horizon, Merck, Mitsubishi Tanabe Pharma, Sanofi-Aventis, and United Therapeutics Leadership, Grant/research support from: NIH, Immune Tolerance Network, Bayer, BMS, Horizon, Pfizer, Employee of: Equity position – Chief Medical Officer, Eicos Sciences, Inc., Elana Bernstein Consultant of: Boehringer Ingelheim, Oliver Distler Consultant of: Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB., Grant/research support from: Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143).

ObjectivesAssess the efficacy and safety of tocilizumab in patients with systemic sclerosis (SSc) in a phase II study.MethodsPatients with SSc were treated for 48 weeks in an open-label extension phase of the faSScinate study with weekly 162 mg subcutaneous tocilizumab. Exploratory end points included modified Rodnan Skin Score (mRSS) and per cent predicted forced vital capacity (%pFVC) through week 96.ResultsOverall, 24/44 (55%) placebo-tocilizumab and 27/43 (63%) continuous-tocilizumab patients completed week 96. Observed mean (SD (95% CI)) change from baseline in mRSS was –3.1 (6.3 (–5.4 to –0.9)) for placebo and –5.6 (9.1 (–8.9 to–2.4)) for tocilizumab at week 48 and –9.4 (5.6 (–8.9 to –2.4)) for placebo-tocilizumab and –9.1 (8.7 (–12.5 to –5.6)) for continuous-tocilizumab at week 96. Of patients who completed week 96, any decline in %pFVC was observed for 10/24 (42% (95% CI 22% to 63%)) placebo-tocilizumab and 12/26 (46% (95% CI 27% to 67%)) continuous-tocilizumab patients in the open-label period; no patients had >10% absolute decline in %pFVC. Serious infection rates/100 patient-years (95% CI) were 10.9 (3.0 to 27.9) with placebo and 34.8 (18.0 to 60.8) with tocilizumab during the double-blind period by week 48 and 19.6 (7.2 to 42.7) with placebo-tocilizumab and 0.0 (0.0 to 12.2) with continuous-tocilizumab during the open-label period.ConclusionsSkin score improvement and FVC stabilisation in the double-blind period were observed in placebo-treated patients who transitioned to tocilizumab and were maintained in the open-label period. Safety data indicated increased serious infections in patients with SSc but no new safety signals with tocilizumab.Trial registration numberNCT01532869; Results.

Introduction Non-invasive biomarkers are needed to identify pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) patients who may benefit from early intervention. We sought to identify novel cytokines that differentiate patients with incident SSc-PAH from those at high risk for PAH. Methods The Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) Registry is a multicenter registry of SSc patients at high risk for PAH (at-risk) or with incident right-heart catheterization-confirmed PAH (definite PAH). Serum from 10 at-risk and 9 definite PAH patients were profiled with Bio-PlexTM bead arrays for 48 cytokines and chemokines. We also evaluated the longitudinal change in cytokine profiles from 3 at-risk patients who subsequently developed definite PAH. Results Clinical features of at-risk versus definite PAH patients were not significantly different except for right-ventricular systolic pressure on echocardiogram (34 ± 7 vs. 45 ± 8 mmHg, p = 0.006), left atrial diameter (2.9 ± 0.5 vs. 3.7 ± 0.4 cm, p = 0.02), 6-minute walk distance (508 ± 115 vs. 393 ± 70 m, p = 0.02), mean pulmonary artery pressure (18 ± 4 vs. 32 ± 6 mmHg, p = 0.01), and pulmonary vascular resistance (111 ± 48 vs. 272 ± 109 dyn/s/cm5, p = 0.009). Serum cytokine profiling identified hepatocyte growth factor (HGF) as the only cytokine significantly different between the at-risk and definite PAH groups (225.8 ± 55.0 vs. 361.6 ± 164.5 pg/mL, qConclusions Definite PAH patients expressed higher levels of HGF than at-risk patients. Further studies are needed to clarify the utility of HGF as a predictive biomarker for SSc-PAH.

Objective.Imatinib has been investigated for the treatment of systemic sclerosis (SSc) because of its ability to inhibit the platelet-derived growth factor receptor and transforming growth factor-β signaling pathways, which have been implicated in SSc pathogenesis. In a 12-month open-label clinical trial assessing the safety and efficacy of imatinib in the treatment of diffuse cutaneous SSc (dcSSc), significant improvements in skin thickening were observed. Here, we report our analysis of sera collected during the clinical trial.Methods.We measured the levels of 46 cytokines, chemokines, and growth factors in the sera of individuals with dcSSc using Luminex and ELISA. Autoantigen microarrays were used to measure immunoglobulin G reactivity to 28 autoantigens. Elastic net regularization was used to identify a signature that was predictive of clinical improvement (reduction in the modified Rodnan skin score ≥ 5) during treatment with imatinib. The signature was also tested using sera from a clinical trial of nilotinib, a tyrosine kinase inhibitor that is structurally related to imatinib, in dcSSc.Results.The elastic net algorithm identified a signature, based on levels of CD40 ligand, chemokine (C-X-C motif) ligand 4 (CXCL4), and anti-PM/Scl-100, that was significantly higher in individuals who experienced clinical improvement than in those who did not (p = 0.0011). The signature was validated using samples from a clinical trial of nilotinib.Conclusion.Identification of patients with SSc with the greatest probability of benefit from treatment with imatinib has the potential to guide individualized treatment. Validation of the signature will require testing in randomized, placebo-controlled studies. Clinicaltrials.govNCT00555581 and NCT01166139.

Background Prostacyclins are routinely used to treat vascular features of systemic sclerosis (SSc, scleroderma) but require parenteral infusion or inhalation. This study evaluated the safety and efficacy of oral treprostinil in digital ulcers secondary to SSc. Methods This was a randomized (1:1) placebo-controlled, multicenter study in adults with SSc and at least one active digital ulcer at entry. Oral treprostinil was administered twice daily and titrated to maximum tolerated dose with clinical assessments at Weeks 5, 10, 15 and 20. The primary endpoint was change in net digital ulcer burden. Secondary outcomes included ulcer healing and prevention, measures of hand function, quality of life, Raynaud phenomenon and global assessments. Simplified data were gathered during open-label follow up. Results Enrolled were 147 patients (109F/38M), mean age 48.8 years with SSc of mean duration 10.5 years. At week 20, mean net ulcer burden was reduced −0.43 ulcers on treprostinil (1.80 vs. 1.37) and −0.10 ulcers on placebo (1.61 vs. 1.51; p = 0.20). There were no effects on ulcer healing or prevention, and small, inconsistent effects on Raynaud phenomenon, global assessment, hand function and quality-of-life measures. In open-label follow-up, there was a continued, small reduction in net ulcer burden (-0.52 month 3, n = 104; −0.64 month 12, n = 36). Common adverse effects were headache, nausea, diarrhea, jaw pain, flushing and other gastrointestinal symptoms. Conclusions Administration of oral treprostinil twice daily over 20 weeks was associated with small and statistically insignificant reduction in net ulcer burden in comparison to placebo.

Background:In the SENSCIS trial in patients with SSc-ILD, nintedanib reduced the rate of decline in forced vital capacity (FVC) over 52 weeks. Elevated CRP is a marker of an inflammatory phenotype and has been associated with a greater rate of decline in FVC and higher mortality in patients with SSc.Objectives:To assess the effects of nintedanib in subgroups by CRP at baseline in the SENSCIS trial.Methods:Patients with SSc-ILD with onset of first non-Raynaud symptom 4.99 mg/L) at baseline.Results:Of patients with available data, 78/270 (28.9%) and 74/261 (28.4%) in the nintedanib and placebo groups, respectively, had CRP >4.99 mg/L at baseline. Compared with patients with lower CRP, those with CRP >4.99 mg/L included a similar proportion of patients who were ATA-positive (61.8% vs 60.2%, respectively), a greater proportion with diffuse cutaneous SSc (63.2% vs 49.3%) and had a higher mean mRSS (13.7 vs 10.2) and lower mean FVC % predicted (68.6% vs 73.9%). The adjusted annual rate of decline in FVC in the placebo group was numerically greater in patients with CRP >4.99 than ≤4.99 mg/L at baseline (-106.6 [SE 27.6] vs -83.0 [17.1] mL/year). The effect of nintedanib vs placebo on reducing the rate of decline in FVC was numerically more pronounced in patients with CRP >4.99 than ≤4.99 mg/L at baseline but the treatment-by-time-by-subgroup interaction p-value did not indicate heterogeneity in the effect of nintedanib between subgroups (p=0.70) (Figure). In the nintedanib and placebo groups, respectively, the proportions of patients with an absolute increase in FVC ≥3% predicted at week 52 were 20.4% and 15.0% in those with CRP ≤4.99 mg/L and 24.4% and 14.9% in those with CRP >4.99 mg/L at baseline (treatment-by-subgroup interaction p=0.59); adjusted mean changes in mRSS at week 52 were -2.2 (SE 0.3) and -2.1 (0.3) in those with CRP ≤4.99 mg/L (difference -0.1 [95% CI -1.0, 0.8]) and -2.3 (0.5) and -1.0 (0.5) in those with CRP >4.99 mg/L at baseline (difference -1.2 [-2.7, 0.2]; treatment-by-visit-by-subgroup interaction p=0.20).Conclusion:In the SENSCIS trial, the rate of decline in FVC over 52 weeks in the placebo group was numerically greater in patients with elevated CRP at baseline. Nintedanib reduced the rate of decline in FVC both in patients with normal and elevated CRP at baseline, with a numerically greater effect in patients with elevated CRP.Disclosure of Interests:Gabriela Riemekasten Consultant of: Cell Trend GmbH, Janssen, Actelion, Boehringer Ingelheim, Speakers bureau: Actelion, Novartis, Janssen, Roche, GlaxoSmithKline, Boehringer Ingelheim, Pfizer, Patricia Carreira Grant/research support from: Actelion, Roche, MSD, Consultant of: GlaxoSmithKline, VivaCell Biotechnology, Emerald Health Pharmaceuticals, Boehringer Ingelheim, Roche, Speakers bureau: Actelion, GlaxoSmithKline, Roche, Lesley Ann Saketkoo Grant/research support from: Corbus Pharmaceuticals, United Therapeutics, Consultant of: Boehringer Ingelheim, Eicos Sciences, Speakers bureau: Boehringer Ingelheim, Martin Aringer Consultant of: Boehringer Ingelheim, Roche, Speakers bureau: Boehringer Ingelheim, Roche, Lorinda Chung Grant/research support from: United Therapeutics, Boehringer Ingelheim, Consultant of: Bristol-Myers Squibb, Boehringer Ingelheim, Mitsubishi Tanabe, Eicos Sciences, Janet Pope Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly & Company, Merck, Roche, Seattle Genetics, UCB, Consultant of: AbbVie, Actelion, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eicos Sciences, Eli Lilly & Company, Emerald, Gilead Sciences, Inc., Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, UCB, Speakers bureau: UCB, Corinna Miede Employee of: Employee of Boehringer Ingelheim, Susanne Stowasser Employee of: Employee of Boehringer Ingelheim, Martina Gahlemann Employee of: Employee of Boehringer Ingelheim, Margarida Alves Employee of: Employee of Boehringer Ingelheim, Dinesh Khanna Shareholder of: Eicos Sciences, Inc./Civi Biopharma, Inc., Grant/research support from: Dr Khanna was supported by NIH/NIAMS K24AR063120, Consultant of: Acceleron, Actelion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Corbus Pharmaceuticals, Horizon Therapeutic, Galapagos, Roche/Genentech, GlaxoSmithKline, Mitsubishi Tanabe, Sanofi-Aventis/Genzyme, UCB

Background: Pulmonary arterial hypertension (PAH) is a morbid complication of systemic sclerosis (SSc). Management of SSc-PAH remains challenging and mortality is high. The postulated role of B-cells in SSc suggests a role for B-cell depletion in SSc-PAH. Methods: We conducted an NIH-sponsored proof-of-concept multicenter, double-blind, randomized controlled trial of rituximab (Rx) in SSc-PAH on stable PAH therapy. Dosing was two 1000 mg infusions 14 days apart. The primary endpoint was change in 6-minute walk distance (6MWD) at 24 weeks. Secondary endpoints included change in 6MWD at other time points, pulmonary vascular resistance (PVR), time to clinical worsening (TTCW), diffusion capacity, and SSc-specific factors. Results: Between 2010–2018, 57 subjects with similar baseline clinical characteristics were randomized 1:1 to Rx or placebo (Pc). Rx was well tolerated without unexpected toxicities. In a longitudinal analysis using data through week 24, 6MWD trended towards improvement after Rx relative to Pc, but did not differ significantly between arms (23.6±11.1m Rx, 0.5±9.7m Pc, p=0.12). A pre-specified secondary analysis using data through week 48 demonstrated improvement at week 24 (25.5±8.8m Rx, 0.4±7.4m Pc, p=0.03) with a loss of effect by week 48 (9.5±12.4m Rx, -7.0±8.6m Pc, p=0.28). Higher proportion of Pc subjects required additional PAH therapies, but changes in PVR and TTCW were not significantly different. Conclusion: Adjunctive B-cell depletion therapy is a safe and potentially effective treatment for SSc-PAH. This is the first controlled trial examining the role of immunotherapy in a serious form of PAH and warrants further study.

Background Abatacept (ABA) is a recombinant fusion protein including extracellular domain of human CTLA4 and hinge– CH2–CH3 of the Fc domain of human IgG. Objectives This phase 2 trial assessed the safety and efficacy of ABA 125 mg subcutaneous (SC) versus placebo SC given every week on skin fibrosis using the modified Rodnan skin score (mRSS) in diffuse cutaneous SSc (dcSSc; clinicaltrials.gov NCT02161406). Methods A 12-month, investigator-initiated, multicenter double-blind, randomized placebo-controlled trial was conducted between September 2014 and February 2018 at 27 US, Canadian and UK sites. Eligible subjects were randomized in a 1:1 ratio to either ABA or matching placebo, stratified by duration of dcSSc (≤18 vs >18 to ≤36 months). Key inclusion criteria included dcSSc with disease duration of ≤ 36 months (defined as first non−Raynaud phenomenon) and mRSS ≥ 10 and ≤ 35 units for disease duration of ≤ 18 months and mRSS ≥ 15 and ≤ 45 units with evidence of active disease for disease duration of >18-36 months. Escape therapy was allowed at 6 months for worsening SSc. Primary outcomes include safety and change in mRSS over 12 months (ΔmRSS). Secondary endpoints include ΔFVC%, ΔHAQ-DI, Δpatient and Δphysician global assessment, and ACR CRISS1 (composite measure in dcSSc). The primary endpoint of ΔmRSS was assessed using a linear mixed model (see Table) with primary end point data censored after initiation of escape therapy. Results 88 subjects were randomized (44/group) and formed the mITT group; 34 (77%) and 35 (80%) completed the 12-month double-blind treatment period in ABA and placebo groups, respectively. At baseline, the mean age was 49 years, 75% were female, mean disease duration was 1.59 years, 60% had disease duration ≤ 18 months, mRSS was 22.4, mean FVC% was 84.3%, and mean HAQ-DI was 1.0. Compliance with both drugs was >98%. ABA was well tolerated with comparable adverse events (AEs), serious AEs, and AEs of special interest (e.g., infections and malignancies) between treatments. There were 3 deaths during the treatment— 2 in ABA (both scleroderma renal crisis-days 11 and 46) and 1 in placebo (sudden cardiac arrest- day 310). The primary endpoint showed an adjusted mean improvement of mRSS of -6.24 in ABA vs. -4.49 in placebo, p= 0.28 (Table). The secondary outcome measures were statistically significant and clinically meaningful (HAQ-DI and physician global assessment) or showed numerical results favoring ABA (Table). A larger proportion of placebo subjects required escape immunosuppressive therapy vs. ABA (36% vs. 16%, p=0.03). Estimates are from a linear mixed model with treatment group, month (3, 6, and 12), treatment x month interaction, duration of dcSSc (≤18 vs >18 to ≤36 months), and baseline outcome measure as fixed effects and participant as a random effect (except for ACR CRISS). For ACR CRISS, treatment differences were assessed by the non-parametric Van Elteren test. Multiple imputation was used for ACR CRISS analysis. Conclusion In patients with early dcSSc, ABA was well tolerated, but ΔmRSS was not statistically significant. Secondary outcome measures showed evidence in favor of ABA, including greater requirement of escape therapy in the placebo group. mRSS showed large variability, despite recruiting an early dcSSc population. References [1] Khanna D, et al. Arthritis Rheumatol2016, 68:299-311 Acknowledgement Project was supported by NIH/NIAID Clinical ACE grant (5UM1AI110557-05) and an investigator-initiated grant by Bristol-Myers Squibb. Disclosure of Interests Dinesh Khanna Shareholder of: Eicos Sciences, Inc, Grant/research support from: Bayer, BMS, Pfizer, Horizon, Consultant for: Actelion Acceleron, Arena, Bayer, BI, BMS, CSL Behring, Corbus, Cytori, GSK, Genentech/Roche, Galapagos, Employee of: Elcos Sciences, Inc, Cathie Spino: None declared, Erica Bush: None declared, Sindhu Johnson: None declared, Lorinda Chung Grant/research support from: United Therapeutics, Consultant for: Reata, Bristol Meyers Squibb, Boehringer Ingelheim, Mitsubishi Tanabe, Eicos, Christopher Denton Grant/research support from: GlaxoSmithKline, Inventiva, CSF Behring, Consultant for: Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Bayer, Jerry Molitor Grant/research support from: Pfizer, Consultant for: Boehringer Ingelheim, Amgen, Viginia Steen Consultant for: CSL Behring, Corbus and Bayer, Paid instructor for: Advisory Board: CSL Behring, Roach, Bayer and Reata, Robert Lafyatis Grant/research support from: Kiniksa, Elpidera, Regeneron, PRISM biolab, Consultant for: Sanofi, Genentech, Formation, Biocon, Bristol Meyers Squibb, Merck, Robert Simms: None declared, Suzanne Kafaja: None declared, Tracy Frech: None declared, Vivian Hsu: None declared, Robin Domsic Consultant for: Eicos Sciences Inc/Civi Biopharma and Boehringer-Ingelheim., Janet Pope Consultant for: Eli Lilly and Company, Jessica Gordon Grant/research support from: Corbus Pharmaceuticals Cumberland Pharmaceuticals, Maureen Mayes Grant/research support from: Maureen Mayes is a clinical trial investigator for Boehringer-Ingelheim; Galapagos, Reata, Sanofi, Merck-Serono, Consultant for: Maureen Mayes is a member of scientific advisory boards for Galapagos NV (Pharma), Boehringer-Ingelheim, Mitsubishi-Tanabe, Astellas: Grant Review Board for Actelion., Speakers bureau: Maureen Mayes received personal fees for being a conference speaker on the use of autoantibodies in connective tissue diseases for Medtelligence, Elena Schiopu Grant/research support from: Bristol Meyers Squibb and Bayer, Amber Young: None declared, Nora Sandorfi: None declared, Jane Park: None declared, Faye Hant: None declared, Elana Bernstein Grant/research support from: I have an investigator-initiated research grant from the Pfizer ASPIRE Rheumatology Program., Consultant for: I am the medical monitor for SLS III, which is sponsored by Genentech, Soumya Chatterjee: None declared, Flavia Castelino Consultant for: Genentech, Boehringer, Ali Ajam Consultant for: Focus Point Global, Yannick Allanore Grant/research support from: Inventiva, F Hoffman La-Roche, Sanofi, BMS, Pfizer, Consultant for: Actelion, Bayer, BMS, Boehringer, Roche, Sanofi, Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Pfizer, BMS, Chemomab, Sanipedia, Speakers bureau: Actelion, BMS; MSD, Janssen, Oliver Distler Grant/research support from: Prof. Distler received research funding from Actelion, Bayer, Boehringer Ingelheim and Mitsubishi Tanabe to investigate potential treatments of scleroderma and its complications, Consultant for: Prof. Distler has/had consultancy relationship within the last 3 years with Actelion, AnaMar, Bayer, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Italfarmaco, iQvia, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Serodapharm and UCB in the area of potential treatments of scleroderma and its complications. In addition, he had/has consultancy relationship within the last 3 years with A. Menarini, Amgen, Abbvie, GSK, Mepha, MSD, Pfizer and UCB in the field of arthritides and related disorders, Ora Gewurz-Singer: None declared, David Fox Grant/research support from: Regeneron, Gilead, Seattle Genetics, Consultant for: Grant reviewer for Pfizer, Daniel Furst Grant/research support from: F. Hoffmann-La Roche, Genentech