Objective Mycophenolate mofetil (MMF) can stabilize or improve lung function in systemic sclerosis–related interstitial lung disease (SSc‐ILD). We hypothesized that combining MMF with pirfenidone (PFD) would produce a significantly more rapid and/or greater improvement in lung function. Methods A randomized (1:1), double‐blind, placebo (PLA)‐controlled phase 2 trial was conducted in SSc‐ILD in which patients received PFD or PLA (801 mg three times daily) along with MMF (1,500 mg twice daily) for 18 months. The primary outcome was change in percent predicted forced vital capacity (FVC‐%). Linear mixed‐effects models assessed treatment differences in a modified intention‐to‐treat population. Results Only fifty‐one of 150 intended subjects (34%) were randomized (MMF+PLA, n = 24; MMF+PFD, n = 27). The FVC‐% improved from baseline to 18 months by 2.24 ± 1.35 (least‐squares mean [LSM] ± SEM) in the MMF+PLA group and 2.09 ± 1.28 in the MMF+PFD group (LSM treatment difference −0.14; P = 0.93). Median time to achieve a ≥3% improvement in FVC‐% was numerically faster in the MMF+PFD versus MMF+PLA group (12.3 vs 17.8 months, respectively), but the difference was not significant (P = 0.33). For secondary outcomes, only the change over 18 months in the Patient‐Reported Outcomes Measurement Information System 29‐item physical function score, favoring MMF+PFD, reached statistical significance (P = 0.04). Although other related patient‐reported outcomes (PROs) numerically favored the MMF+PFD group, as did quantitative high‐resolution computed tomography measures of ILD, the differences between groups did not reach statistical significance. Early withdrawals from study medication and adverse events of special interest were numerically greater with MMF+PFD (n = 8 vs 2 and n = 20 vs 7, respectively). Conclusion In this underpowered study, there was no statistically significant treatment difference in overall change in FVC‐% between groups. MMF+PFD was not as well tolerated as MMF+PLA.

ObjectiveTwo randomized trials for patients with diffuse systemic sclerosis (SSc) demonstrated an overall survival (OS) and event-free survival (EFS) advantage of autologous hematopoietic stem cell transplantation (AHSCT) using CD34+ selected peripheral blood stem cells (PBSCs) compared with monthly cyclophosphamide (CY). We asked if an unmodified PBSC graft followed by maintenance mycophenolate mofetil (MMF) after AHSCT, instead of a CD34+ selected graft, could provide comparable AHSCT outcomes.MethodsTwenty patients with high-risk SSc were enrolled in a prospective, single-arm trial with CY 200 mg/kg and horse antithymocyte globulin (ATG; CY200/ATG), followed by unmanipulated autologous PBSC, and then MMF maintenance starting at 2 months after AHSCT.ResultsPoint estimates of OS and EFS at 5 years after AHSCT were 85% (95% confidence interval [CI] 60.4%-94.9%) and 75% (95% CI 50%-88.7%), respectively. Median follow-up was 7.5 years (range 5.6-11.6) after transplant for living patients. Eight patients (40%) required intensive care unit treatment early after transplant. Early transplant-related mortality occurred in two patients (10%). Five patients developed relapse/progression of SSc after AHSCT. Four of nine patients with anti-RNA polymerase III antibodies had prior scleroderma renal crisis and the lowest quartile of estimated glomerular filtration rate (eGFR) on study entry; all four patients developed prolonged organ failure/death early after transplant.ConclusionWe observed favorable OS and EFS after AHSCT for patients with SSc, using CY200/ATG, unmanipulated PBSCs, and MMF posttransplant maintenance, which was comparable to trials with CD34+ graft selection. We identified a possible risk factor, pretransplant low eGFR, for adverse outcomes after AHSCT.

OBJECTIVE:Systemic sclerosis (SSc) is a rare autoimmune disease characterized by fibrosis of the skin and other organs. SSc is thought to arise in genetically predisposed individuals with occupational triggers, although further environmental etiologies still need to be identified. Limited research exists detailing which environmental factors lead to the downstream inflammatory and fibrotic symptoms experienced by patients with SSc across the United States. This study describes a retrospective cohort of 179,188 individuals with an SSc or SSc-related diagnosis code enrolled in the Medicare beneficiary program between the years 2014 and 2018. METHODS:The incidence of SSc and SSc-related diagnosis codes in all US zip codes with beneficiary counts greater than 11 was calculated. We conducted global and local Moran's Index (Moran's I) as well as a hot spot analysis with the Getis Ord Gi statistic to determine whether SSc and SSc-related diagnosis codes exhibited clustered or dispersed patterns across the United States. We identified clusters of SSc and SSc-related diagnosis code with high incidences in or around Superfund sites, which are federally identified areas of environmental contamination. RESULTS:SSc exhibited clustered patterns in two analyzed cohorts based on global Moran's I statistics of 0.588 and 0.521. Results of local Moran's I indicated clusters of disease in Mississippi, New York, Wisconsin, and Michigan, among others. Some zip codes with high disease incidences were home to at least one Superfund site. CONCLUSION:SSc exhibits nonrandom, clustered distributions in a US Medicare beneficiary cohort composed of 179,188 individuals from 2014 to 2018.

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.

OBJECTIVEHand dysfunction is common in systemic sclerosis (SSc). The objective of this study was to evaluate the capacity of autologous Adipose-Derived Regenerative Cells (ADRCs) to improve hand function in SSc patients.METHODSThe STAR Trial was a prospective, randomized, double-blind trial of ADRCs injected into each finger digit of subjects with SSc. The primary endpoint was change in hand function at 24 and 48 weeks assessed using the Cochin Hand Function Scale (CHFS). Secondary endpoint included the change in Health Assessment Questionnaire-Disability Index (HAQ-DI) at 48 weeks. Separate analysis of subjects with diffuse (dcSSc) and limited cutaneous SSc (lcSSc) was pre-specified.RESULTS88 subjects were randomized to ADRCs (n=48; 32 dSSc:16 lcSSc) or Placebo (n=40; 19 dcSSc: 21 lcSSc). The primary end point was numerically higher for the ADRC group but did not achieve statistical significance (8.9±10.5 vs. 11.0±12.5, p= 0.299). For subjects with dcSSc the between group difference for the CHFS at 48 weeks was 6.3 points (nominal p=0.069). The HAQ-DI secondary endpoint exhibited a difference of 0.17 points (nominal p=0.044) for dcSSc group. 52% of ADRC-treated subjects with dcSSc reported improvement greater than the minimal clinically important difference for both CHFS and HAQ-DI compared with 16% in the placebo group (nominal p=0.016). Small volume adipose harvest and ADRC-treatment was well-tolerated.CONCLUSIONWhile the primary end point of this trial was not achieved, efficacy trends were observed in subjects with dcSSc. Adipose harvest and ADRC injection were demonstrated to be feasible. Further clinical trial of this intervention in dcSSc is warranted.

OBJECTIVES:The Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial compared hematopoietic stem cell transplant to CYC treatment in patients with early SSc with progressive skin and lung or kidney involvement. Here we describe lymphocyte phenotype abnormalities at study entry and the relation to prior DMARD therapy. METHODS:Lymphocyte subsets (n = 26) measured by flow cytometry were compared in 123 heathy controls and 71 SCOT participants, including those given (n = 57) or not given (n = 14) DMARDs within 12 months of randomization. RESULTS:Compared with healthy controls, individuals with SSc showed significant reductions in central memory CD8 T cells, activated total and CD4 T cells, γ/δ T cells, memory B cells, myeloid and plasmacytoid dendritic cells and FOXP3+CD25+ Treg cells and increases in naïve CD4 T cells, effector memory CD4 T cells and effector CD8 T cells. A greater bias towards a IL-4+ Th2/T cytotoxic 2 (Tc2) phenotype based on the Th2:Th1 CD4 ratio and Tc2:Tc1 CD8 T cells was also found. Notably, no difference in any lymphocyte subset was observed between those given or not given prior DMARDs. CONCLUSIONS:In patients with early, severe SSc, significant lymphocyte subset abnormalities were observed. Prior treatment with immunosuppressive therapy did not impact the immunophenotype, suggesting that lymphocyte disturbances in scleroderma appeared to be due to the disease itself. TRIAL REGISTRATION:ClinicalTrials.gov (https://clinicaltrials.gov), NCT00114530.

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.

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.

Introduction: Previous studies reported a progressive decrease in the systemic sclerosis mortality rates in the United States from 1959 to 2002. Identification of areas with clusters of higher mortality rates is important to implement targeted interventions. In this study, we aimed to estimate the mortality rates of scleroderma and to analyze its geographic variability at the state level in the United States. Methods: Mortality rates of scleroderma from 1999 to 2017 were obtained from the CDC Wonder Underlying Cause of Death database and its query system, using International Classification of Diseases, Tenth Revision codes. Age-adjusted rates were calculated by state and demographics. A linear regression model was applied to evaluate trends over time. Results: Over the period studied, a total of 24,525 deaths had scleroderma as the underlying cause of death. The age-adjusted mortality rate was 3.962 per million (95% CI: 3.912–4.012), decreasing progressively from 4.679 (95%CI: 4.423–4.934) in 1999 to 2.993 (95% CI: 2.817–3.170) per million in 2017. The age-adjusted mortality rate was 5.885 (95% CI: 5.802–5.967) and 1.651 (95% CI: 1.604–1.698) per million in females and males, respectively. Per races, the highest age-adjusted mortality rate was in Blacks or African Americans, at 5.703 per million (95% CI: 5.521–5.885), followed by American Indians or Alaska Native at 5.047 per million (95% CI: 4.428–5.667). Clusters of states with higher and lower mortality rates were identified. South Dakota had the highest whereas Hawaii had the lowest mortality rate. Conclusion: We found a trend to a progressive decrease in mortality rates of scleroderma during the years of our study. In addition, we found relevant state-by-state variation in mortality with several geographical clusters with higher mortality rates. Further analyses are warranted in order to better understand the factors associated with the observed geographic disparities.

INTRODUCTION:Given the poor treatment options for pulmonary arterial hypertension associated systemic sclerosis (SSc-PAH) patients, we sought to determine clinical safety and efficacy of Dimethylfumarate (DMF), an Nrf2 agonist, and the effects on biomarkers of oxidative stress on SSc-PAH in an exploratory interventional clinical trial. OBJECTIVES:The primary objectives were to assess the safety and efficacy of treatment with DMF in patients with SSc-PAH. METHODS:This was an investigator-initiated, double-blind, randomized, placebo-controlled trial conducted at two sites in the United States. The primary safety endpoint was the incidence of serious adverse events (SAEs) and all adverse events (AEs) in DMF compared to placebo-treated patients. The primary efficacy endpoint was the change in 6MWD from baseline to the end of treatment at Week 24 in DMF compared to placebo-treated patients. RESULTS:Six participants were randomized to either placebo (n = 2) or DMF (n = 4). Baseline demographics were similar in both groups. A total of 25 adverse events (AEs) occurred in 6 subjects, with 14 AEs (56.0%) having occurred in DMF-treated subjects. 3 occurrences were identified as nausea AEs, and two participants withdrew due to nausea. One participant in the placebo group was withdrawn after a hospitalization SAE due to worsening of heart failure and shortness of breath secondary to anemia. One participant in each group completed protocol. Subjects in the DMF-treated group showed a non-significant reduced decline in 6MWD (relative mean change of -7.07%) from baseline to Week 24 as compared to placebo-treated subjects (relative mean change of -14.97%). CONCLUSION:Patients treated for SSc-PAH with 2 and 3-drug regimens, as is now typical for these patients, tolerate DMF poorly. Our small samples size did not provide power to suggest efficacy. We suggest that Nrf2 is still a valid therapeutic target for future trials, using better tolerated Nrf2 agonists.

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 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. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

You are consulted to evaluate a 56-year-old woman with known Raynaud\u0027s phenomenon, swollen fingers for several months and new hypertension with a blood pressure of 160/100. She also complains of progressive shortness of breath. Her examination shows telangiectasias, sclerodactly and proximal skin sclerosis (thick shiny skin on chest and upper arms), and bibasilar crackles on chest exam. On further laboratory testing, she has evidence of microangiopathic hemolytic anemia, thrombocytopenia, new elevation of serum creatinine, and chest computed tomography (CT) shows evidence of ground glass opacification in both lower lung fields.

Objective To assess the safety and efficacy of lenabasum in diffuse cutaneous systemic sclerosis (dc SS c). Methods A randomized, double‐blind, placebo‐controlled, phase II study was conducted at 9 SS c clinics in the US . Adults with dc SS c of ≤6 years’ duration who were receiving stable standard‐of‐care treatment were randomized to receive lenabasum (n = 27) or placebo (n = 15). Lenabasum doses were 5 mg once daily, 20 mg once daily, or 20 mg twice daily for 4 weeks, followed by 20 mg twice daily for 8 weeks. Safety and efficacy were assessed at weeks 4, 8, 12, and 16. Results Adverse events ( AE s) occurred in 63% of the lenabasum group and 60% of the placebo group, with no serious AE s related to lenabasum. Compared to placebo, lenabasum treatment was associated with greater improvement in the American College of Rheumatology Combined Response Index in diffuse cutaneous Systemic Sclerosis ( CRISS ) score and other efficacy outcome measures that assessed overall disease, skin involvement, and patient‐reported function. The median CRISS score increased in the lenabasum group during the study, reaching 0.33, versus 0.00 in the placebo group, at week 16 ( P = 0.07 by 2‐sided mixed‐effects model repeated‐measures analysis). Gene expression in inflammation and fibrosis pathways was reduced, and inflammation and fibrosis were improved on histologic evaluation of skin biopsy specimens, in the lenabasum group compared to the placebo group (all P ≤ 0.05). Conclusion Despite a short trial duration in a small number of patients in this phase II study in dc SS c, our findings indicate that lenabasum improves efficacy outcomes and underlying disease pathology with a favorable safety profile.

You are consulted to evaluate a 56‐year‐old woman with known Raynaud's phenomenon, finger swelling of several; months’ duration, and new hypertension with a blood pressure of 160/100 mm/Hg. She also reports progressive shortness of breath. Physical examination reveals telangiectasias, sclerodactyly, and proximal skin sclerosis (thick shiny skin on the chest and upper arms), and bibasilar crackles are found on chest examination. Laboratory tests reveal evidence of microangiopathic hemolytic anemia, thrombocytopenia, and elevation of the serum creatinine level (previously normal), and chest computed tomography shows evidence of ground‐glass opacification in both lower lung fields.

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.