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Patients with interstitial lung disease associated with systemic sclerosis were treated with usual care plus placebo or nintedanib. The annual rate of change in forced vital capacity assessed over a 52-week period was −52.4 ml per year with nintedanib and −93.3 ml per year with placebo. There were no differences in other measures of systemic sclerosis.

Scleroderma is a life-threatening autoimmune disease in need of more effective treatment. A randomized trial of myeloablative therapy followed by autologous CD34+ hematopoietic stem-cell transplantation showed outcomes that were superior to those with monthly cyclophosphamide.

Systemic sclerosis is a rare disabling autoimmune disease with few treatment options. The efficacy and safety of tocilizumab, an interleukin 6 receptor-α inhibitor, was assessed in the faSScinate phase 2 trial in patients with systemic sclerosis. We did this double-blind, placebo-controlled study at 35 hospitals in Canada, France, Germany, the UK, and the USA. We enrolled adults with progressive systemic sclerosis of 5 or fewer years' duration from first non-Raynaud's sign or symptom. Patients were randomly assigned (1:1) to weekly subcutaneous tocilizumab 162 mg or placebo. The primary endpoint was the difference in mean change from baseline in modified Rodnan skin score at 24 weeks. This study is registered with ClinicalTrials.gov, number NCT01532869. We enrolled 87 patients: 43 assigned to tocilizumab and 44 assigned to placebo. The least squares mean change in modified Rodnan skin score at 24 weeks was −3·92 in the tocilizumab group and −1·22 in the placebo group (difference −2·70, 95% CI −5·85 to 0·45; p=0·0915). The least squares mean change at 48 weeks was −6·33 in the tocilizumab group and −2·77 in the placebo group (treatment difference −3·55, 95% CI −7·23 to 0·12; p=0·0579). In one of several exploratory analyses, fewer patients in the tocilizumab group than in the placebo group had a decline in percent predicted forced vital capacity at 48 weeks (p=0·0373). However, we detected no significant difference in disability, fatigue, itching, or patient or clinician global disease severity. 42 (98%) of 43 patients in the tocilizumab group versus 40 (91%) of 44 in the placebo group had adverse events. 14 (33%) versus 15 (34%) had serious adverse events. Serious infections were more common in the tocilizumab group (seven [16%] of 43 patients) than in the placebo group (two [5%] of 44). One patient died in relation to tocilizumab treatment. Tocilizumab was not associated with a significant reduction in skin thickening. However, the difference was greater in the tocilizumab group than in the placebo group and we found some evidence of less decline in forced vital capacity. The efficacy and safety of tocilizumab should be investigated in a phase 3 trial before definitive conclusions can be made about its risks and benefits. F Hoffmann-La Roche, Genentech.

ObjectiveTo assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice.MethodsWe performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab.Results254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47–5.32]; p=0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)>10% (OR: 1.03 [0.55–1.94]; p=0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56–3.53], p<0.0001). Patients treated concomitantly with mycophenolate mofetil had a trend for better outcomes as compared with patients receiving rituximab alone (delta FVC: 5.22 [0.83–9.62]; p=0.019 as compared with controls vs 3 [0.66–5.35]; p=0.012).ConclusionRituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial.

ObjectiveTo assess survival and identify predictors of survival in patients with systemic sclerosis-interstitial lung disease (SSc-ILD) who participated in the Scleroderma Lung Studies (SLS) I and II.MethodsSLS I randomised 158 patients with SSc-ILD to 1  year of oral cyclophosphamide (CYC) vs placebo. SLS II randomised 142 patients to 1 year of oral CYC followed by 1 year of placebo vs 2 years of mycophenolate mofetil. Counting process Cox proportional hazard modelling identified variables associated with long-term mortality in SLS I and II. Internal validation was performed using joint modelling.ResultsAfter a median follow-up of 8 years, 42% of SLS I patients died, and when known the cause of death was most often attributable to SSc. There was no significant difference in the time to death between treatment arms in SLS I or II. Higher baseline skin score, older age, and a decline in the forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLCO) over 2 years were independently associated with an increased risk of mortality in SLS I. The Cox model identified the same mortality predictor variables using the SLS II data.ConclusionIn addition to identifying traditional mortality risk factors in SSc (skin score, age), this study demonstrated that a decline in FVC and DLCO over 2 years was a better predictor of mortality than baseline FVC and DLCO. These findings suggest that short-term changes in surrogate measures of SSc-ILD progression may have important effects on long-term outcomes.

ObjectivesSkin fibrosis mediated by activated dermal fibroblasts is a hallmark of systemic sclerosis (SSc), especially in the subset of patients with diffuse disease. Transforming growth factor-beta (TGFβ) and interleukin-6 (IL-6) are key candidate mediators in SSc. Our aim was to elucidate the specific effect of IL-6 pathway blockade on the biology of SSc fibroblasts in vivo by using samples from a unique clinical experiment—the faSScinate study—in which patients with SSc were treated for 24 weeks with tocilizumab (TCZ), an IL-6 receptor-α inhibitor.MethodsWe analysed the molecular, functional and genomic characteristics of explant fibroblasts cultured from matched skin biopsy samples collected at baseline and at week 24 from 12 patients receiving placebo (n=6) or TCZ (n=6) and compared these with matched healthy control fibroblast strains.ResultsThe hallmark functional and molecular-activated phenotype was defined in SSc samples and was stable over 24 weeks in placebo-treated cases. RNA sequencing analysis robustly defined key dysregulated pathways likely to drive SSc fibroblast activation in vivo. Treatment with TCZ for 24 weeks profoundly altered the biological characteristics of explant dermal fibroblasts by normalising functional properties and reversing gene expression profiles dominated by TGFβ-regulated genes and molecular pathways.ConclusionsWe demonstrated the exceptional value of using explant dermal fibroblast cultures from a well-designed trial in SSc to provide a molecular framework linking IL-6 to key profibrotic pathways. The profound impact of IL-6R blockade on the activated fibroblast phenotype highlights the potential of IL-6 as a therapeutic target in SSc and other fibrotic diseases.Trial registration number NCT01532869; Post-results.

ObjectivesAmerican College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS) is a composite endpoint to assess the likelihood of improvement in diffuse systemic sclerosis. ACR-CRISS is a weighted score and includes five core set measures: modified Rodnan skin score, FVC% predicted, health assessment questionnaire–disability index, and patient and clinician global assessments.MethodsWe analysed core set measures from 354 participants who participated in three placebo-controlled trials. We generated 10 development datasets, randomly selected from 2/3 of the participants, stratified by study and treatment group. The remaining participants (1/3 of the participants) formed the validation sets. Risk differences (RDs) between active and placebo treatments were calculated by averaging over the replicate datasets; bootstrap 95% CIs for the RDs to estimate the magnitude of treatment effects.ResultsIn the development sets (n=237), the proportion of participants in the active group had statistically higher improvement in >1 of 5 core set measures versus the placebo group. For example, the proportion who improved by ≥20% in ≥3 core set measures was 49.4% in the active versus338.9% in the placebo; RD: 10.5%, 95% CI4.9 % to 16.1%. In the validation sets (n=117), the proportion who improved by ≥20% in ≥3 core set measures was 50.3% in the active versus35.63% in the placebo (RD:114.8%, 95% CI 3.1% to225.7%). Similar trends were seen with larger percentage cut-offs.ConclusionRevised CRISS, as assessed by the proportion of participants who improved by a certain percentage in ≥3 of 5 core set measures, is a potential new composite outcome measure.

ObjectivesTo evaluate initial combination therapy with ambrisentan plus tadalafil (COMB) compared with monotherapy of either agent (MONO), and the utility of baseline characteristics and risk stratification in predicting outcomes, in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) and the systemic sclerosis (SSc)–pulmonary arterial hypertension (PAH) subpopulation.MethodsThis post hoc analysis of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) study included patients with CTD-PAH from the modified intention-to-treat population. Time to clinical failure (TtCF) was assessed by baseline characteristics, treatment assignment and risk group (low, intermediate and high) at baseline and week 16. TtCF was compared between groups using Kaplan-Meier curves and Cox proportional hazards regression modelling.ResultsThe analysis included 216 patients (COMB, n=117; MONO, n=99). The risk of clinical failure was lower with COMB versus MONO (risk reduction: CTD-PAH 51.7%, SSc-PAH 53.7%), particularly in patients with haemodynamic parameters characteristic of typical PAH without features of left heart disease and/or restrictive lung disease at baseline. The risk of clinical failure was lower with COMB versus MONO in the baseline low-risk group (HR not calculated due to no events in COMB), baseline intermediate-risk group (HR 0.519, 95% CI 0.297 to 0.905) and in the week 16 low-risk group (HR 0.069, 95% CI 0.009 to 0.548).ConclusionsThe benefit of COMB over MONO was demonstrated in patients with CTD-PAH, particularly in those with typical PAH haemodynamic characteristics at baseline. COMB is appropriate for patients categorised as low risk and intermediate risk at baseline and low risk at follow-up.Trial registration number NCT01178073.

Abstract Rationale The Scleroderma Lung Study II (SLS II) demonstrated significant improvements in pulmonary function and dyspnea at 24 months compared with baseline when patients with symptomatic scleroderma–related interstitial lung disease (SSc-ILD) were treated with either cyclophosphamide for 1 year (followed for another year on placebo) or mycophenolate mofetil for 2 years in a randomized, double-blind clinical trial. Physiologic and clinical outcomes of SLS II have been published previously. Objectives The aim of the study was to assess changes from baseline in the extent of SSc-ILD on high-resolution computed tomography (HRCT) measured in the SLS II participants using quantitative image analysis after 2 years and to determine whether these HRCT changes were correlated with the changes in physiologic and clinical measures over the same time interval. Methods Ninety-seven of the 142 randomized subjects (cyclophosphamide group, 47 subjects; mycophenolate mofetil group, 50 subjects) participating in SLS II underwent thoracic volumetric thin-section HRCT at both baseline and 24 months. Quantitative computer-aided diagnosis scores using volumetric HRCT scans were obtained using a previously developed computer-aided system. The scores were quantitative lung fibrosis, quantitative ground glass, quantitative honeycomb, and quantitative interstitial lung disease (QILD), the latter representing the sum of quantitative lung fibrosis, quantitative ground glass, and quantitative honeycomb. These scores were obtained both for the whole lung and for individual lobes. Paired t tests were used for the combined (pooled) cyclophosphamide and mycophenolate mofetil groups to compare 24-month changes from baseline in both the whole lung and the lobe of maximal involvement as determined at baseline (worst lobe). Results At the end of the 24-month trial, QILD in the whole lung was significantly reduced by a mean of 2.51% in the pooled groups (adjusted 95% confidence interval, −4.00 to −1.03%; P = 0.001). There was no significant difference in the QILD score improvement between the cyclophosphamide (−2.66%) and mycophenolate (−2.38%) groups when assessed separately (P = 0.88). For the pooled group, the 24-month changes in QILD scores in the whole lung correlated significantly with other outcomes, including 24-month changes in forced vital capacity (ρ = −0.37), single-breath diffusing capacity of the lung for carbon monoxide (ρ = −0.22), and breathlessness as measured by the Transition Dyspnea Index (ρ = −0.26). Conclusions Treatment of SSc-ILD with either cyclophosphamide for 1 year, followed by placebo for a second year, or mycophenolate for 2 years was associated with a significant reduction (improvement) in the extent of HRCT SSc-ILD assessed by computer-aided diagnosis scores, which correlated well with one or more other measures of treatment response. These findings demonstrate that actual changes in lung structure accompany improvements in physiologic and/or symptomatic measures in SSc-ILD.

Background We report results from a phase II randomised placebo-controlled trial assessing zibotentan, a highly selective endothelin receptor antagonist (ERA), in chronic kidney disease (CKD) secondary to systemic sclerosis (SSc). Methods This trial included three sub-studies: ZEBRA 1—a randomised placebo-controlled, double-blind trial of zibotentan in SSc patients with CKD2 or CKD3 (and glomerular filtration rate (GFR) >45 ml/min) over 26 weeks; ZEBRA 2A—a 26-week placebo-controlled, single-blind trial of zibotentan in scleroderma renal crisis patients not requiring dialysis; and ZEBRA 2B—an open label pharmacokinetic study of zibotentan in patients on haemodialysis. Results Sixteen patients were screened for ZEBRA 1. Of these, 6 patients were randomised to zibotentan and 7 to placebo. In ZEBRA 1, there were 47 non-serious adverse events (AE) during the trial. Twenty-seven occurred in the placebo group and 20 in the zibotentan group. One serious adverse event (SAE) occurred during ZEBRA1, in the placebo arm. Descriptive statistics did not suggest an effect of study drug on serum sVCAM1. Estimated GFR numerically declined in patients treated with placebo at 26 weeks and 52 weeks. In contrast, average eGFR increased in zibotentan-treated cases. The 4 patients in ZEBRA 2A experienced 8 non-serious AEs, distributed equally between placebo and zibotentan. There was one SAE each in placebo and zibotentan groups, both unrelated to study medication. ZEBRA 2B recruited 8 patients, 6 completed first dosing, and 2 completed a second dosing visit. Pharmacokinetic analysis confirmed zibotentan levels within the therapeutic range. Three patients experienced 3 non-serious AEs. One SAE occurred and was unrelated to study drug. Conclusions Zibotentan was generally well-tolerated. ZEBRA 1 did not show any effect of zibotentan on serum sVCAM-1 but was associated with numerical improvement in eGFR at 26 weeks that was more marked at 52 weeks. ZEBRA 2B suggested a feasible dose regimen for haemodialysis patients. Trial registration EudraCT no: 2013-003200-39 (first posted January 28, 2014) ClinicalTrials.gov Identifier: NCT02047708 Sponsor protocol number: 13/0077