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Summary Background 12 months of oral cyclophosphamide has been shown to alter the progression of scleroderma-related interstitial lung disease when compared with placebo. However, toxicity was a concern and without continued treatment the efficacy disappeared by 24 months. We hypothesised that a 2 year course of mycophenolate mofetil would be safer, better tolerated, and produce longer lasting improvements than cyclophosphamide. Methods This randomised, double-blind, parallel group trial enrolled patients from 14 US medical centres with scleroderma-related interstitial lung disease meeting defined dyspnoea, pulmonary function, and high-resolution CT (HRCT) criteria. The data coordinating centre at the University of California, Los Angeles (UCLA, CA, USA), randomly assigned patients using a double-blind, double-dummy, centre-blocked design to receive either mycophenolate mofetil (target dose 1500 mg twice daily) for 24 months or oral cyclophosphamide (target dose 2·0 mg/kg per day) for 12 months followed by placebo for 12 months. Drugs were given in matching 250 mg gel capsules. The primary endpoint, change in forced vital capacity as a percentage of the predicted normal value (FVC %) over the course of 24 months, was assessed in a modified intention-to-treat analysis using an inferential joint model combining a mixed-effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data. The study was registered with ClinicalTrials.gov, number NCT00883129. Findings Between Sept 28, 2009, and Jan 14, 2013, 142 patients were randomly assigned to either mycophenolate mofetil (n=69) or cyclophosphamide (n=73). 126 patients (mycophenolate mofetil [n=63] and cyclophosphamide [n=63]) with acceptable baseline HRCT studies and at least one outcome measure were included in the primary analysis. The adjusted % predicted FVC improved from baseline to 24 months by 2·19 in the mycophenolate mofetil group (95% CI 0·53–3·84) and 2·88 in the cyclophosphamide group (1·19–4·58). The course of the % FVC did not differ significantly between the two treatment groups based on the prespecified primary analysis using a joint model (p=0·24), indicating that the trial was negative for the primary endpoint. However, in a post-hoc analysis of the primary endpoint, the within-treatment change from baseline to 24 months derived from the joint model showed that the % FVC improved significantly in both the mycophenolate mofetil and cyclophosphamide groups. 16 (11%) patients died (five [7%] mycophenolate mofetil and 11 [15%] cyclophosphamide), with most due to progressive interstitial lung disease. Leucopenia (30 patients vs four patients) and thrombocytopenia (four vs zero) occurred more often in patients given cyclophosphamide than mycophenolate mofetil. Fewer patients on mycophenolate mofetil than on cyclophosphamide prematurely withdrew from study drug (20 vs 32) or met prespecified criteria for treatment failure (zero vs two). The time to stopping treatment was shorter in the cyclophosphamide group (p=0·019). Interpretation Treatment of scleroderma-related interstitial lung disease with mycophenolate mofetil for 2 years or cyclophosphamide for 1 year both resulted in significant improvements in prespecified measures of lung function over the 2 year course of the study. Although mycophenolate mofetil was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than cyclophosphamide was not confirmed. These findings support the potential clinical effectiveness of both cyclophosphamide and mycophenolate mofetil for progressive scleroderma-related interstitial lung disease, and the present preference for mycophenolate mofetil because of its better tolerability and toxicity profile. Funding National Heart, Lung and Blood Institute, National Institutes of Health; with drug supply provided by Hoffmann-La Roche and Genentech.

BACKGROUND We conducted a double-blind, randomized, placebo-controlled trial to determine the effects of oral cyclophosphamide on lung function and health-related symptoms in patients with evidence of active alveolitis and scleroderma-related interstitial lung disease. METHODS At 13 clinical centers throughout the United States, we enrolled 158 patients with scleroderma, restrictive lung physiology, dyspnea, and evidence of inflammatory interstitial lung disease on examination of bronchoalveolar-lavage fluid, thoracic highresolution computed tomography, or both. Patients received oral cyclophosphamide (≤2 mg per kilogram of body weight per day) or matching placebo for one year and were followed for an additional year. Pulmonary function was assessed every three months during the first year, and the primary end point was the forced vital capacity (FVC, expressed as a percentage of the predicted value) at 12 months, after adjustment for the baseline FVC. RESULTS Of 158 patients, 145 completed at least six months of treatment and were included in the analysis. The mean absolute difference in adjusted 12-month FVC percent predicted between the cyclophosphamide and placebo groups was 2.53 percent (95 percent confidence interval, 0.28 to 4.79 percent), favoring cyclophosphamide (P

The Scleroderma Lung Study enrolled 158 patients with scleroderma-related interstitial lung disease in a placebo-controlled trial of oral cyclophosphamide (CYC). Although treatment-related benefits in pulmonary function, skin scores, and patient-centered outcomes were demonstrated after 1 year of therapy, the duration of benefit beyond 1 year was unclear.A second year of follow-up was performed to determine if these effects persisted after stopping treatment.A detailed analysis of data obtained over the two years of the study was performed.Using a longitudinal joint model, we analyzed FVC, total lung capacity, transitional dyspnea index, Rodnan skin scores, and the Health Assessment Questionnaire-Disability Index during the second year, after adjusting for baseline values, baseline fibrosis score, and nonignorable missing data. Evaluable subjects (72 CYC; 73 placebo) included 93 who completed all visits plus 52 who completed at least 6 months of therapy and returned at 24 month or had their 24-month data imputed. The beneficial effects of CYC on pulmonary function and health status continued to increase through 18 months, after which they dissipated, whereas skin improvements dissipated after 12 months. In contrast, the positive effect on dyspnea persisted through 24 months. Adverse events were uncommon.One year of CYC improved lung function, skin scores, dyspnea, and health status/disability, effects which either persisted or increased further for several months after stopping therapy. However, except for a sustained impact on dyspnea, all of these effects waned and were no longer apparent at 24 months. Treatment strategies aimed at extending the positive therapeutic effects observed with CYC should be considered. Clinical trial registered with www.clinicaltrials.gov (NCT 000004563).

Background While interstitial lung disease (ILD) is the leading cause of death in patients with systemic sclerosis (SSc), therapeutic options are limited. Although cyclophosphamide (CYC) demonstrated beneficial treatment effects at one year on forced vital capacity (FVC) and self-reported dyspnea (1), these improvements were not sustained at 2 years (2). Uncontrolled studies have demonstrated that mycophenolate (MMF) may improve SSc-ILD; however, no studies have directly compared safety and efficacy outcomes of CYC and MMF in SSc-ILD. Objectives To conduct a double-blind, randomized, placebo-controlled trial (RCT) to compare the effects of CYC versus MMF on SSc-ILD outcomes Methods Between September 2009 and January 2013, 142 SSc-ILD patients from 14 US centers were randomized to receive MMF (titrated as tolerated to 3.0 g/day in divided doses) for 2 years or oral CYC (titrated as tolerated to 2 mg/kg daily) for 1 year followed by an additional year on placebo (See Figure 1). Inclusion criteria were age ≥18 years, duration of disease ≤7 years from onset of the first non-Raynaud9s SSc symptom, forced vital capacity (FVC) 40-80% predicted, hemoglobin-adjusted diffusing capacity for carbon monoxide (DLCO) ≥40% predicted (or 30-39% predicted if no evidence of pulmonary hypertension on echocardiogram and/or right heart catheterization), and evidence of any ground glass opacity on HRCT. The primary endpoint for the study was the FVC% predicted at 2 years, adjusted for baseline FVC. Key secondary endpoints included the transitional dyspnea index (TDI) and quantitative extent of lung fibrosis (QLF) and quantitative extent of ILD (QILD) on HRCT in both the whole lung (WL) and the zone of maximal involvement (ZM). Results Among 142 participants (Mean [SD] age 52.3 [9.7] years), 74% were female and 59% had diffuse cutaneous involvement. The mean disease duration was 2.6 [1.8] years. Baseline pulmonary function was as follows (All Mean [SD]% predicted): FVC 66.5 [9.1]; Total lung capacity (TLC) 65.9 [10.9]; DLCO 54.0 [12.7]. The baseline mean health assessment assessment questionnaire disability index (HAQ-DI) score was 0.72 [0.7]. Baseline QLF scores were 32.5 [23.8] and 8.6 [6.8], for the ZM and WL, respectively. Baseline QILD scores were 63.4 [20.6] and 29.6 [13.7], for the ZM and WL, respectively. Among all participants, 86 (61%) completed the 24-month drug phase, while 20 (14%) withdrew drug prior to 24 months, but completed the 24-month visit. Adverse events were the primary reason for discontinuing treatment prematurely (40%). Twenty participants (14%) failed to complete the 24-month visit. There were 16 deaths during the study period. The majority of deaths (75%) occurred after stopping the study drug (4-17 months afterwards), and the predominant cause of mortality was respiratory failure related to SSc-ILD (56%). Conclusions We herein describe the initial results of the first RCT to compare CYC versus MMF for SSc-ILD. Analyses of the primary and secondary endpoints are underway, the results of which will be available at the time of the EULAR presentation. References Tashkin DP, et al. NEJM 2006;354:2655-2666. Tashkin DP, et al. Am J Respir Crit Care Med 2007;176:1026-34. Disclosure of Interest None declared

Background Cyclophosphamide (CYC), is the only therapy that has been shown thus far to be efficacious in scleroderma-related interstitial lung disease (SSc-ILD). However, the utility of CYC is constrained by its toxicity, which limits treatment to only ≤1 year. Findings from several uncontrolled studies in small numbers of patients with SSc-ILD (n≤17) suggest that mycophenolate mofetil (MMF) is a safe and effective treatment for SSc-ILD. Methods SLS II is a double-blind, double-dummy, parallel-group randomized controlled trial (DB DD PG RCT) comparing the efficacy and safety of MMF (titrated to 3 g/d over 2 years) versus oral CYC (titrated to 2 mg/kg/d for 1 year followed by placebo for another year) in patients with active SSc-ILD (target enrollment 150 patients). Key eligibility criteria included adults, ≤ 7 yrs, any ground glass opacity (GGO) as an indication of “active” disease, and FVC% between 40-80% predicted. Procedures : Spirometry, lung volumes, DLCO, SGRQ, SF-12, modified Rodnan skin score (mRSS), and cough questionnaire at screening and/or baseline and every 3 months for 2 yrs; BDI (baseline); TDI every 3 months for 2 yrs; HRCT (screening and 2 years ;central reading center); toxicity monitoring. Statistical analysis : Primary endpoints: FVC % pred at 2 yrs, adjusted for baseline FVC % pred and “fibrosis” score on screening HRCT and toxicity outcomes over 2 yrs. Results Baseline results are presented in Table 1. Premature discontinuation of study drug (38/130) – due to drug toxicity (13/38); failure to return for 24-month visits (12/26 due); SAEs (38) – 5 felt to be study-related; 1/130 treatment failure (defined by 15% pred decrease in FVC sustained for ≥1 mo). Conclusions A DB DD RCT of oral CYC for 1 yr versus MMF for 2 yrs in patients with progressive SSc-ILD is feasible with a low rate (10%) of discontinuations due to drug toxicity overall. Extent of ILD on HRCT is significantly, albeit modestly, correlated with physiologic impairment, supporting the use of change in HRCT scores from baseline as a key endpoint. Disclosure of Interest : None Declared