Robert W. Simms

2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative

Objective The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. Methods Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by (1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and (2) validating against the combined view of a group of experts on a set of cases with or without SSc. Results It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, seven additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynauds phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. Conclusions The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

Treatment of 100 patients with primary amyloidosis: A randomized trial of melphalan, prednisone, and colchicine versus colchicine only

PURPOSE A clinical trial designed to test whether treatment with melphalan, prednisone, and colchicine (MPC) is superior to colchicine (C) alone was performed in patients with primary amyloidosis (AL), a nonmalignant plasma cell dyscrasia. PATIENTS AND METHODS Patients were randomized to MPC or C with stratification according to sex, time from diagnosis to study entry (ie, less than 3 months or 3 to 12 months), and dominant organ system involvement (ie, cardiac, renal, neurologic, or others). Data were gathered monthly from patients, quarterly from physicians, and annually in the Clinical Research Center. One hundred consecutive patients with AL amyloidosis admitted between 1987 and 1992 who met eligibility requirements were treated and followed for a minimum of 18 months. Fifty patients (group A) received daily oral colchicine and 50 patients (group B) received cycles of oral melphalan and prednisone every 6 weeks for 1 year as well as colchicine. RESULTS The principal outcome measure was median survival, which was compared in the two treatment groups and in the subgroups. The overall survival of all patients from study entry was 8.4 months. Comparing group A (C) to group B (MPC), the survival was 6.7 months versus 12.2 months (P = 0.087). Both treatment groups had poor survival for patients in the cardiac subgroup, longest survival in the renal group, and significant differences favoring MPC treatment only in patients whose major system manifestations were neurologic (P = 0.037) or other (P = 0.007). Multivariate analysis showed a strongly significant treatment effect (P = 0.003) and improved survival associated with not having cardiac or gastrointestinal involvement. CONCLUSIONS MPC was advantageous for patients whose major manifestations of amyloid disease were other than cardiac or renal. Better survival regardless of treatment was noted in patients for whom a satisfactory supportive treatment such as transplant or dialysis exists for their organ failure.

Recombinant human relaxin in the treatment of scleroderma. A randomized, double-blind, placebo-controlled trial.

Relaxin, a heterodimer protein with a molecular weight of 6000, is secreted by the corpus luteum and placenta during pregnancy (1, 2). It is structurally related to insulin and insulin-like growth factor I, and its principal physiologic role seems to be fostering the growth and remodeling of the uterus. Relaxin also loosens the pelvic ligaments and ripens the uterine cervix in preparation for parturition (3). The availability of recombinant human relaxin has permitted focused investigations of its effects on connective tissue. Recombinant human relaxin alone reduces synthesis of dermal fibroblast collagen and enhances the effects of interferon- (4). Relaxin attenuates the actions of profibrotic cytokines, including transforming growth factor- and interleukin-1 (5), and increases secretion of dermal fibroblast collagenase while reducing levels of tissue inhibitor of metalloproteinase (5). Of interest, the effect of relaxin on reduced secretion of collagen and tissue inhibitor of metalloproteinase is dose-dependent, whereas its effect on collagenase is optimal in a narrow range of concentrations (5). Finally, recombinant human relaxin prevents the development of bleomycin-induced pulmonary fibrosis in rodents (6), as well as dermal fibrosis in rodent irritant models (7). In vitro and animal studies suggest that recombinant human relaxin might be therapeutically useful for diseases characterized by fibrosis. Systemic sclerosis (scleroderma) is the prototypical fibrosing disease in humans. Although the pathogenesis of systemic sclerosis is not completely understood, tissue fibrosis dominates the clinical features of the disease and largely determines its morbidity and mortality (8). Scleroderma-related fibrosis includes both the fibrotic intimal hyperplasia of small arteries and arterioles (the Raynaud phenomenon, renal crisis, and pulmonary hypertension), as well as extravascular tissue fibrosis (skin, interstitial lung disease, and tendon involvement) (8). The long-term clinical benefit of preventing or reversing fibrosis in systemic sclerosis has not been tested, and no therapies to date have demonstrated such effects (9). Before porcine relaxin was withdrawn from the market in the early 1960s in response to reformed policies of the U.S. Food and Drug Administration (FDA), open case studies showed that it improved scleroderma-related skin change and healed cutaneous ulcers (10). Phase I studies of recombinant human relaxin in patients with diffuse scleroderma have demonstrated that steady-state serum concentrations of relaxin up to 60 times higher than those seen in normal pregnancy could be safely achieved with continuous subcutaneous infusion (11, 12). The most common drug-related adverse events associated with relaxin treatment have been menometrorrhagia and moderate reversible reductions in hemoglobin. In phase I studies, extent and severity of skin thickening as well as patient global assessment and functional status improved over periods of up to 1 year. However, interpretation of these findings has been hampered by short duration of treatment (11) or inadequacies of open-label design (12). We report the results of a randomized, double-blind, controlled clinical trial comparing placebo with recombinant human relaxin, 25 g/kg of body weight per day and 100 g/kg per day, given for 24 weeks in patients with stable, diffuse, moderate to severe scleroderma. Methods Patients Before screening, all patients gave informed consent according to the principles of the Declaration of Helsinki and in compliance with FDA requirements. Patients were recruited through 13-member institutions of the Scleroderma Clinical Trials Consortium. Men and women 18 to 70 years of age were included if they had a history of systemic sclerosis with diffuse scleroderma (defined as skin involvement proximal to the elbows or knees, excluding the face and neck) and less than 5 years had elapsed since onset of the first non-Raynaud sign or symptom. A baseline modified Rodnan skin score of at least 20, or of at least 16 in the case of truncal involvement, was required for inclusion in the treatment phase of the study. Patients were excluded from this phase if their skin score varied by more than 5 points from screening to the first treatment day. We excluded patients who had systemic sclerosis with limited scleroderma (skin involvement restricted to face and neck and sites distal to elbows and knees); eosinophilic fasciitis; eosinophilia myalgia syndrome; or scleroderma in conjunction with any other definable connective tissue disease, such as rheumatoid arthritis, systemic lupus erythematosus, polymyositis, or dermatomyositis. We also excluded patients with a substantial history of environmental exposure to tainted rapeseed oil, vinyl chloride, trichloroethylene, or silica. In addition, patients with renal crisis in the previous 6 months; chronic renal failure; or severe cardiovascular, gastrointestinal, or pulmonary disease were excluded. Patients were required to discontinue putative disease-modifying treatments for scleroderma (including d-penicillamine, cyclophosphamide, cyclosporine, azathioprine, methotrexate, potassium aminobenzoate, photopheresis, colchicine, or any other experimental treatment) at least 4 weeks before beginning treatment with the study drug. Patients were excluded if they were receiving more than 10 mg of prednisone per day or an equivalent dose of another glucocorticoid. Intervention We administered recombinant human relaxin, 25 g/kg per day or 100 g/kg per day, or placebo for 24 weeks by continuous subcutaneous infusion, using microinfusion pumps (Panomat T-Series 5 mL, Disetronic Medical Systems, Inc., Minneapolis, Minnesota). Recombinant human relaxin was produced by Connetics Corp. (Palo Alto, California) in Escherichia coli (13). The placebo was a sterile acetate buffer solution that was identical in composition to the buffer used for relaxin. Patients were randomly assigned to receive placebo or recombinant human relaxin (25 g/kg per day or 100 g/kg per day). Randomization was performed at a centralized data management organization (Pacific Research Associates, Los Altos, California). Biased coin randomization (14, 15) was used to stratify patients on the basis of disease duration ( 2.5 years or>2.5 to 5 years) and use of d-penicillamine in the previous 6 months (16). The same randomization procedure was used to replace patients who withdrew before completing 4 weeks of treatment. Patient prescriptions for the study medication were forwarded to a centralized pharmacy (Coram Healthcare of Northern California, Hayward, California) for preparation of blinded supplies of the study drug. Each patients dose was based on screening body weight. The dose was adjusted only if body weight changed by 10% or more during the study. Treatment was administered over 24 hours for 24 weeks. The infusion site and needle were changed at least every 72 hours. The dosage of 25 g/kg per day was selected on the basis of pharmacokinetic results from earlier studies. We anticipated that it would be safe and well tolerated and would produce steady-state serum concentrations of relaxin that were approximately three- to fivefold greater than those found in human pregnancy (11). On the basis of preclinical and earlier clinical studies, we hypothesized that this serum concentration would have antifibrotic effects. To measure the potential for a doseresponse effect, we selected the dosage of 100 g/kg per day on the basis of safety and tolerability data from earlier clinical studies (11, 12). Continuous subcutaneous infusion was chosen as the mode of administration to eliminate the need for six daily subcutaneous injections, to conserve drug supply, and to mimic the constancy of relaxin concentrations that are usually seen in pregnancy (11). Study Design The objectives of the study were to assess the efficacy, safety, and doseresponse effect of recombinant human relaxin in patients with diffuse scleroderma. The study was conducted as a randomized, double-blind, placebo-controlled, parallel-treatment clinical trial. Assessments The primary measure of efficacy was the modified Rodnan skin score, a clinical evaluation by palpation of skin thickness in 17 body areas (face, chest, abdomen, right and left fingers, hands, forearms, upper arms, thighs, legs, and feet). Each area receives a score of 0 to 3 for degree of thickness (0=normal, 1=mild thickening, 2=moderate thickening, and 3=severe thickening). The total score ranges from 0 to 51. The modified Rodnan skin score has been the standard measure of outcome in recent clinical trials involving scleroderma (16-18). Many recent studies have confirmed that total skin scoring is both accurate (with an interobserver variability of 4.6 units) and reproducible (with an intraobserver variability of 3.1 units) (19, 20). Skin scoring is in many ways an ideal outcome measure for scleroderma because it is accessible, cost-effective, sensitive to change, and, as a measure of fibrosis, directly relevant to the biological process of disease (21). Before the study began, investigators were trained according to the standards of one experienced observer. All skin scoring for each individual patient was performed by a single investigator. Secondary measures of efficacy were the following: maximal oral aperture; maximal hand extension (18); tenderness and swelling of metacarpophalangeal joints (as a unit), wrists, and knees; enumeration of cutaneous ulcers; functional status according to the Health Assessment Questionnaire (HAQ) (22); global disease assessments by patients and investigators; and pulmonary function tests, including lung diffusion capacity and forced vital capacity. Serum relaxin levels were determined by using enzyme immunoassay (6). The presence of antirelaxin antibody was measured in an enzyme immunoassay that used purified recombinant relaxin and affinity-purified antihuman immunoglobulin as the

B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis

OBJECTIVE To determine the safety of rituximab, to provide preliminary data regarding the potential efficacy of rituximab, and to investigate the effects of rituximab on autoimmunity and fibrosis in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS Fifteen patients with dcSSc, all of whom experienced their first non-Raynauds disease-associated disease manifestation within 18 months of trial entry, were recruited to receive 2 intravenous doses of rituximab (1,000 mg), administered 2 weeks apart. Safety, clinical, and exploratory outcomes were evaluated at baseline and at 6 months. The primary outcome was the change in the modified Rodnan skin thickness score (MRSS) at 6 months compared with baseline. RESULTS Adverse events included frequent infusion reactions and rare infections (urinary tract infection and dental abscess occurred in 1 patient each). The mean change in the MRSS between baseline and 6 months was not significant. Results of pulmonary function tests and other measures of major organ involvement were stable. The modest B cell infiltrates that were present in most skin biopsy specimens at baseline were completely depleted at 6 months in most patients. Autoantibody titers showed only modest and variable changes after treatment. CONCLUSION In this pilot study, treatment with rituximab appeared to be safe and well tolerated among patients with dcSSc. Rituximab treatment resulted in both depletion of circulating B cells and depletion of dermal B cells but had little effect on the levels of SSc-associated autoantibodies. Rituximab treatment did not appear to result in a significant beneficial effect on skin disease. The potential efficacy of rituximab in other organs such as the lung could not be clearly evaluated in this small open-label trial.

Oral iloprost treatment in patients with Raynaud's phenomenon secondary to systemic sclerosis: A multicenter, placebo-controlled, double-blind study

OBJECTIVE To evaluate the efficacy and tolerability of an oral preparation of iloprost, a prostacyclin analog, in patients with Raynauds phenomenon (RP) secondary to systemic sclerosis (scleroderma). METHODS A multicenter, randomized, parallel-group, placebo-controlled double-blind study was performed at university and community-based medical centers. Patients were randomly assigned to receive either 50 microg of iloprost orally twice daily or an identical gelatin-coated capsule containing placebo for 6 weeks. Outcome measures included average total daily duration of RP attacks, average number of RP attacks, and RP condition scored via a standardized daily diary. RESULTS Three hundred eight patients with scleroderma (272 women, 36 men, mean age 49 years [range 18-80]) were enrolled. One hundred fifty seven were assigned to receive iloprost and 151 to receive placebo. One hundred forty-three patients in the iloprost group (91.1%) and 144 in the placebo group (95.4%) completed the 6-week treatment phase. Fifteen of these treated patients (8 iloprost, 7 placebo) failed to complete all of the followup visits. The mean reduction in the average duration of attacks from baseline to week 5-6 was 24.32 minutes in the iloprost group and 34.34 minutes in the placebo group (P = 0.569). Likewise, the mean reduction from baseline to week 5-6 in the daily frequency of attacks was 1.02 in the iloprost group and 0.83 in the placebo group (P = 0.459). The Raynauds condition score, a patient-completed assessment of the severity of RP attacks, was reduced by 1.32 in the iloprost group and 1.00 in the placebo group (P = 0.323). The lack of significant difference between treatment groups did not change when a variety of factors, including use of other vasodilators, duration of disease, classification of scleroderma (limited versus diffuse), or number of baseline digital ulcers were taken into account. Premature withdrawal from the study due to adverse events occurred in 10 patients (6.4%) in the iloprost group and 3 (2.0%) in the placebo group (P = 0.058). CONCLUSION Oral iloprost at a dosage of 50 microg twice daily is no better than placebo for management of RP secondary to scleroderma, either during 6 weeks of treatment or during 6 weeks of posttreatment followup.

The role of vitamin D in corticosteroid-induced osteoporosis: A meta-analytic approach

OBJECTIVE To determine if vitamin D is more effective than no therapy or calcium alone in the management of corticosteroid-induced osteoporosis, and to determine how vitamin D compares with other osteoporosis therapies, e.g., bisphosphonates, calcitonin, or fluoride, for this condition. METHODS We evaluated all formulations of vitamin D, including its active metabolites and analogs. A systematic search for published and unpublished studies was conducted using MEDLINE (1966-December 1997), bibliographic references, abstracts from proceedings of recent national meetings, and contact with pharmaceutical companies and content experts. We included all randomized controlled trials lasting at least 6 months (and reporting extractable results), of patients receiving oral corticosteroids, that compared vitamin D with either 1) no therapy or calcium alone, or 2) bisphosphonates, calcitonin, or fluoride. The primary outcome measure of interest was change in lumbar spine bone mineral density. RESULTS We found a moderate beneficial effect of vitamin D plus calcium versus no therapy or calcium alone (9 trials) (effect size 0.60; 95% confidence interval [95% CI] 0.34, 0.85; P < 0.0001). In comparisons of vitamin D with other osteoporosis therapies, bisphosphonates were more effective than vitamin D (6 trials) (effect size 0.57; 95% CI 0.09, 1.05). Calcitonin was similar in efficacy to vitamin D (4 trials) (effect size 0.03; 95% CI -0.39, 0.45). Fluoride was more effective than vitamin D, but there were only 2 trials. CONCLUSION Vitamin D plus calcium is superior to no therapy or calcium alone in the management of corticosteroid-induced osteoporosis. Vitamin D is less effective than some osteoporosis therapies. Therefore, treatment with vitamin D plus calcium, as a minimum, should be recommended to patients receiving long-term corticosteroids.

Increased Frequency and Compromised Function of T Regulatory Cells in Systemic Sclerosis (SSc) Is Related to a Diminished CD69 and TGFβ Expression

Background Regulatory T cells (Tregs) are essential in the control of tolerance. Evidence implicates Tregs in human autoimmune conditions. Here we investigated their role in systemic sclerosis (SSc). Methods/Principal Findings Patients were subdivided as having limited cutaneous SSc (lcSSc, n = 20) or diffuse cutaneous SSc (dcSSc, n = 48). Further subdivision was made between early dcSSc (n = 24) and late dcSSc (n = 24) based upon the duration of disease. 26 controls were studied for comparison. CD3+ cells were isolated using FACS and subsequently studied for the expression of CD4, CD8, CD25, FoxP3, CD127, CD62L, GITR, CD69 using flow cytometry. T cell suppression assays were performed using sorted CD4CD25highCD127- and CD4CD25lowCD127high and CD3+ cells. Suppressive function was correlated with CD69 surface expression and TGFβ secretion/expression. The frequency of CD4+CD25+ and CD25highFoxP3highCD127neg T cells was highly increased in all SSc subgroups. Although the expression of CD25 and GITR was comparable between groups, expression of CD62L and CD69 was dramatically lower in SSc patients, which correlated with a diminished suppressive function. Co-incubation of Tregs from healthy donors with plasma from SSc patients fully abrogated suppressive activity. Activation of Tregs from healthy donors or SSc patients with PHA significantly up regulated CD69 expression that could be inhibited by SSc plasma. Conclusions/Significance These results indicate that soluble factors in SSc plasma inhibit Treg function specifically that is associated with altered Treg CD69 and TGFβ expression. These data suggest that a defective Treg function may underlie the immune dysfunction in systemic sclerosis.

The Comparative Efficacy of Drug Therapies Used for the Management of Corticosteroid-Induced Osteoporosis: A Meta-Regression

We determined the comparative efficacy of vitamin D, calcitonin, fluoride, and bisphosphonates for the management of corticosteroid‐induced osteoporosis using meta‐regression models. A systematic search for trials was conducted using MEDLINE, bibliographic references, abstracts from national meetings, and contact with pharmaceutical companies and content experts. We included all randomized controlled trials, lasting at least 6 months, of adult patients on oral corticosteroids that evaluated treatment comparisons between vitamin D, calcitonin, bisphosphonates, or fluoride either with no therapy/calcium or with each other and that reported extractable results. The outcome measure of interest was change in lumbar spine bone mineral density (BMD). We identified 45 eligible trials, which provided 49 eligible treatment comparisons (some trials had three arms or more). Our results indicated that bisphosphonates were the most effective class (effect size 1.03; 95% CI: 0.85, 1.17); results were similar even when newer generations of nitrogen‐containing bisphosphonates were excluded from analysis. We found the efficacy of bisphosphonates was enhanced further when used in combination with vitamin D (effect size, 1.31; 95% CI: 1.07, 1.50). Vitamin D and calcitonin were more effective than no therapy/calcium (effect size, 0.46; 95% CI: 0.27, 0.62; and effect size, 0.51; 95% CI: 0.33, 0.67, respectively) and were of similar efficacy, but both were significantly less effective than bisphosphonates. Fluoride appeared effective, but there were too few studies (n = 5) to draw robust conclusions regarding its efficacy compared with the other three therapies. In summary, bisphosphonates are the most effective of evaluated agents for managing corticosteroid‐induced osteoporosis. The efficacy of bisphosphonates is enhanced further with concomitant use of vitamin D.

Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients

BACKGROUND TGF-β has potent profibrotic activity in vitro and has long been implicated in systemic sclerosis (SSc), as expression of TGF-β-regulated genes is increased in the skin and lungs of patients with SSc. Therefore, inhibition of TGF-β may benefit these patients. METHODS Patients with early, diffuse cutaneous SSc were enrolled in an open-label trial of fresolimumab, a high-affinity neutralizing antibody that targets all 3 TGF-β isoforms. Seven patients received two 1 mg/kg doses of fresolimumab, and eight patients received one 5 mg/kg dose of fresolimumab. Serial mid-forearm skin biopsies, performed before and after treatment, were analyzed for expression of the TGF-β-regulated biomarker genes thrombospondin-1 (THBS1) and cartilage oligomeric protein (COMP) and stained for myofibroblasts. Clinical skin disease was assessed using the modified Rodnan skin score (MRSS). RESULTS In patient skin, THBS1 expression rapidly declined after fresolimumab treatment in both groups (P = 0.0313 at 7 weeks and P = 0.0156 at 3 weeks), and skin expression of COMP exhibited a strong downward trend in both groups. Clinical skin disease dramatically and rapidly decreased (P < 0.001 at all time points). Expression levels of other TGF-β-regulated genes, including SERPINE1 and CTGF, declined (P = 0.049 and P = 0.012, respectively), and a 2-gene, longitudinal pharmacodynamic biomarker of SSc skin disease decreased after fresolimumab treatment (P = 0.0067). Dermal myofibroblast infiltration also declined in patient skin after fresolimumab (P < 0.05). Baseline levels of THBS1 were predictive of reduced THBS1 expression and improved MRSS after fresolimumab treatment. CONCLUSION The rapid inhibition of TGF-β-regulated gene expression in response to fresolimumab strongly implicates TGF-β in the pathogenesis of fibrosis in SSc. Parallel improvement in the MRSS indicates that fresolimumab rapidly reverses markers of skin fibrosis. TRIAL REGISTRATION Clinicaltrials.gov NCT01284322.

Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial

Summary BACKGROUND Twelve months of oral cyclophosphamide (CYC) has been shown to alter the progression of scleroderma-related interstitial lung disease (SSc-ILD) when compared to placebo. However, toxicity was a concern and without continued treatment the efficacy disappeared by 24 months. We hypothesized that a two-year course of mycophenolate mofetil (MMF) would be safer, better tolerated and produce longer lasting improvements than CYC. METHODS Patients with SSc-ILD meeting defined dyspnea, pulmonary function and high-resolution computed tomography (HRCT) criteria were randomized in a double-blind, two-arm trial at 14 medical centers. MMF (target dose 1500 mg twice daily) was administered for 24 months in one arm and oral CYC (target dose 2·0 mg/kg/day) administered for 12 months followed by placebo for 12 months in the other arm. The primary endpoint, change in forced vital capacity as a percent 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, and is closed. RESULTS Between November, 2009, and January, 2013, 142 patients were randomized. 126 patients (63 MMF; 63 CYC) with acceptable baseline HRCT studies and at least one outcome measure were included in the analysis. The adjusted FVC % (primary endpoint) improved from baseline to 24 months by 2.17 in the MMF arm (95% CI, 0.53–3.84) and 2·86 in the CYC arm (95% confidence interval 1·19–4·58) with no significant between-treatment difference (p=0·24), indicating that the trial was negative for the primary endpoint. However, in a post-hoc analysis of the primary endpoint, within-treatment improvements from baseline to 24 months were noted in both the CYC and MMF arms. A greater number of patients on CYC than on MMF prematurely withdrew from study drug (32 vs 20) and failed treatment (2 vs 0), and the time to stopping treatment was significantly shorter in the CYC arm (p=0·019). Sixteen deaths occurred (11 CYC; 5 MMF) with most due to progressive ILD. Leukopenia (30 vs 4 patients) and thrombocytopenia (4 vs 0 patients) occurred more often in patients treated with CYC. In post-hoc analyses, within- (but not between-) treatment improvements were also noted in defined secondary outcomes including skin score, dyspnea and whole-lung HRCT scores. INTERPRETATION Treatment of SSc-ILD with MMF for two years or CYC for one year both resulted in significant improvements in pre-specified measures of lung function, dyspnea, lung imaging, and skin disease over the 2-year course of the study. While MMF was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than CYC was not confirmed. These findings support the potential clinical impact of both CYC and MMF for progressive SSc-ILD, as well as the current preference for MMF due to 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/Genentech.