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Objectives: To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD)., Methods: A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification., Results: Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration., Conclusions: Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: Competing interests: JRS reports personal fees from Atlantic, Bayer, Blade, Boehringer Ingelheim, Camurus, Corbus, DRG, Eicos, Eiger Pharmaceuticals, EMD Serono, Guidepoint, Indalo, Mitsubishi and Xenikos; and stock ownership or options in BriaCell and Pacific Therapeutics. VK and MA are employees of Boehringer Ingelheim. OD reports grants and personal fees from Actelion, Bayer, Boehringer Ingelheim and Mitsubishi; personal fees from AbbVie, Acceleron Pharma, Anamar, Amgen, Baecon Discovery, Blade Therapeutics, Catenion, CSL Behring, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, Glenmark Pharma, GlaxoSmithKline, Inventiva, Italfarmaco, IQVIA, Lilly, Medac, Medscape, Menarini, Mepha, Merck Sharp & Dohme, Novartis, Roche, Sanofi, Target BioScience and UCB; personal fees and non-financial support from Pfizer; and patent US8247389; and was a member of the SENSCIS trial steering committee.

Objective: To analyze the efficacy and safety of nintedanib in patients with fibrosing autoimmune disease-related interstitial lung diseases (ILDs) with a progressive phenotype., Methods: The INBUILD trial enrolled patients with a fibrosing ILD other than idiopathic pulmonary fibrosis, with diffuse fibrosing lung disease of >10% extent on high-resolution computed tomography, forced vital capacity percent predicted (FVC%) ≥45%, and diffusing capacity of the lungs for carbon monoxide percent predicted ≥30% to <80%. Patients fulfilled protocol-defined criteria for progression of ILD within the 24 months before screening, despite management deemed appropriate in clinical practice. Subjects were randomized to receive nintedanib or placebo. We assessed the rate of decline in FVC (ml/year) and adverse events (AEs) over 52 weeks in the subgroup with autoimmune disease-related ILDs., Results: Among 170 patients with autoimmune disease-related ILDs, the rate of decline in FVC over 52 weeks was -75.9 ml/year with nintedanib versus -178.6 ml/year with placebo (difference 102.7 ml/year [95% confidence interval 23.2, 182.2]; nominal P = 0.012). No heterogeneity was detected in the effect of nintedanib versus placebo across subgroups based on ILD diagnosis (P = 0.91). The most frequent AE was diarrhea, reported in 63.4% and 27.3% of subjects in the nintedanib and placebo groups, respectively. AEs led to permanent discontinuation of trial drug in 17.1% and 10.2% of subjects in the nintedanib and placebo groups, respectively., Conclusion: In the INBUILD trial, nintedanib slowed the rate of decline in FVC in patients with progressive fibrosing autoimmune disease-related ILDs, with AEs that were manageable for most patients., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Many therapies have been investigated for systemic sclerosis-associated interstitial lung disease (SSc-ILD), including immunosuppressive therapies, antifibrotic agents, immunomodulators and monoclonal antibodies. There is a high unmet medical need to better understand the current evidence for treatment efficacy and safety. This systematic review aims to present the existing literature on different drug treatments investigated for SSc-ILD and to critically assess the level of evidence for these drugs. A systematic review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A structured literature search was performed for clinical trials and observational studies on the treatment of SSc-ILD with pharmaceutical interventions from 1 January 1990 to 15 December 2020. The quality of each reference was assessed using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) criteria. A total of 77 references were reviewed and 13 different treatments were identified. We found high-quality evidence for the use of cyclophosphamide, nintedanib, mycophenolate and tocilizumab. Therefore, we would posit that the clinical community has four valid options for treatment of SSc-ILD. Further research is mandatory to provide more evidence for the optimal treatment strategy in SSc-ILD, including the optimal time to initiate treatment, selection of patients for treatment and upfront combination therapy., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the effects of abituzumab in systemic sclerosis-associated interstitial lung disease (SSc-ILD)., Methods: STRATUS was a phase II, double-blind, parallel-group, multicenter trial (ClinicalTrials.gov: NCT02745145). Adults (≤ 75 yrs) with SSc-ILD on stable mycophenolate were randomized (2:2:1) to receive intravenous abituzumab 1500 mg, abituzumab 500 mg, or placebo every 4 weeks for 104 weeks. The primary endpoint was the annual rate of change in absolute forced vital capacity., Results: STRATUS was terminated prematurely due to slow enrollment (n = 75 screened, n = 24 randomized), precluding robust analysis of efficacy. Abituzumab was well tolerated; no new safety signals were detected., Conclusion: Further investigation of abituzumab for treatment of SSc-ILD is required., (© 2021 The Journal of Rheumatology.)

Objectives: To characterise the safety and tolerability of nintedanib and the dose adjustments used to manage adverse events in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD)., Methods: In the SENSCIS trial, patients with SSc-ILD were randomised to receive nintedanib 150 mg two times per day or placebo. To manage adverse events, treatment could be interrupted or the dose reduced to 100 mg two times per day. We assessed adverse events and dose adjustments over 52 weeks., Results: A total of 576 patients received nintedanib (n=288) or placebo (n=288). The most common adverse event was diarrhoea, reported in 75.7% of patients in the nintedanib group and 31.6% in the placebo group; diarrhoea led to permanent treatment discontinuation in 6.9% and 0.3% of patients in the nintedanib and placebo groups, respectively. In the nintedanib and placebo groups, respectively, 48.3% and 12.2% of patients had ≥1 dose reduction and/or treatment interruption, and adverse events led to permanent discontinuation of the trial drug in 16.0% and 8.7% of patients. The adverse events associated with nintedanib were similar across subgroups defined by age, sex, race and weight. The rate of decline in forced vital capacity in patients treated with nintedanib was similar irrespective of dose adjustments., Conclusions: The adverse event profile of nintedanib in patients with SSc-ILD is consistent with its established safety and tolerability profile in patients with idiopathic pulmonary fibrosis. Dose adjustment is important to minimise the impact of adverse events and help patients remain on therapy., Competing Interests: Competing interests: JRS reports personal fees from Atlantic, Bayer, Blade, Boehringer Ingelheim, Camurus, Corbus, DRG, Eicos, Eiger Pharmaceuticals, EMD Serono, Guidepoint, Indalo, Mitsubishi and Xenikos; and stock ownership or options in BriaCell and Pacific Therapeutics. TMM reports grants and personal fees from GlaxoSmithKline and UCB, and personal fees from Apellis, Bayer, Biogen Idec, Blade, Boehringer Ingelheim, Bristol-Myers Squibb, Galapagos, Galecto, Indalo, Novartis, Respivent, Roche and Trevi. KBH reports grants and personal fees from Actelion Pharmaceuticals, Boehringer Ingelheim and United Therapeutics; personal fees from Bayer; and grants from Genentech, Eiger BioPharmaceuticals and Reata Pharmaceuticals. SA reports grants, personal fees and other remuneration from Boehringer Ingelheim; grants from Bayer, Biogen Idec and Momenta; and personal fees from Medscape, Integrity Continuing Education and Corbus. AA reports personal fees and other remuneration from Boehringer Ingelheim, Taiho Pharmaceutical and Toray; personal fees from Asahi Kasei Pharma; and other remuneration from Shionogi & Co., Ltd, and aTyr Pharma. LKH reports other remuneration from Boehringer Ingelheim (investigator of SENSCIS trial). UC reports personal fees and non-financial support from Boehringer Ingelheim and Roche; and personal fees from AstraZeneca, Fibrogen, Novartis and Pliant Therapeutics. UvW, VK, MG and MA are employees of Boehringer Ingelheim. OD reports grants and personal fees from Actelion, Bayer, Boehringer Ingelheim and Mitsubishi; personal fees from AbbVie, Acceleron Pharma, Anamar, Amgen, Baecon Discovery, Blade Therapeutics, Catenion, CSL Behring, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, Glenmark Pharma, GlaxoSmithKline, Inventiva, Italfarmaco, IQVIA, Lilly, Medac, Medscape, Menarini, Mepha, Merck Sharp & Dohme, Novartis, Roche, Sanofi, Target BioScience and UCB; personal fees and non-financial support from Pfizer; and patent US8247389. TMM, KBH, AA and OD were members of the SENSCIS trial steering committee., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Systemic sclerosis (SSc) is an autoimmune rheumatic disease with heterogeneous clinical manifestations and a variable course in which the severity of the pathology dictates the disease prognosis and course. Among autoimmune rheumatic diseases, SSc has the highest mortality rate among all rheumatic diseases, though there are exciting new therapeutic targets that appear to halt the progression of SSc manifestations such as skin or lung fibrosis. In selected patients, high-intensity regimens with autologous stem cell transplantation can favorably modify the course. In what was once thought to be an untreatable disease, targeted therapies have now changed the outlook of SSc to a treatable disorder. Herein, we discuss the targeted therapies modifying the outlook on selected organ involvement and creating opportunities for future treatment. We also present a framework for defining low disease activity in SSc., (© 2020, American College of Rheumatology.)

Objective: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) shares a number of clinical features and pathogenic mechanisms with idiopathic pulmonary fibrosis (IPF). This study was designed to evaluate the tolerability of the IPF treatment pirfenidone in SSc-ILD. The known gastrointestinal, skin, and liver adverse events (AE) of pirfenidone are of importance given the involvement of these organs in SSc., Methods: All patients received pirfenidone and were randomized 1:1 to either a 2- or 4-week titration starting at 801 mg/day and finishing at a maintenance dose of 2403 mg/day. Patients received pirfenidone for 16 weeks in total. Assessments included treatment-emergent AE (TEAE) and exploratory disease outcomes., Results: Sixty-three patients were randomized; 96.8% experienced a TEAE and more patients reported TEAE during the titration versus the maintenance period. The most commonly reported TEAE were consistent with those observed for pirfenidone in IPF (nausea, headache, fatigue) and were similar regardless of titration schedule. More patients discontinued treatment because of TEAE in the 2- versus 4-week titration group (5 vs 1, respectively); all discontinuation events occurred > 3 weeks after reaching the full dose of pirfenidone. Mycophenolate mofetil (MMF), taken by 63.5% of patients in addition to pirfenidone, did not appear to affect tolerability. Exploratory disease outcomes remained largely unchanged., Conclusion: Pirfenidone showed an acceptable tolerability profile in SSc-ILD, although a longer titration may be associated with better tolerability. Tolerability was not affected by concomitant MMF. The present findings support further investigation of pirfenidone in future clinical trials in patients with SSc-ILD., Trial Registration: ClinicalTrials.gov; www.clinicaltrials.gov NCT01933334.

Objective: Interstitial lung disease (ILD) is common in connective tissue disease (CTD) and is the leading cause of mortality. Investigators have used certain outcome measures in randomized controlled trials (RCT) in CTD-ILD, but the lack of a systematically developed, CTD-specific index that captures all measures relevant and meaningful to patients with CTD-ILD has left a large and conspicuous gap in CTD-ILD research., Methods: The CTD-ILD working group, under the aegis of the Outcome Measures in Rheumatology (OMERACT) initiative, has completed a consensus group exercise to reach harmony on core domains and items for inclusion in RCT in CTD-ILD. During the OMERACT 12 meeting, consensus was sought on domains and core items for inclusion in RCT. In addition, consensus was pursued on a definition of response in RCT. Consensus was defined as ≥ 75% agreement among the participants., Results: OMERACT 12 participants endorsed the domains with minimal modifications. Clinically meaningful progression for CTD-ILD was proposed as ≥ 10% relative decline in forced vital capacity (FVC) or ≥ 5% to < 10% relative decline in FVC and ≥ 15% relative decline in DLCO., Conclusion: There is consensus on domains for inclusion in RCT in CTD-ILD and on a definition of clinically meaningful progression. Data-driven approaches to validate these results in different cohorts and RCT are needed.

Objective: Dyspnoea is a common, multifactorial source of functional impairment among patients with dcSSc. Our objective was to assess the reliability, construct validity and responsiveness to change of the Saint George's Respiratory Questionnaire (SGRQ) in patients with early dcSSc participating in a multicentre prospective study., Methods: At enrolment and 1 year, patients completed the SGRQ (a multi-item instrument with four scales: symptoms, activity, impact and total), a visual analogue scale (VAS) for breathing and the HAQ Disability Index (HAQ-DI) and underwent 6 min walk distance and pulmonary function tests, physician and patient global health assessments and high-resolution CT (HRCT). We assessed internal consistency reliability using Cronbach's α. For validity we examined the ability of the SGRQ to differentiate the presence vs absence of interstitial lung disease (ILD) on HRCT or restrictive lung disease and evaluated the 1 year responsiveness to change using pulmonary function tests and patient- and physician-reported anchors. Correlation coefficients of 0.24-0.36 were considered moderate and >0.37 was considered large., Results: A total of 177 patients were evaluated. Reliability was satisfactory for all SGRQ scales (0.70-0.93). All scales showed large correlations with the VAS for breathing and diffusing capacity of the lung for carbon monoxide in the overall cohort and in the subgroup with ILD. Three of the four scales in the overall cohort and the total scale in the ILD subgroup showed moderate to large correlation with the HAQ-DI and the predicted forced vital capacity (r = 0.33-0.44). Each scale discriminated between the presence and absence of ILD and restrictive lung disease (P ≤ 0.0001-0.03). At follow-up, all scales were responsive to change using different anchors., Conclusion: The SGRQ has acceptable reliability, construct validity and responsiveness to change for use in a dcSSc population and differentiates between patients with and without ILD., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Rationale: Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities., Methods: The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF)., Results: A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed., Conclusion: Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.

Objective: Patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) are thought to have the greatest decline in lung function (forced vital capacity [FVC]% predicted) in the early years after disease onset. The aim of this study was to assess the natural history of the decline in FVC% predicted in patients receiving placebo in the Scleroderma Lung Study and to evaluate possible factors for cohort enrichment in future therapeutic trials., Methods: Patients randomized to receive placebo (n=79) were divided into 3 groups based on the duration of SSc (0-2 years, 2-4 years, and >4 years). Descriptive statistics and a mixed-effects model were used to analyze the rate of decline in the FVC% predicted over a 1-year period. Additional analyses stratified according to the severity of fibrosis on high-resolution computed tomography (HRCT) were performed, and interactions between disease severity and disease duration were explored., Results: The mean±SD decline in the unadjusted FVC% predicted during the 1-year period was 4.2±12.8%. At baseline, 28.5%, 43.0%, and 28.5% of patients were in the groups with disease durations of 0-2 years, 2-4 years, and >4 years, respectively. The rate of decline in the FVC% predicted was not significantly different across the 3 disease groups (P=0.85). When stratified by baseline fibrosis on HRCT, the rate of decline in the FVC% predicted was statistically significantly greater in the group with severe fibrosis (mean annualized decline in the FVC% predicted 7.2% versus 2.7% in the groups with no or moderate fibrosis; P=0.008). The decline observed in the group with severe fibrosis was most pronounced in those with a relatively short disease duration (0-2 years; annualized decline 7.0%)., Conclusion: Among patients with SSc-ILD in the Scleroderma Lung Study, the rates of progression of lung disease were similar irrespective of disease duration. The baseline HRCT fibrosis score is a predictor of a future decline in the FVC% predicted in the absence of effective treatment., (Copyright © 2011 by the American College of Rheumatology.)

The interstitial lung diseases (ILD) are a group of heterogeneous diseases that exert significant morbidity and mortality in connective tissue diseases (CTD). There is no consensus on measures of disease activity or therapeutic responsiveness, which hampers effective drug development and regulatory evaluation of candidate therapies. The CTD-ILD Special Interest Group represents an international multidisciplinary effort to identify consensus on criteria to measure disease activity and therapeutic response in CTD-ILD. We summarize the design of the studies we are conducting and progress leading to the OMERACT 10 and 2010 EULAR meetings.

Objective: Endothelin is implicated as a participatory pathway in systemic sclerosis (SSc). We tested this hypothesis in a 12-month trial of bosentan, a nonselective endothelin receptor antagonist, as a therapy for SSc-related interstitial lung disease (ILD)., Method: Patients with SSc and significant ILD were recruited to this prospective, double-blind, randomized, placebo-controlled, parallel group study. The inclusion criteria were designed to select a cohort enriched for patients with active and progressive disease. Exclusion factors included significant pulmonary hypertension. Patients with a diffusing capacity for carbon monoxide of <80% predicted and a 6-minute walk distance of 150-500 meters or a 6-minute walk distance of > or = 500 meters with a decrease in oxygen saturation received bosentan or placebo. The primary efficacy end point was a change in the 6-minute walk distance from baseline up to month 12. Secondary end points included time to death or worsening results of pulmonary function tests (PFTs). The safety and tolerability of bosentan were also assessed., Results: Among the 163 patients, 77 were randomized to receive bosentan, and 86 were randomized to receive placebo. No significant difference between treatment groups was observed for change in the 6-minute walk distance up to month 12. No deaths occurred in this study group. Forced vital capacity and diffusing capacity for carbon monoxide remained stable in the majority of patients in both groups. Significant worsening of PFT results occurred in 25.6% of patients receiving placebo and 22.5% of those receiving bosentan (P not significant)., Conclusion: No improvement in exercise capacity was observed in the bosentan-treated group compared with the placebo group, and no significant treatment effect was observed for the other end points. Although many outcome variables were stable, bosentan did not reduce the frequency of clinically important worsening. These data do not support the use of endothelin receptor antagonists as therapy for ILD secondary to SSc.

Pulmonary disease is the leading cause of morbidity and mortality in patients with systemic sclerosis (SSc). Recent well-designed trials in SSc-associated interstitial lung disease (SSc-ILD) have provided important insights regarding outcome measures and trial design. Recent investigations into the pathogenesis of SSc-ILD have led to a renewed interest in assessing targeted therapies in SSc-ILD. With this in mind, we propose recommendations for the design of future SSc-ILD studies in this review.

Background: A 36-year-old woman developed new-onset Raynaud phenomenon and rapidly progressive dyspnea over a 2-week period. A lung biopsy demonstrated pauci-inflammatory nonspecific pneumonitis, which proved refractory to systemic corticosteroid and intravenous cyclophosphamide therapy. Her preterminal course in an intensive care unit was typified by sequential organ failure. Postmortem examination showed extensive organ fibrosis, including severe diffuse alveolar damage and parenchymal fibrosis, and a notable lack of potentially treatable tissue inflammation., Investigations: Chest radiography, physical examination, screening for autoantibodies, measurement of serum creatinine, creatine phosphokinase, and brain natriuretic peptide levels, cardiac examination, pulmonary function tests, electrocardiography, transthoracic Doppler echocardiography, right heart catheterization, high-resolution thoracic CT, pulmonary ventilation/perfusion scan, lung biopsy., Diagnosis: Interstitial lung disease associated with diffuse systemic sclerosis., Management: Treatment with oxygen, oral and intravenous corticosteroids, mycophenolate mofetil and intravenous cyclophosphamide.

Background: The 6-min walk test (6MWT) is increasingly used as an outcome measure in interstitial lung disease (ILD)., Aim: To evaluate the usefulness of the 6MWT in a cohort of patients with ILD secondary to systemic sclerosis (SSc) and to correlate with established physiological parameters., Methods: 163 patients with SSc-ILD were recruited for a multicentre, randomised, double-blind clinical trial. Available data at protocol screening included repeated 6MWTs, pulmonary function testing with diffusing capacity, Doppler echocardiography and high-resolution computed tomography of the thorax. Borg Dyspnoea Index was evaluated before and after 6MWT., Results: Mean (standard deviation (SD)) distance walked during walk test 1 was 396.6 (84.55) m compared with 399.5 (86.28) m at walk test 2. The within-subject, intertest correlation as determined by Pearson's correlation coefficient testing was 0.95 (p<0.001). However, only weak correlations of 6MWT with percentage forced vital capacity and the Borg Dyspnoea Index were observed, and no correlation was observed with percentage diffusing capacity., Conclusion: These data confirm the high reproducibility of the 6MWT in patients with SSc-ILD and therefore the validity of the test in this cohort. The lack of correlation of 6MWT with standard physiological parameters of ILD suggests a multifactorial basis for limited exercise capacity in patients with SSc and calls into question the utility of the 6MWT as a measure of outcome in future studies on SSc-ILD.

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 high-resolution computed tomography, or both. Patients received oral cyclophosphamide (< or =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<0.03). There were also treatment-related differences in physiological and symptom outcomes, and the difference in FVC was maintained at 24 months. There was a greater frequency of adverse events in the cyclophosphamide group, but the difference between the two groups in the number of serious adverse events was not significant., Conclusions: One year of oral cyclophosphamide in patients with symptomatic scleroderma-related interstitial lung disease had a significant but modest beneficial effect on lung function, dyspnea, thickening of the skin, and the health-related quality of life. The effects on lung function were maintained through the 24 months of the study., (Copyright 2006 Massachusetts Medical Society.)