Cyclophosphamide versus placebo in scleroderma lung disease
Open accessAbstract
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.
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According to EULAR recommendations, cyclophosphamide should be considered for treatment of systemic sclerosis-associated interstitial lung disease, in particular for patients with progressive interstitial lung disease, based on two high-quality randomized controlled trials.
“According to EULAR recommendations, 145 in view of the results from two high-quality RCTs 146,147 and despite its known toxicity, CYC should be considered for treatment of SSc-ILD, in particular for patients with SSc with progressive ILD.”
From Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: Review of the literature and personalized risk-based prevention strategy (2020) · cites this paper as [146]
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- Authors
- Tashkin, D. P., Elashoff, R., Clements, P. J., Goldin, J., Roth, M. D., Furst, D. E., Arriola, E., Silver, R., Strange, C., Bolster, M., Seibold, J. R., Riley, D. J., Hsu, V. M., Varga, J., Schraufnagel, D. E., Theodore, A., Simms, R., Wise, R., Wigley, F., White, B., Steen, V., Read, C., Mayes, M., Parsley, E., Mubarak, K., Connolly, M. K., Golden, J., Olman, M., Fessler, B., Rothfield, N., & Metersky, M.
- Affiliations
- University of California, Los Angeles (US)
- Boston University (US)
- Medical University of South Carolina (US)
- University of Medicine and Dentistry of New Jersey (US)
- University of Illinois Chicago (US)
- Johns Hopkins University (US)
- Georgetown University (US)
- Wayne State University (US)
- University of California, San Francisco (US)
- University of Alabama at Birmingham (US)
- UConn Health (US)
- ORCID
- Tashkin, Donald P.
- Goldin, Jonathan
- Roth, Michael D.
- Furst, Daniel E.
- Silver, Richard
- Strange, Charlie
- Bolster, Marcy
- Seibold, James R.
- Hsu, Vivien M.
- Varga, John
- Schraufnagel, Dean E.
- Theodore, Arthur
- Simms, Robert
- Wise, Robert
- Wigley, Fredrick
- White, Barbara
- Steen, Virginia
- Mayes, Maureen
- Connolly, M. Kari
- Golden, Jeffrey
- Olman, Mitchell
- Metersky, Mark
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2006-06-22
- Volume
- 354
- Issue
- 25
- Pages
- 2655-2666
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2131014787
- Cited by
- 1,677
- References
- 32
- Citations by year
- 2026: 45 · 2025: 82 · 2024: 85 · 2023: 76 · 2022: 92 · 2021: 138 · 2020: 129 · 2019: 110 · 2018: 76 · 2017: 75 · 2016: 97 · 2015: 64 · 2014: 56 · 2013: 67 · 2012: 65
- FWCI
- 58.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5u01hl060748-02)
- National Heart, Lung, and Blood Institute (UO1 HL 60682, UO1 HL 60750, U01HL060750, UO1 HL 60895, U01HL060682, UO1 HL 60748, U01HL060895, UO1 HL 60839, U01HL060823, UO1HL 60587, U01HL060597, UO1 HL 60606, U01HL060839, U01HL060606, UO1 HL 60794, UO1 HL 50550, U01HL060794, UO1 HL 60838, U01HL060587, UO1 HL 60823, UO1 HL 60597)
- National Center for Research Resources (M01RR000865)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Keywords
- cyclophosphamide, systemic sclerosis, interstitial lung disease, alveolitis, lung function, forced vital capacity, dyspnea, health-related quality of life, adverse events, immunosuppressive therapy
- MeSH terms
- Administration, Oral, Adult, Aged, Aged, 80 and over, Autoimmune Diseases, Bronchoalveolar Lavage Fluid, Cyclophosphamide, Double-Blind Method, Female, Humans, Immunosuppressive Agents, Leukopenia, Male, Middle Aged, Regression Analysis, Respiratory Function Tests, Scleroderma, Systemic, Vital Capacity, Treatment Outcome, Lung Diseases, Interstitial
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