Cyclophosphamide versus Placebo in Scleroderma Lung Disease
Donald P. Tashkin, M.D., Robert Elashoff, Ph.D., Philip J. Clements, M.D., M.P.H., Jonathan Goldin, M.D., Ph.D., Michael D. Roth, M.D., Daniel E. Furst, M.D., Edgar Arriola, Pharm.D., Richard Silver, M.D., Charlie Strange, M.D., Marcy Bolster, M.D., James R. Seibold, M.D., David J. Riley, M.D., Vivien M. Hsu, M.D., John Varga, M.D., Dean E. Schraufnagel, M.D., Arthur Theodore, M.D., Robert Simms, M.D., Robert Wise, M.D., Fredrick Wigley, M.D., Barbara White, M.D., Virginia Steen, M.D., Charles Read, M.D., Maureen Mayes, M.D., Ed Parsley, D.O., Kamal Mubarak, M.D., M. Kari Connolly, M.D., Jeffrey Golden, M.D., Mitchell Olman, M.D., Barri Fessler, M.D., Naomi Rothfield, M.D., Mark Metersky, M.D., for the Scleroderma Lung Study Research Group
Background We conducted a double-blind, randomized, placebo-controlledtrial to determine the effects of oral cyclophosphamide on lungfunction and health-related symptoms in patients with evidenceof active alveolitis and scleroderma-related interstitial lungdisease.
Methods At 13 clinical centers throughout the United States,we enrolled 158 patients with scleroderma, restrictive lungphysiology, dyspnea, and evidence of inflammatory interstitiallung disease on examination of bronchoalveolar-lavage fluid,thoracic high-resolution computed tomography, or both. Patientsreceived oral cyclophosphamide (2 mg per kilogram of body weightper day) or matching placebo for one year and were followedfor an additional year. Pulmonary function was assessed everythree months during the first year, and the primary end pointwas the forced vital capacity (FVC, expressed as a percentageof the predicted value) at 12 months, after adjustment for thebaseline FVC.
Results Of 158 patients, 145 completed at least six months oftreatment and were included in the analysis. The mean absolutedifference in adjusted 12-month FVC percent predicted betweenthe cyclophosphamide and placebo groups was 2.53 percent (95percent confidence interval, 0.28 to 4.79 percent), favoringcyclophosphamide (P<0.03). There were also treatment-relateddifferences in physiological and symptom outcomes, and the differencein FVC was maintained at 24 months. There was a greater frequencyof adverse events in the cyclophosphamide group, but the differencebetween the two groups in the number of serious adverse eventswas not significant.
Conclusions One year of oral cyclophosphamide in patients withsymptomatic scleroderma-related interstitial lung disease hada significant but modest beneficial effect on lung function,dyspnea, thickening of the skin, and the health-related qualityof life. The effects on lung function were maintained throughthe 24 months of the study.
Source Information
From the University of California at Los Angeles, Los Angeles (D.P.T., R.E., P.J.C., J.G., M.D.R., D.E.F., E.A.); Medical University of South Carolina, Charleston (R.S., C.S., M.B.); University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick (J.R.S., D.J.R., V.M.H.); University of Illinois, Chicago (J.V., D.E.S.); Boston University, Boston (A.T., R.S.); Johns Hopkins School of Medicine, Baltimore (R.W., F.W., B.W.); Georgetown University, Washington, D.C. (V.S., C.R.); University of Texas at Houston Medical School, Houston (M. Mayes, E.P.); Wayne State University, Detroit (K.M.); University of California San Francisco, San Francisco (M.K.C., J.G.); University of Alabama, Birmingham (M.O., B.F.); and University of Connecticut Health Center, Farmington (N.R., M. Metersky).
Address reprint requests to Dr. Tashkin at the Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, 10833 Le Conte Ave., Los Angeles, CA 90095-1690, or at dtashkin{at}mednet.ucla.edu.
Cyclophosphamide in Scleroderma Lung Disease
Kuschner W. G., Andreu J.-L., Silva L., Sullivan K. M., McSweeney P. A., Nash R. A., Tashkin D. P., Clements P. J., Roth M. D.
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N Engl J Med 2006;
355:1173-1174, Sep 14, 2006.
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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. 
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