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Effects of 1-Year Treatment with Cyclophosphamide on Outcomes at 2 Years in Scleroderma Lung Disease

¹ Department of Medicine and ² Department of Biomathematics, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California; ³ Department of Medicine, Medical University of South Carolina, Charleston, South Carolina; ⁴ Department of Radiological Sciences, David Geffen School of Medicine, UCLA, Los Angeles, California; ⁵ Pharmaceutical Services, UCLA Medical Center, Los Angeles, California; ⁶ Department of Medicine, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick, New Jersey; ⁷ Department of Medicine, University of Illinois Chicago, Chicago, Illinois; ⁸ Department of Medicine, Boston University, Boston, Massachusetts; ⁹ Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland; ¹⁰ Department of Medicine, Georgetown University, Washington, DC; ¹¹ Department of Medicine, University of Texas Houston Medical School, Houston, Texas; ¹² Department of Medicine, Wayne State University, Detroit, Michigan; ¹³ Department of Medicine, University of California, San Francisco, San Francisco, California; ¹⁴ Department of Medicine, University of Alabama Birmingham, Birmingham, Alabama; and ¹⁵ Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut

Correspondence and requests for reprints should be addressed to Donald P. Tashkin, M.D., Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095-1690. E-mail: dtashkin{at}mednet.ucla.edu

Rationale: 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.

Objectives: A second year of follow-up was performed to determine if these effects persisted after stopping treatment.

Methods: A detailed analysis of data obtained over the two years of the study was performed.

Measurements and Main Results: 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.

Conclusions: 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).

Key Words: cyclophosphamide • interstitial lung disease • scleroderma • systemic sclerosis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The Scleroderma Lung Study was the first randomized, placebo-controlled trial to demonstrate the efficacy of 1 year of treatment with oral cyclophosphamide in scleroderma interstitial lung disease with active alveolitis. What This Study Adds to the Field The present report provides the first evidence that, during an additional year of follow-up in the same patients off of study drug, the benefits of cyclophosphamide persist for several additional months, but are generally no longer apparent at 2 years.

 

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Athol U. Wells, Panagiota Latsi, and W. Joseph McCune
AJRCCM 2007 176: 952-953. [Full Text]  

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