Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease

Abstract

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).

Trial registration: ClinicalTrials.gov NCT00004563.

Figure 1.

Disposition of the 158 randomized participants in the Scleroderma Lung Study over the 24 months of the trial. CYC = cyclophosphamide; D = died; F = failed treatment; PLAC = placebo; W = withdrew from the study.

Figure 2.

Time course from 6 to 24 months of mean values (±SE) for FVC % predicted (A) and TLC % predicted (B) of participants in the placebo and cyclophosphamide (CYC) treatment groups determined from a longitudinal model that adjusted for baseline % predicted values, maximal high-resolution computed tomography–scored fibrosis, and nonignorable missing data (29). For this and subsequent figures, numbers of patients in each treatment group at each visit are shown, along with the P values for the between-treatment differences obtained from Huber's robust regression analysis with multiple imputation (30).

Figure 2.

Time course from 6 to 24 months of mean values (±SE) for FVC % predicted (A) and TLC % predicted (B) of participants in the placebo and cyclophosphamide (CYC) treatment groups determined from a longitudinal model that adjusted for baseline % predicted values, maximal high-resolution computed tomography–scored fibrosis, and nonignorable missing data (29). For this and subsequent figures, numbers of patients in each treatment group at each visit are shown, along with the P values for the between-treatment differences obtained from Huber's robust regression analysis with multiple imputation (30).

Figure 3.

Time course from 6 to 24 months of mean values (±SE) for transition dyspnea index (TDI) determined from the longitudinal model (see legend for Figure 2). CYC = cyclophosphamide.

Figure 4.

Time course from 6 to 24 months of mean values (±SE) for skin thickness scores (modified Rodnan) determined from the longitudinal model (see legend for Figure 2). CYC = cyclophosphamide.