Treatment of Scleroderma-Interstitial Lung Disease With Cyclophosphamide Is Associated With Less Progressive Fibrosis on Serial Thoracic High-Resolution CT Scan Than Placebo: Findings From the Scleroderma Lung Study

doi:10.1378/chest.09-0108

Chest

Volume 136, Issue 5, November 2009, Pages 1333-1340

https://doi.org/10.1378/chest.09-0108 Get rights and content

Background

The Scleroderma Lung Study (SLS) demonstrated significant treatment-associated improvements in pulmonary function and symptoms when patients with scleroderma-related interstitial lung disease (SSc-ILD) were treated with a 1-year course of cyclophosphamide (CYC) in a randomized, double-blinded, placebo-controlled clinical trial. This study examined thoracic high-resolution CT (HRCT) scans obtained during the SLS for treatment-associated changes over time.

Methods

Ninety-eight of the 158 subjects (CYC group, 49 subjects; placebo group, 49 subjects) participating in the SLS underwent thoracic HRCT scans both at baseline and after 12 months of treatment, which were available for analysis. Two independent radiologists visually scored the baseline HRCT scans for the presence of ground-glass opacities (GGOs), fibrosis (FIB), and honeycomb cysts (HCs) on a scale of 0 to 4. The treatment effect at 12 months was assessed by a blinded comparison of baseline and follow-up scans for evidence of stability and improvement (not worse) or deterioration (worse).

Results

At the end of treatment, FIB was significantly worse in the placebo treatment group than in the CYC treatment group (p = 0.014). Furthermore, differences in the 12-month change in FIB between the CYC and placebo groups correlated significantly with other outcome measures, including the 12-month changes in FVC (p < 0.05), total lung capacity (p < 0.05), and dyspnea (p < 0.001) scores. However, no differences were noted between the two groups with respect to changes in either GGOs or HCs.

Conclusions

A 1-year course of treatment of SSc-ILD with CYC was associated with treatment-related changes in FIB scores on HRCT scans, which correlated with other measures of treatment response.

Trial registration

ClinicalTrials.gov Identifier: NCT00004563

Section snippets

Patient Selection

The SLS was a multicenter, randomized, double-blind comparison of a 1-year course of treatment with CYC (≤ 2 mg/kg/d) vs treatment with placebo in 158 patients with dyspnea with active SSc-ILD as defined by evidence on either a HRCT scan (the presence of any GGO through which lung architecture could be seen) or BAL fluid testing (≥ 3.0% neutrophils, ≥ 2.0% eosinophils, or both).⁵ Pulmonary function was assessed every 3 months during the first year; the primary end point was FVC percent

Results

Of the 158 patients who were eligible and randomized into the SLS, 98 patients (CYC group, 49 patients; placebo group, 49 patients) who had both baseline and 12-month HRCT scans and had completed a BAL procedure were analyzed (Fig 1). Table 1 shows the mean values (or percentage of patients) for clinically relevant baseline demographics and disease characteristics for these 98 patients as well as their worst recorded scores for HRCT scan measures of FIB, GGO, and HC (ie, the worst score among

Discussion

SSc-ILD is a serious and therapeutically challenging manifestation of systemic sclerosis, scleroderma. Although a number of agents have been evaluated as treatments for SSc-ILD, only oral CYC has been proven to be effective in a randomized controlled study⁵ demonstrating statistically significant placebo-adjusted improvements in FVC and TLC after 12 months of therapy. A small randomized controlled trial⁶ using IV CYC showed similar results to those with oral CYC, reinforcing this finding. The

Acknowledgments

Author contributions: Drs. Tashkin, Goldin, Elashoff, Roth, Clements, Furst, and Khanna all contributed to the design, oversight, and conduct of the study and in the writing and editing of the manuscript. Drs. Kim and Yan, and Ms. Vasunilashorn all contributed to the processing and statistical analysis of the imaging data and the correlation of the imaging results with the physiologic and patient-centered outcome variables. Dr. Li contributed substantially to the statistical design and analysis

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Citation Excerpt :
We identified 33 publications covering 23 different studies that evaluated cyclophosphamide, with the earliest report on cyclophosphamide published in 1993. Eleven publications were analyses of SLS I, a landmark Phase III study evaluating oral cyclophosphamide versus placebo in patients with SSc and ILD over 1 year [13,47–54]. Cyclophosphamide was either administered as intravenous (IV) pulses (doses most commonly ranging from 0.5–1.0 g/m2 body surface area) or orally (generally 1–2 mg/kg/day).
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.
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Funding/Support: This study was funded by research grants R01 HL072424 (Dr. Golding), 5U01 HL60587 (Dr. Tashkin), 5 P30 CA016042-35 (Dr. Li), P01AT003960 (Dr. Li), and 5U01 HL060606 (Dr. Elashoff) from the National Institutes of Health/National Heart, Lung, and Blood Institute.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).

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Original ResearchInterstitial Lung DiseaseTreatment of Scleroderma-Interstitial Lung Disease With Cyclophosphamide Is Associated With Less Progressive Fibrosis on Serial Thoracic High-Resolution CT Scan Than Placebo: Findings From the Scleroderma Lung Study

Background

Methods

Results

Conclusions

Trial registration

Section snippets

Patient Selection

Results

Discussion

Acknowledgments

Original Research
Interstitial Lung Disease
Treatment of Scleroderma-Interstitial Lung Disease With Cyclophosphamide Is Associated With Less Progressive Fibrosis on Serial Thoracic High-Resolution CT Scan Than Placebo: Findings From the Scleroderma Lung Study