Article

A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma.

Royal Brompton Hospital, Imperial College, London, UK.
Arthritis & Rheumatism (impact factor: 7.87). 01/2007; 54(12):3962-70. DOI:10.1002/art.22204 pp.3962-70
Source: PubMed

ABSTRACT The lack of randomized controlled trials (RCTs) in pulmonary fibrosis in systemic sclerosis (SSc) has hampered an evidence-based approach to treatment. This RCT was undertaken to investigate the effects of intravenous (IV) cyclophosphamide (CYC) followed by azathioprine (AZA) treatment in pulmonary fibrosis in SSc.
Forty-five patients were randomized to receive low-dose prednisolone and 6 infusions (monthly) of CYC followed by oral AZA, or placebo. Primary outcome measures were change in percent predicted forced vital capacity (FVC) and change in single-breath diffusing capacity for carbon monoxide (DLCO). Secondary outcome measures included changes in appearance on high-resolution computed tomography and dyspnea scores. An intent-to-treat statistical analysis was performed.
At baseline, there were no significant group differences in factors linked to outcome, including severity of pulmonary fibrosis and autoantibody status. Sixty-two percent of the patients completed the first year of treatment. Withdrawals included 9 patients (6 from the placebo group) with significant decline in lung function, 2 with treatment side effects (both from the active treatment group), and 6 with non-trial-related comorbidity. No hemorrhagic cystitis or bone marrow suppression was observed. Estimation of the relative treatment effect (active treatment versus placebo) adjusted for baseline FVC and treatment center revealed a favorable outcome for FVC of 4.19%; this between-group difference showed a trend toward statistical significance (P = 0.08). No improvements in DLCO or secondary outcome measures were identified.
This trial did not demonstrate significant improvement in the primary or secondary end points in the active treatment group versus the group receiving placebo. However, for FVC there was a trend toward statistical significance between the 2 groups. This suggests that treatment of pulmonary fibrosis in SSc with low-dose prednisolone and IV CYC followed by AZA stabilizes lung function in a subset of patients with the disease. Therapy was well tolerated with no increase in serious adverse events.

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    Carlotta Nannini, Colin P West, Patricia J Erwin, Eric L Matteson
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    Hyun J Kim, Matthew S Brown, Robert Elashoff, Gang Li, David W Gjertson, David A Lynch, Diane C Strollo, Eric Kleerup, Daniel Chong, Sumit K Shah, Shama Ahmad, Fereidoun Abtin, Donald P Tashkin, Jonathan G Goldin
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Keywords

2 groups
 
6 infusions
 
baseline FVC
 
bone marrow suppression
 
favorable outcome
 
hemorrhagic cystitis
 
intent-to-treat statistical analysis
 
IV CYC
 
low-dose prednisolone
 
lung function
 
Primary outcome measures
 
secondary end points
 
Secondary outcome measures
 
serious adverse events
 
significant decline
 
significant group differences
 
single-breath diffusing capacity
 
systemic sclerosis
 
treatment side effects
 
vital capacity