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.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Hoyles
Rachel K
RK
Royal Brompton Hospital, Imperial College, London, UK.
Ellis
Ross W
RW
Wellsbury
Jessica
J
Lees
Belinda
B
Newlands
Pauline
P
Goh
Nicole S L
NS
Roberts
Christopher
C
Desai
Sujal
S
Herrick
Ariane L
AL
McHugh
Neil J
NJ
Foley
Noeleen M
NM
Pearson
Stanley B
SB
Emery
Paul
P
Veale
Douglas J
DJ
Denton
Christopher P
CP
Wells
Athol U
AU
Black
Carol M
CM
du Bois
Roland M
RM
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D011239:Prednisolone / Q000627:therapeutic use*; D011446:Prospective Studies; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D012129:Respiratory Function Tests; D012595:Scleroderma, Systemic / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D016896:Treatment Outcome
D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D011239:Prednisolone; D001379:Azathioprine