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

Abstract

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-trialrelated 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.Conclusion. 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.

Predicting Treatment Outcomes And Responder Subsets In Scleroderma-Related Interstitial Lung Disease

“…While these beneficial effects were wide-ranging, the overall magnitude of change in FVC was small and dissipated by the end of 24-months (3-4). A small but beneficial effect of intravenous CYC on lung function was also suggested by the Fibrosing Alveolitis in Scleroderma Trial (2). Based on these studies and the known side effects of CYC, some investigators have concluded that the potential risks from CYC outweigh the benefits (5,(7)(8).…”

“…At present, only daily oral or pulse intravenous cyclophosphamide (CYC) have been shown in large randomized, doubleblinded, placebo-controlled trials to alter the course of SSc-ILD (2)(3). While highlighting that SSc-ILD is treatable, the overall magnitude of the response to CYC in these studies was modest and the beneficial effects appeared to fade within a year after stopping treatment (2)(3)(4).…”

“…At present, only daily oral or pulse intravenous cyclophosphamide (CYC) have been shown in large randomized, doubleblinded, placebo-controlled trials to alter the course of SSc-ILD (2)(3). While highlighting that SSc-ILD is treatable, the overall magnitude of the response to CYC in these studies was modest and the beneficial effects appeared to fade within a year after stopping treatment (2)(3)(4). When these features are combined with the potential toxicity associated with CYC (5), there has been considerable controversy about whether all patients with SSc-ILD should be treated or whether therapy should be reserved for patients at the greatest risk for progression or deterioration (6)(7)(8).…”

Treatment of pulmonary fibrosis for twenty weeks with imatinib mesylate in a patient with mixed connective tissue disease

“…Cyclophosphamide is the only therapy that has been shown in randomized controlled trials to have beneficial effects in the treatment of pulmonary fibrosis associated with connective tissue diseases (14,15). In the scleroderma lung study, treatment with oral cyclophosphamide at a dosage of Յ2 mg/kg/day for 12 months resulted in statistically significant improvement.…”

Interstitial Lung Disease in Systemic Sclerosis: Diagnosis and Management

“…In the 45 patient double blind placebo controlled study, there was a trend toward improved FVC in the cyclophosphamide group but this did not achieve statistical significance [48]. Thus, it remains unclear what the true role of IV cyclophophamide might be in the management of SSc related ILD.…”