Background/Purpose: Interstitial lung disease (ILD) is the leading cause of death in patients with systemic sclerosis (SSc). Randomized controlled trials favoured the use of cyclophosphamide (CYC) for treating SSc related ILD (SSc-ILD) (1,2). However, the effects of CYC waned after an additional year off therapy (3) and patients included did not fulfil progressive ILD criteria.

Methods: We conducted a randomized, prospective, double-blind, placebo-controlled multicenter trial to evaluate the efficacy and safety of CYC in combination with prednisone in patients with progressive SSc-ILD (Clinical trial NCT01570764).Patients (≥ 18 years old) with SSc (defined by the American College of Rheumatology (ACR) and/or Leroy and Medsger criteria) and progressive SSc-ILD (defined as ≥ 10% decrease in forced vital capacity (FVC) and/or total lung capacity (TLC), and/or ≥ 15% decrease in diffusing capacity of the lung for carbon monoxide (DLCO) within 3 to 18 months prior to inclusion) were randomly assigned, in a 1:1 ratio, to receive either 0.7 g/m² (maximum 1200 mg) of intravenous (IV) CYC every 4 weeks during 12 months, or placebo. Both groups received 15 mg/day prednisone. The primary endpoint was the proportion of patients who improved or stabilized FVC at 12 months.

Results: Forty patients (13 males and 27 females, 24 (60%) with diffuse cutaneous SSc) were included between January 2013 and March 2017, with 20 patients randomized to each group. In the primary endpoint analysis, the proportion of patients who improved or stabilized FVC at 12 months was 17/20 (85%) in the CYC group and 16/20 (80%) and in the placebo group (relative risk (RR) 1.06 95% confidence interval (CI) (0.51 to 2.19)). Sensitivity analyses showed that the mean change from baseline in FVC at 12 months was 252.1 mL (122.8 to 381.4) in the CYC group and 3.8 mL (-129.3 to 136.9) in the placebo group (mean difference 248.3 (64.3 to 432.4)). The mean change from baseline in the health assessment questionnaire (HAQ) was lower at 12 months in the CYC group (-0.23 [-0.43; -0.02]) compared to the placebo group (0.27 [0.06; 0.48]) (mean difference -0.50 (-0.79 to -0.21)). Similarly, the mean change in the scleroderma-HAQ was significantly lower in the CYC group (-0.22 (-0.42; -0.02)) compared to the placebo group (0.28 (0.08; 0.48)) (mean difference -0.50 (-0.78 to -0.21)). The mean change in the physical component of the SF-36 was also greater in the CYC group (5.5 (0.9; 10.1)) than in the placebo group (-2.6 (-7.0; 1.9)) (mean difference 8.1 (1.7 to 14.3)). There was no significant difference in the mental component scale of the SF-36, nor in DLCO, New York Health Association, or six-minute walk distance. The proportion of patients who developed severe adverse events was similar between the groups ((5/20 (25%) in the CYC group vs. 7/20 (35%) in the placebo group). Two patients died, one in each group.

Conclusion: In patients with progressive SSc-ILD, treatment with oral prednisone and IV CYC did not significantly increase the proportion of patients who improved or stabilized FVC and/or DLCO at 12 months. However, it significantly increasedFVC, and improved HAQ, Scleroderma-HAQ scores, and the physical component of the SF-36 at 12 months.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/intravenous-cyclophosphamide-in-the-treatment-of-progressive-interstitial-lung-diseases-associated-with-systemic-sclerosis-a-prospective-randomized-trial-versus-placebo-sclerocyc/