Adverse events during the Scleroderma Lung Study

Am J Med. 2011 May;124(5):459-67. doi: 10.1016/j.amjmed.2010.12.009.


Background: The Scleroderma Lung Study (SLS) was a 1-year, randomized, controlled trial of oral cyclophosphamide for scleroderma-related pulmonary alveolitis. It concluded that oral cyclophosphamide slowed the decline in the forced vital capacity (% predicted) and had a beneficial effect on dyspnea, skin changes, and several quality of life measures of systemic sclerosis. We now report an in-depth assessment of the toxicity of cyclophosphamide during the year of therapy and the year after therapy was completed, during which time the investigators were still masked to the treatment assignment.

Methods: One-year, double-blind, randomized controlled trial of oral cyclophosphamide versus placebo with 1-year masked follow-up. Adverse events (AEs) were tabulated, described, and compared using descriptive statistics (eg, mean and median) and t, Wilcoxon rank sum, chi-squared, or Fisher's exact tests as appropriate.

Results: During year 1, treatment-related overall AEs occurred more frequently in cyclophosphamide (CYC)-treated patients (overall AEs for CYC=154 events vs placebo=60 events; P=0.002), and especially for mild to moderate leukopenia (CYC=19 subjects vs placebo=0 subjects; P < .0001). For cancer, we followed patients beyond 2 years. There were no differences in the occurrence of cancer (CYC=4 subjects vs placebo=2 subjects), serious related AEs (CYC=8 events vs placebo=13 events), or deaths (CYC=6 subjects vs placebo=6 subjects).

Conclusion: Over 2 years, cyclophosphamide was associated with more AEs than placebo, including overall AEs and relative leukopenia. There were no differences in other AEs, including serious AEs, cancers, or deaths.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Cyclophosphamide / administration & dosage
  • Cyclophosphamide / adverse effects*
  • Double-Blind Method
  • Female
  • Hematuria / chemically induced
  • Humans
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / adverse effects*
  • Incidence
  • Leukocyte Count
  • Leukopenia / chemically induced
  • Male
  • Middle Aged
  • Neoplasms / chemically induced
  • Pulmonary Fibrosis / drug therapy*
  • Pulmonary Fibrosis / etiology
  • Pulmonary Fibrosis / physiopathology
  • Scleroderma, Systemic / complications*
  • Time Factors
  • Vital Capacity / drug effects


  • Immunosuppressive Agents
  • Cyclophosphamide