Low-dose pulse cyclophosphamide in interstitial lung disease associated with systemic sclerosis (SSc-ILD): efficacy of maintenance immunosuppression in responders and non-responders

Semin Arthritis Rheum. 2015 Feb;44(4):437-44. doi: 10.1016/j.semarthrit.2014.09.003. Epub 2014 Sep 8.


Objective: To investigate the long-term disease course of patients with recently deteriorated systemic sclerosis (SSC)-interstitial lung disease (ILD) undergoing continuous immunosuppressive treatment with cyclophosphamide (CYC) as induction therapy.

Methods: A total of 45 consecutive SSc patients were treated with weekly pulses of 500mg of CYC up to 10-g cumulative dose followed by azathioprine (AZA) in those experiencing improvement (>10% increase) or stabilization of both forced vital capacity and diffusion lung capacity for carbon dioxide and by micophenolic acid (MMF) in those experiencing deterioration (>10% decrease of either parameter). The follow-up ranged from 6 to 62 months post-CYC regimen (median = 36 months).

Results: Overall, 39 patients completed the CYC regimen. Of them, 24 (61.5%) experienced improvement or stabilization of lung function parameters and received AZA; the remaining 15 received MMF. During follow-up, lung function parameters improved in 3 (12.5%), remained stable in 18 (75%), and worsened in 3 (12.5%) AZA-treated patients, whereas they worsened in 8 (67%) and remained stable in 4 (33%) MMF-treated patients. The incidence of improvement or stabilization was significantly higher in AZA-treated than in MMF-treated patients (p = 0.001). The time to the decline of lung function was significantly shorter in CYC non-responders, and CYC unresponsiveness was predictive of lung function worsening over time in a multivariate analysis (HR = 9.14; 95% CI: 2.28-36.64; p = 0.0018).

Conclusion: Our study supports the use of low-dose pulse CYC as induction therapy of recently deteriorated SSc-ILD. Moreover, it suggests that AZA should be administered to CYC-responsive patients but does not show any definite effect of MMF in unresponsive patients.

Keywords: Interstitial lung disease; Systemic sclerosis.

MeSH terms

  • Adult
  • Azathioprine / therapeutic use
  • Cyclophosphamide / therapeutic use*
  • Dose-Response Relationship, Drug
  • Drug Therapy, Combination
  • Female
  • Follow-Up Studies
  • Humans
  • Immunosuppressive Agents / therapeutic use*
  • Lung Diseases, Interstitial / drug therapy*
  • Lung Diseases, Interstitial / etiology*
  • Lung Diseases, Interstitial / physiopathology
  • Male
  • Middle Aged
  • Scleroderma, Systemic / complications*
  • Time Factors
  • Treatment Outcome
  • Vital Capacity / physiology


  • Immunosuppressive Agents
  • Cyclophosphamide
  • Azathioprine