Promising Treatment for Scleroderma-Related Interstitial Lung Disease

Cyclophosphamide and mycophenolate mofetil efficacious for scleroderma-related lung disease, according to trial data reported at ACR/ARHP 2015.

Oral cyclophosphamide and mycophenolate mofetil were equally efficacious in improving forced vital capacity (FVC) in patients with scleroderma and symptomatic interstitial lung disease (ILD), according to results from the Scleroderma Lung Study II presented at the 2015 annual meeting of the American College of Rheumatology.1

ILD, the most frequent cause of scleroderma-related mortality, is present in approximately 90% of individuals with scleroderma as revealed by high-resolution computed tomography (HRCT). Changes in pulmonary function tests are present in 40% to 75% of patients with scleroderma.2

Inflammation Postulated as Cause of ILD In Scleroderma; Anti-Inflammatory Agents Potentially Beneficial

“For a sizeable fraction of people with scleroderma, scarring lung disease can be associated with a great deal of suffering and even with death,” stated lead investigator Philip Clements, MD, of the David Geffen School of Medicine at the University of California, Los Angeles, in a press release. “We postulated that the interstitial lung disease seen in scleroderma was caused in part by inflammation. We therefore sought to decrease the inflammation with medications that have strong anti-inflammatory properties, namely cyclophosphamide and mycophenolate mofetil.”

The Scleroderma Lung Study II was built on knowledge gleaned from the Scleroderma Lung Study, a 13-center, double-blind, randomized, placebo-controlled trial of oral cyclophosphamide. That study found that treatment with cyclophosphamide resulted in modest improvements in FVC and total lung capacity over a period of one year in patients with ILD.3 However, the benefits of cyclophosphamide were no longer apparent 24 months following treatment cessation, necessitating further exploration of alternative treatments.4 Alternatives to cyclophosphamide are also desirable due to its high toxicity and potential for adverse effects.5

Methodology and Results

The research team randomly assigned 142 patients to receive either oral cyclophosphamide 2 mg/kg/d for one year followed by matching placebo for the second year, or mycophenolate mofetil up to 1500 mg twice daily for 2 years. The patients included in the study had all been diagnosed with scleroderma for fewer than 7 years, were affected by moderate dyspnea, had an FVC of 45% to 80%, and had any ground-glass opacification on chest HRCT. Baseline characteristics were the same in both treatment groups except for higher modified Rodnan skin scores in the group that received mycophenolate mofetil. Patients were assessed with physical examinations (including modified Rodnan skin scoring), pulmonary function testing, and standardized questionnaires that elicit patient-reported outcomes at baseline and every 3 months for 2 years.

In preliminary analyses at 2 years, patients in both treatment groups showed similar significant improvements in FVC, dyspnea, modified Rodnan skin scores, and interstitial lung change on HRCT scan of the lungs (P<.05). More patients in the cyclophosphamide arm withdrew from study treatment prematurely (36 in the cyclophosphamide arm vs 20 in the mycophenolate mofetil arm; P=.019).


Dr Clements noted that there is a risk of permanent lung damage within the first 5 to 7 years following a diagnosis of scleroderma, making it important for patients to undergo screening with pulmonary function tests at 6-month intervals. “If a patient’s lung function declines, rheumatologists should consider treating him or her as early as possible with cyclophosphamide or mycophenolate mofetil to try to prevent further progressive lung scaring,” he concluded.


  1. Clements PJ, Tashkin D, Roth M, et al. The Scleroderma Lung Study II (SLS II) shows that both oral cyclophosphamide (CYC) and mycophenolate mofetil (MMF) are efficacious in treating progressive interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) [abstract]. Arthritis Rheumatol. 2015;67 (suppl 10).
  2. Solomon JJ, Olson AL, Fischer A, Bull T, Brown KK, Raghu G. Scleroderma lung disease. Eur Respir Rev. 2013;22(127):6-19. doi:10.1183/09059180.00005512.
  3. Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006;354(25):2655-2666.
  4. Tashkin DP, Elashoff R, Clements PJ, et al. Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. Am J Respir Crit Care Med. 2007;176(10):1026-1034.
  5. Martinez FJ, McCune WJ. Cyclophosphamide for scleroderma lung disease. N Engl J Med. 2006;354(25):2707-2709.