Mycophenolate or Cyclophosphamide for Lung Disease?


Lung scarring early in systemic scleroderma can reduce lung function and leave patients gasping for breath. New treatments show promise.

Lung scarring early in systemic scleroderma can reduce lung function and leave patients gasping for breath. Now, a new study finds that both oral cyclophosphamide and mycophenolate mofitil can treat progressive scleroderma-related interstitial lung disease (SSc-ILD) in patients who are losing lung function.  The Scleroderma Lung Study II, which was one of the most popular studies presented at ACR/ARHP 2015 in November, 142 patients were randomized to either 2 mg/kg of oral cyclophosphamide per day for one year followed by a placebo for one year, or to mycophenolate mofitil (MMF) up to 1,500 mg twice a day for two years. The researchers found that both drugs were similarly effective at improving lung function, breathlessness and skin thickening.  In an interview with Rheumatology Network Philip Clements, M.D., a rheumatologist at Ronald Reagan UCLA Medical Center in Los Angeles, said both mycophenolate and cyclophosphamide are equally effective in treating interstitial lung disease in patients with SSc.  "It looks like mycophenolate is as effective as cyclophosphamide, and it's better tolerated and has the potential for fewer long-term side effects," he said. The study was recently featured in a Rheumatology Journal ClubTwitter chat in which physicians discussed MMF as a second line agent, insurance coverage for MMF as treatment for systemic sclerosis/scleroderma (SScl) and MMF as a combo treatment.[[{"type":"media","view_mode":"media_crop","fid":"44698","attributes":{"alt":"©LungsSciencePics/","class":"media-image media-image-right","id":"media_crop_1855131310876","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5031","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"©LungsSciencePics/","typeof":"foaf:Image"}}]] Lung scarring occurs in about 40 percent of people with SSc-ILD, Clements said, and in about 10 -15 percent, the lung involvement is severe. For patients with lung scarring, the damage occurs in the first five to six years of disease progression, Clements said, and stabilizes after six to eight years.  "What we want to do is catch people early," he said.  The main measurement of lung function is vital capacity, the maximum amount of air that a person can take in and blow out. A patient whose vital capacity drops below 75 percent of the expected value needs to see a pulmonologist or rheumatologist, Clements said. Declining lung function plus fibrosis on a high resolution CT scan is a red flag requiring immediate treatment.  "This is not something you wait three to six months to fiddle around with," Clements said.  The study recruited patients who had scleroderma for less than seven years, as determined by their first non-Raynaud sign or symptom of the disease. To be included, patients had to have moderate dyspnea and a forced vital capacity between 45 percent and 80 percent of the norm, as well as signs of scarring on a high-resolution CT scan.  The study did not include a placebo group, but Scleroderma Lung Study I compared cyclophosphamide to a placebo and determined that cyclophosphamide was effective, Clements said.  At 24 months, both groups of patients showed an approximate 4 percent improvement in forced vital capacity. Scores on the transition dyspnea index, a patient-reported measure of difficulty breathing, improved 2.16 points in the cyclophosphamide arm and 1.77 points in the mycophenolate arm. Patients perceived both improvements as clinically significant. Skin thickening improved in both arms, with scores on the Modified Rodnan Skin Score (MRSS) decreasing 5.35 units in the cyclophosphamide arm and 4.9 units in the mycophenolate arm.  In the Scleroderma Lung Study II, side effects were not statistically different between the two treatment groups. However, there were almost twice as many dropouts for all reasons in the cyclophosphamide arm, Clements noted. Thirty-six patients withdrew from the cyclophosphamide arm of the study early, compared with 20 in the mycophenolate arm (p=0.019), the researchers reported.  Mycophenolate mofitil does not affect female fertility as cyclophosphamide does, so the new study offers hope for an effective treatment for women who want to have children. Patients in the study also persisted on mycophenolate mofitil treatment longer than patients in the cyclophosphamide arm.  Mycophenolate will likely become the drug of choice for women who want to have children, Clements said. Other factors in the decision to treat include cost (Medicare prefers to pay for cyclophosphamide over mycophenolate, Clements said, though other insurance providers vary) and method of delivery (intravenous cyclophosphamide monthly or oral mycophenolate daily).  Study researcher Michael Roth, also of the UCLA School of Medicine, is now heading up Scleroderma Lung Study III. That study will compare mycophenolate alone with mycophenolate plus the anti-fibrotic pirfenidone, which was approved for the treatment of idiopathic pulmonary fibrosis in the United States in 2014.   


Clements PJ, Tashkin D, Roth M, Khanna D, Furst DE, Tseng CH, Volkmann ER, Elashoff R.

"The Scleroderma Lung Study II (SLS II) Shows That Both Oral Cyclophosphamide (CYC) and Mycophenolate Mofitil (MMF) Are Efficacious in Treating Progressive Interstitial Lung Disease (ILD) in Patients with Systemic Sclerosis (SSc)."

  Tashkin, et al.

"Cyclophosphamide versus Placebo in Scleroderma Lung Disease."

N Engl J Med 2006; 354:2655-2666. June 22, 2006. DOI: 10.1056/NEJMoa055120 

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