How Do I Treat Symptomatic Interstitial Lung Disease in Scleroderma? Save

We know from the large Scleroderma Lung Study, which I will refer to as SLS I, that cyclophosphamide given orally for one year was superior to placebo for some lung parameters and also the modified Rodnan Skin Score (mRSS) and function as measured by the HAQ Disability Index (1). It is also known that after withdrawing cyclophosphamide in the second year and not providing ongoing immune suppression, there was regression to the mean where by year two the gains from the first year were lost (2). This paradigm of induction and then maintenance therapy is the norm in the treatment of lupus nephritis and (in my opinion) should occur in GPA (ANCA vasculitis) and possibly in scleroderma, too. 

The Scleroderma Lung Study II (SLS II) was presented by Drs. Phil Clements and Elizabeth Volkmann at the 2015 American College of Rheumatology (ACR) meeting in San Francisco (abstracts 1075, 1076). It is important to find more effective therapies in the treatment of SSc ILD that are safe. Patients had to have less than 7 years of SSc and FVC between 45 and 80% of predicted and high-resolution CT (HRCT) scan evidence of interstitial lung disease (ILD). This SLS II compared oral cyclophosphamide (CTX) at 2 mg/kg/day to mycophenylate mofetil (MMF) at 1.5 g/day. CTX was given for 1 year and then no treatment, whereas MMF was given for two years.

The strange thing is these authors knew if cyclophosphamide is given as induction and there is then no maintenance therapy, patients will lose their initial gains in the second year without CTX.  There was equal improvement in the forced vital capacity (FVC% predicted improved by 4% in each group), but the transition dyspnea index and mRSS were numerically better in cyclophosphamide treated patients (mRSS reduction of 6 units in CTX vs. 3 in MMF). There were more discontinuations with CTX (total of 142 patients, where 106 completed two years, and 36 dropped out in the CTX group and 20 in MMF group) and more deaths (11) in CTX compared with MMF (5). 

After spending much time, effort and money for this enormous trial, I am left puzzled. I don’t know what to do. Should I use cyclophosphamide to improve skin, function and at least improve lung parameters equal to MMF and then switch to MMF? Should I abandon cyclophosphamide altogether? Should I use cyclophosphamide for less time or lower dose or intravenously instead of orally for a period of time and then switch to something such as azathioprine? 

Unfortunately, this study does not answer how I should treat the next scleroderma patient with significant lung involvement.  We don’t know what the gold standard of active treatment should be if comparing new drugs, but if MMF is the standard (some registered trials are using MMF), there is a problem in many countries with cost and access for obtaining MMF. So, what should I do in the treatment of scleroderma lung……beats me!

1.    Tashkin DP, Elashoff R, Clements PJ, et al, Scleroderma Lung Study Research Group. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006;354:2655–66.
2.    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.