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SAT0328 An open-label study of ambrisentan with anti-fibrotic agent combination therapy in the treatment of diffuse systemic sclerosis
  1. A Schorpion1,
  2. M Shenin2,
  3. R Neubauer1,
  4. CT Derk1
  1. 1Division of Rheumatology, Hospital of the University of Pennsylvania
  2. 2Division of Rheumatology, Thomas Jefferson University Hospital, Philadelphia, United States


Background Systemic sclerosis (SSc) is marked by immune dysregulation, inappropriate fibrosis and a vasculopathy for which there is currently no universally accepted disease modifying regimen. Ambrisentan, a selective type A endothelin receptor antagonist (ERA) has known benefits in the treatment of the vasculopathy related to pulmonary arterial hypertension and has been postulated to have anti-fibrotic effects. The additive effect of an ERA in combination with an anti-fibrotic agent has not previously been studied in SSc.

Objectives To determine the safety and efficacy of ambrisentan in combination with an anti-fibrotic agent in early diffuse cutaneous systemic sclerosis (dcSSc).

Methods Patients already on anti-fibrotic therapy for early dcSSc with onset of skin sclerosis less than 48 months before study entry were placed on ambrisentan 5mg daily for 12 months in an open-label study. Laboratory and clinical parameters to assess safety, as well as severity and progression of SSc were obtained at specified intervals. The primary outcome measure was the modified Rodnan skin score (mRSS), and secondary outcomes were the Medsger severity score, the Short Form Health Survey (SF)-36 questionnaire, pulmonary function tests (PFTs), and 2D echocardiograms (echo).

Results A total of 15 patients were recruited who were on anti-fibrotic therapy upon entry of the study, most commonly mycophenolate (14 patients) and 1 patient on methotrexate. Of the patients entering the study, 10 patients (66.7%) completed 12 months of treatment with the study drug. Using intention-to-treat analysis, the mRSS improved significantly with a mean difference in mRSS of -8 from study entry to study end (p=0.000167). Among study completers (n=10), there was a trend for improvement in all but one category of the SF-36 while only the physical health component was of statistical significance (p=0.025). The median Medsger severity scores remained unchanged except for a change in median skin score. No statistically significant change was observed in PFTs and in mean estimated pulmonary arterial pressure by echo for those patients in whom data was obtained at baseline and at 12 months (n=12 and n=5, respectively). The most common adverse events included peripheral edema and dizziness. Two patients withdrew from the study due to intolerance of the study drug. Serious adverse events (SAE's) occurred in 4 study subjects and included scleroderma renal crisis (n=1), upper gastrointestinal bleeding (n=1) and infections (n=2). None of the SAEs were deemed to be related to the study drug.

Conclusions In this prospective open-label study of ambrisentan and anti-fibrotic combination therapy in early dcSSc, we observed significant improvements in the mRSS and patient-perceived physical health status on the SF-36. There was no observed change in peripheral vascular involvement and no consistent trend in PFTs. Combination ambrisentan and anti-fibrotic therapy appears relatively safe in this 12-month study. Larger, controlled trials are needed to further investigate the safety and efficacy of combination therapy.

Acknowledgements [C.T. Derk received funding support for this study by Gilead Pharmaceuticals]

Disclosure of Interest A. Schorpion: None declared, M. Shenin: None declared, R. Neubauer: None declared, C. Derk Grant/research support from: Gilead Pharmaceuticals

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