The Recurrence of Digital Ulcers in Patients with Systemic Sclerosis after Discontinuation of Oral Treprostinil.
Prior studies investigating the efficacy of oral treprostinil to treat digital ulcers (DU) in systemic sclerosis (SSc)-associated Raynaud phenomenon have yielded conflicting results. In this investigation, we examined whether DU burden increased after patients withdrew from oral treprostinil that was administered during an open-label extension study.



A multicenter, retrospective study was conducted to determine DU burden in the year after withdrawal from oral treprostinil. DU burden 3-6 months (Time A) and > 6-12 months (Time B) after drug withdrawal was compared with DU burden at baseline, defined as the last day receiving drug in the open-label extension study, by a paired Student t test. Changes in DU burden while receiving drug in the open-label study were compared with changes in DU burden at Time B by a paired Student t test.



Fifty-one patients from 9 clinical sites were included for analysis. DU burden increased significantly from baseline (mean 0.47) to Time A (mean 2.1, p = 0.002, n = 23) and Time B (mean 1.45, p = 0.013, n = 30). Total DU burden decreased during oral treprostinil exposure (mean change -0.6) and then increased by Time B (mean change 1.05, p = 0.0027 for comparison, n = 30). In the year after drug withdrawal, many patients required vasodilator therapy and pain medications. Three patients were hospitalized for complications from DU, and 4 patients required surgery for DU.



Total DU burden increased significantly after discontinuation of oral treprostinil. These data provide supportive evidence of a beneficial effect of oral treprostinil for the vascular complications of SSc and suggest that further study is warranted.
From the Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland; University of Michigan, Ann Arbor, Michigan; Cleveland Clinic, Cleveland, Ohio; Medical College of Wisconsin, Milwaukee, Wisconsin; University of Utah, Salt Lake City, Utah; New York University (NYU) Langone Medical Center, Lake Success; Hospital for Special Surgery, New York, New York; Benaroya Research Institute at Virginia Mason, Seattle, Washington; Georgetown University, Washington, DC; University of North Carolina at Chapel Hill, Chapel Hill; United Therapeutics Corporation, Research Triangle Park, North Carolina, USA.A.A. Shah, MD, MHS, Assistant Professor of Medicine, Director of Clinical and Translational Research, Johns Hopkins Scleroderma Center, Division of Rheumatology, Johns Hopkins University School of Medicine; E. Schiopu, MD, Assistant Professor of Internal Medicine, University of Michigan; S. Chatterjee, MD, Associate Professor of Medicine, Cleveland Clinic; M.E. Csuka, MD, Professor of Medicine, Medical College of Wisconsin; T. Frech, MD, Associate Professor of Medicine, University of Utah; A. Goldberg, MD, Clinical Assistant Professor, NYU Langone Medical Center; R. Spiera, MD, Professor of Clinical Medicine, Hospital for Special Surgery; S.L. Peng, MD, PhD, Vice President, Clinical Development, Benaroya Research Institute at Virginia Mason; R.J. McBride, DrPH, Student, University of North Carolina at Chapel Hill; J.M. Cleveland, MS, Director, Biostatistics, United Therapeutics Corp.; V. Steen, MD, Professor of Medicine, Georgetown University. Ami.Shah@jhmi.edu.
Ami A
AA
Shah
From the Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland; University of Michigan, Ann Arbor, Michigan; Cleveland Clinic, Cleveland, Ohio; Medical College of Wisconsin, Milwaukee, Wisconsin; University of Utah, Salt Lake City, Utah; New York University (NYU) Langone Medical Center, Lake Success; Hospital for Special Surgery, New York, New York; Benaroya Research Institute at Virginia Mason, Seattle, Washington; Georgetown University, Washington, DC; University of North Carolina at Chapel Hill, Chapel Hill; United Therapeutics Corporation, Research Triangle Park, North Carolina, USA.A.A. Shah, MD, MHS, Assistant Professor of Medicine, Director of Clinical and Translational Research, Johns Hopkins Scleroderma Center, Division of Rheumatology, Johns Hopkins University School of Medicine; E. Schiopu, MD, Assistant Professor of Internal Medicine, University of Michigan; S. Chatterjee, MD, Associate Professor of Medicine, Cleveland Clinic; M.E. Csuka, MD, Professor of Medicine, Medical College of Wisconsin; T. Frech, MD, Associate Professor of Medicine, University of Utah; A. Goldberg, MD, Clinical Assistant Professor, NYU Langone Medical Center; R. Spiera, MD, Professor of Clinical Medicine, Hospital for Special Surgery; S.L. Peng, MD, PhD, Vice President, Clinical Development, Benaroya Research Institute at Virginia Mason; R.J. McBride, DrPH, Student, University of North Carolina at Chapel Hill; J.M. Cleveland, MS, Director, Biostatistics, United Therapeutics Corp.; V. Steen, MD, Professor of Medicine, Georgetown University.
Elena
E
Schiopu
From the Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland; University of Michigan, Ann Arbor, Michigan; Cleveland Clinic, Cleveland, Ohio; Medical College of Wisconsin, Milwaukee, Wisconsin; University of Utah, Salt Lake City, Utah; New York University (NYU) Langone Medical Center, Lake Success; Hospital for Special Surgery, New York, New York; Benaroya Research Institute at Virginia Mason, Seattle, Washington; Georgetown University, Washington, DC; University of North Carolina at Chapel Hill, Chapel Hill; United Therapeutics Corporation, Research Triangle Park, North Carolina, USA.A.A. Shah, MD, MHS, Assistant Professor of Medicine, Director of Clinical and Translational Research, Johns Hopkins Scleroderma Center, Division of Rheumatology, Johns Hopkins University School of Medicine; E. Schiopu, MD, Assistant Professor of Internal Medicine, University of Michigan; S. Chatterjee, MD, Associate Professor of Medicine, Cleveland Clinic; M.E. Csuka, MD, Professor of Medicine, Medical College of Wisconsin; T. Frech, MD, Associate Professor of Medicine, University of Utah; A. Goldberg, MD, Clinical Assistant Professor, NYU Langone Medical Center; R. Spiera, MD, Professor of Clinical Medicine, Hospital for Special Surgery; S.L. Peng, MD, PhD, Vice President, Clinical Development, Benaroya Research Institute at Virginia Mason; R.J. McBride, DrPH, Student, University of North Carolina at Chapel Hill; J.M. Cleveland, MS, Director, Biostatistics, United Therapeutics Corp.; V. Steen, MD, Professor of Medicine, Georgetown University.
Soumya
S
Chatterjee
From the Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland; University of Michigan, Ann Arbor, Michigan; Cleveland Clinic, Cleveland, Ohio; Medical College of Wisconsin, Milwaukee, Wisconsin; University of Utah, Salt Lake City, Utah; New York University (NYU) Langone Medical Center, Lake Success; Hospital for Special Surgery, New York, New York; Benaroya Research Institute at Virginia Mason, Seattle, Washington; Georgetown University, Washington, DC; University of North Carolina at Chapel Hill, Chapel Hill; United Therapeutics Corporation, Research Triangle Park, North Carolina, USA.A.A. Shah, MD, MHS, Assistant Professor of Medicine, Director of Clinical and Translational Research, Johns Hopkins Scleroderma Center, Division of Rheumatology, Johns Hopkins University School of Medicine; E. Schiopu, MD, Assistant Professor of Internal Medicine, University of Michigan; S. Chatterjee, MD, Associate Professor of Medicine, Cleveland Clinic; M.E. Csuka, MD, Professor of Medicine, Medical College of Wisconsin; T. Frech, MD, Associate Professor of Medicine, University of Utah; A. Goldberg, MD, Clinical Assistant Professor, NYU Langone Medical Center; R. Spiera, MD, Professor of Clinical Medicine, Hospital for Special Surgery; S.L. Peng, MD, PhD, Vice President, Clinical Development, Benaroya Research Institute at Virginia Mason; R.J. McBride, DrPH, Student, University of North Carolina at Chapel Hill; J.M. Cleveland, MS, Director, Biostatistics, United Therapeutics Corp.; V. Steen, MD, Professor of Medicine, Georgetown University.
Mary Ellen
ME
Csuka
From the Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland; University of Michigan, Ann Arbor, Michigan; Cleveland Clinic, Cleveland, Ohio; Medical College of Wisconsin, Milwaukee, Wisconsin; University of Utah, Salt Lake City, Utah; New York University (NYU) Langone Medical Center, Lake Success; Hospital for Special Surgery, New York, New York; Benaroya Research Institute at Virginia Mason, Seattle, Washington; Georgetown University, Washington, DC; University of North Carolina at Chapel Hill, Chapel Hill; United Therapeutics Corporation, Research Triangle Park, North Carolina, USA.A.A. Shah, MD, MHS, Assistant Professor of Medicine, Director of Clinical and Translational Research, Johns Hopkins Scleroderma Center, Division of Rheumatology, Johns Hopkins University School of Medicine; E. Schiopu, MD, Assistant Professor of Internal Medicine, University of Michigan; S. Chatterjee, MD, Associate Professor of Medicine, Cleveland Clinic; M.E. Csuka, MD, Professor of Medicine, Medical College of Wisconsin; T. Frech, MD, Associate Professor of Medicine, University of Utah; A. Goldberg, MD, Clinical Assistant Professor, NYU Langone Medical Center; R. Spiera, MD, Professor of Clinical Medicine, Hospital for Special Surgery; S.L. Peng, MD, PhD, Vice President, Clinical Development, Benaroya Research Institute at Virginia Mason; R.J. McBride, DrPH, Student, University of North Carolina at Chapel Hill; J.M. Cleveland, MS, Director, Biostatistics, United Therapeutics Corp.; V. Steen, MD, Professor of Medicine, Georgetown University.
Tracy
T
Frech
From the Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland; University of Michigan, Ann Arbor, Michigan; Cleveland Clinic, Cleveland, Ohio; Medical College of Wisconsin, Milwaukee, Wisconsin; University of Utah, Salt Lake City, Utah; New York University (NYU) Langone Medical Center, Lake Success; Hospital for Special Surgery, New York, New York; Benaroya Research Institute at Virginia Mason, Seattle, Washington; Georgetown University, Washington, DC; University of North Carolina at Chapel Hill, Chapel Hill; United Therapeutics Corporation, Research Triangle Park, North Carolina, USA.A.A. Shah, MD, MHS, Assistant Professor of Medicine, Director of Clinical and Translational Research, Johns Hopkins Scleroderma Center, Division of Rheumatology, Johns Hopkins University School of Medicine; E. Schiopu, MD, Assistant Professor of Internal Medicine, University of Michigan; S. Chatterjee, MD, Associate Professor of Medicine, Cleveland Clinic; M.E. Csuka, MD, Professor of Medicine, Medical College of Wisconsin; T. Frech, MD, Associate Professor of Medicine, University of Utah; A. Goldberg, MD, Clinical Assistant Professor, NYU Langone Medical Center; R. Spiera, MD, Professor of Clinical Medicine, Hospital for Special Surgery; S.L. Peng, MD, PhD, Vice President, Clinical Development, Benaroya Research Institute at Virginia Mason; R.J. McBride, DrPH, Student, University of North Carolina at Chapel Hill; J.M. Cleveland, MS, Director, Biostatistics, United Therapeutics Corp.; V. Steen, MD, Professor of Medicine, Georgetown University.
Avram
A
Goldberg
From the Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland; University of Michigan, Ann Arbor, Michigan; Cleveland Clinic, Cleveland, Ohio; Medical College of Wisconsin, Milwaukee, Wisconsin; University of Utah, Salt Lake City, Utah; New York University (NYU) Langone Medical Center, Lake Success; Hospital for Special Surgery, New York, New York; Benaroya Research Institute at Virginia Mason, Seattle, Washington; Georgetown University, Washington, DC; University of North Carolina at Chapel Hill, Chapel Hill; United Therapeutics Corporation, Research Triangle Park, North Carolina, USA.A.A. Shah, MD, MHS, Assistant Professor of Medicine, Director of Clinical and Translational Research, Johns Hopkins Scleroderma Center, Division of Rheumatology, Johns Hopkins University School of Medicine; E. Schiopu, MD, Assistant Professor of Internal Medicine, University of Michigan; S. Chatterjee, MD, Associate Professor of Medicine, Cleveland Clinic; M.E. Csuka, MD, Professor of Medicine, Medical College of Wisconsin; T. Frech, MD, Associate Professor of Medicine, University of Utah; A. Goldberg, MD, Clinical Assistant Professor, NYU Langone Medical Center; R. Spiera, MD, Professor of Clinical Medicine, Hospital for Special Surgery; S.L. Peng, MD, PhD, Vice President, Clinical Development, Benaroya Research Institute at Virginia Mason; R.J. McBride, DrPH, Student, University of North Carolina at Chapel Hill; J.M. Cleveland, MS, Director, Biostatistics, United Therapeutics Corp.; V. Steen, MD, Professor of Medicine, Georgetown University.
Robert
R
Spiera
From the Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland; University of Michigan, Ann Arbor, Michigan; Cleveland Clinic, Cleveland, Ohio; Medical College of Wisconsin, Milwaukee, Wisconsin; University of Utah, Salt Lake City, Utah; New York University (NYU) Langone Medical Center, Lake Success; Hospital for Special Surgery, New York, New York; Benaroya Research Institute at Virginia Mason, Seattle, Washington; Georgetown University, Washington, DC; University of North Carolina at Chapel Hill, Chapel Hill; United Therapeutics Corporation, Research Triangle Park, North Carolina, USA.A.A. Shah, MD, MHS, Assistant Professor of Medicine, Director of Clinical and Translational Research, Johns Hopkins Scleroderma Center, Division of Rheumatology, Johns Hopkins University School of Medicine; E. Schiopu, MD, Assistant Professor of Internal Medicine, University of Michigan; S. Chatterjee, MD, Associate Professor of Medicine, Cleveland Clinic; M.E. Csuka, MD, Professor of Medicine, Medical College of Wisconsin; T. Frech, MD, Associate Professor of Medicine, University of Utah; A. Goldberg, MD, Clinical Assistant Professor, NYU Langone Medical Center; R. Spiera, MD, Professor of Clinical Medicine, Hospital for Special Surgery; S.L. Peng, MD, PhD, Vice President, Clinical Development, Benaroya Research Institute at Virginia Mason; R.J. McBride, DrPH, Student, University of North Carolina at Chapel Hill; J.M. Cleveland, MS, Director, Biostatistics, United Therapeutics Corp.; V. Steen, MD, Professor of Medicine, Georgetown University.
Stanford L
SL
Peng
From the Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland; University of Michigan, Ann Arbor, Michigan; Cleveland Clinic, Cleveland, Ohio; Medical College of Wisconsin, Milwaukee, Wisconsin; University of Utah, Salt Lake City, Utah; New York University (NYU) Langone Medical Center, Lake Success; Hospital for Special Surgery, New York, New York; Benaroya Research Institute at Virginia Mason, Seattle, Washington; Georgetown University, Washington, DC; University of North Carolina at Chapel Hill, Chapel Hill; United Therapeutics Corporation, Research Triangle Park, North Carolina, USA.A.A. Shah, MD, MHS, Assistant Professor of Medicine, Director of Clinical and Translational Research, Johns Hopkins Scleroderma Center, Division of Rheumatology, Johns Hopkins University School of Medicine; E. Schiopu, MD, Assistant Professor of Internal Medicine, University of Michigan; S. Chatterjee, MD, Associate Professor of Medicine, Cleveland Clinic; M.E. Csuka, MD, Professor of Medicine, Medical College of Wisconsin; T. Frech, MD, Associate Professor of Medicine, University of Utah; A. Goldberg, MD, Clinical Assistant Professor, NYU Langone Medical Center; R. Spiera, MD, Professor of Clinical Medicine, Hospital for Special Surgery; S.L. Peng, MD, PhD, Vice President, Clinical Development, Benaroya Research Institute at Virginia Mason; R.J. McBride, DrPH, Student, University of North Carolina at Chapel Hill; J.M. Cleveland, MS, Director, Biostatistics, United Therapeutics Corp.; V. Steen, MD, Professor of Medicine, Georgetown University.
Ryan J
RJ
McBride
From the Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland; University of Michigan, Ann Arbor, Michigan; Cleveland Clinic, Cleveland, Ohio; Medical College of Wisconsin, Milwaukee, Wisconsin; University of Utah, Salt Lake City, Utah; New York University (NYU) Langone Medical Center, Lake Success; Hospital for Special Surgery, New York, New York; Benaroya Research Institute at Virginia Mason, Seattle, Washington; Georgetown University, Washington, DC; University of North Carolina at Chapel Hill, Chapel Hill; United Therapeutics Corporation, Research Triangle Park, North Carolina, USA.A.A. Shah, MD, MHS, Assistant Professor of Medicine, Director of Clinical and Translational Research, Johns Hopkins Scleroderma Center, Division of Rheumatology, Johns Hopkins University School of Medicine; E. Schiopu, MD, Assistant Professor of Internal Medicine, University of Michigan; S. Chatterjee, MD, Associate Professor of Medicine, Cleveland Clinic; M.E. Csuka, MD, Professor of Medicine, Medical College of Wisconsin; T. Frech, MD, Associate Professor of Medicine, University of Utah; A. Goldberg, MD, Clinical Assistant Professor, NYU Langone Medical Center; R. Spiera, MD, Professor of Clinical Medicine, Hospital for Special Surgery; S.L. Peng, MD, PhD, Vice President, Clinical Development, Benaroya Research Institute at Virginia Mason; R.J. McBride, DrPH, Student, University of North Carolina at Chapel Hill; J.M. Cleveland, MS, Director, Biostatistics, United Therapeutics Corp.; V. Steen, MD, Professor of Medicine, Georgetown University.
Jody M
JM
Cleveland
From the Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland; University of Michigan, Ann Arbor, Michigan; Cleveland Clinic, Cleveland, Ohio; Medical College of Wisconsin, Milwaukee, Wisconsin; University of Utah, Salt Lake City, Utah; New York University (NYU) Langone Medical Center, Lake Success; Hospital for Special Surgery, New York, New York; Benaroya Research Institute at Virginia Mason, Seattle, Washington; Georgetown University, Washington, DC; University of North Carolina at Chapel Hill, Chapel Hill; United Therapeutics Corporation, Research Triangle Park, North Carolina, USA.A.A. Shah, MD, MHS, Assistant Professor of Medicine, Director of Clinical and Translational Research, Johns Hopkins Scleroderma Center, Division of Rheumatology, Johns Hopkins University School of Medicine; E. Schiopu, MD, Assistant Professor of Internal Medicine, University of Michigan; S. Chatterjee, MD, Associate Professor of Medicine, Cleveland Clinic; M.E. Csuka, MD, Professor of Medicine, Medical College of Wisconsin; T. Frech, MD, Associate Professor of Medicine, University of Utah; A. Goldberg, MD, Clinical Assistant Professor, NYU Langone Medical Center; R. Spiera, MD, Professor of Clinical Medicine, Hospital for Special Surgery; S.L. Peng, MD, PhD, Vice President, Clinical Development, Benaroya Research Institute at Virginia Mason; R.J. McBride, DrPH, Student, University of North Carolina at Chapel Hill; J.M. Cleveland, MS, Director, Biostatistics, United Therapeutics Corp.; V. Steen, MD, Professor of Medicine, Georgetown University.
Virginia
V
Steen
D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005385:Fingers / Q000098:blood supply*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011928:Raynaud Disease / Q000188:drug therapy* / Q000209:etiology; D012008:Recurrence; D012189:Retrospective Studies; D012595:Scleroderma, Systemic / Q000150:complications*; D012883:Skin Ulcer / Q000188:drug therapy* / Q000209:etiology
D000959:Antihypertensive Agents; D011464:Epoprostenol; C427248:treprostinil
DIGITAL ULCERS; RAYNAUD PHENOMENON; SYSTEMIC SCLEROSIS; TREPROSTINIL DIOLAMINE