Recombinant Human Relaxin in the Treatment of Scleroderma

A Randomized, Double-Blind, Placebo-Controlled Trial

  1. James R. Seibold, MD;
  2. Joseph H. Korn, MD;
  3. Robert Simms, MD;
  4. Phillip J. Clements, MD, MPH;
  5. Larry W. Moreland, MD;
  6. Maureen D. Mayes, MD, MPH;
  7. Daniel E. Furst, MD;
  8. Naomi Rothfield, MD;
  9. Virginia Steen, MD;
  10. Michael Weisman, MD;
  11. David Collier, MD;
  12. Fredrick M. Wigley, MD;
  13. Peter A. Merkel, MD, MPH;
  14. Mary Ellen Csuka, MD;
  15. Vivien Hsu, MD;
  16. Susan Rocco, BS;
  17. Mark Erikson, BS;
  18. John Hannigan, MS;
  19. W. Scott Harkonen, MD; and
  20. Martin E. Sanders, MD
  1. From University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick, New Jersey; Boston University Medical Center and Massachusetts General Hospital, Boston, Massachusetts; University of California, Los Angeles, School of Medicine, Los Angeles, California; University of Alabama at Birmingham, Birmingham, Alabama; Wayne State University, Detroit, Michigan; Virginia Mason Research Center, Seattle, Washington; University of Connecticut Health Center, Farmington, Connecticut; Georgetown University Medical Center, Washington, D.C.; University of California, San Diego, San Diego, California; University of Colorado Health Sciences Center, Denver, Colorado; Johns Hopkins Bayview Medical Center, Baltimore, Maryland; Medical College of Wisconsin, Milwaukee, Wisconsin; and Connetics Corp., Palo Alto, California.

    Abstract

    Background: Relaxin is a pregnancy-related hormone that has tissue remodeling and antifibrotic effects. Systemic sclerosis (scleroderma) is characterized by fibrosis of the skin, vasculature, and internal organs.

    Objective: To assess the efficacy, safety, and dose–response effect of recombinant human relaxin in patients with scleroderma.

    Design: Multicenter, parallel-group, randomized, double-blind, placebo-controlled trial.

    Setting: Academic referral centers.

    Patients: 68 patients who had had stable, diffuse scleroderma (moderate to severe) for less than 5 years.

    Intervention: Recombinant human relaxin, 25 or 100 µg/kg of body weight per day, or placebo administered by continuous subcutaneous infusion over 24 weeks.

    Measurements: Modified Rodnan skin score was the primary efficacy measure. Secondary measurements were pulmonary function, the Health Assessment Questionnaire, and other measures of scleroderma that reflected fibrosis.

    Results: Patients who received 25 µg/kg of recombinant human relaxin per day had significantly lower skin scores than those who received placebo (mean change, −3.6 at 4 weeks [P = 0.021], −7.5 at 12 weeks [P < 0.001], and −8.7 at 24 weeks [P = 0.040]). Similar trends were noted in other outcome measures, including forced vital capacity, measures of oral aperture and hand extension, functional status, and global assessment. Patients who received 100 µg/kg of relaxin per day did not differ from those who received placebo. Drug-related adverse events included menometrorrhagia, reversible anemia, and complications of the subcutaneous drug administration system (site irritation and local infection).

    Conclusions: Twenty-four weeks of recombinant human relaxin, 25 µg/kg per day, is associated with reduced skin thickening, improved mobility, and improved function in patients with moderate to severe diffuse scleroderma.

    Article and Author Information

    • Acknowledgments: The authors thank the following persons for their generous contributions to this work: Deborah McCloskey (Coordinator), University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School; Raza Jafry, MD (Subinvestigator), and Mona Jaboin and Melynn Nuite (Coordinators), Boston University Medical Center; the staff of the General Clinical Research Center at Boston University Medical Center; Rita Jepson (Coordinator), University of California, Los Angeles, School of Medicine; Tina Parkhill (Coordinator), University of Alabama at Birmingham; Massoud Soleimani, MD (Subinvestigator), and Zora Injic (Coordinator), Wayne State University; Kristen Neely (Coordinator), Virginia Mason Research Center; Dolores Vasquez-Abad, MD (Subinvestigator), and Fran Ingenito (Coordinator), University of Connecticut Health Center; Mark Brodeur (Coordinator), Georgetown University Medical Center; Paul DeMarco (Subinvestigator) and Denise Mathes (Coordinator), University of California, San Diego, Division of Rheumatology; Jann Wagner (Coordinator), University of Colorado Health Sciences Center; Barbara White, MD, and Alan Matsumoto, MD (Subinvestigators), and Gwen Leatherman (Coordinator), Johns Hopkins Bayview Medical Center; Richard P. Polisson, MD, MHS, Andree Phillips, MD, and Karen Herlyn, MD (Subinvestigators), and Beatrice Mendez (Coordinator), Massachusetts General Hospital and the Mallinckrodt General Clinical Research Center at Massachusetts General Hospital; and Judi Himmel (Coordinator), Medical College of Wisconsin. They also thank Beverly Grove, Connetics Corp., for clinical services support, and all of the patients who volunteered to participate in the study.

    • Grant Support: By Connetics Corp., Palo Alto, California.

    • Requests for Single Reprints: James R. Seibold, MD, Scleroderma Program, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, One Robert Wood Johnson Place, New Brunswick, NJ 08903-0019.

    • Requests To Purchase Bulk Reprints (minimum, 100 copies): the Reprints Coordinator; phone, 215-351-2657; e-mail, reprints{at}mail.acponline.org.

    • Current Author Addresses: Drs. Seibold and Hsu: University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, One Robert Wood Johnson Place, New Brunswick, NJ 08903-0019.

    • Drs. Korn and Simms: Boston University Medical Center, 80 East Concord Street, Boston, MA 02118.

    • Dr. Clements: University of California, Los Angeles, School of Medicine, Division of Rheumatology, 1000 Veteran Avenue, Room 32-59, Los Angeles, CA 90095-1670.

    • Dr. Moreland: University of Alabama at Birmingham, Division of Clinical Immunology and Rheumatology, 1717 Sixth Avenue South, Room 068, Birmingham, AL 35294-7201.

    • Dr. Mayes: Wayne State University, 4707 St. Antoine Boulevard, Detroit, MI 48201.

    • Dr. Furst: Virginia Mason Research Center, 1000 Seneca Street, Seattle, WA 98101.

    • Dr. Rothfield: University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1310.

    • Dr. Steen: Division of Rheumatology, Immunology, and Allergy, Georgetown University Medical Center, 3800 Reservoir Road, NW, LL Gorman Building, Washington, DC 20007-2197.

    • Dr. Weisman: Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite B131, Los Angeles, CA 90048.

    • Dr. Collier: University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Box E115, Denver, CO 80262.

    • Dr. Wigley: Johns Hopkins Bayview Medical Center, 5501 Hopkins Bayview Circle, JHAAC 3B.24, Baltimore, MD 21224.

    • Dr. Merkel: Boston University Medical Center, 80 East Concord Street, Boston, MA 02118.

    • Dr. Csuka: Medical College of Wisconsin, Division of Rheumatology, FMLH East 650, 9200 West Wisconsin Avenue, Milwaukee, WI 53226.

    • Ms. Rocco, Mr. Erikson, Mr. Hannigan, and Drs. Harkonen and Sanders: Connetics Corp., 3400 West Bayshore Road, Palo Alto, CA 94303.

    • Author Contributions: Conception and design: J.R. Seibold, R. Simms, P.J. Clements, M.D. Mayes, D.E. Furst, P.A. Merkel, S. Rocco, J. Hannigan, W.S. Harkonen, M.E. Sanders.

    • Analysis and interpretation of the data: J.R. Seibold, J.H. Korn, R. Simms, D.E. Furst, P.A. Merkel, S. Rocco, J. Hannigan, W.S. Harkonen, M.E. Sanders.

    • Drafting of the article: J.R. Seibold, F.M. Wigley, S. Rocco, J. Hannigan, M.E. Sanders.

    • Critical revision of the article for important intellectual content: J.R. Seibold, J.H. Korn, R. Simms, P.J. Clements, L.W. Moreland, M.D. Mayes, D.E. Furst, N.F. Rothfield, V. Steen, M. Weisman, F.M. Wigley, P.A. Merkel, M.E. Csuka, V. Hsu, S. Rocco, M. Erikson, J. Hannigan, M.E. Sanders.

    • Final approval of the article: J.R. Seibold, J.H. Korn, R. Simms, P.J. Clements, L.W. Moreland, M.D. Mayes, D.E. Furst, N.F. Rothfield, V. Steen, M. Weisman, D.H. Collier, F.M. Wigley, P.A. Merkel, M.E. Csuka, V. Hsu, S. Rocco, M. Erikson, M.E. Sanders.

    • Provision of study materials or patients: J.R. Seibold, J.H. Korn, R. Simms, P.J. Clements, L.W. Moreland, M.D. Mayes, D.E. Furst, N.F. Rothfield, V. Steen, M. Weisman, D.H. Collier, F.M. Wigley, P.A. Merkel, M.E. Csuka, V. Hsu.

    • Statistical expertise: J. Hannigan.

    • Obtaining of funding: M.E. Sanders.

    • Administrative, technical, or logistic support: S. Rocco, M. Erikson, M.E. Sanders.

    • Collection and assembly of data: J.R. Seibold, R. Simms, F.M. Wigley, P.A. Merkel, S. Rocco.

    Summary for Patients

    • Summaries for Patients:Using a Pregnancy-Related Hormone, Relaxin, to Treat Scleroderma Ann Intern Med June 6, 2000 132:871
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    1. Ann Intern Med June 6, 2000 vol. 132 no. 11 871-879
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