title: Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial.
abstract: OBJECTIVE
  Ischaemic digital ulcers (DUs) are common in patients with systemic sclerosis (SSc) and are a cause of disease-related morbidity. In an earlier trial, treatment with bosentan, an oral endothelin receptor antagonist, reduced the occurrence of new DUs by 48%. The present study (RAPIDS-2, for 'RAndomized, double-blind, Placebo-controlled study with bosentan on healing and prevention of Ischemic Digital ulcers in patients with systemic Sclerosis') was conducted to more fully evaluate the effects of bosentan treatment on DUs associated with SSc.
  
  
  METHODS
  This double-blind, placebo-controlled trial conducted at 41 centres in Europe and North America randomised 188 patients with SSc with at least 1 active DU ('cardinal ulcer') to bosentan 62.5 mg twice daily for 4 weeks and 125 mg twice daily thereafter for 20 weeks (n=98) or matching placebo (n=90; total 24 weeks). The two primary end points were the number of new DUs and the time to healing of the cardinal ulcer. Secondary end points included pain, disability and safety.
  
  
  RESULTS
  Over 24 weeks, bosentan treatment was associated with a 30% reduction in the number of new DUs compared with placebo (mean ± standard error: 1.9±0.2 vs 2.7±0.3 new ulcers; p=0.04). This effect was greater in patients who entered the trial with more DUs. There was no difference between treatments in healing rate of the cardinal ulcer or secondary end points of pain and disability. Peripheral oedema and elevated aminotransferases were associated with bosentan treatment.
  
  
  CONCLUSIONS
  Bosentan treatment reduced the occurrence of new DUs in patients with SSc but had no effect on DU healing. Bosentan was well tolerated and may be a useful adjunct in the management of patients with SSc with recurrent DUs.
authors.affiliation: Department of Biomedicine, Division of Rheumatology, DENOTHE Center, University of Florence, Florence, Italy. cerinic@unifi.it
authors.forename: Marco
authors.initials: M
authors.lastname: Matucci-Cerinic
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Denton
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Furst
authors.forename: Maureen D
authors.initials: MD
authors.lastname: Mayes
authors.forename: Vivien M
authors.initials: VM
authors.lastname: Hsu
authors.forename: Patrick
authors.initials: P
authors.lastname: Carpentier
authors.forename: Fredrick M
authors.initials: FM
authors.lastname: Wigley
authors.forename: Carol M
authors.initials: CM
authors.lastname: Black
authors.forename: Barri J
authors.initials: BJ
authors.lastname: Fessler
authors.forename: Peter A
authors.initials: PA
authors.lastname: Merkel
authors.forename: Janet E
authors.initials: JE
authors.lastname: Pope
authors.forename: Nadera J
authors.initials: NJ
authors.lastname: Sweiss
authors.forename: Mittie K
authors.initials: MK
authors.lastname: Doyle
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hellmich
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Medsger
authors.forename: Adele
authors.initials: A
authors.lastname: Morganti
authors.forename: Fabrice
authors.initials: F
authors.lastname: Kramer
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Korn
authors.forename: James R
authors.initials: JR
authors.lastname: Seibold
mesh_terms: D000328:Adult; D000077300:Bosentan; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D065128:Endothelin Receptor Antagonists; D005260:Female; D005385:Fingers / Q000098:blood supply*; D006229:Hand Dermatoses / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D008297:Male; D008875:Middle Aged; D012595:Scleroderma, Systemic / Q000150:complications*; D012883:Skin Ulcer / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014945:Wound Healing
chemical_list: D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D000077300:Bosentan
references.citation: Arthritis Rheum. 2004 Dec;50(12):3985-93
references.pmid: 15593188
references.citation: J Rheumatol. 2007 Dec;34(12):2423-30
references.pmid: 17985402
references.citation: Clin Rev Allergy Immunol. 2009 Jun;36(2-3):150-75
references.pmid: 19067252
references.citation: J Rheumatol. 2008 Sep;35(9):1801-8
references.pmid: 18709692
references.citation: Medicine (Baltimore). 2002 Mar;81(2):139-53
references.pmid: 11889413
references.citation: Rheumatology (Oxford). 2006 Dec;45(12):1573
references.pmid: 17043046
references.citation: N Engl J Med. 2002 Mar 21;346(12):896-903
references.pmid: 11907289
references.citation: BMJ. 1989 Mar 4;298(6673):561-4
references.pmid: 2467711
references.citation: Ann Rheum Dis. 2007 Jun;66(6):754-63
references.pmid: 17234652
references.citation: J Rheumatol. 1992 Sep;19(9):1407-14
references.pmid: 1279170
references.citation: Rheumatology (Oxford). 2009 Jun;48 Suppl 3:iii19-24
references.pmid: 19487218
references.citation: Arthritis Rheum. 1980 May;23(5):581-90
references.pmid: 7378088
references.citation: Arthritis Rheum. 2003 May;48(5):1190-9
references.pmid: 12746891
references.citation: Ann Rheum Dis. 2006 Oct;65(10):1336-40
references.pmid: 16793845
references.citation: Arthritis Rheum. 1997 Nov;40(11):1984-91
references.pmid: 9365087
references.citation: Arthritis Rheum. 2002 Sep;46(9):2410-20
references.pmid: 12355489
references.citation: Circulation. 2006 Jul 4;114(1):48-54
references.pmid: 16801459
references.citation: Ann Rheum Dis. 2004 Sep;63(9):1009-14
references.pmid: 15308510
references.citation: Ann Intern Med. 2000 Mar 21;132(6):425-34
references.pmid: 10733441
references.citation: Ann N Y Acad Sci. 2007 Sep;1110:448-54
references.pmid: 17911460