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Figure 1.
Flow of Study Participants for DUAL-1
Flow of Study Participants for DUAL-1

aBecause multiple exclusions may apply to individual patients, subcategories will not sum to the total.

bCalculated as weight in kilograms divided by height in meters squared.

cBecause treatment could extend beyond week 16, and because premature discontinuation of treatment could occur after week 16, values will not sum to the number randomized for each group.

End of study, for all patients, was defined as the time when the last patient completed the week-16 visit. Within 7 days afterwards, patients completed the end of treatment visit, and within 30 days, they underwent the end-of-study visit. Patients who prematurely discontinued study drug in period 1 (randomization to week 16) or period 2 (after week 16 to end of study) completed the end-of-treatment visit within 7 days of the last administered dose; these patients (upon consent) continued to undergo follow-up every 3 months until the end of study. Adverse events were monitored throughout the study. The term completed study refers to continued participation until the end of study. AST indicates aspartate aminotransferase; ALT, alanine aminotransferase; ULN, upper limit of normal; BMI, body mass index; ITT, intention-to-treat.

Figure 2.
Flow of Study Participants for DUAL-2
Flow of Study Participants for DUAL-2

aBecause multiple exclusions may apply to individual patients, subcategories will not sum to the total.

bCalculated as weight in kilograms divided by height in meters squared.

cBecause treatment could extend beyond week 16, and because premature discontinuation of treatment could occur after week 16, values will not sum to the number randomized for each group.

dIndicates the independent data monitoring committee’s early termination of the trial.

End of study, for all patients, was defined as the time when the last patient completed the week-16 visit. Within 7 days afterwards, patients completed the end of treatment visit, and within 30 days, they underwent the end-of-study visit. Patients who prematurely discontinued study drug in period 1 (randomization to week 16) or period 2 (after week 16 to end of study) completed the end-of-treatment visit within 7 days of the last administered dose; these patients (upon consent) continued to undergo follow-up every 3 months until the end of study. Adverse events were monitored throughout the study. The term completed study refers to continued participation until the end of study. BMI indicates body mass index; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ULN, upper limit of normal; ITT, intention-to-treat.

Figure 3.
Time to First Digital Ulcer Complication Up to End of Treatment in DUAL-1 and DUAL-2
Time to First Digital Ulcer Complication Up to End of Treatment in DUAL-1 and DUAL-2

Digital ulcer complications were defined as any of the following (resulting from digital ulcer worsening): (1) critical ischemic crisis necessitating hospitalization; (2) gangrene, (auto) amputation; (3) failure of conservative management: surgical and chemical sympathectomy, vascular reconstructions, or any unplanned surgery in the management of hand systemic sclerosis manifestations; (4) use of parenteral prostanoids; (5) use of endothelin receptor antagonists; (6) required class 2, 3, or 4 narcotics or a >50%-increase in the existing dose compared with baseline; (7) initiation of systemic antibiotics for the treatment of infection attributed to digital ulcers.

A, Treatment effect for macitentan, 3 mg vs placebo: hazard ratio (HR), 0.77 (95% CI, 0.38-1.57); log-rank P = .47; for macitentan, 10 mg vs placebo: HR, 1.12 (95% CI, 0.58-2.15); log-rank P = .74. The median duration (Q1, Q3) of treatment exposure was 41.4 weeks (22.1, 59.9) in the macitentan, 3-mg group, 37.4 weeks (18.3, 63.5) in the macitentan, 10-mg group, and 43.1 weeks (22.9, 65.1) in the placebo group.

B, Treatment effect of macitentan, 3 mg vs placebo: HR, 1.19 (95% CI, 0.61-2.33); log-rank P = .62; for macitentan, 10 mg vs placebo: HR, 1.08 (95% CI, 0.4-2.15); log-rank P = .84. The median duration (Q1, Q3) of treatment exposure was 40.5 weeks (17.7, 61.7) in the macitentan, 3-mg group, 38.6 weeks (15.0, 62.1) in the macitentan, 10-mg group, and 37.4 weeks (17.0, 58.1) in the placebo group.

Table 1.  
Patient and Disease Characteristics at Baseline
Patient and Disease Characteristics at Baseline
Table 2.  
Effect of Macitentan on the Incidence of Digital Ulcers to Week 16 in DUAL-1 and DUAL-2
Effect of Macitentan on the Incidence of Digital Ulcers to Week 16 in DUAL-1 and DUAL-2
Table 3.  
Effect of Macitentan at Week 16 on Selected Outcomes in DUAL-1 and DUAL-2
Effect of Macitentan at Week 16 on Selected Outcomes in DUAL-1 and DUAL-2
1.
Matucci-Cerinic  M, Kahaleh  B, Wigley  FM.  Review: evidence that systemic sclerosis is a vascular disease. Arthritis Rheum. 2013;65(8):1953-1962.
PubMedArticle
2.
Guillevin  L, Hunsche  E, Denton  CP,  et al.  Functional impairment of systemic scleroderma patients with digital ulcerations. Clin Exp Rheumatol. 2013;31(2)(suppl 76):71-80.
PubMed
3.
Walker  UA, Tyndall  A, Czirják  L,  et al.  Clinical risk assessment of organ manifestations in systemic sclerosis. Ann Rheum Dis. 2007;66(6):754-763.
PubMedArticle
4.
Steen  V, Denton  CP, Pope  JE, Matucci-Cerinic  M.  Digital ulcers: overt vascular disease in systemic sclerosis. Rheumatology (Oxford). 2009;48(suppl 3):iii19-iii24.
PubMedArticle
5.
Hachulla  E, Clerson  P, Launay  D,  et al.  Natural history of ischemic digital ulcers in systemic sclerosis. J Rheumatol. 2007;34(12):2423-2430.
PubMed
6.
Amanzi  L, Braschi  F, Fiori  G,  et al.  Digital ulcers in scleroderma. Rheumatology (Oxford). 2010;49(7):1374-1382.
PubMedArticle
7.
Matucci-Cerinic  M, Seibold  JR.  Digital ulcers and outcomes assessment in scleroderma. Rheumatology (Oxford). 2008;47(suppl 5):v46-v47.
PubMedArticle
8.
Distler  JH, Allanore  Y, Avouac  J,  et al.  EULAR Scleroderma Trials and Research group statement and recommendations on endothelial precursor cells. Ann Rheum Dis. 2009;68(2):163-168.
PubMedArticle
9.
Kim  HS, Park  MK, Kim  HY, Park  SH.  Capillary dimension measured by computer-based digitalized image correlated with plasma endothelin-1 levels in patients with systemic sclerosis. Clin Rheumatol. 2010;29(3):247-254.
PubMedArticle
10.
Knock  GA, Terenghi  G, Bunker  CB, Bull  HA, Dowd  PM, Polak  JM.  Characterization of endothelin-binding sites in human skin and their regulation in primary Raynaud’s phenomenon and systemic sclerosis. J Invest Dermatol. 1993;101(1):73-78.
PubMedArticle
11.
Korn  JH, Mayes  M, Matucci Cerinic  M,  et al.  Digital ulcers in systemic sclerosis. Arthritis Rheum. 2004;50(12):3985-3993.
PubMedArticle
12.
Matucci-Cerinic  M, Denton  CP, Furst  DE,  et al.  Bosentan treatment of digital ulcers related to systemic sclerosis. Ann Rheum Dis. 2011;70(1):32-38.
PubMedArticle
13.
Gatfield  J, Mueller Grandjean  C, Sasse  T, Clozel  M, Nayler  O.  Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells. PLoS One. 2012;7(10):e47662.
PubMedArticle
14.
Iglarz  M, Landskroner  K, Bauer  Y,  et al.  Comparison of macitentan and bosentan on right ventricular remodeling in a rat model of non-vasoreactive pulmonary hypertension. J Cardiovasc Pharmacol. 2015;66(5):457-467.
PubMedArticle
15.
Masi  A, Rodnan  GP, Medsger  TA  Jr,  et al.  Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum. 1980;23(5):581-590.
PubMedArticle
16.
LeRoy  EC, Black  C, Fleischmajer  R,  et al.  Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15(2):202-205.
PubMed
17.
Herrick  AL, Roberts  C, Tracey  A,  et al.  Lack of agreement between rheumatologists in defining digital ulceration in systemic sclerosis. Arthritis Rheum. 2009;60(3):878-882.
PubMedArticle
18.
Steen  VD, Medsger  TA  Jr.  The value of the Health Assessment Questionnaire and special patient-generated scales to demonstrate change in systemic sclerosis patients over time. Arthritis Rheum. 1997;40(11):1984-1991.
PubMedArticle
19.
Bruce  B, Fries  JF.  The Stanford Health Assessment Questionnaire: a review of its history, issues, progress, and documentation. J Rheumatol. 2003;30(1):167-178.
PubMed
20.
Hilbe  J. Negative Binomial Regression. 2nd ed. New York, NY: Cambridge University Press; 2011.
21.
van Buuren  S.  Multiple imputation of discrete and continuous data by fully conditional specification. Stat Methods Med Res. 2007;16(3):219-242.
PubMedArticle
22.
Pulido  T, Adzerikho  I, Channick  RN,  et al.  SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809-818.
PubMedArticle
23.
Raghu  G, Million-Rousseau  R, Morganti  A,  et al.  Macitentan for the treatment of idiopathic pulmonary fibrosis. Eur Respir J. 2013;42(6):1622-1632.
PubMedArticle
24.
Kowal-Bielecka  O, Landewé  R, Avouac  J,  et al.  EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2009;68(5):620-628.
PubMedArticle
25.
Tingey  T, Shu  J, Smuczek  J, Pope  J.  Meta-analysis of healing and prevention of digital ulcers in systemic sclerosis. Arthritis Care Res (Hoboken). 2013;65(9):1460-1471.
PubMedArticle
26.
Hachulla  E, Hatron  PY, Carpentier  P,  et al.  Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis (published online May 20, 2015). Ann Rheum Dis. doi:10.1136/annrheumdis-2014-207001.
27.
Denton  CP, Krieg  T, Guillevin  L,  et al.  Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis. Ann Rheum Dis. 2012;71(5):718-721.
PubMedArticle
28.
Walker  KM, Pope  J, participating members of the Schleroderma Clinical Trials Consortium; Canadian Scleroderma Research Group.  Treatment of systemic sclerosis complications: what to use when first-line treatment fails. Semin Arthritis Rheum. 2012;42(1):42-55.
PubMedArticle
29.
Morelli  S, Ferri  C, Polettini  E,  et al.  Plasma endothelin-1 levels, pulmonary hypertension, and lung fibrosis in patients with systemic sclerosis. Am J Med. 1995;99(3):255-260.
PubMedArticle
30.
Yamane  K, Miyauchi  T, Suzuki  N,  et al.  Significance of plasma endothelin-1 levels in patients with systemic sclerosis. J Rheumatol. 1992;19(10):1566-1571.
PubMed
31.
Vancheeswaran  R, Magoulas  T, Efrat  G,  et al.  Circulating endothelin-1 levels in systemic sclerosis subsets. J Rheumatol. 1994;21(10):1838-1844.
PubMed
32.
Iglarz  M, Binkert  C, Morrison  K,  et al.  Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008;327(3):736-745.
PubMedArticle
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Original Investigation
May 10, 2016

Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic SclerosisDUAL-1 and DUAL-2 Randomized Clinical Trials

Author Affiliations
  • 1Department of Internal Medicine, University of Michigan Scleroderma Program, Ann Arbor
  • 2Centre for Rheumatology and Connective Tissue Disease, Royal Free Hospital, London, United Kingdom
  • 3Division of Rheumatology, University of Pennsylvania, Philadelphia
  • 4Department of Dermatology, University of Cologne, Cologne, Germany
  • 5Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
  • 6Department of Medicine, Division of Rheumatology, University of Western Ontario, London, Ontario, Canada
  • 7Department of Experimental and Clinical Medicine, Division of Rheumatology, AOUC, University of Florence, Florence, Italy
  • 8Division of Rheumatology, UCLA, Los Angeles
JAMA. 2016;315(18):1975-1988. doi:10.1001/jama.2016.5258
Abstract

Importance  Digital ulcers in patients with systemic sclerosis are associated with pain and poor quality of life. Endothelin-1 promotes vasculopathy in systemic sclerosis after macitentan, an endothelin-1 blocker.

Objective  To evaluate the efficacy of macitentan in reducing the number of new digital ulcers in patients with systemic sclerosis.

Design, Setting, and Participants  Two international, randomized, double-blind, placebo-controlled trials (DUAL-1, DUAL-2) were conducted between January 2012 and February 2014. Participants were patients with systemic sclerosis and active digital ulcers at baseline. Target enrollment for each study was 285 patients.

Interventions  Patients were randomized (1:1:1) to receive oral doses of 3 mg of macitentan, 10 mg of macitentan, or placebo once daily and stratified according to number of digital ulcers at baseline (≤3 or >3).

Main Outcomes and Measures  The primary outcome for each trial was the cumulative number of new digital ulcers from baseline to week 16. Treatment effect was expressed as the ratio between treatment groups.

Results  In DUAL-1, among 289 randomized patients (mean age 51.2 years; 85.8% women), 226 completed the study. The adjusted mean number of new digital ulcers per patient over 16 weeks was 0.94 in the 3-mg macitentan group (n = 95) and 1.08 in the 10-mg macitentan group (n = 97) compared with 0.85 in the placebo group (n = 97) (absolute difference, 0.09 [95% CI, −0.37 to 0.54] for 3 mg of macitentan vs placebo and 0.23 [−0.27 to 0.72] for 10 mg of macitentan vs placebo). Among 265 patients randomized in DUAL-2 (mean age 49.6 years; 81.9% women), 216 completed the study. In DUAL-2, the adjusted mean number of new digital ulcers was 1.44 in the 3-mg macitentan group (n = 88) and 1.46 in the 10-mg macitentan group (n = 88) compared with 1.21 in the placebo group (n = 89) (absolute difference, 0.23 [95% CI, −0.35 to 0.82] for 3 mg of macitentan vs placebo and 0.25 [95% CI, −0.34 to 0.84] for 10 mg of macitentan vs placebo). Adverse events more frequently associated with macitentan than with placebo were headache, peripheral edema, skin ulcer, anemia, upper respiratory tract infection, diarrhea, and nasopharyngitis.

Conclusions and Relevance  Among patients with systemic sclerosis and active ischemic digital ulcers, treatment with macitentan did not reduce new digital ulcers over 16 weeks. These results do not support the use of macitentan for the treatment of digital ulcers in this patient population.

Trial Registration  clinicaltrials.gov Identifiers: NCT01474109, NCT01474122

Introduction

Quiz Ref IDSystemic sclerosis is a chronic multisystem autoimmune disease characterized by systemic vascular dysfunction and fibroblast dysregulation.1 Microvascular involvement contributes to the pathogenesis of the hallmark manifestations in systemic sclerosis, including pulmonary arterial hypertension, scleroderma renal crisis, Raynaud phenomenon, and digital ischemia.1 Digital ulcers are a clinical manifestation of digital ischemia that occur in 35% to 68% of patients with systemic sclerosis25 and are associated with pain, disfigurement, poor quality of life, and disability.2,6

Quiz Ref IDSystemic sclerosis–related vasculopathy is associated with the initiation and progression of systemic sclerosis and the development of digital ulcers.7 Endothelin-1 (ET-1) is a mediator of vascular hypertrophy, proliferation, inflammation, and fibrosis.8 ET-1 is overexpressed in plasma in patients with systemic sclerosis, especially those with digital ulcers.9 ET receptors are up-regulated in microvessels of skin in systemic sclerosis.10 The dual ET-receptor antagonist (ERA) bosentan significantly reduced the number of new digital ulcers in 2 randomized clinical trials (RCTs) of patients with systemic sclerosis with digital ulcers.11,12 Macitentan is a novel dual ERA13,14 approved for long-term treatment of pulmonary arterial hypertension.

DUAL-1 and DUAL-2 are 2 RCTs that evaluated whether macitentan reduces the number of new digital ulcers and their associated disability in patients with systemic sclerosis and active ischemic digital ulcers. DUAL-1 and DUAL-2 also evaluated the safety and tolerability of macitentan in this patient population.

Methods
Study Design

DUAL-1 and DUAL-2 were phase 3, randomized, double-blind, placebo-controlled, multicenter, parallel-group trials, designed to fulfill the regulatory requirement for providing substantial evidence of effectiveness. Patients were enrolled in DUAL-1 at 70 centers in 17 countries from January 2012 to November 2013 and in DUAL-2 at 73 centers in 20 countries from February 2012 to February 2014. Investigational sites were specific to each study; although, 6 countries were involved in both trials (eFigure in Supplement 1). The trial protocols (Supplement 2 and Supplement 3) were approved by ethics committees at each center and the studies were performed in accordance with the principles of the Declaration of Helsinki and within the regulations of each country. Written informed consent was obtained from all patients. An independent data monitoring committee regularly reviewed unblinded efficacy and safety data, and an international liver safety board assessed all hepatic events (eTable 1 in Supplement 1).

Participant Selection

Inclusion criteria were age of at least 18 years; physician diagnosis of systemic sclerosis according to the 1980 American College of Rheumatology classification criteria15 with limited or diffuse cutaneous systemic sclerosis16; at least 1 visible, active ischemic digital ulcer located at or distal to the proximal interphalangeal joint that developed or worsened within 8 weeks prior to screening; and a history of additional active digital ulcers prior to screening (≥1 within 6 months or ≥2 within 12 months). Quiz Ref IDAn active digital ulcer was defined as a finger lesion with visually discernible depth and a loss of continuity of epithelial coverage associated with pain not attributable to other etiologies.

Patients were excluded if they had digital ulcers not due to systemic sclerosis, or if they had comorbidities that could affect assessment of hand function. Other exclusion criteria included any severe organ failure or life-threatening condition; tobacco use within 6 months before screening; treatment with phosphodiesterase type 5 inhibitors; treatment with prostanoids or ERAs within 3 months prior to screening or any investigational drug within 1 month prior to screening; and disease-modifying agents given for less than 3 months or at a nonstable dose for at least 1 month prior to screening.

Study Procedures

In each study, patients were randomly assigned (1:1:1) to receive 3 mg of macitentan, 10 mg of macitentan, or matching oral placebo once daily. Treatment allocation was stratified by number of digital ulcers at randomization (≤3 and >3) with a block size of 6. Each patient was randomized via a centralized Interactive Response System (ICON) and received a unique randomization number. The patients, investigators, and study sponsor remained blinded to treatment until database lock.

Patients were assessed at randomization and every 4 weeks up to week 16 (period 1). Between week 16 and the end of the study they were assessed every 3 months (period 2) (eTable 2 in Supplement 1). Patients continued double-blind treatment until the end of study, which occurred for all patients when the last patient completed the week-16 visit. Within 7 days of the end of the study, patients completed the end of treatment visit. Within 30 days of the end of the study, patients underwent their end-of-study visit. Patients who prematurely discontinued the study drug in period 1 or 2 completed the end of treatment visit within 7 days of the last administered dose. These patients underwent follow-up every 3 months until the end of the study. Adverse events (AEs) were monitored throughout the study.

Outcome Measures

The primary efficacy end point was the cumulative number of new digital ulcers from baseline to week 16. Digital ulcers that occurred and healed between visits were not recorded as new. Complete healing was defined as complete epithelialization of the ischemic digital ulcer, regardless of residual pain. Since there is low interrater reliability in assessing digital ulcers,17 each patient was assessed for digital ulcers by the same investigator throughout the study. All investigators were trained to visualize and score the stages and types of digital ulcers in face-to-face meetings and were provided with a reference document to use during the study.

Other prespecified end points included the evaluation of hand function (assessed by the change between baseline and week 16 in Health Assessment Questionnaire-Disability Index [HAQ-DI]18 and Hand Disability in Systemic Sclerosis-Digital Ulcers [HDISS-DU] scores [eMethod in Supplement 1]); the evaluation of digital ulcer burden (assessed by the proportion of patients with or without multiple new digital ulcers at week 16 and by the change from baseline to week 16 in the total number of digital ulcers); the change from baseline to week 16 in the patient- and physician-reported global assessment of digital ulcer activity (severity of illness and global improvement; score range, 1-7); the proportion of patients with complete healing of all digital ulcers at week 16; the change from baseline to week 16 in overall hand pain related to digital ulcers (score range, 1-10); the change from baseline to week 16 in the Scleroderma Health Assessment Questionnaire visual analog scales (SHAQ-VAS; score range, 1-3) for overall global assessment of disease and for activity limitation due to digital ulcers and to Raynaud phenomenon19; and the evaluation of digital ulcer complications (assessed by the proportion of patients with digital ulcer complications at the end of treatment and the time from randomization to first digital ulcer complication up to the end of treatment).

Statistical Analyses

For the primary end point, the null hypotheses were that the mean cumulative number of new digital ulcers per patient up to week 16 was the same between placebo vs 10-mg macitentan groups and between placebo vs 3-mg macitentan groups. A sample size of 95 patients per treatment group (285 patients in total) was calculated by statistical simulations on the basis of a 2-sided comparison at the 5% significance level using an unstratified Pitman permutation test, 90% power, an overdispersion of 0.76, and an estimated 45% reduction in new digital ulcers at week 16 (based on an RCT comparing bosentan vs placebo, in which the mean number of new digital ulcers up to week 24 was 4.4 for placebo and 2.4 for bosentan).12 The use of a binomial-2 regression (NB-2) model20 adjusted for the number of digital ulcers at randomization (≤3 or >3) was introduced before study start. With the same sample size, it was estimated that a significant difference between the active and the placebo groups could be determined with greater than 97% power. The treatment effect was expressed as the ratio of incidence rates of new digital ulcers over 16 weeks between each of the macitentan dose groups and the placebo group, and presented with corresponding 95% CIs. The incidence rates were calculated as the cumulative number of new digital ulcers observed up to week 16 and were standardized to 16 weeks to account for different exposure times among patients. The main imputation rules for missing values for the primary end point are explained in eTable 3 in Supplement 1. This imputation method relies on the assumption of a constant rate of new digital ulcers occurring over time, as observed in previous studies11,12 and verified post hoc for these analyses.

A post hoc sensitivity analysis was performed using multiple imputation by fully conditional specification.21 Variables used for imputation were treatment group, number of digital ulcers at randomization, and the count of new digital ulcers at each visit up to week 16 (eTable 4 in Supplement 1). Additional predefined sensitivity analyses of the primary end point were performed, as detailed in eTable 4 (Supplement 1). A prespecified subgroup analysis evaluated the primary end point by number of digital ulcers at randomization (≤3 or >3).

For other efficacy end points evaluating a change from baseline to week 16, treatment differences were analyzed using analysis of covariance. Treatment differences for binary efficacy end points were expressed as odds ratios (ORs) calculated using logistic regression. Treatment differences were adjusted for baseline values. Missing data at week 16 were imputed using the last observation carried forward, and for HAQ-DI, the standard scoring was used.19 For time-to-event analyses, Kaplan-Meier estimates were calculated and proportional hazard models were used to compute hazard ratios (HRs) and 95% CIs. All analyses were adjusted for the number of digital ulcers at randomization (≤3 or >3). Safety data were summarized descriptively.

The primary end point analysis was performed in the intention-to-treat population, whereas all other efficacy end point analyses were performed in the modified intention-to-treat population (defined as all randomized patients who received ≥1 dose of study treatment and had ≥1 post-baseline primary efficacy assessment). The safety analysis included all randomized patients who received at least 1 dose of study treatment. The studies were planned to be reported separately. All analyses were conducted using SAS version 9.3 (SAS Institute Inc), using a significance threshold of 5% with 2-sided P values.

Results
Patient Characteristics

In the DUAL-1 study, 289 patients were randomized to receive 3 mg of macitentan (n = 95), 10 mg of macitentan (n = 97), or placebo (n = 97) (Figure 1). In the DUAL-2 study, 265 patients were randomized to receive 3 mg of macitentan (n = 88), 10 mg of macitentan (n = 88), or placebo (n = 89) (Figure 2). In each study, groups were balanced with respect to patient demographics, disease characteristics, and concomitant medications (Table 1). In DUAL-1, the number of digital ulcers at baseline ranged from 1 to 13 (mean, 3.4), and 201 patients (69.6%) presented with 3 or fewer digital ulcers. In DUAL-2, the number of digital ulcers at baseline ranged from 1 to 18 (mean, 3.5), and 180 patients (67.9%) presented with 3 or fewer digital ulcers. DUAL-2 was terminated prematurely based on recommendations by the independent data monitoring committee, which had overall responsibility for safeguarding the interests of the study participants by monitoring safety and efficacy data. Although formal interim analyses were not predefined, the committee concluded, after reviewing unblinded data during a routine safety monitoring meeting (November 2013), that while risks of macitentan appeared modest, the possibility of any benefit was small and additional data were not expected to result in a positive primary outcome. The committee recommended that DUAL-2 be halted and study treatment was discontinued in all patients (93.0% of planned patients had been enrolled and 74.7% of those underwent ≥16 weeks of treatment).

Development of New Digital Ulcers

The 2 trials did not achieve the primary end point of a reduction of cumulative number of new digital ulcers over 16 weeks (Table 2). In DUAL-1, the adjusted mean numbers of new digital ulcers per patient over 16 weeks were 0.94 in the 3 mg of macitentan group, 1.08 in the 10 mg of macitentan group, and 0.85 in the placebo group, and observations were similar in DUAL-2 (adjusted mean number of new digital ulcers per patient over 16 weeks: 1.44 in the 3 mg of macitentan group, 1.46 in the 10 mg of macitentan group, and 1.21 in the placebo group). In DUAL-1, the absolute difference for the cumulative number of new digital ulcers from baseline to week 16 was 0.09 (95% CI, −0.37 to 0.54) and the rate ratio was 1.10 (95% CI, 0.66 to 1.83) (P = .71) for 3 mg of macitentan vs placebo; for 10 mg of macitentan vs placebo, the absolute difference was 0.23 (95% CI, −0.27 to 0.72) and the rate ratio was 1.27 (95% CI, 0.76 to 2.11) (P = .36).

In DUAL-2, the absolute difference for the cumulative number of new digital ulcers from baseline to week 16 was 0.23 (95% CI, −0.35 to 0.82) and the rate ratio was 1.19 (95% CI, 0.77 to 1.86) (P = .43) for 3 mg of macitentan vs placebo; for 10 mg of macitentan vs placebo, the absolute difference was 0.25 (95% CI, −0.34 to 0.84) and the rate ratio was 1.21 (95% CI, 0.77 to 1.89) (P = .41). These results were confirmed using multiple imputation and other prespecified sensitivity analyses (eTable 4 in Supplement 1). The amount of missing data for the primary end point is shown in eTable 5 (Supplement 1; patients with ≥1 missing assessment: DUAL-1, 23.5% [n = 68]; DUAL-2, 24.9% [n = 66]). The absence of a treatment effect was also observed in the subgroups of patients with 3 or fewer digital ulcers at baseline vs greater than 3 (Table 2). In DUAL-1, 64.1% (59) of patients in the 3 mg of macitentan group, 63.0% (58) of patients in the 10 mg of macitentan group, and 67.0% (63) of patients in the placebo group had no new digital ulcers by week 16. In DUAL-2, 56.0% (47) of those in the 3 mg of macitentan group, 54.8% (46) of patients in the 10 mg of macitentan group, and 59.8% (52) of patients in the placebo group had no new digital ulcers by week 16 (Table 3).

Hand Function, Digital Ulcers Burden, and Time to Digital Ulcers Complications

There were no treatment effects with either dose of macitentan vs placebo in either trial with respect to other efficacy end points, including hand function, digital ulcer burden, patient- and physician-reported outcomes, complete healing of digital ulcers, and overall hand pain related to digital ulcers and SHAQ (Table 3). In all groups, patients showed reduction from baseline to week 16 in total number of digital ulcers, severity of disease (patient- and physician-rated), pain, and interference with daily activity. There was little change in hand function (Table 3). In both trials, no differences between groups were observed in time to first digital ulcer complications (Figure 3). Digital ulcer complications were observed in 17.6% of patients in DUAL-1 and in 21.2% of patients in DUAL-2 (eTable 6 in Supplement 1).

Safety and Tolerability

In both trials, patients were exposed to treatment on average for 40 weeks (eTable 7 in Supplement 1). In this period, the frequency of patients in DUAL-1 with at least 1 AE was 71.3% among those in the 3 mg of macitentan group, 76.3% for 10 mg of macitentan , and 73.2% for the placebo group, and in DUAL-2, the frequency of patients with at least 1 AE was 83.0% among those in the 3 mg of macitentan group, 85.1% for 10 mg of macitentan, and 78.7% for the placebo group (eTable 7 in Supplement 1). The most frequently reported AEs (incidence rate, 10% and >3% difference between placebo and either macitentan group) in each trial were headache, peripheral edema, skin ulcer, anemia, upper respiratory tract infection, diarrhea, and nasopharyngitis. AEs leading to premature discontinuation occurred in 13.8% of patients in the 3 mg of macitentan group, 14.4% for 10 mg of macitentan, and 10.3% of patients in the placebo group in DUAL-1, and in DUAL-2, AEs leading to premature discontinuation occurred in 9.2% of patients in the 3 mg of macitentan group, 17.2% for 10 mg of macitentan, and 14.6% of patients in the placebo group. Skin ulcer, infected skin ulcer, and increased alanine aminotransferase/aspartate aminotransferase were the most frequently reported AEs leading to treatment discontinuation. Incidences of serious AEs in DUAL-1 were 18.1% in the 3 mg of macitentan group, 14.4% for 10 mg of macitentan, and 13.4% in the placebo group, and in DUAL-2, 11.4% in the 3 mg of macitentan group, 24.1% for 10 mg of macitentan, and 14.6% in the placebo group, with infections being the most common. There was 1 death due to cardiac arrest in DUAL-1 in a patient receiving 10 mg of macitentan. There were 2 deaths (1 due to unspecified natural causes and 1 due to cardiac failure) in DUAL-2. Both patients were in the 10 mg of macitentan group. All deaths were considered unrelated to study treatment. There were no differences in alanine aminotransferase, aspartate aminotransferase, bilirubin, or hemoglobin between study groups (eTable 7 in Supplement 1).

Discussion

Quiz Ref IDIn 2 randomized, placebo-controlled trials of patients with systemic sclerosis and active ischemic digital ulcers at baseline, macitentan did not reduce the cumulative number of new digital ulcers over 16 weeks compared with placebo. Regardless of treatment, patients had few new digital ulcers, and their overall digital ulcer condition remained stable over 16 weeks. Macitentan was well tolerated, with a safety profile similar to that observed in patients with pulmonary arterial hypertension22 and idiopathic pulmonary fibrosis.23

Few therapies are available for digital ulcers in patients with systemic sclerosis. The EUSTAR 2009 treatment recommendations in systemic sclerosis for managing digital ulcers endorse using intravenous iloprost and bosentan,24 and evidence supporting the use of PDE-5 inhibitors is recently available.25 Bosentan is the only treatment indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease, following 2 randomized clinical trials, RAPIDS-1 and RAPIDS-2.11,12 Because bosentan is not approved in all of the countries where the DUAL studies were conducted, DUAL-1 and DUAL-2 did not compare macitentan to bosentan. Instead, the trials were placebo-controlled with safeguards in place in case of progression of digital ulcer severity. The choice of bosentan as an active comparator would have limited the scope of the studies. Current European guidelines state that bosentan should be considered in diffuse systemic sclerosis with multiple digital ulcers after failure of calcium antagonists and prostanoids.24 DUAL-1 and DUAL-2 were designed to fulfill the regulatory requirements for demonstrating the effectiveness of macitentan vs placebo.

Based on results of the RAPIDS trials, the inclusion criteria of DUAL-1 and DUAL-2 were designed to enroll patients with high likelihood of developing new digital ulcers. The number of active digital ulcers at baseline ranged from 1 to 18 in the 2 studies. Although most participants (69.6%) had 3 or fewer digital ulcers at baseline, the average number of digital ulcers was 3.5, thus the study population consisted of systemic sclerosis patients with active digital ulcers.

The average number of new digital ulcers over 16 weeks was low, ranging from 0.85 to 1.46 ulcers across the treatment groups in both studies. Approximately 60% of patients did not develop new digital ulcers. Even among patients with more than 3 active digital ulcers at baseline, the average number of new digital ulcers over 16 weeks ranged from 1.16 to 2.66 in the 3 treatment groups. In RAPIDS-1,11 patients treated with placebo with 1 to 3 active digital ulcers at baseline developed, a mean (SD) of 2.2 (2.0) new digital ulcers over 16 weeks, and those with more than 3 active digital ulcers at baseline developed 5.1 (3.9) new ulcers. Overall, 42% of the patients in RAPIDS-1 had more than 3 new digital ulcers over 16 weeks.11 Results were similar in RAPIDS-2.12 DUAL-1 and DUAL-2 were designed with the expectation that patients receiving placebo would develop more digital ulcers.

Quiz Ref IDPatients enrolled in DUAL-1 and DUAL-2 had similar demographics and disease characteristics as patients enrolled in prior systemic sclerosis digital ulcer trials. The low number of new digital ulcers observed suggests that the epidemiology of digital ulcers in systemic sclerosis may be changing and reflect earlier diagnosis, better care, and greater availability of treatments. A similarly low incidence of new digital ulcers in patients with systemic sclerosis was also observed in a recent study.26 Standard management of digital ulcers has improved in recent years with the widespread use of bosentan, PDE-5 inhibitors, and prostacyclin and its analogs.27,28 It is possible that patients with more severe active ulcers were treated with these medications and not recruited into the DUAL trials or that the studies enrolled a population with refractory digital ulcers that did not respond well to standard treatments. Enrolled patients may have exhausted other treatment options.

The overexpression of ET-1 and ET receptors in skin, the epidermis, and blood vessels in systemic sclerosis is well documented.10,2931 However, the specific role of ET-1 in the pathogenesis of digital vasculopathy and the development of digital ulcers in systemic sclerosis is incompletely understood. Although bosentan and macitentan both block the ETA and ETB receptors, a reduction in the formation of new digital ulcers has only been observed with bosentan.11,12 Macitentan is a more potent ERA than bosentan on ET receptors in vitro and on biomarkers (eg, plasma ET-1) and other measures (eg, blood pressure and cardiac remodeling) in in vivo models of pulmonary hypertension.32 It is unclear why this relative higher potency of macitentan did not result in an effect on digital ulcers. Further research is necessary to delineate mechanisms of vascular involvement in systemic sclerosis as it relates to digital ulcers. The etiology of digital ulceration in systemic sclerosis is multifactorial, involving ischemic, inflammatory, and mechanical mechanisms, all of which influence clinical outcomes of digital ulcers, including repetitive microtrauma, thinning, dry skin, and underlying calcinosis.

Limitations of the DUAL-1 and DUAL-2 studies include the lack of a clear classification system of digital ulcers that considers digital ulcer morphology and the different ulcer features, including presence of underlying calcinosis, size, bedding, perilesional skin, and borders, which potentially affect digital ulcer assessment and counts.6,7 The DUAL studies involved 73 centers in 20 countries. Although efforts were made to standardize the definition and the reporting of new active digital ulcers, some variability across the study sites in measuring new digital ulcers was likely, and the absence of interrater reliability data to quantify this is a limitation. In addition, 23.5% of participants in DUAL-1 and 24.9% of those in DUAL-2 were missing primary outcome data at 16-week follow-up. However, the primary end point considers the cumulative number of new digital ulcers up to week 16, and the consistency of sensitivity analyses suggests that missing data did not significantly affect statistical inference. Differences in physician attitudes and standard practices,17 and the lower than expected number of new digital ulcers after 16 weeks may have ultimately influenced the ability to demonstrate any treatment effect in the DUAL trials.

Conclusions

Among patients with systemic sclerosis and active ischemic digital ulcers, treatment with macitentan did not reduce the number of new digital ulcers over 16 weeks. These results do not support the use of macitentan for the treatment of digital ulcers in this patient population.

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Article Information

Corresponding Author: Dinesh Khanna, MD, University of Michigan Scleroderma Program, Division of Rheumatology, Department of Internal Medicine, Ste 7C27, 300 N Ingalls St, SPC 5422, Ann Arbor, MI 48109 (khannad@med.umich.edu).

Author Contributions: Dr Khanna had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Matucci-Cerinic, and Furst contributed equally.

Study concept and design: Khanna, Denton, Merkel, Krieg, Papadakis, Pope, Matucci-Cerinic, Furst.

Acquisition, analysis, or interpretation of data: Khanna, Denton, Merkel, Krieg, Le Brun, Marr, Papadakis, Pope, Matucci-Cerinic, Furst.

Drafting of the manuscript: Khanna, Denton, Merkel, Krieg, Le Brun, Marr, Papadakis, Pope, Matucci-Cerinic, Furst.

Critical revision of the manuscript for important intellectual content: Khanna, Denton, Merkel, Krieg, Le Brun, Marr, Papadakis, Pope, Matucci-Cerinic, Furst.

Statistical analysis: Le Brun.

Obtained funding: Papadakis.

Administrative, technical, or material support: Papadakis.

Study supervision: Khanna, Denton, Merkel, Krieg, Marr, Papadakis, Pope, Matucci-Cerinic, Furst.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Khanna reports receipt of grants from EMD Serono, Bristol-Myers Squibb, Bayer, InterMune, the National Institutes of Health (NIH)/the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the Scleroderma Foundation, and the Pulmonary Hypertension Association; and consulting fees from Actelion, Astra-Zeneca, Bayer, Biogen Idec, Bristol-Myers Squibb, Cytori, EMD Serono, Genentech/Roche, GlaxoSmithKline, and Sanofi-Aventis/Genzyme. Mr Le Brun, Ms Marr, and Dr Papadakis report being employees of and holding stocks in Actelion Pharmaceuticals Ltd. Dr Denton reports having acted as a consultant for and receiving speaker fees from Actelion, GlaxoSmithKline, Bayer, Inventiva, and Takeda; and receipt of research grant support from Actelion, CSL Behring, GlaxoSmithKline, and Novartis. Dr Pope reports having been a consultant for Actelion and Bayer. Dr Merkel reports receipt of consulting fees from Actelion, Alexion, ChemoCentryx, Genentech/Roche, and Sanofi; research funding from Actelion, Bristol-Myers Squibb, Celgene, ChemoCentryx, and GlaxoSmithKline; and receipt of research grants from NIH, the US Food and Drug Administration, and the American College of Rheumatology and Vasculitis Foundation. Dr Krieg reports receipt of research grants and speakers fees from Actelion. Dr Matucci-Cerinic reports receipt of grant/research support and/or speaker’s bureau attendance from Actelion, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, and Abbott. Dr Furst reports receipt of grant/research support from AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech, UCB; consulting fees from AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Cytori, Janssen, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech, UCB; and speaker’s fees (CME only) from AbbVie, Actelion, and UCB.

Funding/Support: DUAL-1 and DUAL-2 were funded by Actelion Pharmaceuticals Ltd.

Role of the Funder/Sponsor: Actelion Pharmaceuticals Ltd was involved in the design and conduct of the study; oversaw the collection, management, and statistical analysis of the data; and contributed to the interpretation of the data and the preparation, review, and approval of the manuscript. The final decision on manuscript submission was made by the authors; the sponsor did not have the ability to veto publication of study results.

Collaborators

The DUAL-1 and DUAL-2 principal investigators who contributed to the recruitment of patients in the studies are listed by country.

DUAL-1: Australia: Jane Zochling, MD, Menzies Research Institute, Hobart; Wendy Stevens, MD, St Vincent’s Hospital, Fitzroy; Susanna Proudman, MD, Royal Adelaide Hospital, Adelaide; John Feenstra, MD, Wesley Hospital, Auchenflower; Peter Youssef, MD, Royal Prince Alfred Hospital, Camperdown. Belarus: Nikolay Soroka, MD, Minsk Clinical Hospital #9, Minsk; Tamara Tyabut, MD, Minsk City Hospital #1, Minsk; Elena Ivanovna Mikhailova, MD, Gomel Regional Clinical Hospital, Gomel. Bulgaria: Rasho Rashkov, MD, MHAT ‘Sv. Ivan Rilski’ EAD Sofia, Sofia; Anastas Batalov, MD, MHAT ‘Kaspela’ EOOD Plovdiv, Plovdiv; Kiril Yablanski, MD, MHAT ‘Sveti Pantaleymon’ Pleven OOD, Pleven. Canada: Edward Keystone, MD, Mount Sinai Hospital, Toronto; Janet Pope, MD, St Joseph's HealthCare London, London; Niall Jones, MD, 124th Street Rheumatology Clinic, Edmonton; James Dunne, MD, St Paul’s Hospital, Vancouver; Ariel Masetto, MD, CHUS Hopital Fleurimont, Sherbrooke. Chile: Renato Jiménez Calabresse, MD, Centro de Estudios Clinicos V, Viña del Mar; Pedro Claudio Miranda Cabezas, MD, Centro de Estudios Reumatologicos, Santiago; Marta Ofelia Aliste Silva, MD, private office Marta Aliste Silva, Santiago; Imgadt Annelise Goecke Sariego, MD, Prosalud, Santiago. Colombia: William José Otero Escalente, MD, SERVIMED EU, Bucaramanga. Croatia: Branimir Anić, MD, Klinički bolnički centar Zagreb, Zagreb; Dušanka Martinović Kaliterna, MD, Klinički bolnički centar Split, Split; Jadranka Morović-Vergles, MD, Klinički bolnica Dubrava, Zagreb; Srdan Novak, MD, Klinički bolnički centar Rijeka, Rijeka; Višnja Prus, MD, Klinički bolnički centar Osijek, Osijek; Marinko Artuković, MD, Klinički bolnica Sveti Duh, Zagreb. Czech Republic: Tomáš Soukup, MD, PhD, Faculty Hospital Hradec Králové, Hradec Králové; Radim Bečvař, MD, PhD, Revmatologický ústav Praha, Prague; Zdeněk Fojtík, MD, PhD, FN Brno, Brno. France: Luc Mouthon, MD, Hôpital Cochin, Paris. Germany: Florian Kollert, MD, Medizinische Univeritätsklinik Freiburg, Freiburg; Thomas M Krieg, MD, Universität zu Köln, Cologne; Gabriela Riemekasten, PD, MD, Universitätsmedizin Berlin, Berlin; Nina Lahner, MD, Rhur-Universität Bochum, Bochum; Gerhard Fierlbeck, MD, Eberhard-Karls-Universität, Tübingen; Keihan Ahmadi-Simab, MD, Asklepios Klinik Altona, Hamburg; Curt Diehm, MD, Akademie für Gefässkrankheiten, Karlsbad. Hungary: Gabriella Szücs, MD, Debreceni Egyetem Klinikai Központ, Debrecen; Gábor Kumánovics, MD, Pésci Tudományegetem Klinikai Központ, Pécs; György Nagy, MD, Budai Irgalmasrendi Kórhaz, Budapest. India: Sarvajeet Pal, MD, Advance Rheumatology Clinic, Hyderabad; Sarath Chandra Mouli Veeravalli, MD, Krishna Institute of Medical Sciences, Secunderabad; Debashish Danda, MD, Christian Medical College Hospital, Tamil Nadu. Italy: Clodeveo Ferri, MD, Azienda Ospedaliera Poloclinico di Modena, Modena; Marco Matucci Cerinic, MD, Azienda Ospedaliera-Universitaria Careggi, Florence; Franco Cozzi, MD, Azienda Ospedaliera di Padova, Padova; Gianfranco Ferraccioli, MD, Complesso Integrato Columbus, Rome. Poland: Piotr Wiland, MD, Uniwersytet Medyczny we Wrocławiu. Jana Mikulicza-Radeckiego we Wrocławiu, Wrocław; Lidia Rudnicak, MD, Centralny Szpital Kliniczny MSWiA, Warszawa; Robert Zwolak, MD, NZOZ Reumed, Lublin; Jadwiga Roszkiewicz, MD, Uniwersyteckie Centrum Kliniczne, Gdańsk. Russian Federation: Valentin Oleynikov, MD, Penza Regional Clinical Hospital, Penza; Natalya Nikulenkova, MD, Regional Clinical Hospital, Vladimir; Olga Lesnyak, MD, Sverdloovsk Regional Clinical Hospital #1, Ekaterinburg. Ukraine: Igor Kaydashev, MD, City Clinical Hospital #1, Poltava; Oleksandr Kurytar, MD, Dnipropetrovsk Regional Clinicl Hospital, Dnipropetrovsk; Olena Piura, MD, Kyiv Regional Clinical Hospital, Kiev; Valentyna Chopyak, MD, Lviv Regional Clinical Hospital, Lviv. United States: Soumya Chatterjee, MD, The Cleveland Clinical Foundation, Cleveland, OH; Daniel E. Furst, MD, UCLA David Geffen School of Medicine, Los Angeles; Vivien Hsu, MD, University of Medicine & Dentistry of New Jersey, New Brunswick; Laura Hummers, MD, Johns Hopkins University School of Medicine, Baltimore, Maryland; Richard Martin, MD, Michigan State University, Grand Rapids; Robyn Domsic, MD, University of Pittsburgh, Pittsburgh, PA; Elena Schiopu, MD, and Dinesh Khanna, MD, University of Michigan, Ann Arbor; Joseph Shanahan, MD, Shanahan Rheumatology and Immunotherapy, Raleigh, NC; Frederik T. Murphy, MD, DO, Altoona Center for Clinical Research, Duncansville, PA; Jeffrey Kaine, MD, Sarasota Arthritis Research Center, Sarasota, FL; William Davis, MD, Ochsner Medical Center, New Orleans, LA; Rafael Grau, MD, University of Arizona Arthritis Center, Tucson.

DUAL-2: Argentina: Alicia Eimon, MD, Centro de Educacion Medica e Investigaciones Clinicas, Buenos Aires; Luis Jose Catoggio, MD, Hospital Italiano de Buenos Aires, Buenos, Aires; Hugo Armando Laborde, MD, Clinica del Tórax, Buenos Aires; Francisco Caeiro, MD, Hospital Privado Centro Medico de Cordoba, Cordoba; Veronica Gabriela Savio, MD, Hospital Italiano de Cordoba, Cordoba; Cristina Beatriz Amitrano, MD, Sanatoria San Jose, Buenos Aires. Belgium: Marie Vanthuyne, MD, PhD, Cliniques Universitaires Saint Luc, Brussels. China: Xioafeng Zeng, MD, Peking Union Medical College, Beijing; Xiao Zhang, MD, Guangdong General Hospital, Guangzhou; Ping Zhu, MD, Xijing Hospital, Shanxi. Colombia: Carlos Jaime Velásquez-Franco, MD, Clinica Universitaria Bolivariana, Medellin; Philippe Selim Chalem Choueka, MD, Fundacion Instituto du Reumatologia, Bogota; Patricia Julieta Vélez Sanchez, MD, Centro Integral de Reumatologia e Inmunologia, Bogota. Germany: Walter Hermann, MD, Kerckhoff-Klinik, Bad Nauheim; Michael Sticherling, MD, Hautlink Universitätsklinikum Erlangen, Erlangen; Kerstin Steinbrink, MD, Department of Dermatology, University Medical Centre, Johannes Gutenberg University, Mainz; Rüdiger Hein, MD, Klinikum rechts der Isar Technische Universität München, Munich; Roland Aschoff, MD, Universität Dresden, Dresden. Greece: Petros Sfikakis, MD, General University Hospital LAIKO/A', Athens; Lukas Settas, MD, Euromedica-Kyanos Stavros, Thessaloniki. Ireland: Alexander Fraser, MD, Mid-Western Regional Hospital, Limerick; Douglas Veale, MD, St Vincents Univeristy Hospital, Dublin. Israel: Alexandra Balbir-Gurman, MD, B. Shine Rheumatology Unit, Ramban Health Care Campus, Rappaport Faculty of Medicine, Technion, Haifa; Merav Lidar, MD, The Chaim Sheba Medical Center, Tel-Hashomer; Irena Litinsky, MD, Tel Aviv Sourasky Medical Center, Tel-Aviv; Yair Levy, MD, Meir Medical Center, Kfar Saba. Mexico: Sandra Miriam Carrillo-Vazquez, MD, Hospital Angeles Lindavista, Mexico City; Tatiana Rodriguez-Reyna, MD, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubrian, Mexico DF; Gabriel Medrano-Ramirez, MD, Clinica Diagnostico y Tratamiento de las Enfermedades Reumaticas, Mexico DF; Jorge Morales-Torres, MD, Morale Vargas Centro de Investigacion, Leon; Cesar Francisco Pacheco-Tena, MD, Investigación y Biomedicina de Chihuahua, Chihuahua; Adriana Sanchez-Ortiz, MD, Unidad de Artritis y Reumatismo, Guadalajara. Netherlands: Madelon C. Vonk, MD, UMC St Radboud, Nijmegen. New Zealand: Simon Stebbings, MBBS, Dunedin Hospital, Dunedin; Kamal Solanki, MD, Waikato Hospital, Hamilton; Richard Steele, MD, Wellington Hospital, Wellington; Kristine (Pek Ling) Ng, MD, North Shore Hospital, Aukland. Poland: Anna Zubrzycka-Sienkiewicz, MD, Reumatika- Centrum Reumatologii NZOZ, Warszaw; Marek Brzosko, MD, Department of Rheumatology and Internal Diseases, Pomeranian Medical University, Szczecin; Jacek C. Szepietowski, MD, SPSK Nr 1 Wrocław, Wrocław; Pawel Hrycaj, MD, Prywatna Praktyka Lekarska, Poznań. Portugal: Ivone Fernandes Santos da Silva, MD, Hospital Santo António, Centro Hospitalar do Porto, Porto; Lelita da Conceiçao dos Santos, MD, Hospitais da Universidade de Coimbra, Coimbra; Paulo Jorge Clemente Coelho, MD, Instituto Português de Reumatologia, Lisboa. Puerto Rico: Grissel Rios, MD, University of Puerto Rico, San Juan. Russian Federation: Tatiana Chernykh, MD, Voronezh State Medical Academy, Vorobnezh; Elena Grunina, MD, City Clinical Hospital #5, Nizhniy Novgorod; Marina Stanislav, MD, Scientific Research Institute of Rheumatology, Moscow. South Africa: Mahmood Ally, MD, Syeve Biko Hospital, Pretoria; Asgar Kalla, MD, Groote Schuur Hospital, Cape Town. Turkey: Ahmet Merih Birlik, MD, Dokuz Eylul Universitesi, Izmir. Ukraine: Volodymyr Kovalenko, MD, National Scientific Center, Kiev; Andriy Petrov, MD, Crimean Republican Institution, University Clinic, Symferopol; Sergiy Shevchuk, MD, National Medical University, Vinnytsya; Mykola Stanislavchuk, MD, Vinnytsia Regional Clinical Hospital, Vinnystsya; United Kingdom: Marina Anderson, MD, University Hospital Aintree, Liverpool; Cristopher P. Denton, MD, The Royal Free Hospital, London; Ariane Herrick, MD, Salford Royal NHS Foundation Trust, Salford; Jill Belch, MD, Ninewells Hospital & Medical School, Dundee. United States: Lorinda Chung, MD, Stanford University School of Medicine, Redwood City, CA; Mary Ellen Csuka, MD, Medical College of Wisconsin, Milwaukee; Tracy Frech, MD, University of Utah, Salt Lake City; Avram Goldberg, MD, North Shore Long Island Jewish Health System, Great Neck, NY; Bashar Kahaleh, MD, University of Toledo Medical Center, Toledo, OH; Maureen D. Mayes, MD, MPH, University of Texas Medical School at Houston, Houston; Naomi Rothfield, MD, University of Connecticut Health Center, Farmington; Robert William Simms, MD, Boston University School of Medicine, Boston, MA; Robert Spiera, MD, The Hospital for Special Surgery, New York; Virgina Steen, MD, Georgetown University Medical Center, Washington, DC; John Varga, MD, Northwestern University—Feinberg School of Medicine, Chicago, IL; David Sikes, MD, Florida Medical Clinic, Zephyrhills; Chris T. Derk, MD, and Peter A. Merkel, MD, The University of Pennsylvania, Philadelphia; Michael D. Kohen, MD, Millennium Research, Ormond Beach, FL.

Additional Contributions: The authors express their gratitude to all investigators, study staff, and patients who participated in these studies.

References
1.
Matucci-Cerinic  M, Kahaleh  B, Wigley  FM.  Review: evidence that systemic sclerosis is a vascular disease. Arthritis Rheum. 2013;65(8):1953-1962.
PubMedArticle
2.
Guillevin  L, Hunsche  E, Denton  CP,  et al.  Functional impairment of systemic scleroderma patients with digital ulcerations. Clin Exp Rheumatol. 2013;31(2)(suppl 76):71-80.
PubMed
3.
Walker  UA, Tyndall  A, Czirják  L,  et al.  Clinical risk assessment of organ manifestations in systemic sclerosis. Ann Rheum Dis. 2007;66(6):754-763.
PubMedArticle
4.
Steen  V, Denton  CP, Pope  JE, Matucci-Cerinic  M.  Digital ulcers: overt vascular disease in systemic sclerosis. Rheumatology (Oxford). 2009;48(suppl 3):iii19-iii24.
PubMedArticle
5.
Hachulla  E, Clerson  P, Launay  D,  et al.  Natural history of ischemic digital ulcers in systemic sclerosis. J Rheumatol. 2007;34(12):2423-2430.
PubMed
6.
Amanzi  L, Braschi  F, Fiori  G,  et al.  Digital ulcers in scleroderma. Rheumatology (Oxford). 2010;49(7):1374-1382.
PubMedArticle
7.
Matucci-Cerinic  M, Seibold  JR.  Digital ulcers and outcomes assessment in scleroderma. Rheumatology (Oxford). 2008;47(suppl 5):v46-v47.
PubMedArticle
8.
Distler  JH, Allanore  Y, Avouac  J,  et al.  EULAR Scleroderma Trials and Research group statement and recommendations on endothelial precursor cells. Ann Rheum Dis. 2009;68(2):163-168.
PubMedArticle
9.
Kim  HS, Park  MK, Kim  HY, Park  SH.  Capillary dimension measured by computer-based digitalized image correlated with plasma endothelin-1 levels in patients with systemic sclerosis. Clin Rheumatol. 2010;29(3):247-254.
PubMedArticle
10.
Knock  GA, Terenghi  G, Bunker  CB, Bull  HA, Dowd  PM, Polak  JM.  Characterization of endothelin-binding sites in human skin and their regulation in primary Raynaud’s phenomenon and systemic sclerosis. J Invest Dermatol. 1993;101(1):73-78.
PubMedArticle
11.
Korn  JH, Mayes  M, Matucci Cerinic  M,  et al.  Digital ulcers in systemic sclerosis. Arthritis Rheum. 2004;50(12):3985-3993.
PubMedArticle
12.
Matucci-Cerinic  M, Denton  CP, Furst  DE,  et al.  Bosentan treatment of digital ulcers related to systemic sclerosis. Ann Rheum Dis. 2011;70(1):32-38.
PubMedArticle
13.
Gatfield  J, Mueller Grandjean  C, Sasse  T, Clozel  M, Nayler  O.  Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells. PLoS One. 2012;7(10):e47662.
PubMedArticle
14.
Iglarz  M, Landskroner  K, Bauer  Y,  et al.  Comparison of macitentan and bosentan on right ventricular remodeling in a rat model of non-vasoreactive pulmonary hypertension. J Cardiovasc Pharmacol. 2015;66(5):457-467.
PubMedArticle
15.
Masi  A, Rodnan  GP, Medsger  TA  Jr,  et al.  Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum. 1980;23(5):581-590.
PubMedArticle
16.
LeRoy  EC, Black  C, Fleischmajer  R,  et al.  Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15(2):202-205.
PubMed
17.
Herrick  AL, Roberts  C, Tracey  A,  et al.  Lack of agreement between rheumatologists in defining digital ulceration in systemic sclerosis. Arthritis Rheum. 2009;60(3):878-882.
PubMedArticle
18.
Steen  VD, Medsger  TA  Jr.  The value of the Health Assessment Questionnaire and special patient-generated scales to demonstrate change in systemic sclerosis patients over time. Arthritis Rheum. 1997;40(11):1984-1991.
PubMedArticle
19.
Bruce  B, Fries  JF.  The Stanford Health Assessment Questionnaire: a review of its history, issues, progress, and documentation. J Rheumatol. 2003;30(1):167-178.
PubMed
20.
Hilbe  J. Negative Binomial Regression. 2nd ed. New York, NY: Cambridge University Press; 2011.
21.
van Buuren  S.  Multiple imputation of discrete and continuous data by fully conditional specification. Stat Methods Med Res. 2007;16(3):219-242.
PubMedArticle
22.
Pulido  T, Adzerikho  I, Channick  RN,  et al.  SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809-818.
PubMedArticle
23.
Raghu  G, Million-Rousseau  R, Morganti  A,  et al.  Macitentan for the treatment of idiopathic pulmonary fibrosis. Eur Respir J. 2013;42(6):1622-1632.
PubMedArticle
24.
Kowal-Bielecka  O, Landewé  R, Avouac  J,  et al.  EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2009;68(5):620-628.
PubMedArticle
25.
Tingey  T, Shu  J, Smuczek  J, Pope  J.  Meta-analysis of healing and prevention of digital ulcers in systemic sclerosis. Arthritis Care Res (Hoboken). 2013;65(9):1460-1471.
PubMedArticle
26.
Hachulla  E, Hatron  PY, Carpentier  P,  et al.  Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis (published online May 20, 2015). Ann Rheum Dis. doi:10.1136/annrheumdis-2014-207001.
27.
Denton  CP, Krieg  T, Guillevin  L,  et al.  Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis. Ann Rheum Dis. 2012;71(5):718-721.
PubMedArticle
28.
Walker  KM, Pope  J, participating members of the Schleroderma Clinical Trials Consortium; Canadian Scleroderma Research Group.  Treatment of systemic sclerosis complications: what to use when first-line treatment fails. Semin Arthritis Rheum. 2012;42(1):42-55.
PubMedArticle
29.
Morelli  S, Ferri  C, Polettini  E,  et al.  Plasma endothelin-1 levels, pulmonary hypertension, and lung fibrosis in patients with systemic sclerosis. Am J Med. 1995;99(3):255-260.
PubMedArticle
30.
Yamane  K, Miyauchi  T, Suzuki  N,  et al.  Significance of plasma endothelin-1 levels in patients with systemic sclerosis. J Rheumatol. 1992;19(10):1566-1571.
PubMed
31.
Vancheeswaran  R, Magoulas  T, Efrat  G,  et al.  Circulating endothelin-1 levels in systemic sclerosis subsets. J Rheumatol. 1994;21(10):1838-1844.
PubMed
32.
Iglarz  M, Binkert  C, Morrison  K,  et al.  Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008;327(3):736-745.
PubMedArticle
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