RHEUMATOLOGY

Rheumatology 2010;49:583587
doi:10.1093/rheumatology/kep413
Advance Access publication 29 December 2009

Concise report
Effect of the dual endothelin receptor antagonist
bosentan on Raynauds phenomenon secondary
to systemic sclerosis: a double-blind prospective,
randomized, placebo-controlled pilot study
Van Anh Nguyen1,*, Klaus Eisendle1,*, Ingrid Gruber2, Beate Hugl2,
Daniela Reider1 and Norbert Reider1

Abstract
Objective. To investigate the efficacy of the endothelin receptor antagonist, bosentan, in patients with RP
secondary to SSc without pre-existing digital ulcers.
Methods. Single-centre, randomized, prospective, double-blinded comparison of bosentan and placebo.
Patients received either 62.5 mg bosentan twice daily for 4 weeks, followed by 125 mg twice daily for
12 weeks or matching doses of placebo.

Conclusions. Bosentan is not effective in SSc-related RP without pre-existing digital ulcers, but it might
benefit functional impairment in those patients.
Trial Registration. European Union Drug Regulating Authorities Clinical Trials, https://eudract.emea.
europa.eu, EudraCT-Nr 2004-002686-21.
Key words: Raynauds phenomenon, Systemic sclerosis, Bosentan, Endothelin receptor antagonist, Clinical
trial, HAQ-disability index, United Kingdom Functional score.

Introduction
RP is defined as episodic excessive vasospastic response
of the blood vessels to cold, stress or medication, leading
to pallor and cyanosis/redness of the distal extremities [1].
The severity varies from mild, infrequent episodes to
severe daily attacks that may significantly alter the quality
1

Department of Dermatology and 2Department of Vascular Surgery,

Innsbruck Medical University, Innsbruck, Austria.
Submitted 8 January 2009; revised version accepted
6 November 2009.
Correspondence to: Klaus Eisendle, Department of Dermatology,
Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck,
Austria. E-mail: klaus.eisendle@uki.at
*Van Anh Nguyen and Klaus Eisendle equally contributed to this work.

of life, and become complicated by fingertip ulceration

and gangrene in patients with SSc (scleroderma), an autoimmune disease characterized by vascular pathology,
cutaneous and visceral fibrosis [2]. Such trophic changes
are frequently accompanied by wound healing disorders,
with a heightened risk for infections and amputation.
The physiopathological mechanisms of SSc-associated
RP are still unclear [3]. Evidence suggests endothelial cell
injury, with subsequent imbalance of vascular factors in
favour of vasoconstriction. Proliferative structural vascular
alterations and platelet activation with increased viscosity
and aggregation may be additional causative factors. In
recent years, the role of ET-1 in the aetiopathogenesis of
vascular dysfunction in SSc has gained considerable
attention [4]. ET-1, found in high concentrations in

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CLINICAL
SCIENCE

Results. Of the 17 patients enrolled, 16 completed the study and 1 withdrew from the study due to the
reversible development of peripheral oedema. Compared with placebo, bosentan did not improve the
frequency, duration, pain or severity of RP attacks. However, in contrast to placebo, bosentan significantly
improved the functional scores. With respect to baseline, the scleroderma HAQ disability index changes
were in favour of bosentan at Weeks 12 (P = 0.03) and 20 (P = 0.01), and the United Kingdom functional
score changes at Weeks 8 (P = 0.038) and 16 (P = 0.039).

Van Anh Nguyen et al.

plasma of SSc patients, is a potent endogenous vasoconstrictor and acts via the receptors ETs A and B.
At present, no complete satisfactory treatment exists
for RP secondary to SSc [5]. Recent studies revealed
bosentan, an oral ET receptor antagonist, to be effective
in the treatment of pulmonary hypertension and in the
prevention of new digital ulcers in SSc [6]. Herein, we
investigated for the first time the effectiveness of bosentan
on vasospastic symptoms and functional disability in
patients with SSc-related RP without pre-existing digital
ulcers in a randomized, double-blind, placebo-controlled
prospective pilot study.

and seven in the winter of 2006. Bosentan was provided

by Actelion (Allschwil, Switzerland), blinding and encapsulation of the tablets were performed by an independent
dermatologist of our department. The primary outcome
was the change in severity of RP attacks, measured by
the Raynaud condition score (RCS), and its related variables frequency, duration and pain at the end of the treatment period at Week 16 compared with the baseline. The
secondary outcome was the effect of duration at Weeks
20 and 24 and the effect of bosentan on SSc-related functional impairment after drug discontinuation at Weeks 20
and 24.

Methods

Measurements

Selection of patients
Outpatients with RP secondary to lc/dcSSc and CREST
syndrome were selected. Patients fulfilled the ACR criteria
for diagnosis of SSc [7] or had three of five features of
CREST syndrome. In addition, all patients experienced
abnormal capillaries of the fingernail fold, including
drop-out, dilatation and microhaemorrhages. To be eligible, patients had to be at least 18 years old and suffer
from three or more painful RP attacks a week. Patients
were excluded if they had primary RP or RP not associated with SSc, active digital ulcer or gangrene, abnormal
haemostasis, platelet alterations and evidence of uncontrolled cardiovascular, pulmonary, hepatic or renal disease. Other exclusion criteria were treatment
with prostanoids within 3 months of enrolment, previous
use of bosentan or other ET receptor blockers,
phosphodiesterase-V-inhibitors and any medication contraindicating the administration of bosentan. Vasodilator
drugs for arterial hypertension and the use of hand warmers or electric gloves were allowed, whereas topical
treatment with glyceryl nitrate and therapy with paraffin
wax hand baths were discontinued 4 weeks before starting the study. Women of child-bearing potential were
required to have a negative pregnancy test before study
initiation and apply effective contraceptive methods. All
subjects were informed about the nature and aim of the
study, and gave their informed written consent to participate. The study was approved by the institutional ethics
committee at the Medical University of Innsbruck and the
Austrian Ministry of Health.

Study design
The study was designed as a prospective, randomized,
single-centre, observer-blinded, placebo-controlled trial
and was conducted over the cold winter months to maximize the development of RP as well as to minimize the
seasonal effects on RP. A 2-week pre-treatment period
was followed by 16 weeks of treatment with study medication and 8 weeks of post-treatment follow-up. Patients
were reviewed every 4 weeks. In all, 17 patients with
SSc-related RP were randomly assigned to receive
either 62.5 mg bosentan twice daily for 4 weeks, followed
by 125 mg twice daily for 12 weeks, or matching doses of
placebo. Ten patients were recruited in the winter of 2005

584

At each visit, the presence of digital ulcers was recorded;

blood samples were collected for routine laboratory analysis and pregnancy test carried out in women of
child-bearing age. Participants were asked to complete
questionnaires that monitored their functional abilities
and perceived pain due to RP. They quantified the severity
of pain to which RP affected their daily activity by means
of a 100-mm visual analogue scale (VAS) with 0 representing minimum and 100 representing maximum severity.
The functional ability status was evaluated using the scleroderma HAQ disability index (HAQ-DI) and United
Kingdom Functional score (UKFS) [8, 9]. While HAQ-DI
measures physical disability in eight domains of function
(dressing/grooming, arising, eating, walking, hygiene,
reach, grip and activity), UKFS focuses on disability
caused by proximal muscle weakness and skin tightness
in the upper and lower limbs. Questions were scored from
zero (without difficulty/able to perform in a normal manner)
to three (unable to do/impossible to achieve). Patients
were instructed to record daily the total number and duration of each RP attack and the overall discomfort due to
RP attacks, expressed by RCS, on a 010 ordinal scale (0
points: subject did not feel handicapped, 10 points: subject felt extremely handicapped by RP). Symptom diaries
were collected each month, and data from the RP attack
diary were averaged over a 4-week period.

Statistical analysis
Calculations were performed using SPSS statistical software (SPSS for Windows, version 14.0; SPSS, Chicago,
IL, USA), and values were expressed by mean, showing
the 95% CIs. P < 0.05 was considered statistically significant. Differences from baseline were assessed for paired
data at various observation times by the Wilcoxon signed
rank test. For between-group evaluation, the absolute
changes from baseline values were compared using the
non-parametric MannWhitney U-test.

Results
Demographic data
Both treatment groups were comparable in terms of sex,
age, disease duration, distribution of SSc types and vasodilating drugs (Table 1). Of the 17 female patients, 9 were
randomized to receive bosentan and 8 to receive placebo.

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Bosentan in RP and SSc

TABLE 1 Details of the demographic and clinical characteristics of patients in the bosentan and placebo group
Characteristic

Placebo

Bosentan

No. of patients
Age, median (range) S.D., years
Female sex, n (%)
Current smokers, n (%)
Clinical history
Duration of disease, median (range) S.D., years
Limited SSc, n (%)
Diffuse SSc, n (%)
CREST, n (%)
Clinical features
Capillaroscopic changes, n (%)
Esophageal alterations, n (%)
Pulmonary alterations, n (%)
Renal alterations, n (%)
Therapy before study
ACE inhibitors, n (%)
AGTR1 antagonists, n (%)
Calcium channel blockers, n (%)

8
63.5 (4573) 9.9
8 (100)
0 (0)

9
43 (3664) 11.2
9 (100)
1 (11.1)

Sixteen patients completed the study, one patient withdrew due to treatment-related peripheral oedema. No
serious adverse reactions or effects on routine haematological or biochemical parameters were observed. During
the study, one placebo and two bosentan patients developed digital ulceration with similar healing time.

Primary outcome: overall discomfort (RCS and VAS),

frequency and duration of RP attacks
RCS improved in both bosentan and placebo patients, but
the difference within and between the groups failed to
reach statistical significance. At Week 16, RCS was
reduced by 36% (95% CI 75, 4) with placebo, whereas
the percentage reduction settled down to 31% (95% CI
66, 4) with bosentan (Fig. 1a). No difference in VAS was
seen at the primary endpoint (Week 16). However, at
Week 4, bosentan patients reported a significant increase
in severity of RP pain of 22 mm (95% CI 3, 41; P = 0.018)
on VAS that remained higher than the baseline through
Week 16, though not statistically significant. This was in
contrast to placebo patients, showing no significant differences in VAS compared with baseline. Comparing
baseline VAS changes between both groups, placebo
was significantly better with a 27% (95% CI 93, 147)
improvement for placebo vs a 531% (95% CI 266,
1328) worsening for bosentan (P = 0.028) at Week 4 and
with 53% (95% CI 90, 16253) improvement for placebo vs 253% (95% CI 93, 599) worsening for bosentan
(P = 0.01) at Week 20.
At baseline, no differences in the number and average
daily duration of RP attacks were measurable between the
treatment groups. During the study period, the average
daily frequency of RP attacks significantly decreased in
both groups. For bosentan, there was a significant
decrease from baseline at Weeks 12 and 20 and for placebo at Weeks 8, 12 and 16. At Week 16, the placebo

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5
3
1
4

(110) 3.0
(37.5)
(12.5)
(50)

4
3
3
3

(111) 3.2
(33.3)
(33.3)
(33.3)

8
2
3
1

(100)
(25)
(37.5)
(12.5)

9
3
6
0

(100)
(33.3)
(66.7)
(0)

2 (25)
2 (25)
4 (50)

2 (22.2)
1 (11.1)
5 (55.5)

response was 57% (95% CI 86, 27; P = 0.017),

whereas bosentan produced a non-significant reduction
in episode frequency of
30% (95% CI
62, 2;
P = 0.08). At Weeks 16 and 20, a significant reduction in
the average daily duration of attacks was observed in both
groups compared with baseline: 60% (95% CI 91,
26; P = 0.028) and 71% (95% CI 95, 47; P = 0.018)
for placebo and 26% (95% CI 39, 13; P = 0.012) and
44% (95% CI
68,
21; P = 0.012) for bosentan.
Between-group comparison revealed no significant difference in the reduction of number and duration of RP
attacks.

Secondary outcome: functional assessment

(HAQ-DI, UKFS)
The baseline HAQ-DI was 0.81 (95% CI 0.3, 1.3) in bosentan patients and 0.5 (95% CI 0.2, 1.2) in placebo
patients. A statistically significant decrease (improvement)
of 39% (95% CI 69, 9; P = 0.028) and 39% (95% CI
73, 4; P = 0.028) from baseline was seen with bosentan, whereas a non-significant increase (worsening) of
51% (95% CI 39, 140) and of 12.8% (95% CI 20, 45)
was noted at Weeks 12 and 20 with placebo (Fig. 1b).
Between-group comparison of the baseline changes confirmed a statistically significant difference at Weeks 12
(P = 0.03) and 20 (P = 0.01). The baseline UKFS was 3.5
(95% CI 0, 7) in the bosentan group and 6.6 (95% CI 3, 11)
in the placebo group. Bosentan patients recorded a significant improvement in the UKFS of 42% (95% CI 75,
8; P = 0.041) at Week 8 and of 35% (95% CI 65, 6;
P = 0.039) at Week 16, whereas placebo patients displayed a non-significant worsening of 25% (95% CI
21, 71) at Week 8 and a non-significant improvement
of
5% (95% CI
61, 52) at Week 16 (Fig. 1c).
Between-group comparison confirmed a significant
difference in the baseline changes at Weeks 8

585

Van Anh Nguyen et al.

FIG. 1 The mean percentage changes from baseline with

of RCS (a), HAQ-DI (b) and UKFS (c) at different
control visits.

ulcers, nailfold capillaroscopy, thermography or serum

ET-1 levels.

(a)

Discussion

S.D.

40

Mean percentage changes

from baseline in RCS

20
0
20
40
60
80
100
120
Baseline

Week 4

Week 8

Week 12

Treatment
Placebo

200
*

150
Mean percentage changes
from baseline in HAQ-DI

Week 20

Follow-up

Bosentan

(b)

Week 16

100
*

50
0
50
100
Baseline

Week 4

* P 0.05

(c)

Bosentan

Placebo

100
*

80
Mean percentage changes
from baseline in UKFS

Week 8 Week 12 Week 16 Week 20 Week 24

Follow-up
Treatment

60

40
20
0
20
40
60
80
100
Baseline

Week 4

Week 8

Week 12 Week 16 Week 20 Week 24

Treatment
* P 0.05

Bosentan

Follow-up
Placebo

An asterisk indicates a significant difference between the

two groups.
(P = 0.038) and 16 (P = 0.021). At Week 24, both HAQ-DI
and UKFS re-approached baseline values in the bosentan
group.

Digital ulcers, nailfold capillaroscopy, thermography

and vascular markers
No statistical differences were observed between the
treatment groups regarding the development of digital

586

This is the first randomized, double-blind, placebocontrolled pilot study, assessing the efficacy of bosentan
in treating patients with SSc-related RP without
pre-existing digital ulcers.
Compared with placebo, bosentan failed to reduce
RCS, or the number and duration of RP attacks. In contrast, bosentan was shown to be effective in improving
functional disabilities. HAQ-DI and UKFS decreased significantly and returned to baseline values after treatment.
VAS data provided an opposite result, with worsening in
severity of RP pain at the start of therapy, which remained
higher than the baseline, although not statistically significant. An explanation for the observed dissociation
between improved functional disabilities and ineffectiveness of bosentan regarding RP might be the variation in
the pathophysiological mechanisms of SSc-related RP.
This supports the hypothesis that factors other than
ET-1 may additionally contribute to its development.
The initial worsening of VAS could also be explained by
a tissue and/or vascular remodelling as a result of bosentan therapy. In such a case, the high VAS would decrease
to lower values if the treatment period had been extended.
Thus, this pilot study is restricted by its limitations. It is
too underpowered to detect small treatment effects,
misses temperature correction and is a parallel rather
than a crossover design. Furthermore, due to the small
numbers, the CIs are often very wide. Nevertheless, our
observations confirm other blinded studies, revealing similar findings in SSc patients with RP and pre-existing digital ulcers. Several reports described the successful, but
non-blinded approach of bosentan in the treatment of digital ulcers in SSc patients [1015]. Recently, two
double-blinded studies showed prevention of new digital
ulcers and improvement of HAQ-DI with bosentan.
Consistent with our findings, the authors were unable to
demonstrate the effectiveness of RP [6, 16]. However, two
non-controlled and open-label studies reported both
accelerated healing of digital ulcers and improvement of
RP [17, 18]. Similarly, one case report revealed improvement in HAQ-DI, pain, number and severity of RP attacks
in two SSc patients without pre-existing digital ulcers [19],
whereas another non-blinded study failed to document
any beneficial effect on HAQ-DI, VAS or development of
digital ulcers [20]. Data regarding the clinical benefit of
bosentan on SSc-related RP are contradictory at first
glance, but a clearer picture emerges when only
placebo-controlled trials in which bosentan is considered
to be ineffective in SSc-related RP are taken into account,
emphasizing the importance of placebo-controlled trials.
In summary, we conclude that bosentan is not effective
in SSc-associated RP without pre-existing digital ulcers.
However, given the small number of patients, a larger
study might show more clearly its benefits in improving
the functional impairment in those patients.

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Bosentan in RP and SSc

Rheumatology key messages

Bosentan is not effective against RP in patients with
RP secondary to SSc.
. Bosentan might benefit functional impairment in
patients with RP secondary to SSc.
.

Acknowledgement
Funding: Medication was provided
Pharmaceuticals, Austria GmbH.

by

Actelion

Disclosure statement: N.R. received bosentan as a gift

from Actelion and a grant for study expenses. All other
authors have declared no conflicts of interest.

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