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Ann Rheum Dis. 2007 October; 66(10): 1398–1399.
PMCID: PMC1994313

Bosentan therapy for patients with severe Raynaud's phenomenon in systemic sclerosis

Raynaud's phenomenon (RP) is present in more than 95% of patients with systemic sclerosis (SSc). Its frequency and severity in combination with the presence of digital ulcers affect the quality of life of patients.1 Although the aetiology of RP is multifactorial, endothelin‐1 has been suggested to play a role in its pathogenesis.2 Bosentan, an endothelin‐1 receptor antagonist, has been shown to be effective in preventing the occurrence of new digital ulcers when compared with placebo.3

Against this background, we hypothesized that bosentan can be a useful and effective strategy in SSc patients with RP. Therefore we assessed the effects of bosentan on RP on subjective and objective outcome parameters. Patients were allowed to continue their oral vasodilating therapy, but parenteral prostanoids had to be stopped one month before study entry.

Fifteen patients (14 women, one man; mean age 52 years, range 34–70) were included. All had limited cutaneous SSc with a median disease duration of four years (range 2–8) and a median RP duration of 10 years (range 4–17). A pretreatment period of four weeks was followed by 16 weeks of bosentan treatment, and a four‐week follow‐up period. Bosentan was administered as 62.5 mg twice a day for 4 weeks, then 125 mg twice a day for 12 weeks. Patients had to keep a diary of RP attacks during the complete study period, and photoelectric plethysmography (PEP) during cooling and rewarming4 was assessed at baseline, after eight and 16 weeks of treatment, and at the end of the follow‐up period.

Bosentan treatment resulted in a significant reduction in the daily duration, number and severity of RP attacks. The outdoor temperature was, however, significantly higher from week 12 until the end of the study. A significant improvement was already seen after eight weeks of treatment during which the outdoor temperature was stable (table 11).

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Table 1 Outcome data of the Raynaud's phenomenon diary*

Despite the reported improvement in RP, blood flow determined by PEP during cooling and rewarming did not improve during treatment with bosentan (fig 11).

figure ar73684.f1
Figure 1 Photoelectric plethysmography (PEP) during cooling and rewarming. Mean values at baseline ([filled square]), week 8 ([filled triangle]), week 16 ([filled triangle]) and week 20 (♦).

In conclusion, treatment with bosentan resulted in an encouraging improvement in the frequency, duration and severity of RP attacks in patients with SSc, but we could not demonstrate an objective improvement in blood flow. The subjective improvement is in contrast with the results of the RAPIDS‐1 study, a large randomized placebo‐controlled trial in which bosentan was compared with placebo in the prevention of digital ulcers.3 One might argue that our improvement was caused by seasonal temperature differences or a placebo effect, but no difference in outdoor temperature was seen until week 12. Also, our results show a higher percentage of improvement than the approximately 20–30% found in placebo‐controlled trials of RP.5,6,7 The absence of effect on blood flow, however, confirms the previously found negative results, but an objective improvement in blood flow was not always found in positive RP trials.8 Another explanation for the lack of improvement in PEP could be intraindividual variations and the moderate reproducibility of PEP.9,10

Therefore, besides the use of a placebo group, a valid and reproducible test is needed for follow‐up evaluation of RP trials.


PEP - Photoelectric plethysmography

RP - Raynaud's phenomenon

SSc - systemic sclerosis


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