Rheumatology Advance Access originally published online on November 20, 2006
Rheumatology 2007 46(2):363-364; doi:10.1093/rheumatology/kel383
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LETTERS TO THE EDITOR |
Assessment of digital vascular structure and function in response to bosentan in patients with systemic sclerosis-related Raynaud's phenomenon
Rheumatic Diseases Centre and 1Biostatistics Group, University of Manchester, Hope Hospital, Salford M6 8HD
Correspondence to: Dr A. L. Herrick. E-mail: ariane.herrick{at}manchester.ac.uk
SIR, In recent years, endothelin (ET)-1 has been strongly implicated in the pathogenesis of systemic sclerosis (SSc) [1] and it has recently been shown that the ET-1 receptor antagonist bosentan confers benefit in SSc-related digital ulceration [2]. ET-1, as well as being a potent vasocontrictor, has effects on vascular remodelling [3], and it is therefore possible that bosentan, by blocking ET-1, might favourably influence the structural vascular abnormality which is known to play a major role in SSc-related digital vascular disease [4, 5].
Against this background, our aim was to measure, in an open study, the effects of bosentan (acute and after 6 months’ treatment) on digital vascular structure and function in patients with SSc-related Raynaud's phenomenon.
Eighteen patients (7 males, 11 females; median age 52 yrs, range 34–74 yrs), were recruited into the study. All had SSc (12 limited cutaneous and 6 diffuse cutaneous disease). The median duration of Raynaud's phenomenon was 15 yrs, range 3–61 yrs. The treatment period was 24 weeks. The dose administered was 62.5 mg bd for 4 weeks, then 125 mg bd for the remainder of the study. The study was approved by the Salford and Trafford Local Research Ethics Committee. All patients signed informed consent.
At baseline the subject had an acclimatization period, at an ambient room temperature of 23°C, prior to the vascular physiological measurements outlined subsequently. Outcome measures, obtained/performed at baseline, were as follows:
- The disability index of the health assessment questionnaire (HAQ).
- Visual analogue scales (VAS) for Raynaud's phenomenon, digital ulceration and overall disease activity.
- Laser Doppler imaging (a measure of microvascular blood flow) of the dorsum of the left hand. The mean perfusion was measured (a) in the dorsum of the hand and (b) in the fingertips. The distal dorsal difference (DDD) was calculated, by subtracting the mean dorsal value from the mean finger value, as previously described [6].
- Endothelial-dependent (in response to acetylcholine chloride) and endothelial-independent (in response to sodium nitroprusside) iontophoresis (measures of microvascular function), as previously described [7]. Iontophoresis was performed over 90 s at a charge of 30 µA, with chambers applied to the index and middle proximal phalanx, using 1% solutions of acetylcholine chloride and sodium nitroprusside.
- Nailfold capillary density and dimensions (measures of microvascular structure), measured using videomicroscopy, with a magnification of 300x in the non-dominant ring finger. The total number of capillaries in the distal row per millimetre was recorded, as well as total capillary width, arterial diameter, venous diameter and apical diameter. Diameters were the mean of the same five recognizable capillaries from each visit (or as many capillaries up to five that were available for analysis) [8].
- Finger systolic pressures (a measure of digital artery function). Digital systolic pressures at finger temperatures of 23°C and 15°C were measured by inflating a suitably sized finger cuff to 200 mmHg for a period of 5 min and rapidly releasing the cuff to measure the pressure. The digital systolic pressures were then divided by the brachial pressure and plotted for each visit.
All measurements were repeated at 4 h post 62.5 mg bosentan, and at 4, 8, 16 and 24 weeks, excepting the HAQ and VAS (which were not requested at 4 h) and the laser Doppler imaging studies (which were only performed at 4 h and at 24 weeks). The data were subjected to repeated-measures analysis of variance.
Of the 18 patients recruited into the study, 13 completed, only one withdrew because of side effects (altered liver function tests at the 16-week visit). None of the parameters measured was significantly different during/after 24 weeks’ treatment with bosentan and there was no evidence of any linear trends. Figure 1 shows a sequence of nailfold capillaroscopy images.
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In conclusion, treatment with bosentan was not associated with any measurable changes in microvascular structure or function, in finger systolic pressures or patient opinion. While these findings offer no evidence that bosentan confers benefit, there are a number of possible reasons for these ‘negative’ results:
- This was an uncontrolled study, and it is possible that there might have been deterioration without treatment. In other words, bosentan stabilized (rather than improved), SSc-related digital vascular disease.
- The period of study (6 months) was too short to observe changes in vascular structure and function.
- All patients had well-established disease (evidenced by the long duration of Raynaud's phenomenon). Although the benefit of bosentan in SSc-related digital ulceration was most marked in those patients most severely affected) [2], it could be argued that for vascular remodelling to occur patients must be studied early in their disease, when structural microvascular change is more likely to be reversible.
Therefore, future studies should ideally include a placebo control, be longer-term, and include patients with early disease.
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Acknowledgement |
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We are grateful to Actelion for supplying bosentan.
Conflict of interest statement. A. H. has undertaken consultant work for Actelion. The other authors have declared no conflicts of interest.
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References |
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TopAcknowledgementReferences |
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- Mayes MD. (2003) Endothelin and endothelin receptor antagonists in systemic rheumatic disease. Arthritis Rheum 48:1190–9.[CrossRef][Web of Science][Medline]
- Korn JH, Mayes M, Matucci Cerinic M, et al. (2004) Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 50:3985–93.[CrossRef][Web of Science][Medline]
- Kirchengast M and Munter K. (1999) Endothelin-1 and endothelin receptor antagonists in cardiovascular remodeling. PSEBM 221:312–25.[CrossRef][Medline]
- Campbell PM and LeRoy EC. (1975) Pathogenesis of systemic sclerosis: a vascular hypothesis. Sem Arthritis Rheum 4:351–68.[CrossRef][Medline]
- Rodnan GP, Myerowitz RL, Justh GO. (1980) Morphological changes in the digital arteries of patients with progressive systemic sclerosis (scleroderma) and Raynauds phenomenon. Medicine 59:393–408.[Medline]
- Clark S, Campbell F, Moore T, Jayson MI, King TA, Herrick AL. (1999) Laser Doppler imaging—a new technique for quantifying microcirculatory flow in patients with primary Raynaud's phenomenon and systemic sclerosis. Microvascular Research 57:284–91.[CrossRef][Web of Science][Medline]
- Anderson ME, Moore TL, Lunt M, Herrick AL. (2004) Digital iontophoresis of vasoactive substances as measured by laser Doppler imaging—a non-invasive technique by which to measure microvascular dysfunction in Raynaud's phenomenon. Rheumatology 43:986–91.
[Abstract/Free Full Text] - Anderson ME, Allen PD, Moore T, Hillier V, Taylor CJ, Herrick AL. (2005) Computerised nailfold video capillaroscopy—a new tool for the assessment of Raynaud's phenomenon. J Rheumatol 32:841–8.
[Abstract/Free Full Text]
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