Skip Navigation


Rheumatology Advance Access originally published online on May 9, 2007
Rheumatology 2007 46(7):1079-1082; doi:10.1093/rheumatology/kem085
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
46/7/1079    most recent
kem085v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Gunawardena, H.
Right arrow Articles by McHugh, N. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gunawardena, H.
Right arrow Articles by McHugh, N. J.
Related Collections
Right arrow Systemic Sclerosis
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Maximum blood flow and microvascular regulatory responses in systemic sclerosis

H. Gunawardena, N. D. Harris1, C. Carmichael2 and N. J. McHugh

Rheumatology, Royal National Hospital for Rheumatic Diseases, 1Clinical Measurements, Royal National Hospital for Rheumatic Diseases, University of Bath, Bath and 2University of Bath, Bath, UK.

Correspondence to: N. J. McHugh, Rheumatology, Royal National Hospital for Rheumatic Diseases, Bath, BA1 1RL, UK. E-mail: neil.mchugh{at}rnhrd-tr.swest.nhs.uk


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objectives. To investigate microvascular function using laser Doppler imaging (LDI) following response to hyperaemia, neurovascular reflex and iontophoresis in systemic sclerosis (SSc) in comparison with primary Raynaud's phenomenon (PRP) and age-matched controls. A secondary aim was to evaluate if SSc patients with a higher Medsger vascular score have lower endothelial responses.

Methods. Twenty patients with SSc, 10 PRP and 17 controls were studied. Patients with SSc were scored using the vascular component of the Medsger severity scale. A baseline LDI scan was performed on the dorsal aspect of both hands. Digital responses were quantified following maximum hyperaemic response (MHR), contralateral vasoconstrictor response (CLVc) and iontophoresis with acetylcholine (Ach)-endothelial dependent and sodium nitroprusside (SNP)-endothelial independent. Mean blood flow was quantified over a standard region of interest.

Results. MHR was lower in SSc patients compared with controls (P < 0.001). A similar trend was seen when comparing SSc with PRP although this did not reach significance (P = 0.07). CLVc and Ach/MHR were lower in SSc vs PRP (P < 0.05) and controls (P < 0.001). No difference was observed in MHR, CLVc and Ach/MHR between PRP and controls. Overall, SNP/MHR was similar in all the three groups. SSc patients with a higher Medsger vascular score had lower endothelial-dependent (P < 0.01) and independent (P < 0.05) responses.

Conclusion. SSc patients have abnormal microvascular regulatory responses compared with PRP and controls. This study also suggests that the degree of endothelial dysfunction may be related to the degree of peripheral vascular involvement.

KEY WORDS: Endothelin, Microvascular, Laser Doppler imaging, Raynaud's phenomenon, Systemic sclerosis


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Systemic sclerosis (SSc) is an autoimmune disorder characterized by vasculopathy and tissue fibrosis [1]. Early disease is mediated through microvascular dysfunction secondary to a number of factors including endothelial damage, over-expression of specific adhesion molecules and perivascular inflammatory cell infiltration [2–5]. In SSc, pathological changes are observed not just in affected skin but also normal skin, indicating early changes in endothelial function [6]. Markers of endothelial activation including endothelial leucocyte-adherence molecule type 1 [7], vascular endothelial growth factor, soluble vascular cell adhesion molecule-1, endothelin-1 (ET-1), IL-6 and IL-10 are all increased in SSc [8–10]. In particular, the balance of vasoactive peptides (ET-1, nitric oxide and prostacyclin) is disturbed and this combined with pro-inflammatory mediators affects vascular integrity and components of the extra-cellular matrix [11]. In addition to changes in endothelial cell function, microvascular disease in SSc is also characterized by abnormal neurovascular control secondary to neuronal damage [12, 13]. The combined effect of all these factors leads to changes in vascular tone and structure with eventual fibro-occlusion of the microvasculature. This pathological hallmark lesion is implicated in a number of clinical manifestations of SSc including Raynaud's phenomenon, digital ulceration, pulmonary arterial hypertension (PHT) and hypertensive renal crisis.

There is a need for accurate and sensitive techniques to quantify microvascular disease in SSc. Laser Doppler imaging (LDI) is a tool to measure cutaneous microvascular flow and previous studies have shown how laser Doppler can demonstrate abnormalities in vascular function in patients with SSc [14–20]. Early detection of microvascular changes and the relationship with disease progression or severity may provide further insights into the pathophysiology of SSc, with clinical implications in terms of disease monitoring. In this study, we have developed an LDI protocol to measure baseline microvascular flow and then assess changes in tissue perfusion following both a physiological challenge [maximum hyperaemic response (MHR) and neurovascular regulatory response] and pharmacological challenge (iontophoresis: endothelium-dependent and -independent response). The primary aim was to compare microvascular regulatory responses in SSc patients with primary Raynaud's phenomenon (PRP) and age-matched control subjects. In addition, we have evaluated how digital microvascular responses relate to clinical disease based on the Medsger peripheral vascular severity score [21].


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
Patients
Patients currently attending our institution were invited to participate in the study and positive respondents were recruited including 20 patients fulfilling the American College of Rheumatology (formerly, the American Rheumatology Association) preliminary criteria for the classification of SSc [22]. Ten patients with PRP (no clinical or serological evidence of connective tissue disease over 2 yrs) and 17 healthy controls were also recruited. Patients continued their regular medications including specific oral vasodilator therapy. The vascular domain of the Medsger SSc disease severity scale was performed prior to LDI assessment [21]. In summary, the scale scores patients from 0 to 4 depending on clinical peripheral vascular features. Patients with a history of Raynaud's scored 1 (mild), digital pitting scars scored 2 (moderate), digital ulcerations scored 3 (severe) and those with digital gangrene scored 4 (end-stage). All patients were screened for isolated pulmonary hypertension (PHT) with lung function and echocardiography. Where indicated a right heart catheter was performed.

The study was approved by the Bath Local Ethics Committee and all patients and controls gave informed written consent. Exclusion criteria included those unable to give informed consent, subjects with a history of uncontrolled systemic hypertension, hyperlipidaemia, cardiac failure, hepatic failure, diabetics, smokers and pregnant or lactating women.

LDI protocol
Scanning red LDI-2 (Moor Instruments Ltd, Axmister, Devon) was performed after resting the subject in a temperature-controlled room at 23°C for 20 min. A baseline scan of both hands (dorsal aspect of both sets of fingers) was initially performed including baseline flux of the individual fingers (index, middle and ring) to establish the degree of variability between sites.

To assess microvascular responses, the following procedures were applied. The dorsal aspect of the ring finger of the right hand was heated at 44°C by application of a Peltier temperature-controlled sprung metal plate (VU Instruments, Amsterdam) for 6 min to elicit a MHR. Serial LDI of the heated area was then performed over 10 min (maximum of eight scans) to determine the maximum blood flow quantified in LDI flux perfusion units (Fpu). Single spot laser Doppler flowmetry was performed over the right middle finger nailbed in response to immersion of the contralateral hand in water at 18°C for 30 s to determine the contralateral vasoconstrictor response (CLVc). This neurovascular regulatory response was quantified as a percentage reduction in blood flow following immersion (mean flow in Fpu) compared with mean flow (Fpu) for 10 s prior to immersion. Maximum nitric oxide-dependent and -independent vasodilator response using iontophoresis was assessed last. Two Perspex chambers were used; one was filled with 1 ml of 2% acetylcholine chloride (Ach) (Sigma) mixed with 4 ml of sterile water (applied to the positive electrode) and the other chamber filled with 5% sodium nitroprusside (SNP) (50 mg powder for infusion, Faulding DBL) made up with 5 ml of sterile water (applied to the negative electrode). The dorsal aspect (the region between the distal interphalangeal and proximal interphalangeal joint) of the index finger was placed in the Ach water chamber and the middle finger into the SNP water chamber. A 250 µA current was applied for 3 min, using Moor Instruments Iontophoresis controller and both drugs were iontophoresed simultaneously. The current was monitored during iontophoretic application for each subject. LDI was performed at baseline and then again at 1-min intervals after iontophoresis, to determine maximum perfusion response to Ach and SNP in Fpu. The maximum vasodilation to Ach and SNP was recorded, and then expressed as a percentage of the MHR.

The distance of the scanner to the subject was kept as uniform as possible (between 45 and 50 cm). Blood flow was quantified using in-built image analysis software over the region of interest (ROI); this was defined using the colour flux image and confirmed on the corresponding photographic image. Because of unavoidable minor differences, for example a slight difference in finger position in the iontophoresis chamber, the ROI was not always the same but was within the range of 0.4–0.6 cm2 between subjects. The ROI between serial scans in the individual subjects was the same for data analysis including assessment at baseline and microvascular responses. Prior to each study session, the LDI was recalibrated using a flux standard supplied with LDI.

Statistical analysis
Statistics were conducted using SPSS for Windows (version 12) software. All data were tested to see if assumptions of normality held true. The assumptions of normality cannot be assumed within the data set particularly due to the small sample size, therefore non-parametric tests were used throughout. To compare baseline flow variability between individual fingers and hands, Friedman's test and the Wilcoxon-signed rank test were used, respectively. The Kruskal–Wallis test was used when comparing the three study groups in terms of their MHR, CLVc and iontophoresis responses. When the Kruskal–Wallis test showed a statistically significant result the Mann–Whitney U-test was used to test individual differences between two individual study groups. Any dichotomized data were also analysed using the Mann–Whitney test. Spearman's rank order correlation was used to test for an association between disease duration and vascular responses. When comparing results, median values and inter-quartile ranges (IQR) were used as the data are non-parametric. P-values <0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
Table 1 summarizes the main features of the three study groups. Patients in the PRP group were younger but SSc patients and controls were age matched. Duration of Raynaud's phenomenon was similar between SSc and PRP patients. Three patients had diffuse cutaneous SSc (all had a modified Rodnan skin score of >14) and 17 limited cutaneous SSc (all had a Rodnan skin score <14) [23, 24]. There were no significant differences in microvascular responses between disease subtypes, although the number of patients assessed with diffuse disease was small. Eleven patients scored 1 on the Medsger vascular scale, seven patients scored 2 and two patients scored 3. In the SSc group, 10 patients were on calcium channel blockers (CCB) and three on ACE inhibitors for treatment of their Raynaud's phenomenon. Two patients with PRP were on a CCB. No patient had received intra-venous prostanoids within 6 months of their LDI study or were on endothelial receptor antagonists.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Clinical features

 
Following acclimatization, the mean blood flow was analysed individually between the index, middle and ring fingers to assess the degree of variability of baseline flow. There was no significant difference in baseline flux between fingers in any of the subject groups (supplementary data are available at Rheumatology Online). In addition, there was no difference in overall baseline flow between hands in the SSc patients (data not shown).

Figure 1 illustrates overall laser Doppler protocol results. MHR was significantly lower in SSc vs controls (P < 0.001) and lower in SSc compared with PRP (P = 0.07). CLVc percentage decrease was found to be significantly lower in patients with SSc vs PRP (P < 0.05) and controls (P < 0.001). Endothelial-dependent (Ach) response was significantly lower in the SSc group compared with PRP (P < 0.01) and controls (P < 0.001). No significant difference was observed in MHR, CLVc, Ach/MHR between PRP and the control group. Endothelial-independent (SNP) response was similar in all three groups. There was no significant difference in MHR, CLVc or vasodilator responses in SSc patients on vasoactive medication compared with those not on medications and so these results have not been reported. The current during iontophoresis was standardized and the voltage within the range of the microcirculatory controller for all subjects.


Figure 1
View larger version (27K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		FIG. 1. Microvascular responses in patients with SSc, PRP and normal control subjects. The maximum hyperaemic response (MHR) is quantified in absolute flux perfusion units (Fpu). The contralateral vasoconstrictor response (CLVc) is expressed as a percentage reduction in flux perfusion. Ach, endothelial-dependent and SNP; endothelial-independent responses are expressed as percentage of the MHR. Results are shown as median values with inter-quartile ranges (*P < 0.001: SSc vs Controls, **P < 0.05: SSc vs PRP, ***P < 0.01: SSc vs PRP).

 
No correlation was observed between disease duration and microvascular responses (data not shown). However, SSc patients with a Medsger peripheral vascular score ≥2 had a significantly lower Ach/MHR (P < 0.01) and SNP/MHR response (P < 0.05) in comparison the rest of the SSc group who scored 1 (Table 2). CLVc percentage decrease was also lower in those with higher vascular scores but this was not statistically significant. Only one patient had isolated PHT (severe) based on symptoms and pulmonary artery pressure on catheterization and this patient had the lowest endothelial responses out of the entire study group.


View this table:
[in this window]
[in a new window]

  		TABLE 2. Endothelial responses and disease severity (vascular score)

 

   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
Vascular dysfunction is one of the hallmarks of SSc and involves both the macro and microvasculature. Early in the disease process, there are abnormalities in vascular tone with subsequent changes in endothelial cell and neurovascular function. The key mediator in this process appears to be endothelial cell injury leading to a cascade of deleterious effects including vasoconstriction, fixed structural microvascular changes and tissue fibrosis. Raynaud's phenomenon is often the presenting feature of SSc and may precede skin- and organ-based disease by many years. Methods to try to elucidate whether patients presenting with Raynaud's phenomenon have an underlying connective tissue disease are limited. Autoimmune serological investigations may be helpful but changes seen on video nailfold capillaroscopy usually occur once the disease is established.

Other non-invasive methods including laser Doppler have been shown to detect changes in SSc microvasculature particularly when combined with iontophoresis. Early studies using single probe fibre-optic laser Doppler flowmetry showed inconsistent or variable results and this may have been due to heterogeneity of the area of skin studied [14–19]. Scanning LDI has the advantage of analysing blood flow over a larger surface area which is more reproducible [20, 25] and physiological day-to-day variability of iontophoresis has been previously assessed [25]. Other potential variables include current density, voltage effects and the type of solution used for iontophoresis [25–27]. The choice of solution mixed with Ach or SNP has been shown not to affect the voltage required for iontophoretic transfer [27]. In our study, we have used a large surface area combined with low-current density and the application of current through distilled water alone did not produce vasodilation (data not shown).

The potential disadvantage of previous laser Doppler studies is the lack of a biological reference. Baseline blood flow is commonly used but is quite variable even in controlled conditions and we feel is not a good reference point. In this study, we have used MHR as a biological reference (maximum vasodilation is achieved using a 44°C stimulus) and expressed maximum vasodilation with Ach and SNP against MHR, in order to improve reproducibility. In a previous pilot study, we have demonstrated good reproducibility of the technique [28], and thermal hyperaemic response was also assessed by another group [29]. With this protocol, we assess iontophoretic response at one site in relation to MHR on an adjacent finger. However, baseline flow between the three fingers used (and between hands) prior to the microvascular challenges did not show any significant variability in any of the subject groups.

MHR in itself is a useful marker of overall microvascular function. Vasodilation secondary to hyperaemia is mediated through an axonal reflex and a nitric oxide-dependent response [30, 31]. Recent studies have determined ‘thermal hyperaemia’ in patients with SSc compared with PRP and controls [29, 32]. SSc patients showed a blunted peak response and our data have demonstrated similar findings with lower MHR in the SSc group. We have also demonstrated a significantly lower CLVc in SSc compared with PRP and controls. The CLVc is a neurovascular reflex which measures sympathetic function. In normal subjects, when the ipsilateral hand is placed in cold water, vasoconstriction occurs in the contralateral warm hand via a central mechanism and this reflex is controlled primarily through efferent pre-ganglionic myelinated axonal fibres [33]. Structural damage affects myelinated and unmyelinated nerve fibres in both diffuse cutaneous SSc and limited cutaneous SSc contributing to vascular dysfunction [12-13], and we have demonstrated a blunted contralateral response in SSc patients. This damage to parasympathetic nerves may be related to endothelial cell injury leading to axonal damage.

Our study shows Ach endothelial-dependent vasodilation is impaired at an early stage in SSc, secondary to loss of vasodilator mediators in particular nitric oxide. Previous studies have shown SNP endothelial-independent response is also impaired [16, 20]. Overall, we have demonstrated similar SNP responses in our SSc, PRP patients and controls as shown in a previous study [18]. There was no correlation with any of the measures and disease duration. However, when the patients were stratified based on the Medsger peripheral vascular score those SSc patients with more severe disease had a significantly lower Ach endothelial-dependent response and SNP endothelial-independent response compared with those with Raynaud's alone. Therefore, it appears that disease severity in terms of peripheral vascular manifestations is associated with a defect in endothelium-dependent vasodilation and endothelial-independent smooth muscle dilation. In this study, some patients continued on their vasoactive treatments. However, there was no significant difference in microvascular responses when comparing SSc patients on vasodilators and those not on treatments. In addition, drugs may influence vascular tone but are unlikely to have a significant effect on endothelial function or microvascular structure.

Another question is whether patients with organ involvement in particular PHT have more severe mircovascular changes that can be detected using LDI. Certainly, markers of endothelial damage are higher in SSc compared with controls [6–10, 34] and further elevated in those with systemic organ involvement [8, 35]. It is well established that endothelial cell dysfunction plays a critical role in the pathogenesis of digital ulceration and isolated PHT. Of interest, the one patient with PHT had the lowest endothelial responses out of the entire group. These preliminary results appear promising and further work needs to be done to see if microvascular assessment using LDI can be used as a marker of overall disease severity.

In conclusion, patients with SSc have abnormal microvascular responses compared with patients with PRP and controls. This study confirms previous work that shows microvascular assessment may be a useful method of investigating patients who present with Raynaud's phenomenon. This study also suggests that the degree of microvascular dysfunction may be related to disease severity, particularly digital vascular manifestations. Further longitudinal studies are required to evaluate how endothelial cell function changes in relation to other markers of disease progression and in response to potential disease modifying treatments.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
H.G. was funded by an unrestricted educational grant from Actelion Pharmaceuticals, UK.

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Campbell PM, LeRoy EC. Pathogenesis of systemic sclerosis: a vascular hypothesis. Semin Arthritis Rheum (1975) 4:351–68.[CrossRef][Medline]
  2. Yamane K. Endothelin and collagen vascular disease: a review with special reference to Raynaud's phenomenon and systemic sclerosis. Intern Med (1994) 33:579–82.[Web of Science][Medline]
  3. Herrick AL. Vascular function in systemic sclerosis. Curr Opin Rheumatol (2000) 12:527–33.[CrossRef][Web of Science][Medline]
  4. Denton CP, Black CM. Targeted therapy comes of age in scleroderma. Trends Immunol (2005) 26:596–602.[CrossRef][Web of Science][Medline]
  5. von Bierbrauer A, Barth P, Willert J, Baerwald C, Mennel HD, Schmidt JA. Electron microscopy and capillaroscopically guided nailfold biopsy in connective tissue diseases: detection of ultrastructural changes of the microcirculatory vessels. Br J Rheumatol (1998) 37:1272–8.[Abstract/Free Full Text]
  6. Prescott RJ, Freemont AJ, Jones CJ, Hoyland J, Fielding P. Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol (1992) 166:255–63.[CrossRef][Web of Science][Medline]
  7. Claman HN, Giorno RC, Seibold JR. Endothelial and fibroblastic activation in scleroderma. The myth of the ‘uninvolved skin’. Arthritis Rheum (1991) 34:1495–501.[Web of Science][Medline]
  8. Kuryliszyn-Moskal A, Klimiuk PA, Sierakowski S. Soluble adhesion molecules (sVCAM-1, sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 in patients with systemic sclerosis: relationship to organ systemic involvement. Clin Rheumatol (2005) 24:111–16.[CrossRef][Web of Science][Medline]
  9. Choi JJ, Min DJ, Cho ML, et al. Elevated vascular endothelial growth factor in systemic sclerosis. J Rheumatol (2003) 30:1529–33.[Abstract/Free Full Text]
  10. Sato S, Hasegawa M, Takehara K. Serum levels of interleukin-6 and interleukin-10 correlate with total skin thickness score in patients with systemic sclerosis. J Dermatol Sci (2001) 27:140–6.[CrossRef][Web of Science][Medline]
  11. Mayes MD. Endothelin and endothelin receptor antagonists in systemic rheumatic disease. Arthritis Rheum (2003) 48:1190–9.[CrossRef][Web of Science][Medline]
  12. Kahaleh B, Matucci-Cerinic M. Raynaud's phenomenon and scleroderma. Dysregulated neuroendothelial control of vascular tone. Arthritis Rheum (1995) 38:14. (Review).[Medline]
  13. Terenghi G, Bunker CB, Liu YF, et al. Image analysis quantification of peptide-immunoreactive nerves in the skin of patients with Raynaud's phenomenon and systemic sclerosis. J Pathol (1991) 164:245–52.[CrossRef][Web of Science][Medline]
  14. Anderson ME, Hollis S, Moore T, Jayson MI, Herrick AL. Non-invasive assessment of vascular reactivity in forearm skin of patients with primary Raynaud's phenomenon and systemic sclerosis. Br J Rheumatol (1996) 35:1281–8.[Abstract/Free Full Text]
  15. Khan F, Litchfield SJ, McLaren M, Veale DJ, Littleford RC, Belch JJ. Oral L-arginine supplementation and cutaneous vascular responses in patients with primary Raynaud's phenomenon. Arthritis Rheum (1997) 40:352–7.[Web of Science][Medline]
  16. La Civita L, Rossi M, Vagheggini G, et al. Microvascular involvement in systemic sclerosis: laser Doppler evaluation of reactivity to acetylcholine and sodium nitroprusside by iontophoresis. Ann Rheum Dis (1998) 57:52–5.[Abstract/Free Full Text]
  17. Anderson ME, Campbell F, Hollis S, Moore T, Jayson MI, Herrick AL. Non-invasive assessment of digital vascular reactivity in patients with primary Raynaud's phenomenon and systemic sclerosis. Clin Exp Rheumatol (1999) 17:49–54.[Web of Science][Medline]
  18. Khan F, Belch JJ. Skin blood flow in patients with systemic sclerosis and Raynaud's phenomenon: effects of oral L-arginine supplementation. J Rheumatol (1999) 26:2389–94.[Web of Science][Medline]
  19. Anderson ME, Moore TL, Hollis S, Clark S, Jayson MI, Herrick AL. Endothelial-dependent vasodilation is impaired in patients with systemic sclerosis, as assessed by low dose iontophoresis. Clin Exp Rheumatol (2003) 21:403.[Web of Science][Medline]
  20. Anderson ME, Moore TL, Lunt M, Herrick AL. 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 (2004) 43:986–91.[Abstract/Free Full Text]
  21. Medsger TA Jr, Silman AJ, Steen VD, et al. A disease severity scale for systemic sclerosis: development and testing. J Rheumatol (1999) 26:2159–67.[Web of Science][Medline]
  22. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum (1980) 23:581–90.[Web of Science][Medline]
  23. LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol (1988) 15:202–5.[Web of Science][Medline]
  24. Clements PJ, Lachenbruch PA, Seibold JR, et al. Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol (1993) 20:1892–6.[Web of Science][Medline]
  25. Kubli S, Waeber B, Dalle-Ave A, Feihl F. Reproducibility of laser Doppler imaging of skin blood flow as a tool to assess endothelial function. J Cardiovasc Pharmacol (2000) 36:640–8.[CrossRef][Web of Science][Medline]
  26. Ramsay JE, Ferrell WR, Greer IA, Sattar N. Factors critical to iontophoretic assessment of vascular reactivity: implications for clinical studies of endothelial dysfunction. J Cardiovasc Pharmacol (2002) 39:9–17.[CrossRef][Web of Science][Medline]
  27. Khan F, Newton DJ, Smyth EC, Belch JJ. Influence of vehicle resistance on transdermal iontophoretic delivery of acetylcholine and sodium nitroprusside in humans. J Appl Physiol (2004) 97:883–7.[Abstract/Free Full Text]
  28. Harris ND, Hiscock S, Elvins DM, McHugh NJ. Maximum hyperaemic response as a biological reference for Laser Doppler blood flow measurements [abstract]. Microcirculation (2004) 11:527.[CrossRef][Web of Science]
  29. Boignard A, Salvat-Melis M, Carpentier PH, et al. Local hyperaemia to heating is impaired in secondary Raynaud's phenomenon. Arthritis Res Ther (2005) 7:1103–12.[CrossRef]
  30. Minson CT, Berry LT, Joyner MJ. Nitric oxide and neurally mediated regulation of skin blood flow during local heating. J Appl Physiol (2001) 91:1619–26.[Abstract/Free Full Text]
  31. Kellogg DL Jr, Liu Y, Kosiba IF, O'Donnell D. Role of nitric oxide in the vascular effects of local warming of the skin in humans. J Appl Physiol (1999) 86:1185–90.[Abstract/Free Full Text]
  32. Salvat-Melis M, Carpentier PH, Minson CT, et al. Digital thermal hyperaemia impairment does not relate to skin fibrosis or macrovascular disease in systemic sclerosis. Rheumatology (2006) 45:1490–6.[Abstract/Free Full Text]
  33. Zakrzewska-Pniewska B, Jablonska S, Kowalska-Oledzka E, Blaszczyk M, Hausmanowa-Petrusewicz I. Sympathetic skin response in scleroderma, scleroderma overlap syndromes and inflammatory myopathies. Clin Rheumatol (1999) 18:473–80.[CrossRef][Web of Science][Medline]
  34. Kuwana M, Okazaki Y, Yasuoka H, Kawakami Y, Ikeda Y. Defective vasculogenesis in systemic sclerosis. Lancet (2004) 364:603–10.[CrossRef][Web of Science][Medline]
  35. Vancheeswaran R, Magoulas T, Efrat G, et al. Circulating endothelin-1 levels in systemic sclerosis subsets–a marker of fibrosis or vascular dysfunction? J Rheumatol (1994) 21:1838–44.[Web of Science][Medline]
Submitted 11 January 2007; revised version accepted 14 March 2007.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 The Journal of RheumatologyHome page
E. ROSATO, F. BORGHESE, S. PISARRI, and F. SALSANO
Laser Doppler Perfusion Imaging Is Useful in the Study of Raynaud's Phenomenon and Improves the Capillaroscopic Diagnosis
J Rheumatol, October 1, 2009; 36(10): 2257 - 2263.
[Abstract] [Full Text] [PDF]

Home page
 Rheumatology (Oxford)Home page
M. Rossi, L. Bazzichi, C. Di Maria, F. Franzoni, K. Raimo, A. Della Rossa, G. Santoro, and S. Bombardieri
Blunted increase of digital skin vasomotion following acetylcholine and sodium nitroprusside iontophoresis in systemic sclerosis patients
Rheumatology, July 1, 2008; 47(7): 1012 - 1017.
[Abstract] [Full Text] [PDF]

Home page
 Rheumatology (Oxford)Home page
M. Roustit, G. H. Simmons, P. Carpentier, and J. L. Cracowski
Abnormal digital neurovascular response to local heating in systemic sclerosis
Rheumatology, June 1, 2008; 47(6): 860 - 864.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
46/7/1079    most recent
kem085v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Gunawardena, H.
Right arrow Articles by McHugh, N. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gunawardena, H.
Right arrow Articles by McHugh, N. J.
Related Collections
Right arrow Systemic Sclerosis
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?