Rheumatology Advance Access originally published online on May 16, 2006
Rheumatology 2006 45(12):1490-1496; doi:10.1093/rheumatology/kel116
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Digital thermal hyperaemia impairment does not relate to skin fibrosis or macrovascular disease in systemic sclerosis
1Inserm ESPRI HP2 Laboratory, EA 3745, Grenoble Medical School, 2Inserm Clinical Research Center 03, 3Vascular Medicine Department, Grenoble University Hospital, Grenoble, France and 4Department of Human Physiology, University of Oregon, Eugene, OR, USA.
Correspondence to: Jean-Luc Cracowski, M.D. Ph.D., Inserm CIC 03, Centre d'Investigation Clinique de Grenoble, CHU de Grenoble, 38043 Grenoble Cedex 09, France. E-mail: Jean-Luc.Cracowski{at}ujf-grenoble.fr
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Abstract |
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Objectives. Thermal hyperaemia is impaired in patients with systemic sclerosis (SSc). The objective of these studies was to determine whether this was consecutive to skin fibrosis, microangiopathy or macroangiopathy.
Methods. Using laser Doppler flowmetry, we first compared the thermal hyperaemia on the third left finger pad and on the left forearm in 21 patients with non-diffuse systemic sclerosis (SSc), in comparison with primary Raynaud's phenomenon and healthy volunteers. Second, we tested whether the altered thermal hyperaemia correlated to the digital pressure index at baseline, and following the thermal challenge.
Results. In the first study, thermal hyperaemia of the finger pad was impaired in terms of both amplitude and kinetics, but not on the forearm in patients with SSc. In the seven SSc patients without cutaneous fibrosis, the response was similarly altered in terms of amplitude and kinetics. In the second study, we observed a weak correlation between the digital systolic blood pressure index. However, in the 15 SSc patients tested at 44°C, the median digital systolic blood pressure index was 1.04 (0.84–1.24) at baseline vs 1.08 (0.87–1.29) at 44°C (NS), while seven of them had an abnormal response in terms of kinetic. Furthermore, only one patient showed a clear-cut decrease in digital systolic blood pressure at 44°C.
Conclusion. In patients with SSc, digital thermal hyperaemia is impaired, but does not relate to the skin fibrosis or to an associated macroangiopathy in most cases. Further studies are required to determine whether its impairment reflects a functional or structural microvascular damage.
KEY WORDS: Vasodilatation, Microcirculation, Raynaud's phenomenon, Systemic sclerosis.
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Introduction |
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Microvascular dysfunction is an early event in the pathogenesis of systemic sclerosis (SSc). Microvascular dysfunction involves an endothelial dysfunction, which is characterized in scleroderma by a decreased endothelium-dependent flow-mediated relaxation, increased lymphocyte binding and an alteration of neurovascular controls [1]. Accurate and sensitive measurement techniques are a key issue in the quantification of this vascular dysfunction. Among the different techniques available, local heating of skin can be assessed using laser Doppler flowmetry [2]. Local heating evokes a vasodilatation that is mediated by at least two independent mechanisms—an initial peak in cutaneous blood flow during the first 10 min is mediated by a calcitonin gene-related peptide (CGRP) and substance P-dependent axon reflex [2, 3], followed by a secondary plateau that is primarily mediated by nitric oxide (NO) [3, 4]. We previously showed that both the initial rise and the secondary plateau were impaired in patients with secondary Raynaud's phenomenon (RP) in comparison with subjects with primary RP [5]. However, the exact mechanisms leading to the altered response in this study were unclear. The possible explanations for this phenomenon include: (i) skin fibrosis, which could alter transmission of the thermal and/or Laser Doppler signals, (ii) an inability to increase cutaneous blood flow due to macrovascular disease, as narrowing of digital and/or ulnar arteries may result in a reduction of the lumen and digital flow [1, 6] and (iii) a functional and/or structural microangiopathy.
To answer these questions, we conducted two consecutive clinical studies. We first tested whether a regional variation of the thermal hyperaemia was present in patients with SSc, including patients with no skin fibrosis, in comparison with primary RP and healthy volunteers. We secondly tested in a larger cohort of patients with both limited and diffuse SSc whether the altered thermal hyperaemia correlated to the digital pressure index at baseline, and following the thermal challenge.
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Patients and methods |
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First study design and population
We enrolled 63 subjects at the Inserm Clinical Research Center, Grenoble University Hospital, from December 2004 to May 2005: 21 patients suffering from SSc, 21 patients with primary RP and 21 healthy volunteers. Those subjects were involved in a larger cohort study of the vascular phenotype of SSc. All subjects gave informed written consent, the study being approved in January 2004 by the Institutional Review Board of Grenoble University Hospital, France. Patients suffering from SSc were recruited from the Vascular Medicine Department. Patients with RP and healthy volunteers were recruited through local newspaper advertisements. The criteria for inclusion in the study in the SSc cohort were diagnosis of SSc according the criteria of LeRoy and Medsger [7], and age above 18 yrs. The SSc was classified as limited form of SSc (lSSc), limited cutaneous (lcSSc) or diffuse cutaneous SSc (dcSSc) with the criteria of LeRoy et al. [8]. Primary RP was diagnosed according to the criteria of LeRoy and Medsger [9]. Exclusion criteria were cigarette smoking, diabetes mellitus, hypercholesterolaemia or any associated severe disease (cancer, cardiac and pulmonary failure, myocardial infarction, angina pectoris). Furthermore, patients taking statins, nitrates or non-steroidal anti-inflammatory drugs were excluded. All patients were asked to discontinue any vasodilatator therapy given for RP one week before inclusion and until the end of the study. Patients unable to discontinue vasodilatator therapies during the study period were not included.
The onset of the disease was defined as the first occurrence of symptoms of SSc apart from RP. Digital pitting scars, oesophageal dysfunction and RP were diagnosed clinically. Skin thickness was quantified using the modified Rodnan skin score [10]. The diagnosis of pulmonary fibrosis was suspected on the basis of clinical data and systematic radiographs, and confirmed in all cases by computed tomography scans.
All subjects arrived between 8 and 9 a.m. After clinical examination, subjects were placed in the supine position in a quiet room with a stable ambient temperature, with both forearms resting at heart level. Blood pressure and heart rate were measured. Laser Doppler probes were attached to the distal pad of the third left finger and to the ventral face of the left forearm, 10 cm below the humerus medial epicondyle. They were left in place during the whole laser Doppler measurements. Following 30 min of rest, the hyperaemia was studied in the following sequence: post-occlusive hyperaemia with a 30 min recovery period, followed by thermal hyperaemia. The recovery periods were determined in previous experimentations [5], so that the cutaneous blood flow returned to baseline values within this period.
Laser Doppler measurements
Integrated laser Doppler probes (PR457, Perimed, Järfälla, Sweden) with local heating devices were used to increase the local temperature of the skin and to quantify the local thermal hyperaemic response. Cutaneous blood flow was measured using a laser Doppler flowmeter (PeriFlux System 5000, Perimed, Järfälla, Sweden, 780 nm laser diode). The laser Doppler flowmeter was interfaced to a personal computer through a converter using Perisoft® (Perimed, Järfälla, Sweden) data acquisition software. Laser Doppler blood flow was recorded in arbitrary perfusion units (PU), which are related to red blood cell flux in the microcirculation of the surface tissue.
Post-occlusive hyperaemia
After 10 min of rest, to allow for the measurement of baseline cutaneous blood flow, digital blood flow was occluded for 5 min by inflating a cuff placed on the left arm to 50 mmHg above the systolic blood pressure. The cuff was then released and the flow responses were recorded. The amplitude of the response was determined by the peak hyperaemic blood flow, expressed in absolute value (PU). The kinetics of the response was characterized by measuring the time to peak hyperaemia, expressed in seconds.
Thermal hyperaemia
The PR457 laser probes were heated from skin temperature to 42°C over 1 s, and was maintained for 30 min, and was then heated to 44°C for 5 min. Laser Doppler flow measured over the first 30 min is characterized in healthy controls by an initial peak within the first 10 min, followed by a nadir, and finally rising to a sustained plateau. Maximal skin blood flow was achieved by heating to 44°C. The amplitude of the response was determined by the initial thermal peak, 10–30 min thermal plateau, and 44°C thermal plateau, expressed as blood flow in absolute value (PU). Flux values for the initial peak were averaged over a 1 min period for the initial thermal peak. Flux values for the thermal plateau and for the 44°C measurements were averaged over a 3 min period. In subjects whose initial peak was delayed or lacking, the maximal value of the first 10 min was measured as the mean signal over a 1 min period. The kinetics of the response was determined by the time to initial thermal peak. The time to peak was determined from the onset of the probe heating to the peak, or to the maximal value when no clear peak was observed. The day-to-day reproducibility of the thermal hyperaemia was assessed in a previous study [5].
Second study design and population
In the second study, we enrolled 39 patients with lcSSc and dcSSc during the meeting of the French patient association of scleroderma, at Paris, in May 2005. All subjects gave written informed consent. The study was approved in April 2005 by the Institutional Review Board of Grenoble University Hospital, France. The same inclusion criteria applied, without exclusion criteria. Patients were not asked to discontinue their vasodilator therapy. The same clinical parameters were recorded.
Patients were placed in a sitting position in a quiet room with a stable ambient temperature, with the left forearm resting at heart level. Brachial blood pressure and heart rate were recorded. Laser probes (PR457) were attached to the distal pad of the third left finger. Digital systolic arterial pressure was measured at baseline, and thermal hyperaemia was performed. Digital systolic arterial pressure was measured once again at the end of the heating period, at 44°C in 15 patients.
Finger systolic blood pressure measurements
Using the Perimed PF 5050 Pressure Unit, we measured the digital systolic blood pressure on the left middle finger. Briefly, finger pressure measurements were performed by placing the cuff on the root of the third finger and attaching the laser Doppler probe on the finger pad. The cuff was first inflated 50 mmHg higher than the humeral systolic blood pressure. The cuff pressure was then deflated linearly until the laser Doppler probe detected the return of blood perfusion, known as finger systolic blood pressure. The baseline digital systolic pressure index was defined as the ratio of the baseline digital systolic pressure over the humeral systolic blood pressure. Similarly, 44°C digital systolic pressure index was defined as the ratio of the 44°C digital systolic pressure recorded at the end of the thermal challenge over the humeral systolic blood pressure. Four consecutive measurements were performed and we averaged the last three for each subject.
The reproducibility of the baseline and 44°C digital pressure measurements was assessed as a pilot study in eight subjects. Each measurement was repeated 2 h after the first series on the same subject using the methodology described above. The median absolute difference for the baseline digital systolic pressure index was 0.12 (0.07–0.15) for a median of the means of 1.27 (1.12–1.50). The median absolute difference for the 44°C digital systolic pressure index was 0.11 (0.03–0.18) for a median of the means of 1.27 (1.17–1.48). The coefficients of correlation for the baseline and 44°C digital systolic pressure index were 0.84 and 0.75, respectively. Bland and Altman plots were constructed to measure the agreement between successive measures. For the two measures, more than 95% of the differences were less than two standard deviations, and neither proportional error nor systematic errors were detected.
Data analysis
Based on our previous study, the mean 44°C thermal plateau was 413 PU (S.D. 159) in the patients with primary RP [5]. In the first study, sample size calculations were based on the objective to detect a difference in the mean 44°C thermal plateau of at least 33% between groups, with 
= 0.05 and power (1–ß) = 0.8. In the second study, we studied the whole cohort of patients available.
Quantitative data are expressed as the mean±S.D. or median, 10th and 90th percentiles. In the two studies, the amplitude of the hyperaemic responses followed a normal distribution and was expressed as mean (S.D.) whereas time to peaks followed a log distribution and was expressed as median (10th and 90th percentiles). Qualitative data are expressed as number and percentage. Normality and variance homogeneity analysis were tested prior to quantitative data analysis [analysis of variance, (ANOVA) and Student's t-test for between groups comparisons, and correlation tests for the relationship between quantitative variables]. When data did not follow a normal distribution, non-parametric statistical methods were performed: Kruskal–Wallis NOVA, Mann–Whitney test for between groups comparisons, and Spearman rank correlation test for the relationship between quantitative variables. Two-sided significance tests were used throughout. Proportions were compared by using chi-square tests or Fisher's exact test when appropriate. P-values <0.05, corrected by Bonferroni's method for multiple comparison, were considered significant.
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Results |
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Clinical and biological characteristics
The demographic, clinical and biological characteristics of the 63 patients enrolled in the first study are listed in Table 1. Among the 21 patients with SSc, one patient was on methotrexate and one on cyclophosphamide. Among patients in the RP and SSc group, respectively, 1 and 8 were on calcium channel blockers, and 1 and 3 of were on buflomedil, a vasodilator. Both calcium channel blockers and buflomedil were stopped 7 days before enrollment in the study.
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The demographic and clinical characteristics of the 39 patients enrolled in the second study are listed in Table 2. Among the 22 patients with lcSSc, 13 patients were under calcium channel blockers, three under buflomedil, three under conversion enzyme inhibitors or angiotensin II Type 1 receptor blockers, three under synthetic antimalarial, one under cyclophosphamide, one under ilomedine and three under corticoids. Among the 17 patients with dcSSc, eight were on calcium channel blockers, three on buflomedil, three were on conversion enzyme inhibitors or angiotensin II Type 1 receptor blockers, three were on iloprost, a prostacyclin analogue, four were on corticoids, two were on bosentan and one was on azathioprine.
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First study—regional variation of the thermal response, and role of skin fibrosis in patients with non-diffuse SSc
Thermal hyperaemia was altered in terms of amplitude on the finger pad in patients with SSc (Table 3). Conversely, the response observed at the forearm was comparable with controls. Similarly, the kinetics profile was altered in patients with SSc on the finger pad but not on the forearm (Table 3, Fig. 1).
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In order to test whether cutaneous fibrosis itself could have explained the altered thermal hyperaemia, we analysed the SSc group according to the cutaneous changes. In the seven patients with lSSc (i.e. RP associated with autoantibodies and SSc-type nailfold capillary pattern without any cutaneous fibrosis) as well as in the 14 with lcSSc, thermal hyperaemia was altered in terms of amplitude on the finger pad (Fig. 1). The median initial thermal peak was 266 PU (19–568) vs 336 (69–492), the median 10–30 min thermal plateau was 241 PU (18–514) vs 280 (119–435), the median 44°C thermal plateau was 226 (23–497) vs 310 s (59–480) in the lSSc and lcSSc groups, respectively (NS). Similarly, the median time to thermal maximum was 205 PU (25–676) vs 206 (104–1294) in the lSSc and lcSSc groups, respectively.
For the post-occlusive hyperaemic response, we observed a non-significant trend towards a difference for the mean peak hyperaemic blood flow [315 PU (162), 269 (141) and 256 (142) PU for the healthy controls, primary RP, non-diffuse SSc groups, respectively], and the median time to peak hyperaemia (48 s (21–102), 51 (24–148) and 65 (16–205) PU for the healthy controls, primary RP, non-diffuse SSc groups, respectively) on the finger pad. However, similarly to the thermal response, no difference between groups was observed for the peak hyperhaemic blood flow on the forearm (data not shown).
Second study—correlation between thermal hyperaemia and systolic digital pressure in patients with lcSSc and dcSSc
At baseline, we observed no differences in terms of amplitude between patients with lcSSc and dcSSc (Table 4). Conversely, only 26% of the patients with dcSSc exhibited the classical thermal response, including an initial peak within the first 10 min. We tested whether the altered thermal hyperaemia was a consequence of a digital artery narrowing, by correlating thermal hyperaemia to digital pressure measurements. We observed a weak correlation between the digital systolic blood pressure index and the 44°C thermal plateau (R = 0.28, P = 0.07), and the time to thermal maximum (R = 0.37, P = 0.05), but no correlation was found with the initial thermal peak. The 44°C thermal plateau was lower in the 31 patients with RP affecting the thumb [248 PU (105–438) vs 467 (300–600), P = 0.002]. Eighty per cent of the patients without an initial thermal peak exhibited digital pitting scars in contrast with only 52% of those with a normal response (P = 0.07). Furthermore, three patients were under iloprost for severe digital ulcers at time of inclusion. Their median 44°C thermal plateau was 185 PU (25–75th percentiles 53–258) vs 293 (10–90th percentiles 143–529) in the 36 other patients (no statistical analysis was done due to the low number of subjects). Neither the kinetic nor the amplitude of the thermal hyperaemia correlated to the Rodnan skin's score. Patients with pulmonary fibrosis had a similar response compared with those without pulmonary fibrosis.
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Then, we tested whether thermal hyperaemia correlates to the digital systolic blood pressure index following the thermal hyperaemia, assuming that a drop of pressure at 44°C would indicate a macroangiopathy. Fifteen patients were tested, 10 presenting with lcSSc and five with dcSSc. Their median cutaneous blood flow at 44°C was 270 (158–533), while their median time to thermal maximum was 765 (136–1537). Their median digital systolic blood pressure was 1.04 (0.84–1.24) at baseline vs 1.08 (0.87–1.29) at 44°C (NS). Seven patients did not have an initial thermal peak. Only one patient showed a clear-cut decrease in digital systolic blood pressure at 44°C (Fig. 2). This patient exhibited an initial thermal peak, but had a low amplitude of thermal plateau. When the 44°C plateau flux was divided by the systolic digital pressure, the vascular conductance was within a normal range, suggesting that the drop of cutaneous blood flow was consecutive to a proximal artery narrowing. In contrast, in all other patients, the digital systolic blood pressure increased or remained stable, while seven of them had an abnormal response in terms of kinetic (Fig. 2).
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Discussion |
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We first showed a regional variation of the thermal hyperaemia in patients with non-diffuse SSc, as both the amplitude and the kinetics of the response were impaired on the finger pad, but not on the forearm. However, this impairment did not rely on the presence of skin fibrosis as digital thermal hyperaemia was still abnormal in patients without any sclerodactyly. Secondly, we showed that there was a weak positive correlation between thermal hyperaemia and the digital systolic pressure index at baseline. However, detailed analysis showed that in most patients, the altered response was not associated with a drop of the digital systolic pressure index at 44°C. Thermal hyperaemia, when associated with digital systolic pressure measurements, therefore discriminates patients with a specific microangiopathy, from those with an associated macroangiopathy.
Scleroderma spectrum disorders are heterogeneous and rare vascular diseases with a large variation of clinical manifestations in individual patients. At one end of the spectrum is lSSc according to LeRoy and Medsger [7], which includes the presence of RP and a typical capillaroscopy scleroderma pattern or positivity for Scl-70 or anticentromere antibodies. At the other end of the spectrum is SSc, which associates cutaneous changes and visceral involvement. We chose to use LeRoy's classification, instead of that of the American College of Rheumatology for our vascular pathophysiological studies. This enables the inclusion of patients presenting with early systemic sclerosis, i.e. with microvascular abnormalities despite the lack of cutaneous involvement. The patients enrolled in the first study were representative of the early phase of SSc and were less severe than those enrolled in our previous study [5], as their illness duration was short, and most of them did not exhibit visceral complications. Much attention was given to potential bias that may interfere with vascular reactivity, and no hypercholesterolaemic, diabetic, hypertensive or cigarette smoker was included. In addition, all subjects stopped their oral vasodilatators 7 days prior to the enrollment. Laser Doppler flowmetry data was expressed as arbitrary PU (1 PU = 10 mV), and red blood cell count was not provided as it did not add any significant information. We initially intended to express data as vascular conductance (i.e. flux divided by arterial pressure) rather than flux. However, we were unable to do so given the fact that we did not record the finger blood pressure in the first study, and that dividing the flux by the brachial artery blood pressure could be incorrect for patients with digital arteriopathy, as suggested by the second study.
In the first study, thermal hyperaemia was abnormal, suggesting that microangiopathy is an early event in the disease process, but the impairment was limited to the finger sites, the response being normal on the forearm unaffected by skin fibrosis. However, cutaneous fibrosis does not explain this impaired response, as patients without sclerodactyly still had abnormal responses on the finger pad. In the second study, we enrolled non-selected patients suffering from limited and diffuse cutaneous SSc. We observed a correlation between the amplitude and the kinetics of the thermal response and the digital systolic pressure index, but the correlation was weak, and was not found for the initial thermal peak. Narrowing of ulnar and digital arteries have previously been described in patients with SSc [6, 11]. Thus, we further investigated whether the inability to increase cutaneous blood flow in response to local heating was due to an angiopathy of the arterial vessels above the finger pad, by measuring the digital systolic pressure at baseline and 44°C in a subgroup of patients. Our data clearly showed that in most patients, thermal hyperaemia is impaired without any drop of digital pressure. Only one patient had a clear-cut drop of pressure. However, while the amplitude of the flux response was impaired, this patient still exhibited the classical double wave response, and calculation of her vascular conductance was normal, suggesting that the drop of pressure explained the drop of cutaneous blood flow.
Local hyperaemia to heating comprises two local separate mechanisms: an initial peak that is axon reflex-mediated; and a sustained plateau phase that is NO-dependent [2, 3]. The initial rapid-phase vasodilatation relies on C-fibre sensory nerves that cause vasodilatation via the release of CGRP and substance P [2]. Previous studies showed that patients with SSc exhibited a reduction in the number of CGRP neurons in the skin [12]. Our data further show that the axon reflex vasodilatation is impaired in SSc, and strengthen the hypothesis that sensory nerves function is blunted in patients with SSc. Furthermore, the late-onset thermal plateau relies partly on NO release [3]. Thermal hyperaemia, therefore, could provide an integrated measure of microvascular dysfunction in SSc, including the CGRP-dependent axon-reflex and the NO-dependent phases. In the present study, we cannot rule out the possibility that the impaired thermal hyperaemia is related solely to a decreased capillary density. However, a decreased capillary density, while potentially being able to decrease the amplitude of the thermal response is unlikely to explain the altered kinetics of the response, specifically the axon reflex peak. As this issue remains unresolved with our data, future studies are required to determine the part of microvascular dysfunction vs structured vascular defects in the altered digital thermal hyperaemia.
New developments in methodologies aimed at measuring vascular function are required to further understand the pathophysiology of SSc and enable an evaluation of the response to treatments. The laser Doppler single probe technique has been widely used to perform post-occlusive hyperaemia and cold challenges. The response of skin cutaneous blood flow to cold challenges does not significantly differ between primary RP and SSc [13, 14]. The post-occlusive hyperaemia may distinguish patients with primary RP from those with secondary RP [13, 15]. However, post-occlusive hyperaemia does not lead to a maximal vasodilatation and is therefore variable [16]. In contrast, thermal hyperaemia causes maximal skin vasodilatation [2] in a similar way than a high dose (28 mM) sodium nitroprusside infused through a microdialysis fiber [3, 4], with a good reproducibility [5].
Patients with secondary RP may present recurrent digital ulcerations and infarctions. This complication is painful and may lead to impaired digital function and tissue loss. The treatment is based on intravenous iloprost [17] or bosentan, a non-specific endothelin-1 receptor blocker [18]. In our study, we observed trends supporting the idea that an abnormal response to local heating could be correlated to the presence of digital pitting scars or active ulcers. No strong conclusion should be driven from these data as the aim of the second study was not to test such a hypothesis. Further cohort studies are required to test whether thermal hyperaemia could predict patients at risk of digital ulcers among those presenting with secondary RP, and could help to distinguish patients requiring preventive endothelin antagonist treatment [18].
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Conclusion |
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TopAbstractIntroductionPatients and methodsResultsDiscussionConclusionReferences |
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In patients with SSc, digital thermal hyperaemia is impaired, but does not relate to the skin fibrosis or to an associated macroangiopathy in most cases. Thermal hyperaemia could enable an integrated study of neural and endothelial microvascular function, but further studies are required to determine whether its impairment reflects a functional or structural microvascular damage.
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Acknowledgments |
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We thank the patient association ‘Association des Sclérodermiques de France’ for patient participation and financial support, the ‘Groupe Français de Recherche sur la Sclérodermie’ and the Délégation Régionale à la Recherche Clinique of Grenoble University Hospital for financial support. We thank the Clinical Research Center of Grenoble University Hospital for reviewing the protocols corresponding to these studies. We also thank Mrs Dominique Abry and Nicole Henquin for taking part to the laser Doppler measurements.
The authors have declared no conflicts of interest.
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