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Maurice Raynaud first described color changes and symptoms of the fingers due to cold-induced vasospasm and restricted blood flow in his medical school thesis in 1862. Raynaud’s phenomenon is common and exists as an uncomplicated primary Raynaud phenomenon and a Raynaud phenomenon secondary to underlying diseases and medication. Mechanisms contributing to altered vasoconstrictor activity are endothelial and not-endothelial. Cold-induced vasospasm is probably a thermoregulatory problem and effects are mediated by sympathetic activity and selective stimulation of alpha2c-adrenoreceptors.

Vasospastic disorders are prevalent in the general population and can affect individuals of any age. Primary (or idiopathic) vasospastic disorders often have a benign course; treatment focuses on the control of symptoms. Secondary vasospastic disorders occur owing to an underlying condition and have an increased risk of complications, including tissue loss and digital ulcerations; treatment should focus on the underlying condition. In this review, we discuss the pathophysiology, clinical presentation, diagnosis, and management of vasospastic disorders, including Raynaud syndrome, acrocyanosis, livedo reticularis, and pernio.

INTRODUCTION Raynaud phenomenon is a medical condition in which the spasm of the arteries causes episodes of reduced blood flow. Potential disorders in the microcirculation of the oral mucosa may promote the occurrence of lesions. OBJECTIVES The aim of the study was to investigate the association of the frequency of oral cavity lesions with oral microcirculatory dysfunction in patients with primary Raynaud phenomenon (PRP) in comparison with healthy control group. PATIENTS AND METHODS Measurements of oral capillary flow were performed using laser doppler flowmetry (LDF) in 61 patients with PRP. In a group of 31 of 61 patients (group 1), the measurements were made during a Raynaud phenomenon (RP) attack. The RP attack was caused by stress initiated by the examination or the first visit itself. The RP attack was not deliberately caused by a cold test, vibration40w56 or any stress test. After 10 to 14 days, the measurements were repeated in all 61 patients and in the control group, and a dental examination was performed. Follow‑up visits were conducted every 3 months for a period of 12 months to monitor oral mucosa. RESULTS Differences in LDF were found between various anatomical points in both the PRP and control groups. On the first visit, the LDF flow in group 1 was significantly lower at all examined points in comparison with those in the control group. On the second visit, differences were observed in the LDF of the teeth and oral mucosa temperature in all patients with PRP in comparison with controls. Oral cavity lesions reported in the past and at follow‑up were significantly more common in patients with PRP. CONCLUSIONS Patients with PRP have dysfunction in the microcirculation of the oral mucosa and they more often have lesions in the oral cavity.

Background Raynaud’s phenomenon (RP) is a functional vascular disease, presenting with recurrent episodes of ischemia of extremities in response to cold and emotional stress. Investigating cutaneous microcirculation is an important tool in understanding the complex neuro-immuno-vascular interactions in its pathophysiological mechanisms. Since there is no available data on vascular responsiveness in RP in the paediatric population, we investigated skin perfusion and heat-induced hyperaemia in comparison with clinical severity and laboratory parameters of the disease. Methods Fifty two adolescents (27 patients with primary RP and 25 age-matched healthy controls) were investigated in the study. Patients were divided into two groups according to the symptoms existing within the previous 2 months. Following baseline microcirculation measurement with Laser Doppler flowmetry (Periflux 5000 system), all subjects underwent local heating test at 42 °C and 44 °C. Besides routine laboratory parameters, immune-serological tests and the vasoactive sensory neuropeptides somatostatin and pituitary adenylate-cyclase activating polypeptide (PACAP) were measured. Results Baseline perfusion measured in perfusion units (PU) at 32 °C was significantly lower in symptomatic RP patients (97.6 ± 22.4 PU) compared with both healthy volunteers (248.3 ± 23.5 PU, p 0.05) when compared with healthy subjects (555.9 ± 28.2 PU). Both the area under the response curve and the latency to reach the maximum flow were significantly increased in both RP groups (symptomatic 164.6 ± 7.4 s, p

Background Autoantibodies (autoAbs) help in diagnosis and predicting clinical phenotypes in systemic sclerosis (SSc). Objectives To determine the clinical utility of 13 SSc-related autoAbs in SSc patients in Greece. Methods 131 consecutive patients with SSc (111 female, mean age 58.1±14 years; 49 with diffused cutaneous SSc [dcSSc] and 82 with limited cutaneous SSc [lcSSc]) were analyzed by a multiplex line immunoassay (Euroimmun) for autoAbs against 13 SSc-related antigens. Twenty two patients with primary Raynaud phenomenon (RP), and 22 healthy controls were also analyzed Results ANA by indirect immunofluorescence was present in 128 (97.7%) patients with SSc. Excluding anti-Ro52, 113 (89.3%) SSc patients were positive for at least one autoAb: anti-Topo I abs in 54 (41.2%), anti-CENPA in 37 (28.2%, all reactive with CENPB), anti-RNA polymerase III (RP11) in 19 (14.5%), anti-RNA polymerase III (RP155) in 13 (9.9%), anti-fibrillarin in 4 (3.1%), anti-Ku in 6 (4.6%), anti-NOR90 in 8 (6.1%), anti-PM/Scl100 in 2 (1.5%), and anti-PM/Scl75 in 4 (3.1%). There was no immunoreactivity for Th/To or PDGFR. Overall, 102 (77.9%) SSc patients had autoAbs against Topo I, CENPA or CENPB, RP11 or RP155. Anti-Topo I abs were strongly associated with dcSSc, interstitial lung disease (ILD) (p Conclusions Anti-Scl70, anti-CENP and anti-RNA pol III are the most prevalent autoAbs in SSc. Anti-Topo I and anti-NOR90 abs are associated with ILD and/or PAH. Disclosure of Interest C. Liaskos: None declared, E. Marou: None declared, T. Simopoulou: None declared, M. Barmakoudi: None declared, G. Efthymiou: None declared, T. Scheper Employee of: Euroimmun AG, W. Meyer Employee of: Euroimmun AG, D. Bogdanos: None declared, L. Sakkas: None declared

Item does not contain fulltext BACKGROUND: Medicinal treatment of vasospastic Raynaud phenomenon is limited to primarily vasodilator medicines. OBJECTIVE: To explore the possible beneficial effects and tolerability of 120 mg two times a day of Ginkgo Biloba special extract EGb 761 in patients suffering from Raynaud disease (RD) (primary Raynaud phenomenon). METHODS: In a placebo-controlled, double-blind, pilot study, 41 patients with RD were randomized to either the active treatment group (EGb 761, n = 21) or placebo group for 10 weeks, after an initial 2-week run-in phase. The primary efficacy variables were self-reported changes of the frequency, duration, and severity of vasospastic attacks between the placebo-controlled run-in phase and the end of the study. RESULTS: Most of the patients were female, and both groups were perfectly matched with respect to demographic characteristics. The frequency of daily attacks reduced from 3.6 +/- 2.3 to 2.4 +/- 2.6 (-33%) in the EGb 761 group and from 2.9 +/- 2.0 to 2.0 +/- 1.8 (-31%) in the placebo group with no significant difference according to the ordinary least squares test (P = 0.3564). Furthermore, no significant differences were found with respect to the duration and severity of vasospastic attacks between the EGb 761 and placebo groups (P = 0.4392 and P = 0.7187, respectively). In all, 17 adverse events (AEs) were reported, 6 AEs from 5 patients in the EGb 761 group and 11 AEs from 8 patients in the placebo group. Serious AEs did not occur. CONCLUSION: EGb 761 treatment showed an excellent safety profile in patients with RD but could not demonstrate a statistically significant reduction in clinically relevant symptoms compared with placebo. 01 maart 2012

To assess health-related quality of life (HRQL) in patients with primary Raynaud phenomenon (RP).The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) questionnaire and the EQ-5D questionnaire were administered to 81 patients with primary RP who had been referred to a rheumatological department. The scores were compared with data of control subjects.In the physical dimensions of the SF-36, the subjects who had RP had significantly lower scores (worse HRQL) than controls (47.6 +/- 9.8 vs. 52.2 +/- 9.3, P = 0.021). The physical component score (PCS) was correlated with age (P = 0.003) and the number of comorbidities (P = 0.004). The mental health component score (MCS) was significantly lower in RP subjects than in controls (41.9 +/- 9.4 vs. 46.1 +/- 10.7, P = 0.006). As regards anxiety/depression (of the EQ-5DA/D), considerably more RP patients (77.7%) reported at least some related problems as compared with controls (60.0%) (chi = 7.93; P = 0.005). Fifty-two RP patients (64.2%) and 178 controls (57.8%) described themselves as moderately anxious/depressed, whereas 11 RP patients (13.5%), and 7 controls (2.2%) reported extreme anxiety/depression (P0.0001).This study shows a reduction of the HRQL in patients with primary RP, compared with control subjects. The psychologic wellbeing represents the most involved area, whereas physical functioning and symptoms are significantly influenced by age and comorbidities. Moreover, these patients are more anxious/depressed (EQ-5DA/D). Longitudinal studies are needed to validate our findings, to explore the causal relationship between primary RP and emotional factors, and to possibly lead to encouraging behavioral therapies.

Objective.Evaluate objective assessment of digital microvascular function using laser speckle contrast imaging (LSCI) in a cross-sectional study of patients with primary Raynaud phenomenon (RP) and systemic sclerosis (SSc), comparing LSCI with both infrared thermography (IRT) and subjective assessment using the Raynaud Condition Score (RCS) diary.Methods.Patients with SSc (n = 25) and primary RP (n = 18) underwent simultaneous assessment of digital perfusion using LSCI and IRT with a cold challenge on 2 occasions, 2 weeks apart. The RCS diary was completed between assessments. The relationship between objective and subjective assessments of RP was evaluated. Reproducibility of LSCI/IRT was assessed, along with differences between primary RP and SSc, and the effect of sex.Results.There was moderate-to-good correlation between LSCI and IRT (Spearman rho 0.58–0.84, p < 0.01), but poor correlation between objective assessments and the RCS diary (p > 0.05 for all analyses). Reproducibility of IRT and LSCI was moderate at baseline (ICC 0.51–0.63) and immediately following cold challenge (ICC 0.56–0.86), but lower during reperfusion (ICC 0.3–0.7). Neither subjective nor objective assessments differentiated between primary RP and SSc. Men reported lower median daily frequency of RP attacks (0.82 vs 1.93, p = 0.03). Perfusion using LSCI/IRT was higher in men for the majority of assessments.Conclusion.Objective and subjective methods provide differing information on microvascular function in RP. There is good convergent validity of LSCI with IRT and acceptable reproducibility of both modalities. Neither subjective nor objective assessments could differentiate between primary RP and SSc. Influence of sex on subjective and objective assessment of RP warrants further evaluation.

Introduction The aim of this study is to investigate pulsatility of digital arteries of hands by means of photoplethysmography (PPG) in patients with primary Raynaud phenomenon (PRP) and systemic sclerosis (SSc) and to compare the results with those obtained in healthy controls. Methods One hundred five patients with SSc, 96 patients with PRP and 85 healthy controls were recruited in this study. Nailfold videocapillaroscopy and PPG were performed in healthy controls and patients. In patients with SSc, the capillaroscopic pattern was classified as early, active and late group pattern. A baseline PPG was recorded simultaneously in all 10 fingers of the hands. The photoplethysmographic curves were evaluated for morphology and amplitude of sphygmic wave. Results In healthy controls group, PPG shows the presence of photoplethysmographic homogeneous pattern and high mean value of sphygmic wave amplitude. In PRP group, PPG demonstrates homogeneous photoplethysmographic pattern and low mean value of sphygmic wave amplitude. Finally, in the SSc group, photoplethysmographic pattern is dyshomogeneous, and the mean value of sphygmic wave amplitude is intermediate between the other 2 groups. The PPG findings are different in the 3 capillaroscopic groups of patients with SSc and 2 subsets of disease. Conclusion PPG represents a technique noninvasive to evaluate simultaneously in all 10 fingers of hands digital arteries pulsatility. PPG improves the evaluation of vascular damage in patients with primary and sclerodermic RP.

Background Nailfold Video Capillaroscopy (NVC) is a reliable and safe method to qualitatively differentiate Primary (PRP) from Secondary Raynaud Phenomenon (SRP) allowing early diagnosis of systemic sclerosis (SSc) SRP-associated (“early” scleroderma pattern)1,2. Quantitative evaluation by NVC was demonstrated to be of great value for the analysis of abnormal capillary parameters2. Objectives To investigate the presence of diameter abnormalities, i.e. dilations >20μm, and their localization at level of capillaries, during the NVC follow up of PRP subjects, before their transition to SRP. Methods We performed a case-control study, over a total population of 191 PRP subjects (mean RP duration: 7.70 years), with a NVC follow-up of 42.77±35.80 months (3.56±2.98 years). PRP subjects were then classified as SSc SRP-associated, based on the appearance of the “early” scleroderma pattern and/or ANA positivity. Concomitant therapies and comorbidities were evaluated to avoid confounding factors3. A single operator performed the NVC and results were separately checked by three experts (PC,SA,CM), in blind. Practically, the observer (TAC), using a dedicated software (Videocap, DS MediGroup, Milan, Italy), measured on NVC images the major dilation of capillary loop's branches (arterial, venous, apical). The mean diameter value for each enlarged branch (arterial, venous, apical) and therefore the total mean diameter value of all observed dilations, were calculated in each PRP subject. Mean diameter values were then correlated with all the considered clinical variables. Mann Whitney U and χ2 tests were used to calculate the differencies in the observed values between the two populations. Results A significant presence of abnormal dilations for both arterial and venous branches, was found in PRP subjects before their transition to SRP, compared to stable PRP subjects (p

Objectives We evaluated two microcirculatory function-tests, the Laser Doppler (LD)-Anemometry and the Laser Doppler Imager (LDI)-Flowmetry in their value to further elucidate functional behavior of the “Vibration-induced white finger syndrome” (VWF) and to distinguish between Raynaud's phenomenon (RP) of idiopathic or vibration origin. Participants and Methods Ninety-four patients, suffering from RP were studied (78 patients with primary RP and 16 patients with VWF). Measurement of blood cell velocity (BCV) before and after provocation was obtained by nailfold capillary microscopy and an included Laser detector (“Anemometry“). Digital blood flux was recorded by LDI-Flowmetry during a standardized cooling and rewarming thermal challenge. Results “Time to peak” of BCV, a measure of maximal reactive hyperemia was longer in VWF in comparison to primary RP (30.37 versus 19.29 sec P Conclusion Based on the fact, that prolongation of reactive hyperemia, an indicator of impaired endothelium-dependent vasodilation is also frequently found in peripheral arterial occlusive disease, it is hypothesized that VWF is not only a microcirculatory vasospastic disorder, but may also be related to atherosclerosis. Anemometry, in association with an appropriate provocation-test, could represent a useful non-invasive method for objectifying diagnosis of VWF in patients with RP.

To the Editor: In their Commentary, Dr Kraemer and colleagues draw attention to the importance of moderators of treatmentoutcomes, theoftenunsatisfactorywaythesearedealt with (if at all) in randomized clinical trials (RCTs), and the potentially seriousconsequencesof thisneglectonpatientcare. They propose that every RCT should include a search for putative moderators of treatment outcome. Although acknowledgingthatpositiveresultsof suchanalysesrarelyprovideproof of theexistenceof thesemoderators, they stress that the importanceresides inthehypotheses that theanalysesgenerate.These hypotheses can then be tested in subsequent adequately poweredandpopulatedRCTs.However, itmaytakeyears todesign, acquire adequate funding for, and execute such an RCT. As an alternative, conducting N-of-1 trials can be valuable to further investigate information on moderators of treatment outcome. As a hypothetical example, suppose an RCT had been conducted to test the efficacy of drug treatment of primary Raynaud phenomenon, that no overall benefit of the drug had been found, but analysis of putative moderators of treatment outcome had suggested that women might respond favorably, although this result was not statistically significant. Women with Raynaud phenomenon could then be included in N-of-1 trials, in which they would be treated in a double-blind crossover design with multiple treatment pairs with either the drug or a placebo in random order. The presence or absence of differences in symptom scores during treatment would then prove or disprove the effectiveness of this drug for the patient. Pooling the results of all of these N-of-1 trials may substantiate that sex is a moderator of treatment outcome. Moreover, comparison of responders and nonresponders in these N-of-1 trials may be used to identify additional moderators of treatment outcome. This approach may obviate the need for RCTs, which would be a great boon in the case of rare chronic diseases. It has an additional advantage in that daily patient care can be integrated with clinical research. N-of-1 trials have their own limitations. They are not applicable to surgical or acute medical conditions. However, for chronic medical conditions, they may be invaluable in the quest for “tailored therapy,” one of the holy grails of clinical medicine.