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Objective: Raynaud's phenomenon is a common symptom of systemic sclerosis. We previously reported that elbow heating increases angiopoietin-1 in the fingertips and alleviates Raynaud's phenomenon. Angiopoietin-1 levels decrease in patients with systemic sclerosis with severe capillary damage. We aimed to conduct a prospective study to confirm whether the increase in angiopoietin-1 caused by heating modifies capillary morphology., Methods: The left ring fingers of 19 patients with systemic sclerosis were monitored six times at 4-week intervals using capillaroscopy, during which both elbows were heated using disposable heating pads for 8 weeks. Blood samples were collected from the same fingertips four times-before heating, twice during heating, and once after heating-to measure angiopoietin-1., Results: In six patients, the peak increase in angiopoietin-1 occurred 4 weeks after the start of heating, whereas in seven patients, the peak value was observed 4 weeks after the termination thereof. No change in the density of the front-row capillaries was observed by capillaroscopy. The proportion of hairpin-shaped capillaries increased from 20.2 % during the preheating period to 26.6 % during the heating period (p = 0.00107). When a correlation coefficient of 0.6 or higher was set as significant, there was a strong correlation between changes in fingertip angiopoietin-1 levels and changes in the proportion of hairpin-shaped capillaries in six patients., Conclusion: Increased angiopoietin-1 levels in the fingertip due to elbow heating may improve the peripheral capillary morphology in patients with systemic sclerosis., Competing Interests: Declaration of competing interest Research expenses and labor costs for Y.S. and A.W. were provided by Kobayashi Pharmaceutical Co., Ltd. Additionally, N.I., T.M., E.K., and Y.M. received support from Kobayashi Pharmaceutical Co., Ltd. A.K. declares no conflicts of interest regarding this paper., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Juvenile Sjögren's disease (jSjD) is a rare autoimmune disease characterized by exocrine gland involvement and systemic manifestations, including small vessel vasculitis and Raynaud's phenomenon (RP). We aimed to investigate the microvascular status in jSjD patients by nailfold videocapillaroscopy (NVC) and the potential correlations with clinical and serological features., Methods: Clinical data from thirteen consecutive jSjD patients (11 females and 2 males), with a mean age of 16 ± 4 years, diagnosed before 16 years of age (mean age at diagnosis 12 ± 3) according to the 2016 American College of Rheumatology/EULAR criteria for adult SjD, were collected including age- and sex-matched healthy controls (HCs). Clinical, laboratory, and instrumental data were collected, together with NVC examination. Non-specific and specific NVC parameters were investigated, such as capillary density, capillary dilations, giant capillaries, microhaemorrhages and abnormal shapes. Associations between NVC findings and clinical/serological features were explored and analysed using parametrical and non-parametrical tests., Results: Capillary density reduction correlated significantly with articular involvement (arthralgias) (p = 0.024). Microhaemorrhages correlated with lower C3 levels (p = 0.034). No specific NVC pattern for jSjD was identified, whereas abnormal capillary shapes were significantly higher in jSjD patients than HCs (p = 0.005). NVC abnormalities were not associated with SjD-specific instrumental tests (biopsy, imaging, Schirmer's test). RP was present in 8% of jSjD patients., Conclusions: The reduction of capillary density, as well as microhaemorrhages at NVC analysis, are significantly associated with some clinical aspects like articular involvement and serum biomarkers (C3 reduction). The NVC is suggested as safe and further analysis in jSjD patients., (© 2024. The Author(s).)

Background: Detection of early capillaroscopic alterations in the preclinical phase may prove useful in patients with non-scleroderma connective tissue disease (CTD). We aimed to verify whether certain capillaroscopic alterations, alone or in combination, might be predictive of CTD., Methods: We retrospectively collected data on patients with Raynaud's phenomenon who underwent capillaroscopy conducted by highly expert examiners with a degree in vascular medicine at our institutions. Included subjects were divided in two groups: those developing rheumatic disease during follow-up, and those without subsequent diagnosis of CTD. Notably, we excluded subjects who presented with an evident scleroderma pattern or rheumatic disease during their initial examination., Results: We included a total of 76 patients, 60 of whom developed CTD during follow-up, which spanned in this group 23±7 months, and 16 who did not develop CTD during follow-up, which spanned 23±9 months. The following features were significantly associated with Raynaud's phenomenon: 1) angiotectonic disorder (P<0.001); 2) nonhomogeneous loop morphology (P<0.001); 3) avascular areas (P<0.001); 4) pseudo-avascular areas (P<0.001), and, albeit to a lesser degree; and 5) ectasias (P<0.050). Notably, the initial capillaroscopic pattern did not undergo any changes in subsequent tests., Conclusions: Although certain pathological characteristics of the capillaroscopic pattern are non-specific and not diagnostic if considered individually, they can be significantly suggestive for latent CTD when found in combination. At the very least, they warrant an in-depth diagnostic analysis and a lengthy follow-up.

Background: CXCL4, a chemokine with anti-angiogenic property, is involved in systemic sclerosis (SSc) related pulmonary arterial hypertension (PAH)., Objective: To investigated the contribution of CXCL4 to SSc development by focusing on the correlation of circulatory CXCL4 levels with their peripheral vasculopathy, and the effect of CXCL4 on endothelial cell dysfunction and the potential signaling., Methods: We measured the plasma CXCL4 levels in 58 patients with SSc, 10 patients with the very early diagnosis of SSc (VEDOSS), and 80 healthy controls (HCs). Then, CXCL4 concentrations were correlated with clinical features, especially the peripheral vasculopathy. These observations were further validated in an additional cohort. Moreover, we studied the anti-angiogenic effects of CXCL4 and the underlying downstream signaling in human umbilical vein endothelial cells (HUVECs) in vitro., Results: Circulating CXCL4 levels were 103.62 % higher in patients with SSc and 201.51 % higher in patients with VEDOSS than matched HCs, which were confirmed in two independent cohorts. CXCL4 levels were associated with digital ulcers (DU) and nailfold videocapillaroscopy (NVC) abnormalities in SSc. The proliferation, migration, and tube formation of HUVECs were inhibited by CXCL4 or SSc derived plasma, which reversed by CXCL4 neutralizing antibody, but failed by CXCR3 inhibitor. CXCL4 downregulated the transcription factor Friend leukaemia integration factor-1 (Fli-1) via c-Abl signaling. Furthermore, CXCL4 blocked the transforming growth factor (TGF) -β or platelet-derived growth factor (PDGF) induced cell proliferation of HUVECs., Conclusions: CXCL4 may contribute to peripheral vasculopathy in SSc by downregulating Fli-1 via c-Abl signaling in endothelial cells and interfering angiogenesis., Competing Interests: Declaration of Competing Interest The data presented in this manuscript are original and have not been published or submitted elsewhere. All listed authors have approved the manuscript and agreed with the submission. The authors declare that they have no conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

Objective: The purpose of this article was to review our clinical experience with COVID-19 patients observed in the Cardiovascular Division of Pompidou Hospital (University of Paris, France) and the Department of Neurology of the Eastern Piedmont University (Novara, Italy), related to the impact on the cardiovascular, hematological, and neurologic systems and sense organs., Patients and Methods: We sought to characterize cardiovascular, hematological, and neurosensory manifestations in patients with COVID-19 and variants. Special attention was given to initial signs and symptoms to facilitate early diagnosis and therapy. Indications of ECMO (extracorporeal membrane oxygenation) for cardiorespiratory support were evaluated., Results: Preliminary neurosensorial symptoms, such as anosmia and dysgeusia, are useful for diagnosis, patient isolation, and treatment. Early angiohematological acro-ischemic syndrome includes hand and foot cyanosis, Raynaud digital ischemia phenomenon, skin bullae, and dry gangrene. This was associated with neoangiogenesis, vasculitis, and vessel thrombosis related to immune dysregulation, resulting from "cytokine storm syndrome". The most dangerous complication is disseminated intravascular coagulation, with mortality risks for both children and adults., Conclusions: COVID-19 is a prothrombotic disease with unique global lethality. A strong inflammatory response to viral infection severely affects cardiovascular and neurological systems, as well as respiratory, immune, and hematological systems. Rapid identification of acro-ischemic syndrome permits the treatment of disseminated intravascular coagulation complications. Early sensorial symptoms, such as gustatory and olfactory loss, are useful for COVID-19 diagnosis. New variants of SARS-CoV-2 are emerging, principally from United Kingdom, South Africa, and Brazil. These variants seem to spread more easily and quickly, which may lead to more cases of COVID.

Importance: Calcitonin gene-related peptide (CGRP) antagonists have demonstrated tremendous promise in migraine management. However, these medications decrease reflex vasodilatory response, which may lead to exacerbation of microvascular disease in susceptible patients, such as patients with Raynaud phenomenon (RP)., Objective: To investigate the microvascular complications of CGRP antagonists in patients with underlying RP., Design, Setting, and Participants: This retrospective cohort study was performed from May 18, 2018, to September 15, 2020, in Mayo Clinic Health System patients with Raynaud phenomenon while undergoing CGRP antagonist therapy to treat migraine. Inclusion criteria were age older than 18 years, history of migraine, past or current treatment with CGRP antagonists, and diagnosis of primary or secondary RP., Exposure: Treatment with CGRP antagonists., Main Outcomes and Measures: The main outcome measure was microvascular complications (eg, worsening RP, digital ulcerations, and gangrenous necrosis) after initiation of treatment with a CGRP antagonist. Patient demographic and clinical characteristics were compared between those who experienced complications and those who did not., Results: A total of 169 patients (163 [96.4%] female; 151 [89.3%] non-Hispanic White; mean [SD] age, 46 [13] years) were identified. Of the 169 patients, 9 (5.3%) exhibited microvascular complications, ranging from worsening RP to gangrene and autonecrosis that required distal digit amputation. Comparative analysis did not find statistically significant differences in demographic or clinical characteristics between the 2 cohorts. All 9 patients with complications were female (mean [SD] age, 40 [12] years). Five of the 9 patients (55.6%) had previously diagnosed RP; in 3 the RP was primary, and 2 it was secondary to scleroderma. The other 4 patients (44.4%) were newly diagnosed with RP. Eight of the 9 patients (88.9%) had chronic migraine; 4 had migraine with aura, and 5 had migraine without aura. The CGRP antagonist agents temporally associated with the microvascular complications included galcanezumab (in 3 patients), erenumab (in 5 patients), and fremanezumab (in 1 patient)., Conclusions and Relevance: The results of this study indicate that microvascular complications of CGRP antagonist use in patients with underlying RP are uncommon. The incidence of serious adverse events, although rare, warrant caution when considering the use of these agents in patients with RP.

Objective: A key unanswered question in systemic sclerosis (SSc) is how microvascular abnormality and fibrosis inter-relate. Our aim was to use state-of-the-art non-invasive imaging methods to gain new insights into pathophysiology, comparing patients with different subtypes of SSc, including early dcSSc, not only to healthy controls but also to patients with causes of Raynaud's phenomenon not progressing to fibrosis., Methods: Laser Doppler imaging, nailfold capillaroscopy, spectroscopy, and ultrasound measured (respectively) perfusion, microvascular structure, oxygenation/oxidative stress, and skin thickening in the hands of 265 subjects: 31 patients with primary Raynaud's phenomenon (PRP), 35 with undifferentiated connective tissue disease (UCTD), 93 with limited cutaneous SSc (lcSSc), 46 with diffuse cutaneous SSc (dcSSc, including 27 'early') and 60 healthy controls., Results: Mean perfusion was reduced in SSc groups compared to controls (lcSSc 172 perfusion units [standard deviation 157], late-dcSSc 90 [145], early-dcSSc 68 [137] vs. controls 211 [146]; p = 0.0002) as was finger-oxygenation (lcSSc 12.1 [13.6] arbitrary units [AU], late-dcSSc 12.2 [8.4], early-dcSSc 11.1 [11.3] vs controls 14.9 [10.5]; p = 0.0049). Oxidative stress was increased at the hand-dorsum in SSc groups (p = 0.0007). Perfusion positively correlated with oxygenation (r = 0.23, p < 0.001), and capillary density negatively with skin thickness (r = -0.26, p < 0.001)., Conclusion: Our findings lend support to the hypothesis that in SSc, particularly early dcSSc, (but not in PRP or UCTD), reduced perfusion (together with structural microvascular abnormality) associates with reduced oxygenation, with oxidative stress and with skin thickening/fibrosis, most likely driving a vicious cycle which ultimately results in irreversible tissue injury. Findings in skin may mirror alterations in internal organs., Competing Interests: Declaration of competing interest The authors declare no conflicts of interests., (Copyright © 2020. Published by Elsevier Inc.)

Immune checkpoint inhibitors, including antiprogrammed death cell protein 1 (anti-PD-1) and anti cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), have been associated with a range of autoimmune-related side effects since their introduction in cancer treatment. Small vessel digital necrosis, referred to as the acral vascular syndrome, is a rare but serious complication that can result in loss of digits. Here we present a case report of acral vascular syndrome and review possible aetiologies. A 45- year-old woman with invasive ductal carcinoma of the left breast presented to the emergency department during neoadjuvant treatment with carboplatin, docetaxel and pembrolizumab with complaints of severe pain in her right third digit. She had physical findings consistent with ischaemic necrosis and gangrene of the distal phalanx. Angiography demonstrated Raynaud's phenomenon in the distal portion of the digits. Laboratory testing showed a weakly positive RNA polymerase III antibody level. Her case resulted in surgical amputation of her affected digit after partial resolution of symptoms with prednisone, vasodilators and antibiotics., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Digital ulcers (DUs) represent one major burden for patients with systemic sclerosis (SSc). The objectives of our study were to evaluate blood flow in SSc-DUs with laser speckle contrast analysis (LASCA) and to correlate the skin perfusion to clinical and laboratory data., Methods: Forty DUs in 31 consecutive patients with SSc according to 2013 ACR/EULAR criteria (20 with limited cutaneous disease, 3 males) were prospectively examined with LASCA. Clinical and laboratory data were collected at the same time. DUs were classified according to clinical features and presence of infection., Results: At LASCA analysis, patients with diffuse SSc had lower mean values of blood flow compared with those with limited disease at the finger affected by DUs (88.80 vs 44.40, p = 0.036) and at the periulcer area (p = 0.041). The presence of infection was associated to a higher flow at the finger with DU (103.02 vs 58.05 p = 0.04), at the level of ulcer (217.63 vs 67.15, p < 0.001), and at the periulcer area (p = 0.001). The ratio between the blood flow at the ulcer area and the finger base (UA/FB) showed a bimodal trend in patients with infected DUs and in those without infections. Infection was positive correlated to the time of healing (HT) (r = 0.648, p = 0.023), while in DUs without infection a negative correlation to HT (r = - 0.46, p = 0.015) was identified., Conclusions: This study demonstrates for the first time that the UA/FB ratio may predict the healing time of DUs in SSc patients and may be crucial for the prognostic stratification of patients. Infection remains one of the main predictors of DU healing.Key Points• The prognostic value of laser speckle contrast analysis (LASCA) in patients with digital ulcers (DUs) in systemic sclerosis remains to be clarified.• LASCA may be able to predict the haling time of the digital ulcers.• The presence of infection of the wound bed may greatly influence the LASCA parameters and the healing time of the digital ulcer.

The Raynaud's condition score is a 11-point scale severity score used in Raynaud's phenomenon clinical trials since 1998. The Raynaud's condition score diary has been recommended for use in clinical trials assessing efficacy of interventions on scleroderma related Raynaud's phenomenon. However, this score has never been formally validated in French. We thus performed a translation and a linguistic validation of the Raynaud's condition score through a forward/backward translations process followed by an expert review and cognitive patient interviews. The translations led to a French version of the Raynaud's condition score that was linguistically valid, and conceptually equivalent to the original English version. This "Score de Raynaud" will be usable to perform and harmonize clinical trials in French-speaking patients with secondary Raynaud's phenomenon., (Copyright © 2019 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background: Infrared Thermography (IRT) has been used for over 30 years in the assessment of Raynaud Phenomenon (RP) and other peripheral microvascular dysfunctions in adults but, to date, very little experience is available on its use in children for this purpose. The first aim of the study was to assess reproducibility of thermographic examination after cold exposure by comparing inter-observer agreement in thermal imaging interpretation. The secondary aim was to evaluate whether IRT is reliable to diagnose and differentiate peripheral circulation disturbances in children., Methods: Children with clinical diagnosis of primary Raynaud's phenomenon (PRP), secondary RP (SRP), acrocyanosis (AC) and age-matched controls underwent sequential measurements of skin temperature at distal interphalangeal (DIP) and metacarpophalangeal (MCP) joints with IRT at baseline and for 10 min after cold challenge test. Intraclass correlation coefficient (ICC) was calculated for inter-rater reliability in IRT interpretation, then temperature variations at MCP and DIP joints and the distal-dorsal difference (DDD) were analysed., Results: Fourteen PRP, 16 SRP, 14 AC and 15 controls entered the study. ICC showed excellent agreement (> 0.93) for DIPs and MCPs in 192 measures for each subject. Patients with PRP, SRP and acrocyanosis showed significantly slower recovery at MCPs (p < 0.05) and at DIPs (p < 0.001) than controls. At baseline, higher temperature at DIPs and lower at MCPs was observed in PRP compared with SRP with significantly lower DDD (p < 0.001). Differently from AC, both PRP and SRP showed gain of temperature at DIPs and less at MCPs after cold challenge. PRP but not SRP patients returned to DIPs basal temperature by the end of re-warming time. Analysis of DDD confirmed that controls and PRP, SRP and AC patients significantly differed in fingers recovery pattern (p < 0.05)., Conclusion: IRT appears reliable and reproducible in identifying children with peripheral microvascular disturbances. Our results show that IRT examination pointed out that PRP, SRP and AC patients present significant differences in basal extremities temperature and in re-warming pattern after cold challenge therefore IRT can be suggested as an objective tool for diagnosis and monitoring of disease.

In kidney biopsies reviews, scleroderma renal crisis (SRC) is characterized by vascular endothelial injuries, C4d deposits on peritubular vessels, and acute and chronic injuries coexisting on the same biopsy. The clinical signs of thrombotic microangiopathy (TMA) are described in systemic sclerosis (SSc), nevertheless, it has not been related to acute injuries described on kidney biopsies. We report a case of SRC in a patient with scleroderma-dermatomyositis overlap syndrome, which also showed clinical and histopathological data of TMA. On fundus examination, a severe acute hypertensive retinopathy was found. The kidney biopsy showed severe endothelial damage with widening of mucoid cells at the level of the intima, focal concentric proliferation on most small arterioles, and C3, C4d, and IgM deposits along the capillary walls. The genetic study of complement only showed the presence of membrane cofactor protein (MCP) risk haplotypes, without other genetic complement disorders. We understand that in a patient with TMA and SSc, the kidney damage would be fundamentally endothelial and of an acute type; moreover, we would observe clear evidence of complement activation. Once further studies correlate clinical-analytical data with anatomopathological studies, it is likely that we will be forced to redefine the SRC concept, focusing on the relationship between acute endothelial damage and complement activation.

Nailfold capillaroscopy (NFC) is a reproducible, simple, low-cost, and safe imaging technique used for morphological analysis of nail bed capillaries. It is considered to be extremely useful for the investigation of Raynaud's phenomenon and for the early diagnosis of systemic sclerosis (SSc). The capillaroscopic pattern typically associated with SSc, scleroderma ("SD") pattern, is characterized by dilated capillaries, microhemorrhages, avascular areas and/or capillary loss, and distortion of the capillary architecture. The aim of these recommendations is to provide orientation regarding the relevance of NFC, and to establish a consensus on the indications, nomenclature, the interpretation of NFC findings and the technical equipments that should be used. These recommendations were formulated based on a systematic literature review of studies included in the database MEDLINE (PubMed) without any time restriction.

A 60-year-old female was diagnosed with progressive systemic sclerosis and interstitial lung disease of two months' duration. The patient was treated for Raynaud phenomenon with aspirin, nifedipine, colchicine, and naproxen. Two weeks after treatment, she developed widespread erythematous patches with blistering eruptions on the face, torso, and extremities, and also had erosion on the oral mucosa. Skin biopsy for histopathology and direct immunofluorescent studies were suggestive of lupus erythematosus. To the best of our knowledge, this is the first case of toxic epidermal necrolysis-like acute cutaneous lupus erythematosus in a patient with progressive systemic sclerosis.

Objectives: Despite increasing interest in nailfold capillaroscopy, objective measures of capillary structure and blood flow have been little studied. We aimed to test the hypothesis that structural measurements, capillary flow, and a combined measure have the predictive power to separate patients with systemic sclerosis (SSc) from those with primary Raynaud's phenomenon (PRP) and healthy controls (HC)., Methods: 50 patients with SSc, 12 with PRP, and 50 HC were imaged using a novel capillaroscopy system that generates high-quality nailfold images and provides fully-automated measurements of capillary structure and blood flow (capillary density, mean width, maximum width, shape score, derangement and mean flow velocity). Population statistics summarise the differences between the three groups. Areas under ROC curves (A Z ) were used to measure classification accuracy when assigning individuals to SSc and HC/PRP groups., Results: Statistically significant differences in group means were found between patients with SSc and both HC and patients with PRP, for all measurements, e.g. mean width (μm) ± SE: 15.0 ± 0.71, 12.7 ± 0.74 and 11.8 ± 0.23 for SSc, PRP and HC respectively. Combining the five structural measurements gave better classification (A Z  = 0.919 ± 0.026) than the best single measurement (mean width, A Z  = 0.874 ± 0.043), whilst adding flow further improved classification (A Z  = 0.930 ± 0.024)., Conclusions: Structural and blood flow measurements are both able to distinguish patients with SSc from those with PRP/HC. Importantly, these hold promise as clinical trial outcome measures for treatments aimed at improving finger blood flow or microvascular remodelling., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aim: Raynaud's phenomenon (RP) is a microvascular disorder characterized by episodic peripheral vasospasm and ischemia and is commonly found in patients with autoimmune diseases (AID). The vasomotor homoeostasis and endothelial cells damage are involved in RP. Endothelial microparticles (EMPs) may act as a biomarker for endothelial damage. The aim of this study is to investigate the correlation between the levels of microparticles (MPs) and microvasculopathy in AID with RP., Methods: Thirty-seven patients with AID and RP (RP group) and 27 patients with AID but without RP (non-RP group) were enrolled. The microvasculopathy score of RP was graded by nailfold capillary microscopy. The plasma levels of MPs were measured by flow cytometry utilizing specific labels for endothelial MPs (CD105 and CD144) and annexin V staining for phosphatidylserine bearing-MPs (annexin V+MPs)., Results: The levels of circulating EMPs (CD105+ p = 0.005, CD144+ p = 0.004), and the annexin V+ MPs (p < 0.001) were significantly elevated in the RP group compared with the non-RP group. Moreover, the high microvasculopathy scores were closely related with annexinV+ MPs levels in the RP group (p = 0.041)., Conclusions: Levels of circulating EMPs and annexin V+ MPs are elevated in AID patients with RP indicate the endothelial damage and endothelial dysfunctions. In addition, levels of annexin V+ MPs can predict the severity of microvasculopathy in AID with RP., (Copyright © 2016. Published by Elsevier B.V.)

Objectives: Raynaud's phenomenon (RP) can be the first manifestation of systemic sclerosis (SSc) or other connective tissue diseases (CTDs), often preceding an overt disease by years. It is not known if markers of endothelial damage are detectable in those RP patients who subsequently develop a CTD., Methods: We studied 82 RP patients at their first evaluation to correlate the levels of endothelial markers with the subsequent development of an overt disease 36months later. We measured plasma levels of tissue-type plasminogen activator (t-PA) and von Willebrand factor (vWF), two markers of endothelial damage, and interleukin-6 (IL-6), a pro-inflammatory cytokine. Thirty sex- and age-matched healthy subjects (HS) served as controls., Results: At baseline, 67 patients showed capillaroscopic normal pattern (CNP) and 15 patients, of which 11 were very early SSc, had capillaroscopic scleroderma pattern (CSP). Plasma levels of t-PA, vWF and IL-6 were higher in patients with CNP (p=0.0001) than in HS and even much higher in patients with CSP (p=0.0001). In patients with CNP and RP of recent onset (<18months), vWF plasma levels were higher when autoantibodies were present (p=0.020). After 36months, among 48 RP patients with CNP who remained in follow-up, 24 were diagnosed as primary and 24 as secondary RP. In secondary RP, basal levels of t-PA, IL-6 and particularly vWF were higher than in primary RP (p=0.005, p=0.004, p=0.0001 respectively) and HS (p=0.0001 for all)., Conclusions: Our findings indicate that markers of endothelial damage are elevated in RP patients who subsequently develop SSc or other CTDs, even in the absence of capillaroscopic abnormalities., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This study aimed to detect by nailfold videocapillaroscopy (NVC) the presence of age-related capillary morphological patterns in a large cohort of subjects affected by primary Raynaud's phenomenon (PRP). NVC was performed in 877 patients affected by PRP, divided into three age groups: <35, 35-55 and >55 years. The following qualitative parameters were assessed and compared in the three groups of patients: apical dilations, irregular (non-homogeneous) dilations, venous branch dilations, microhaemorrhages, tortuosities and subpapillary venous plexus visibility. Patients with either irregular dilations or venous branch dilations were found significantly younger than those without (p < 0.0001). The presence of either irregular or venous branch dilations seems to exclude the presence of apical dilations. Patients with microhaemorrhages were found significantly younger than those without (p = 0.05), and 81 % of patients without microhaemorrhages did not show irregular and venous branch dilations. The subpapillary venous plexus seems more visible in subjects with age < 35, as well as in those with age > 55 years (p < 0.0001). A statistically significant negative correlation was found between presence of apical and irregular dilations (p < 0.0001), apical dilations and venous branch dilations (p = 0.02), apical dilations and tortuosities (p = 0.0005), microhaemorrhages and tortuosities (p < 0.0001) and venous branch dilations and tortuosities (p = 0.02). Finally, a statistically significant positive correlation was found between irregular and venous branch dilations (p < 0.0001), irregular dilations and microhaemorrhages (p < 0.0001) and venous branch dilations and microhaemorrhages (p < 0.0001). In conclusion, our study detected different age-related morphological capillary changes mainly in younger patients with PRP, as well as statistically significant correlations between the presence of different capillary variables.

Background: Raynaud's phenomenon is a microvascular disorder that results in exaggerated vasoconstriction over vasodilatation secondary to an alteration in autonomic control. Though benign, it can result in severe ulceration and ultimately gangrene associated with disfiguration and permanent deformity. We present a case of severe secondary Raynaud's phenomenon in a black-African patient from a resource-limited setting, with focus on the difficulties encountered in the diagnosis and treatment., Case Presentation: A 43-year-old female Cameroonian farmer with a 7-year history of episodic paresthesia in her fingers and toes (when exposed to cold) presented to our emergency department with severe pain, ulceration, and "darkening" of her fingertips over a period of 2 days. An examination revealed bilateral ulceration and dry gangrene of her fingers and toes, based on which a diagnosis of secondary Raynaud's phenomenon due to a connective tissue disease was proposed. Results of paraclinical investigations were normal. Lifestyle modification along with a calcium channel blocker and phosphodiesterase type 5 inhibitor provided significant relief., Conclusions: An early diagnosis and knowledge on appropriate treatment of Raynaud's phenomenon is of vital importance to prevent permanent tissue damage and disability. Relying on biphasic color change for the diagnosis of Raynaud's phenomenon in black Africans can be potentially misleading.

Objective: The objectives of our study were to describe the MRI findings of pedal phalangeal bone marrow edema in patients with Raynaud phenomenon (RP) and discuss the clinical implications of these MRI findings., Conclusion: There is a progressive distal-to-proximal pattern of pedal phalangeal bone marrow edema on MRI in patients with RP. This knowledge may allow early diagnosis and treatment of rheumatologic disorders that are potentially associated with RP.

Objective: To explore whether polymorphic variants of the HTR1B gene are associated with the susceptibility of Raynauds' Phenomenon (RP) coursed by vibration., Methods: 148 subjects exposed to vibration for more than 2 years were classified into either induced white finger (VWF) group (n = 72), or non-VWF group (n = 76). Vibration exposure levels were measured and assessed following ISO 5349-1:2001 protocol. All workers were genotyped by sequencing for the single nucleotide polymorphisms (SNPs) in the 5'-flanking and coding region of HTR1B. Genetic characteristics and linkage disequilibrium (LD) were analyzed with Haploview. Serum serotonin levels of each subject were detected using ELISA. The association between the susceptibility of vascular damage and genotype was analyzed via logistic regression., Results: 7 known SNPs were obtained and their allele frequencies were inserted into the Hardy-Weinberg equilibrium. rs6297 variant genotype had an increased risk of VWF compared with wild genotype (OR = 2.14, 95% CI = 1.04- 4.58, P < 0.05). rs6298 mutant type (AG+GG) was found to have a significant interaction on vibration exposure LN(CEI), accounting for VWF occurrence. LN(5-HT) level is significantly different between the VWF group (x¯±s= 1.99±1.09 ng/mL) and the non-VWF group (x¯±s= 2.72±1.47 ng/mL)., Conclusions: Serotonin levels may affect the progression of secondary RP. Polymorphic variants of the HTR1B gene are associated with the susceptibility of secondary RP in vibration-exposed occupational populations of Chinese Han people.

CXCL4 is an antiangiogenic and immunomodulatory chemokine. We aimed to investigate serum levels of CXCL4 in primary Sjögren's syndrome (pSS), looking for associations with disease features. Thirty-nine consecutive pSS patients underwent clinical-serological assessment and nailfold videocapillaroscopy (NVC). Thirty-six patients and 30 controls affected by osteoarthritis were also investigated for serum levels of CXCL4 and soluble E-selectin (sE-selectin). CXCL4 was higher in pSS patients than in controls (1.79 [0.2-11.18] vs 1.023 ng/ml [0.02-14.45], p < 0.05), particularly in those without anti-La/SSB antibodies (2.89 [1.01-11.18] vs 1.69 ng/ml [0.2-2.72], p < 0.05), while it was lower in pSS patients with a focus score ≥1 at lip biopsy (1.44 [0.86-2.1] vs 2.24 ng/ml [1.64-3.25], p < 0.05) and clinically evident lymphadenopathy (1.53 [0.38-1.7] vs 2.08 ng/ml [1.45-3.03], p < 0.05). CXCL4 correlated with disease duration (r = 0.35, p < 0.05) and sE-selectin (r = 0.45, p < 0.01). Patients with Raynaud's phenomenon (RP) had more frequently abnormal CXCL4 levels than patients without RP (11/15 vs 3/21, p < 0.001), enlarged capillaries (14/16 vs 7/23, p < 0.001) and capillary loss at NVC (14/16 vs 6/23, p < 0.001). The hitherto unknown association of increased serum CXCL4 with features of microvascular impairment in pSS, along with the negative association with features of lymphocytic response (i.e., the absence of subset disease-specific autoantibodies, a low focus score, and the absence of lymphadenopathy) suggest clarifying the possible implication of this chemokine in pSS pathogenesis in larger studies.

Systemic sclerosis (SSc) is a connective tissue disease frequently associated with Raynaud's Phenomenon (RP). Among possible pharmacological treatments, phosphodiesterase 5 inhibitors are considered in cases of severe non -responsive RP. We present the case of a male SSc patient wh presented with critical finger ischemia and concomitant appearance of myocardial fibrosis after sudden interruption of sildenafil treatment.

Pseudo-pseudo Meigs' syndrome (PPMS) has been reported to be a rare presentation of patients with systemic lupus erythematosus (SLE). However, such a presentation is not common in other forms of connective tissue disease. We presented a case of gross ascites, pleural effusion, and marked elevation of CA-125 level (PPMS-like features) that led to a diagnosis of MCTD. The patient responded to systemic steroid therapy., (© The Author(s) 2015.)

Raynaud's phenomenon is a clinical symptom that can commonly present to a primary care provider or generalist. Proper identification of an underlying connective tissue disease in a patient with Raynaud's could allow for the prevention of possible critical digital ischemia. Capillaroscopy is a tool which can identify abnormalities associated with connective tissue disease. Patients presenting with a complaint of Raynaud's phenomenon were assessed with capillaroscopy. In twenty consecutive Raynaud patients, 8 digits were assessed by a ×200 magnification dermatoscope and an image was obtained. Each image was assessed for the following abnormalities: drop-out (<9 capillaries in 1 mm); microhemorrhage; dilated loops; and neoangiogenesis. These 160 images were then shown to 20 primary care physicians, who assessed these same abnormalities. The interrater reliability, a measure of agreement, of individual primary care providers with the expert provider was assessed using kappa statistics. Three raters had slight agreement (in the range 0 to 0.20), one rater had fair agreement (0.21 to 0.40), 11 raters had moderate agreement (0.41 to 0.60), five raters had substantial agreement (0.61 to 0.80), and no rater had almost perfect agreement (0.81 to 1.00) (14). The total agreement from the 20 primary care providers (n = 3,156) was moderate (Κ = 0.50, 95 % CI 0.49, 0.55). For the four providers with the slight to fair interrater reliabilities, the most common disagreement was providing a positive diagnosis when the expert rater diagnosed the digit negative. Ten of the twenty primary care providers provided at least one additional diagnosis following an abnormal diagnosis (n = 35 digits or 35 % of the 1556 abnormal ratings by the primary care providers). The four providers with the poorest interrater reliabilities were not among the ten providers who participated in making these additional specific diagnoses. These providers achieved the moderate agreement with the expert provider for diagnoses of microhemorrhage (Κ = 0.64, 95 % CI 0.57, 0.70), but fair agreement with the expert provider for diagnoses of dilated (Κ = 0.27, 95 % CI 0.20, 0.34) and neoangiogenesis (Κ = 0.22, 95 %CI 0.13, 0.31). Capillaroscopy is a potentially contributive clinical exam skill that could assist primary care providers and generalists in identifying and qualifying changes associated with the common presentation of Raynaud's disease. However, formal training is needed to ensure accuracy and reproducibility. Furthermore, training and scoring systems should address time constraints of busy primary care practitioners.

Background: Patients with systemic lupus erythematosus seem to belong to different serological and clinical subgroups of the disease. Genetic background can cause the appearance of these subgroups., Objective: To determine whether Brazilian patients who have systemic lupus erythematosus and Raynaud's phenomenon differ from those who do not., Methods: Retrospective analysis of 373 medical records of systemic lupus erythematosus patients studied for demographic, clinical and serological data. A comparative analysis was performed of individuals with and without RP., Results: There was a positive association between Raynaud's phenomenon and age at diagnosis (p=0.02), presence of anti-Sm (p=0.01) antibodies and anti-RNP (p<0.0001). Furthermore, a negative association was found between Raynaud's phenomenon and hemolysis (p=0.01), serositis (p=0.01), glomerulonephritis (p=0.0004) and IgM aCL (p=0.004) antibodies., Conclusion: Raynaud's phenomenon patients appear to belong to a systemic lupus erythematosus subset with a spectrum of clinical manifestations located in a more benign pole of the disease.

Increased risk of developing systemic lupus erythematosus (SLE) has been reported in patients with Klinefelter syndrome. Here, we describe a 16-year-old Japanese patient with trisomy X (47,XXX) who developed mixed connective tissue disease (MCTD) and Sjögren's syndrome. She had polyarthritis, edematous fingers with Raynaud's phenomenon, sicca syndrome, interstitial lung disease, possible myositis, and was positive for anti-nuclear antibody, anti-nRNP antibody and rheumatoid factor. This is the first report in the literature of a case of MCTD with female polysomy X, which further supports the link between the presence of extra X chromosome(s) and the development of autoimmune diseases., (© The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Objective: To monitor in systemic sclerosis (SSc) the evolution of digital ulcer (DU) status by analysing blood perfusion (BP) using laser speckle contrast analysis (LASCA)., Methods: Hand BP was recorded by LASCA in twenty SSc patients with recent onset fingertip DUs before and after 10days of local/systemic treatment. Regions of interest (ROIs) to analyse BP were created al the level of ulcer, peri-ulcer, periungual and fingertip areas. Visual analogue pain scale (VAS) was also administered to patients before and after follow-up., Results: A statistically significant increase of BP was observed from T0 to T1 in the ROIs created at the level of the ulcer area (p<0.0001), as well as a significant decrease of BP was observed in the peri-ulcer area (p<0.0001). A statistically significant decrease of both ulcer size (p<0.0001) and VAS (p=0.001) was observed, whereas no significant variation of both periungual and fingertip BP was detected., Conclusions: LASCA may safely monitor DU evolution in SSc patients, by evaluating its blood perfusion and area during standard treatment. This may be useful to monitor DU evolution during treatment in clinical trials., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: Nailfold videocapillaroscopy (NVC), the current gold standard for detection of capillary abnormalities suggestive of an SSc-spectrum disorder, is not widely available: a key question is whether lower-magnification, easy-to-use dermoscopy compares favourably. This is especially relevant given the inclusion of capillaroscopic abnormality within the 2013 classification criteria for SSc. Our objectives were to examine the ability to classify capillaries and to evaluate abnormality (severity), by both NVC and dermoscopy, to determine whether these differ between general and specialist rheumatologists, and to compare intra- and interrater reliability of both techniques., Methods: NVC and dermoscopy images were acquired from all 10 nailbeds of 32 subjects with a range of capillary abnormalities. Images were graded (using a web-based interface) on a 0-3 scale of severity: normal (0), mildly (1), definitely (2) and grossly abnormal (3), and an unclassifiable category. Raters graded images from four subjects (40 nailbeds) using each technique, with five repeated images to estimate intrarater reliability., Results: Forty-eight rheumatologists from 12 countries participated in the study (22 generalists, 26 specialists). While most images could be graded by both techniques, more were graded by NVC (84% vs 70%) and were systematically scored higher by NVC (mean difference 0.43 between the ratings). Agreement between the techniques was moderate. Intra- and interrater reliability were comparable for the two techniques in the classifiability of images and the grading of severity., Conclusion: Our results suggest that dermoscopy is comparable to NVC, although NVC images were more likely to be classifiable and were graded more severely., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The aim of this study was to investigate the influence of the Multiwave Locked System (MLS) laser therapy on clinical features, microvascular changes in nailfold videocapillaroscopy (NVC) and circulating modulators releasing as a consequence of vascular endothelium injury such as vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang-2) in patients with primary and secondary Raynaud's phenomenon. Seventy-eight RP patients and 30 healthy volunteers were recruited into the study. All patients with RP received MLS laser irradiation for 3 weeks. Clinical, NVC and laboratory investigations were performed before and after the MLS laser therapy. The serum concentration of VEGF and Ang-2 were determined by an enzyme-linked immunosorbent assay (ELISA). After 3 weeks of MLS laser therapy, the clinical improvement manifested by decreasing of the number of RP attacks, mean duration of Raynaud's attack and pain intensity in RP patients was observed. After MLS laser therapy in 65% of patients with primary and in 35% with secondary RP, an increase in the loop number and/or a reduction in avascular areas in NVC were observed. In comparison with a control group, higher serum concentration of VEGF and Ang-2 in RP patients was demonstrated. After MLS laser therapy, a reduction of Ang-2 in both groups of RP patients was found. Our results suggest that NVC may reflect microvascular changes associated with clinical improvement after MLS laser therapy in patients with primary and secondary RP. Ang-2 serum levels may be a useful marker of microvascular abnormalities in RP patients treated with MLS laser therapy.

Vascular manifestations can be seen early in the pathogenesis of inflammatory rheumatic diseases. Animal experiments, laboratory and clinical findings indicated that acute or long-term vibration exposure can induce vascular abnormalities. Recent years, in addition to Raynaud's phenomenon (RP), vibration as a risk factor for other rheumatic diseases has also received corresponding considered. This review is concentrated upon the role of vibration in the disease of systemic sclerosis (SSc). In this review, we are going to discuss the main mechanisms which are thought to be important in pathophysiology of vascular injury under the three broad headings of "vascular", "neural" and "intravascular". Aspects on the vibration and vascular inflammation are briefly discussed. And the epidemiological studies related to vibration studies in SSc and other rheumatic diseases are taken into account.

Objectives: To evaluate the morphological and functional abnormalities of the microcirculation associated with markers of vascular injury in patients with early systemic sclerosis (SSc)., Method: Forty-six patients with early SSc were compared with 80 patients with definite SSc, 40 patients with primary Raynaud's phenomenon (PRP), and 45 healthy subjects. Widefield nailfold capillaroscopy (NFC) (10-25 × magnification), videocapillaroscopy (200 × magnification), and laser Doppler imaging (LDI) assessment were performed in all participants. The number of capillaries/mm, enlarged, giant and ramified capillaries, microhaemorrhages, and the avascular score were determined by widefield NFC and videocapillaroscopy. Fingertip blood flow (FBF) was measured using LDI before and after cold stimulus (CS). Serum endothelin-1 (ET-1), von Willebrand factor (vWF), and transforming growth factor beta-1 (TGF-β1) were measured by enzyme-linked immunosorbent assay (ELISA)., Results: Upon both widefield NFC and videocapillaroscopy, patients with early SSc showed significantly higher numbers of capillaries/mm, lower enlarged and giant capillaries, and a lower avascular score than definite SSc patients (p < 0.001). They also had more enlarged capillaries, microhaemorrhages and a higher avascular score compared to PRP and controls (p < 0.001). FBF before and after CS were significantly higher in controls than in PRP, early SSc, and definite SSc patients (p < 0.001), with no difference between early and definite SSc. Serum levels of ET-1, vWF, and TGF-β1 were similar between early and definite SSc patients., Conclusions: Early SSc patients showed functional changes and vascular injury marker levels similar to patients with established disease. Nonetheless, the morphological changes were less severe in early SSc, thus providing an opportunity for further prevention of vasculopathy progression.