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Objectives: Although systemic lupus erythematosus (SLE) most commonly occurs in reproductive-age women, some are diagnosed after the age of 50. Recognizing that greater than one-third of SLE criteria are cutaneous, we undertook a systematic review and meta-analysis to evaluate differences in cutaneous manifestations in early- and late-onset SLE patients., Methods: We searched the literature using PubMed, CINAHL, Web of Science, and Cochrane Library. We excluded studies that did not include ACR SLE classification criteria, early-onset controls, that defined late-onset SLE as <50 years of age, or were not written in English. Two authors rated study quality using the Newcastle Ottawa Quality Scale. We used Forest plots to compare odds ratios (95% CI) of cutaneous manifestations by age. Study heterogeneity was assessed using I(2)., Results: Overall, 35 studies, representing 11,189 early-onset and 1727 late-onset patients with SLE, met eligibility criteria. The female:male ratio was lower in the late-onset group (5:1 versus 8:1). Most cutaneous manifestations were less prevalent in the late-onset group. In particular, malar rash [OR = 0.43 (0.35, 0.52)], photosensitivity [OR = 0.72 (0.59, 0.88)], and livedo reticularis [OR = 0.33 (0.17, 0.64)] were less common in late-onset patients. In contrast, sicca symptoms were more common [OR = 2.45 (1.91, 3.14)]. The mean Newcastle Ottawa Quality Scale score was 6.3 ± 0.5 (scale: 0-9) with high inter-rater reliability for the score (0.96)., Conclusions: Overall, cutaneous manifestations are less common in late-onset SLE patients, except sicca symptoms. Future studies should investigate etiologies for this phenomenon including roles of immune senescence, environment, gender, and immunogenetics., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: We performed a literature review assessing possible benefits of statins in systemic sclerosis (SSc)., Methods: PubMed, Embase, Cochrane Databases, and Medline were searched. Full-text English publications were identified in which the effects of statins in SSc were examined. Letters, review articles, and studies on morphea were excluded., Results: In all, 18 of 404 studies were relevant. In vitro, statins decreased transcription and translation of IL-6 and collagen, with reversal via mevalonate. Animal studies demonstrated reduced production of Ras (a protein superfamily of GTPases), Rho (part of the Ras superfamily), and extracellular signal-regulated kinases (ERK), less fibrosis and myofibroblast transdifferentiation, and improved macrovasculature. In human studies, IL-6, an inflammatory cytokine, was reduced. Usually endothelial progenitor cell concentrations increased, and flow-mediated dilatation improved. Raynaud's phenomenon, digital ulcers, and physician global assessments improved in the majority of studies of statin treatment in SSc. None of the 256 patients receiving statins experienced transaminitis or myopathy., Conclusions: Not all findings were consistent. However, in general, in vitro, animal, and human studies demonstrated benefit in SSc pathophysiology, likely mediated through inhibition of lipid intermediate synthesis. Clinical improvement in SSc circulatory complications was observed. Statins seemed safe and well tolerated in SSc. Larger longer-term multi-site randomized trials are needed to further determine the role of statins as adjunctive treatment of this complex, heterogeneous connective tissue disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: The aim of the study was to assess the association between plethysmographically measured vasospasms during stepwise cooling and recovery, as an index for digital ischaemia, and nailfold capillaroscopic pattern (NCP) severity in patients with primary or secondary RP, including SSc., Methods: In 381 consecutive patients with suspected RP without a history of digital ulcers, NCP (assessed by widefield videocapillaroscopy), fingertip photoelectric plethysmography during cooling and recovery and clinical characteristics were analysed. NCPs were graded as follows: normal, non-specific, early and active. The mean ischaemic time was defined as the mean time of perfusion loss during cooling and recovery of five fingers., Results: In the patients with loss of perfusion during cooling and recovery, the NCP was normal in 152, non-specific in 96, early in 61 and active in 39 patients. The mean ischaemic time was positively associated with the severity of NCP, with P < 0.05 for each two- or three-grade increase and independent of underlying SSc. The difference was most pronounced during recovery., Conclusion: We demonstrate that the degree of vasospasm and ischaemia provoked by stepwise cooling and recovery are positively associated with NCP in patients with RP of different aetiologies and without a history of digital ulcers., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Secondary Raynaud's phenomenon is a frequent condition related to occupational exposure to local vibration but has not been described in musicians. This study aims to describe cold-induced blanching of the right second and (in particular) third digits in a 67-year-old double bass player following decades of cumulative repetitive blunt trauma to the fingers from slapping the strings., Methods: A physical examination was undertaken and systolic blood pressure measured before and after cold provocation., Results: At 10 deg C the brachial systolic blood pressure was 156 mm Hg while blood pressure was immeasurable at the finger level, corresponding to a finger/brachial index of 0% of the second and third fingers., Conclusion: This is the first reported case of objectively verified, playing-related Raynaud's phenomenon in a musician.

Objective: Among Basque handball players, the repeated impact of a ball on the palms of their hands hundreds of thousands of times throughout their sporting careers produces Raynaud syndrome. Treating this patient group is complex. Our objective was to assess the efficacy of digital periarterial sympathectomy in this patient group., Methods: The study included all of the federated amateur and professional Basque handball patients who presented with Raynaud syndrome assessed in the vascular surgery service between January 2005 and December 2012. The postoperative assessment included a physical examination, basal photoplethysmography and photoplethysmography after heat hyperemia, and arteriography or magnetic resonance angiography., Results: All 182 digital periarterial sympathectomies in the 114 fingers of 60 patients were in Porter functional class III or IV. All patients were discharged within the first 48 hours. Follow-up results, with a mean of 2 years ± 5 months, were 100%. All patients presented immediate pain remission, recovery of comfort, normal nail growth, rapid healing of all ulcers, distal anhidrosis, and return to active sport participation. The results remain steady in 58 patients (93.5%). Mean time until return to sports activity was 9.95 ± 1.61 weeks., Conclusions: Digital periarterial sympathectomy is a simple, relatively nonaggressive technique without adverse side effects and with excellent medium-term results. In patients with Raynaud syndrome refractory to medical treatment and with threat to the viability of one or several fingers, digital periarterial sympathectomy can be the first treatment option, especially in cases of arteritis associated with very severe spasms., (Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Raynaud's phenomenon (RP) is a major cause of pain and disability in patients with autoimmune connective tissue diseases (CTDs), particularly systemic sclerosis (SSc). The clinician must perform a comprehensive clinical assessment in patients with RP to differentiate between primary (idiopathic) and secondary RP, in particular (for rheumatologists), secondary to an autoimmune CTD, as both the prognosis and treatment may differ significantly. Key investigations are nailfold capillaroscopy and testing for autoantibodies (in particular, those associated with SSc). Patients with RP and either abnormal nailfold capillaroscopy or an SSc-specific antibody (and especially with both) have a high risk of transitioning to an autoimmune CTD. Both nailfold capillaroscopy and autoantibody specificity may help the clinician in predicting organ-based complications. The management of CTD-associated RP requires a multifaceted approach to treatment, including patient education and conservative ('non-drug') measures. Patients with CTD-associated RP often require pharmacological treatment, which in the first instance is usually a calcium channel blocker, although other agents can be used. There is an increasing tendency to use phosphodiesterase type 5 inhibitors early in the treatment of CTD-associated RP. Oral therapies are commonly associated with side effects (often due to systemic vasodilation) that may result in failure of dose escalation and/or permanent discontinuation. Intravenous prostanoid therapy and surgery (e.g., botulinum toxin injection and digital sympathectomy) can be considered in severe RP. Patients with CTD-associated RP can develop a number of ischaemic digital complications (primarily ulcers and critical ischaemia), which may be associated with significant tissue loss. Future research is required to increase the understanding of the pathogenesis and natural history of RP (to drive therapeutic advances), and to explore/develop drug therapies, including those that target the mechanisms mediating cold-induced vasoconstriction, and locally acting therapies free of systemic side effects., (Copyright © 2016. Published by Elsevier Ltd.)

We report a new clinical manifestation of neonatal Behcet's disease. A newborn from a mother with active Behcet's disease during pregnancy, who develops vasomotor phenomena (Raynaud) with oral ulcerations in the second day of life. Neonatal mucocutaneous lesions have been reported previously in few newborns of pregnant women with active Behçet disease. Although neonatal disease is a very infrequent situation, with a mostly transient and favorable course, clinicians should be aware of serious potential complications associated with this entity.

Currently, there is no satisfactory treatment for Raynaud's phenomenon (RP) in systemic sclerosis (SSc). Recently, it has been reported that botulinum toxin A (BTX-A) injection was effective for the treatment of RP in SSc patients. The objective was to assess the efficacy and safety of BTX-A on RP in Japanese SSc patients. In the prospective, case series study, 10 Japanese SSc patients with RP received 10 U of BTX-A injections into the hand. The change in severity of RP, including the frequency of attacks/pain, color changes, duration time of RP and the severity of pain, was assessed by Raynaud's score and pain visual analog scale (VAS) at each visit during 16 weeks. The recovery of skin temperature 20 min after cold water stimulation was examined by thermography at baseline and 4 weeks after injection. The number of digital ulcers (DU) and adverse effects were assessed at each visit. BTX-A injection decreased Raynaud's score and pain VAS from 2 weeks after injection, and the suppressive effect was continued until 16 weeks after injection. Skin temperature recovery after cold water stimulation at 4 weeks after injection was significantly enhanced compared with that before injection. All DU in five patients were healed within 12 weeks after injection. Neither systemic nor local adverse effects were observed in all cases. We conclude that BTX-A injection significantly improved the activity of RP in SSc patients without any adverse events, suggesting that BTX-A may have possible long-term preventive and therapeutic potentials for RP in Japanese SSc patients., (© 2015 Japanese Dermatological Association.)

a-Ku are rare antibodies, which are reported in course of connective tissue diseases. Their prevalence ranges from 0 to 10% , 2%, on average. The main symptoms associated with the presence of a-Ku antibodies include: myositis, arthritis, Raynaud`s phenomenon and skin lesions. The above features are often defined as autoimmune clinical syndrome associated with a-Ku antibodies. In recent years, three cases with the presence of a-Ku antibodies were observed at the Department of Rheumatology and Connective Tissue Diseases. Case 1, a 77-year-old man, with the diagnosis of mixed connective tissue disease according to Raynaud`s phenomenon, myositis, arthritis and presence of a-ribonucleoprotein antibodies. Moreover, secondary Sjögren syndrome (SS) and myasthenia gravis were diagnosed. Case 2, a 56-year-old woman with longstanding history of Raynaud`s phenomenon, sclerodactyly, myositis and arthritis. Based on clinical manifestations and additional tests, systemic sclerosis and myositis were diagnosed. Case 3, a 46-year-old woman with SS diagnosis, long-standing history of Raynaud`s phenomenon, arthralgia and polyneuropathy. Moreover, HCV infection with the presence of cryoglobulin was confirmed. The presence of a-Ku antibodies in high titers was found in all cases. The clinical conditions improved after steroid and immunosuppressive therapy. In conclusion, clinical syndromes with the presence of a-Ku antibodies are associated with a wide range of non-specific symptoms, regarding muscle, joint and skin involvement, in particular. The conditions are more often diagnosed in the elderly; in the majority of cases, they are characterized by mild courses, good response to steroid therapy and good prognosis.

Vasculopathy in systemic sclerosis is a severe, in many cases irreversible, manifestation that can lead to amputation. While the classical clinical manifestations of the disease have to do with the involvement of microcirculation, proximal vessels of upper and lower limbs can also be affected. This involvement of large vessels may be related to systemic sclerosis, vasculitis or atherosclerotic, and the differential diagnosis is not easy. To conduct a proper and early diagnosis, it is essential to start prompt appropriate treatment. In this review, we examine the involvement of large vessels in scleroderma, an understudied manifestation with important prognostic and therapeutic implications., (Copyright © 2015 Elsevier España, S.L.U. All rights reserved.)

Objective: To determine the relationships between systemic sclerosis (SSc)-related autoantibodies, as well as their clinical associations, in a well-characterized Australian patient cohort., Methods: Serum from 505 Australian SSc patients were analyzed with a commercial line immunoassay (EuroLine; Euroimmun) for autoantibodies to centromere proteins CENP-A and CENP-B, RNA polymerase III (RNAP III; epitopes 11 and 155), the 90-kd nucleolar protein NOR-90, fibrillarin, Th/To, PM/Scl-75, PM/Scl-100, Ku, topoisomerase I (topo I), tripartite motif-containing protein 21/Ro 52, and platelet-derived growth factor receptor. Patient subgroups were identified by hierarchical clustering of the first 2 dimensions of a principal components analysis of quantitative autoantibody scores. Results were compared with detailed clinical data., Results: A total of 449 of the 505 patients were positive for at least 1 autoantibody by immunoblotting. Heatmap visualization of autoantibody scores, along with principal components analysis clustering, demonstrated strong, mutually exclusive relationships between CENP, RNAP III, and topo I. Five patient clusters were identified: CENP, RNAP III strong, RNAP III weak, topo I, and other. Clinical features associated with CENP, RNAP III, and topo I were consistent with previously published reports concerning limited cutaneous and diffuse cutaneous SSc. A novel finding was the statistical separation of RNAP III into 2 clusters. Patients in the RNAP III strong cluster had an increased risk of gastric antral vascular ectasia, but a lower risk of esophageal dysmotility. Patients in the other cluster were more likely to be male and to have a history of smoking and a history of malignancy, but were less likely to have telangiectasia, Raynaud's phenomenon, and joint contractures., Conclusion: Five major autoantibody clusters with specific clinical and serologic associations were identified in Australian SSc patients. Subclassification and disease stratification using autoantibodies may have clinical utility, particularly in early disease., (© 2015, American College of Rheumatology.)

Objective: Digital vasculopathy (comprising RP, digital ulceration and critical digital ischaemia) is responsible for much of the pain and disability experienced by patients with SSc. However, there is a limited evidence base to guide clinicians in the management of SSc-related digital vasculopathy. Our aim was to produce recommendations that would be helpful for clinicians, especially for those managing patients outside specialist centres., Methods: The UK Scleroderma Study Group set up several working groups to develop a number of consensus best practice pathways for the management of SSc-specific complications, including digital vasculopathy., Results: This overview presents the background and best practice consensus pathways for SSc-related RP, digital ulceration and critical ischaemia. Examples of drug therapies, including doses, are suggested in order to inform prescribing practice., Conclusion: A number of treatment algorithms are provided that are intended to provide the clinician with accessible reference tools for use in daily management., (© 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.)

Postural tachycardia syndrome (POTS) is a syndrome of excessive tachycardia with orthostatic challenge, and relief of such symptoms with recumbence. There are several proposed subtypes of the syndrome, each with unique pathophysiology. Numerous symptoms such as excessive tachycardia, lightheadedness, blurry vision, weakness, fatigue, palpitations, chest pain, and tremulousness are associated with orthostatic intolerance. Other co-morbid conditions associated with POTS are not clearly attributable to orthostatic intolerance. These include chronic headache, fibromyalgia, functional gastrointestinal or bladder disorders, cognitive impairment, and sleep disturbances. Dermatological manifestations of POTS are also common and wide ranging, from livedo reticularis to Raynaud's phenomenon, from cutaneous flushing to erythromelalgia. Here, we provide three illustrative cases of POTS with dermatological manifestations. We discuss the potential pathophysiology underlying such dermatological manifestations, and how such mechanisms could in turn help guide development of management.

Raynaud's phenomenon and digital ulcers (DUs) are frequent among systemic sclerosis (SSc) patients. Our aim was to investigate the diagnostic and predictive value for DU of endothelial dysfunction biomarkers (flow-mediated dilatation (FMD), serum levels of endothelin-1 (ET-1), and ADMA), angiogenic/angiostatic biomarkers (vascular endothelial growth factor (VEGF), endoglin, and endostatin), and nailfold videocapillaroscopy (NVC). We compared our results with a literature review. In a cohort study of 77 SSc patients, we followed two groups of patients: (i) naïve DU patients (39) and (ii) active DU at baseline (38 patients) for 3 years. Telangiectasia (p < 0.001) and diffuse disease subset (p = 0.001) were significantly more frequent in patients with active DU at enrolment. Additionally, NVC late scleroderma pattern (AUC 0.846, 95%CI 0.760-0.932), lower values of FMD (AUC 0.754, 95%CI 0.643-0.864), increased serum levels of ET-1 (AUC 0.758, 95%CI 0.649-0.866), ADMA (AUC 0.634, 95%CI 0.511-0.757), and endoglin as well as low VEGF serum levels (AUC 0.705, 95%CI 0.579-0.830) were significantly associated to new DU events in the 3-year follow-up. Cox regression analysis showed that FMD > 9.41 % (HR 0.37, 95%CI 0.14-0.99); ET-1 >11.85 pmol/L (HR 3.81, 95%CI 1.41-10.26) and late NVC pattern (HR 2.29, 95%CI 0.97-5.38) were independent predictors of DU recurrence. When estimating the probability of occurrence of first DU in naïve DU patients, only late NVC pattern (HR 12.66, 95%CI 2.06-77.89) was an independent predictor factor. In conclusion, late scleroderma patterns in NVC are the best independent predictors of SSc patients who are at risk of developing DU. Endothelial dysfunction assessed by FMD and ET-1 was also found to be an independent predictor of DU recurrence in a 3-year follow-up.

Raynaud phenomenon (RP) and associated digital ischemia can be among the most vexing clinical problems for patients with systemic sclerosis (scleroderma). Understanding the treatment approach to RP and associated ischemia and how to prevent digital ulcers is important for clinicians caring for these patients. This article reviews the management of RP and digital ischemic ulcers. The magnitude of the problem and pathophysiology of RP are first discussed, with an emphasis on recent advances in understanding of the disease process. Options for the practical pharmacologic and nonpharmacologic interventions for RP and digital ischemic ulcers are detailed., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Abnormal regulation of the alternative pathway of the complement system is a well-described trigger of microangiopathy leading to atypical hemolytic uremic syndrome (aHUS). However, the involvement of complement dysregulation in distal angiopathy has not been reported in adults. We describe the clinical course of a patient with severe distal angiopathy (amputation of all fingers and toes) followed 3 years later by aHUS with end-stage renal disease. This course was attributed to a circulating monoclonal immunoglobulin A λ light chain (IgAλ) with unusual properties: it bound complement factor H (CFH) and impaired CFH-glycosaminoglycan interaction and cell-surface protection. Local complement activation with distal angiopathy and microvascular injury was suggested by deposition of IgA, C4d, and C5b-9 in limb and preglomerular arteries. We therefore postulated that the monoclonal IgAλ inhibited activity of endothelial cell-bound CFH, which led to local activation of complement, vasoconstriction (distal angiopathy), and aHUS. While the patient was dependent on dialysis and plasma exchange, treatment with the anti-C5 antibody eculizumab induced remission of distal angiopathy and aHUS. During eculizumab treatment, kidney transplantation was performed. The patient had normal kidney function at the 3-year follow-up. We suggest that the association of distal angiopathy and aHUS in this patient is clearly linked to anti-CFH properties of the monoclonal IgAλ., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Antisynthetase syndrome is an inflammatory myopathy frequently associated with pulmonary manifestations, especially interstitial lung diseases, and uncommonly pulmonary hypertension. In the context of a suggestive clinical and radiological picture, positive anti-RNA synthetase antibodies confirm the diagnosis. Anti-Jo1, anti-PL7, and anti-PL12 antibodies are the more commonly encountered. The presence of a number of extra-thoracic manifestations in association with pulmonary disease may suggest the diagnosis. These include: myalgia or muscular deficit, Raynaud's phenomenon, polyarthritis, fever, mechanics hands. Serum creatine kinase levels are usually increased. Electromyogram, muscular magnetic resonance imaging or muscle pathology are not mandatory to make the diagnosis. There is a high variability in symptoms and severity, between patients but also during the course of the disease in the same patient. The presence of an interstitial lung disease is a major prognostic factor and an indication for more intensive treatment, principally with systemic corticosteroids with or without immunosuppressive drugs. Improving respiratory physicians' knowledge of this disease, which is often revealed by its pulmonary manifestations, should help diagnosis, therapeutic management, and possibly prognosis., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Primary Raynaud's phenomenon may be insistent in patients under medical therapy, and intrauterine devices may be an unnoticed reason in these patients. Fluctuations in female sex hormone status were reported to be associated with the emergence of primary Raynaud's phenomenon symptoms. The use of intrauterine devices was not reported to be associated with Raynaud's phenomenon previously. Intrauterine device may stimulate vascular hyperactivity regarding hormonal or unknown mechanisms that result in Raynaud's phenomenon. We present a postmenopausal patient who complained of primary Raynaud's phenomenon symptoms and had recovery after the removal of her copper intrauterine device., (© The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Systemic sclerosis is an orphan connective tissue disease characterized by alterations of the microvasculature, disturbances of the immune system and massive deposition of collagen and other matrix substances in the skin and internal organs. A major achievement of the recent years has been the validation of new classification criteria, allowing earlier diagnosis and earlier treatment of systemic sclerosis, before irreversible fibrosis and organ damage appeared ("window of opportunity"). Raynaud's phenomenon is usually the first sign of the disease and is considered as the main sentinel sign for the identification of very early systemic sclerosis. Systemic sclerosis is clinically heterogeneous and disease course remains unpredictable. Its prognosis depends on cardiopulmonary involvement and recent studies aim to identify serum or genetic biomarkers predictive of severe organ involvement. Moreover, the prospective follow-up of large cohorts has provided and will offer critical material to identify strong prognostic factors. Whereas the outcomes of vascular manifestations of the disease has been recently improved due to targeted therapy, recent data have highlighted that mortality has not changed over the past 40 years. This reflects the absence of efficacy of current available drugs to counteract the fibrotic process. Nevertheless, several targeted immunity therapies, commonly with proven efficacy in other immune diseases, are about to be investigated in systemic sclerosis. Indeed, promising results in small and open studies have been reported. This article deals with recent insights into classification criteria, pathogenesis, organ involvements, outcome and current and possible future therapeutic options in systemic sclerosis., (Copyright © 2014 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Cigarette smoking is known to cause a multitude of harmful effects throughout the body. There are only a few accounts in the literature of these effects as related to the hands. This is a review of the literature, demonstrating the collected knowledge of decreased hand vascularity due to tobacco use and assessing the evidence connecting smoking and supposed resultant maladies, including Raynaud's phenomenon, hand-arm vibration syndrome, Buerger's disease, Dupuytren's contracture, carpal tunnel syndrome, effects on skin and fingernails, decreased skin and bone healing, complications of digit replantation and complex regional pain syndrome. Also presented is the possible increased risk of congenital hand malformations as related to maternal smoking.

We report a case of a 76-year-old woman with isolated unilateral Raynaud phenomenon revealing giant-cell arteritis with diffuse arterial lesions and bilateral renal artery stenosis. Doppler ultrasonography showed bilateral stenosis of the subclavian and axillary arteries. Angio-CT PET enlightened diffuse arterial lesions, mainly involving the aorta and the brachial and femoral arteries as well as bilateral renal ostial stenosis with right kidney ischemia. Diagnosis of giant-cell arteritis was made on the temporal artery biopsy. Corticosteroid therapy led to rapid clinical and radiological improvement. Clinical manifestations of giant-cell arteritis may be atypical. Diffuse arterial disease may exist in the absence of cephalic symptoms or significant inflammatory biological features. Ostial renal artery stenosis may induce potentially threatening renal ischemia., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Fabry disease (FD) is a lysosomal disorder leading to progressive systemic involvement, including microvascular damage that leads to neurological and cardiovascular disorders. We hypothesize that the latter could be documented at an early stage by performing a microcirculation study with nailfold capillaroscopy and evaluation of Raynaud phenomenon.The objective was to measure the prevalence of Raynaud phenomenon and nailfold capillaroscopic abnormalities in FD.This cross-sectional study included a standardized questionnaire and a nailfold capillaroscopy that assessed previously reported patterns in FD (dystrophic and giant capillaries, avascular fields, irregular architecture, dilatation and density of capillaries, hemorrhage), and was conducted on 32 Fabry patients and 39 controls. Capillaroscopic photographs were reviewed by 2 independent blinded investigators.Twelve Fabry patients (38%) suffered from Raynaud phenomenon, 5 were males (ie, 50% of male Fabry patients), compared with 2 controls (13%) (P < 0.001), of whom none were males (P < 0.001). Raynaud phenomenon was concomitant or before the occurrence of pain in the extremities in 42% of Fabry patients.More ramified capillaries were significantly observed in Fabry patients (12/32, 38%) than in controls (5/39, 13%, P = 0.016).Secondary Raynaud phenomenon should lead to screening for FD, especially in men. By extension, in high-risk populations for FD, the presence of Raynaud phenomenon and ramified capillaries should be assessed.

Patients with systemic sclerosis frequently have Raynaud's phenomenon and digital ischemic ulcers. Iloprost, a synthetic prostacyclin analogue, may be effective in these cases. Searching in Epistemonikos database, which is maintained by screening 20 databases, we identified three systematic reviews including seven randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded iloprost may lead to little or no difference in the frequency or severity of secondary Raynaud, and it is associated to adverse effects and important costs.

Localized scleroderma (LSc) primarily affects skin, whereas systemic sclerosis (SSc) affects skin and various internal organs. LSc and SSc are considered to be basically different diseases, and there is no transition between them. However, LSc and SSc have several common characteristics, including endothelial cell dysfunction, immune activation, and excess fibrosis of the skin, and there exist several SSc cases complicated with LSc during the course of SSc. Clinical and laboratory characteristics of SSc patients with LSc remain unclear. We investigated the clinical and laboratory features of 8 SSc patients with LSc among 220 SSc patients (3.6%). The types of LSc included plaque (5/8), guttate (2/8), and linear type (1/8). All cases were diagnosed as having SSc within 5 years before or after the appearance of LSc. In three cases of SSc with LSc (37.5%), LSc skin lesions preceded clinical symptoms of SSc. Young age, negative antinuclear antibody, and positive anti-RNA polymerase III antibody were significantly prevalent in SSc patients with LSc. The positivity of anticentromere antibody tended to be prevalent in SSc patients without LSc. No significant difference in the frequency of complications, such as interstitial lung disease, reflux esophagitis, and pulmonary artery hypertension, was observed. The awareness of these characteristic of SSc with LSc are essential to establish an early diagnosis and treatment., (© 2015 Japanese Dermatological Association.)

Children experiencing severe neurological deficit due to acute ischemic stroke may benefit from endovascular intervention. The authors describe the use of mechanical thrombectomy in the treatment of embolic occlusion secondary to an atrial myxoma in a pediatric patient. This case involved an 11-year-old boy with a history notable for Raynaud syndrome and a distal extremity rash who presented to the emergency department with dense hemiparesis secondary to thromboembolic occlusion of the M1 segment of the middle cerebral artery. Following mechanical thrombectomy, the patient's pediatric National Institutes of Health Stroke Scale score improved from a 16 to a 7. In the setting of acute pediatric stroke due to atrial myxoma emboli, mechanical thrombectomy may be a first-line 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.

The occupational uses with vibratory tools or vehicles provoked health disorders of users. We reviewed narratively our articles of 35 yr studies and their related literatures, and considered the pathophysiology of the hand-arm vibration disorders. Concerning the risk factors of health impairments in workers with vibratory tools, there are two conflicting schools of the researchers: The peripheral school emphasizes that vibration only makes predominant impairments on hands and arms, showing typically Raynaud's phenomenon in the fingers. In the systemic school, the health disorders are produced by combination with vibration, noise and working environment, namely vibratory work itself, leading to diversified symptoms and signs in relation to systemic impairments. Our 35 yr studies have evidently supported the systemic school, including disorders of the central and autonomic nervous systems. The genesis is vibratory work itself, including vibration, noise, cold working environment, ergonomic and biodynamic conditions, and emotional stress in work. Because the health disorders yield in the whole body, the following measures would contribute to the prevention of health impairments: the attenuation of vibration and noise generated form vibratory machines and the regulations on operating tool hours. In conclusion, this occupational disease results from systemic impairments due to long-term occupational work with vibratory tools.

Background: The oesophagus is the first gastrointestinal (GI) tract involved in systemic sclerosis (SSc), followed by the anorectum., Objective: Evaluation of oesophageal and anorectal involvement and their correlations in patients with very early diagnosis of SSc (VEDOSS)., Patients and Methods: 59 patients with VEDOSS, evaluated with oesophageal and anorectal manometry and investigated with lung function tests and chest HRCT. Demographic data, oesophageal and anorectal symptoms, Raynaud's phenomenon, autoantibodies, videocapillaroscopy patterns, puffy fingers and digital ulcers were recorded for all patients., Results: In 4 patients oesophageal manometry and in 17 patients anorectal manometry was not performed because of scarce tolerance. Oesophageal peristalsis was absent in 14 patients; its pressure and speed were significantly lower in 41 patients (p<0.001 and p=0.005, respectively). The maximum pressure and mean pressure (Pmax and Pm) of lower oesophageal sphincter were significantly lower (p=0.012 and p=0.024, respectively). Patients with a diffusing capacity of the lung for carbon monoxide<80% presented a hypotonic lower oesophageal sphincter (p=0.008) and an abnormal peristalsis (p<0.001); patients with a diffusing capacity of the lung for carbon monoxide>80% showed only an abnormal peristalsis (<0.001). The anal resting pressure (ARP) at 4.3 cm and 2 cm from anal edge and the anal canal Pm were significantly decreased (p<0.001 and p=0.010, respectively). The maximum voluntary contraction was significantly abnormal in its Pmax and Pm (p=0.017 and p=0.005) and in its duration (p=0.001). In patients with a positive HRCT, the ARP and the canal Pmax and Pm were significantly lower; patients with negative HRCT presented only an abnormal ARP., Conclusions: In patients with VEDOSS, oesophageal and anorectal disorders are frequently detected, showing that very early SSc is characterised by GI involvement., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Raynaud's phenomenon (RP) is a reversible vasospastic response of the extremities to cold or emotion, and can be the first manifestation or may be present before the development of an overt systemic sclerosis (SSc). The disturbance of the balance between vasodilation and vasoconstriction is not limited to the peripheral microcirculation of the skin, but it is also observed in other organs, such as the choroidal plexus of the eye. We aimed to examine the choroidal thickness (CT), the macular thickness and ganglion cell complex (GCC) average in thirty consecutive patients, without visual symptoms, classified as primary RP (pRP), RP secondary to suspected SSc, and overt SSc. All the patients underwent rheumatologic and ophthalmologic examination, capillaroscopy, test for anti-nuclear antibodies, anti-dsDNA, and anti-extractable nuclear antigens. Ophthalmologic examination included: best corrected visual acuity; slit lamp biomicroscopy; intraocular pressure measurements, fundus examination, and Spectral Domain-Optical Coherence Tomography (SD-OCT) with enhanced depth imaging scan system. Twenty-seven healthy subjects similar for gender and age were analyzed. In pRP, CT was significantly thinner than controls in the outer nasal and temporal regions. In secondary RP, the inner and outer nasal areas were significantly thinner than controls. In SSc, the central, inner inferior, inner nasal, inner superior, outer temporal, outer inferior, and outer nasal regions were significantly thinner than controls. A decreasing trend of central foveal thickness was noted. All the patients had GCC average significantly lower than controls. A thinning of choroidal and macular thickness, as well as of GCC was observed in patients with pRP and becomes more severe and extensive in RP secondary to suspected SSc and overt SSc. To our knowledge, this is the first study to analyze the choroidal features using SD-OCT in RP. These data may be clinically useful in suggesting an early involvement of ocular microcirculation with significant reduction of choroidal perfusion., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Systemic sclerosis sine scleroderma is a rare form of limited systemic sclerosis. These patients are without skin involvement, but do not differ in its clinical or laboratory features and prognosis from classical systemic sclerosis. In the absence of cutaneous signs/symptoms, its diagnosis is delayed leading to significant morbidity and mortality. We report a case of sixty year old female who presented to us with dyspnoea on exertion and Raynaud's phenomenon. She was investigated and was found to have this disorder with pulmonary artery hypertension.

We report a case of hypothenar hammer syndrome. The case presents necessary diagnostic measures and discusses the etiology of this syndrome. Additionally, the case reviews treatments, which culminated in the eventual use of ulnar artery bypass with autogenous basilica vein to treat and resolve the ischemic fingers of the patient., (© The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Objectives: High-resolution MR angiography (HR-MRA) demonstrates blood flow in the digital arteries, which correlates with the severity of Raynaud's phenomenon (RP). This study investigates whether baseline HR-MRA of the hand can predict the treatment response to udenafil, a new PDE5-inhibitor, in patients with secondary RP., Methods: Baseline MRA and Doppler ultrasound were obtained in 12 patients with secondary RP. The patients were treated with udenafil 100 mg/day for 4 weeks and changes in blood flow were measured. Blood flow on MRA was scored on a 4-point scale: 0, no visible flow; 1, visible flow to the proximal phalanx; 2, to the middle phalanx; and 3, to the distal phalanx. Peak systolic velocity (PSV) was measured to determine blood flow. Paired t-test and ANOVA were used to determine the treatment response of the different MRA scores., Results: On baseline MRA, 53.3% of digital arteries had an MRA score of 0, 25.8% MRA score of 1, 9.2% MRA score of 2, and 11.6% MRA score of 3. Overall, 4-week udenafil treatment improved digital flow (p<0.05) in all MRA scores. Digital arteries with MRA score 2 showed the best response with improvement in PSV by 14.5 mm/sec (p<0.01), whereas improvement in arteries of MRA scores 1 and 3 were not better than an MRA score of 0 (all, p>0.05)., Conclusions: Digital arteries with moderate blood flow observed on MRA respond best to treatment with udenalfil. Therefore, baseline MRA may help predict treatment response in patients with secondary RP.

Objectives: A previous study found that time to diagnosis was significantly longer from onset of Raynaud's phenomenon for women compared to men with diffuse systemic sclerosis (SSc) and that, in limited SSc, it was more than twice as long for women than men. That study was limited, however, by the small number of men in disease subtype subgroups. The objective of the present study was to investigate the association of sex with time to diagnosis of SSc using a substantially larger patient sample., Methods: Association between sex and time to diagnosis was assessed overall and stratified based on diffuse versus limited disease using Kaplan-Meier curves and Cox proportional hazards models., Results: There were 1,129 patients in the study (median age=56.0 years; 978 [86.6%] women). Time to diagnosis was significantly longer for women (median=1.1 years) than men (median 0.8= years; p=0.037) with diffuse SSc following onset of Raynaud's phenomenon. There were no significant or substantive sex differences in time to diagnosis after Raynaud's onset in limited SSc or from onset of first non-Raynaud's disease manifestation in diffuse or limited SSc., Conclusions: Time to diagnosis was significantly longer for women compared to men with diffuse SSc following onset of Raynaud's phenomenon, but the difference was small and unlikely to be clinically significant. There were no differences in time to diagnosis following Raynaud's onset in limited disease or following onset of first non-Raynaud's disease manifestation in diffuse or limited disease. Overall, sex does not appear to influence time to diagnosis meaningfully.

Objectives: To determine the prevalence and correlates of antiphospholipid antibodies (APLA) in systemic sclerosis (SSc)., Methods: Nine hundred and forty SSc patients were tested for APLA using an ELISA assay at recruitment. Clinical manifestations were defined as present, if ever present from SSc diagnosis. Logistic regression analysis was used to determine the associations of APLA., Results: One or more types of APLA were present in 226 (24.0%) patients. Anticardiolipin (ACA) IgG (ACA-IgG) antibodies were associated with right heart catheter-diagnosed pulmonary arterial hypertension (PAH), with higher titres corresponding with a higher likelihood of PAH (moderate titre (20-39 U/ml) ACA-IgG odds ratio [OR] 1.70, 95% CI: 1.01-2.93, p=0.047; high titre (>40 U/ml) ACA-IgG OR 4.60, 95% CI:1.02-20.8, p=0.047). Both ACA-IgM (OR 2.04, 95% CI: 1.4-3.0, p<0.0001) and ACA-IgG (OR 1.84, 95% CI: 1.2-2.8, p=0.005) were associated with interstitial lung disease (ILD). Increasing ACA-IgM and IgG titres were associated with increased likelihood of ILD. ACA-IgG was a marker of coexistent pulmonary hypertension and ILD (ILD-PH) (OR 2.10, 95% CI: 1.1-4.2, p=0.036). We also found an association between ACA-IgG and digital ulcers (OR 1.76, 95% CI: 1.16-2.67, p=0.008) and ACA-IgM and Raynaud's phenomenon (OR 2.39, 95% CI: 1.08-5.27, p=0.031). There was no association between APLA and SSc disease subtype, peak skin score, presence of other autoantibodies, mortality or other disease manifestations., Conclusions: The association of APLA with PAH, ILD, ILD-PH, Raynaud's phenomenon and digital ulcers suggests that endothelial abnormalities and small vessel thrombosis may be important in the pathogenesis of these disease features.

While severe adverse effects are rare, evidence suggests significant physiological effects may be associated with the use of electrical incapacitation devices, or TASERs. In this case, a 28 year old Caucasian female with chronic, stable systemic lupus erythematosus (SLE) was voluntarily tased in a work-related training procedure. Days later, she presented to the emergency room with an acute flare of her lupus and a constellation of symptoms that lead to new diagnoses of antiphospholipid syndrome (APS), Raynaud phenomenon, acute lower left extremity deep vein thrombosis (DVT), and diffuse bilateral pulmonary emboli (PEs). Due to the temporal relationship of these complications and this patient's history of autoimmune disorders, it is reasonable to believe that an APS was both induced by the tasing event and associated with her lupus.

Objectives: Previous studies indicate that the arteriovenous anastomoses (AVAs) and the arterioles with the nutritive flow are involved in the pathophysiologic process disturbing hand blood flow in systemic sclerosis (SSc). However, impact of different part of the microvascular system involved in digital ulcers (DU) is not well known. Here, we aimed to assess the vasomotor activity of the AVAs in the hands of patients with and without DU in SSc., Methods: Simultaneous recordings were made of laser Doppler flux in the finger pulp and thenar eminence, together with ipsilateral radial artery blood velocity and mean arterial blood pressure (MAP) in 22 non-smoking SSc patients and 13 aged-matched healthy controls., Results: AVA responses in the finger pulp to spontaneous vasoconstrictor nerve impulses were abolished in 64% of the SSc patients. Correlation and cross-spectra analysis showed positive correlation between blood flow changes and MAP changes, indicating a passive vascular bed in the SSc finger pulp with blood flow variations depending on short-term variability in MAP. Dysfunctional AVAs were identified in all the patients with a history of DU (n=8), while none of the patients with normal AVA function had episodes of DU (n=8) (p= 0.017)., Conclusions: We found that in SSc patients with DU there is a dysfunction of the AVAs of the finger pulp. This proof-of-concept study supports the notion that AVA dysfunction may play a critical role in SSc related DU. AVA dysfunction may be a part of autonomic dysfunction in SSc.

Objective: To evaluate the safety and efficacy of N-acetylcysteine (NAC) orally on digital microcirculation blood flow in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc)., Methods: This was a randomized, double-blind, placebo-controlled trial in which 42 patients with SSc received oral NAC at a dose of 600mg tid (21 patients, mean age 45.6±9.5 years) or placebo (21 patients, mean age 45.0±12.7 years) for four weeks. The primary endpoint was the change in cutaneous microcirculation blood flow before and after cold stimulation measured by laser Doppler imaging (LDI) at weeks 0 and 4. The frequency and severity of RP and the number of digital ulcers were also measured at weeks 0 and 4. The adverse events were recorded in the fourth week., Results: There was no significant change in digital blood flow assessed by LDI before or after cold stimulus after four weeks of NAC or placebo. Both groups showed significant improvement in the frequency and severity of RP attacks, with no difference between the two groups. At the end of the study, the placebo group had three digital ulcers, while the NAC group showed no ulcers. NAC was well tolerated and no patient discontinued the treatment., Conclusions: NAC orally at a dose of 1800mg/day showed no vasodilator effect on hands' microcirculation after four weeks of treatment in patients with RP secondary to SSc., (Copyright © 2014 Elsevier Editora Ltda. All rights reserved.)