Cutaneous vasculitis associated with molecular tergeted therapies: systematic review of the literature.

Cutaneo us vasculitis (CV) has a broad spectrum of etiologies, and drugs are one of the main culprits. With the increasing use of targeted therapies in medicine, especially in rheumatology and oncology, the number of CV cases reported due to these drugs has increased. Therefore, the recognition and treatment of CV associated with targeted agents have become more and more important. In the literature, anti-TNFs (n = 73, 59.5%), secukinumab (n = 7, 6%), rituximab (n = 5, 4%), tocilizumab (n = 1, 0.8%), ustekinumab (n = 8, 6.5%), abatacept (n = 3, 2.4%), Janus kinase inhibitors (n = 3, 2.4%), alemtuzumab (n = 3, 2.4%), and immune checkpoint inhibitors (n = 20, 16%) have been reported as responsible agents. However, our knowledge of the pathogenetic mechanisms is fairly limited, and the standardized management is yet to be established. Furthermore, though it is uncommon, this complication may pose a safety issue. In this manuscript, we reviewed the literature on CV with or without systemic involvement related to targeted agents. We also proposed the pathogenetic mechanisms of these adverse events. Thus, we aimed to make it easier for clinicians to manage similar cases by reviewing the diagnosis and treatment processes.

Mucopolysaccharide polysulfate promotes microvascular stabilization and barrier integrity of dermal microvascular endothelial cells via activation of the angiopoietin-1/Tie2 pathway.

BACKGROUND: Mucopolysaccharide polysulfate (MPS) is a heparinoid and MPS-containing formulations are widely used as moisturizers for dry skin and to treat peripheral vascular insufficiency. Although MPS has therapeutic effects in skin diseases with microvascular abnormalities, the effects of MPS on microvascular function remain incompletely understood. OBJECTIVE: The aim of this study was to evaluate the functional activities of MPS on human pericytes (HPC) and human dermal microvascular endothelial cells (HDMEC) in vitro, and on microvascular permeability of the skin. METHODS: The protein expression of angiopoietin (Ang)-1 in HPC, and platelet-derived growth factor-BB (PDGF-BB) and phosphorylated tyrosine-protein kinase receptor 2 (Tie2) in HDMEC were measured in the presence or absence of MPS. The vascular barrier was evaluated by the expressions of claudin-5 and vascular endothelial (VE)-cadherin, and transendothelial electrical resistance (TEER). RESULTS: In HPC, MPS dose-dependently enhanced Ang-1 secretion, which activated Tie2 in HDMEC. In HDMEC, MPS significantly increased the production of PDGF-BB, which is important for the recruitment of HPC to the vascular endothelium, and significantly increased the phosphorylation of Tie2, which results in the activation of the Ang-1/Tie2 signaling . MPS significantly increased the expression of tight junction protein claudin-5 and TEER in the HDMEC. Moreover, the intradermal injection of MPS prevented vascular endothelial growth factor-induced increase in vascular permeability in mouse skin. CONCLUSION: We found that MPS promoted microvascular stabilization and barrier integrity in HDMEC via Ang-1/Tie2 activation. These results suggest that MPS might improve microvascular abnormalities in various diseases accompanied by disturbances in Ang-1/Tie2 signaling.

Clinical and neuroimaging findings in 33 patients with MCAP syndrome: A survey to evaluate relevant endpoints for future clinical trials.

Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient.

Recurrent cutaneous necrotising eosinophilic vasculitis.

Recurrent cutaneous necrotising eosinophilic vasculitis (RCNEV) is a rare disease that was first described in 1994. We report a case of RCNEV treated with corticosteroid, and 18 cases that we identified in the literature. Our review of the literature shows that RCNEV was frequently identified in middle-aged females from Asia and usually presents as erythematous to purpuric papuloplaques, angio-oedema on the extremities, as well as peripheral eosinophilia. Histopathologically, RCNEV is characterised by exclusively eosinophilic infiltration around the vascular plexus, the absence of leukocytoclasis and fibrinoid degeneration of vascular walls. Although, RCNEV responds to corticosteroid treatment, relapses have occurred during dose tapering. We also discuss the mechanisms of vascular destruction, the differential diagnosis and steroid-sparing therapies for RCNEV.

Primary livedoid vasculopathy associated with mononeuritis multiplex.

A 40-year-old woman presented with painful ulcerations on the bilateral lower extremities. A biopsy confirmed the diagnosis of livedoid vasculopathy (LV). She was treated initially with aspirin and pentoxifylline, and with the addition of dipyridamole she has had no recurrence of her ulcerations to date. Despite this positive response to treatment she reported numbness and paresthesias in her legs. Nerve conduction studies confirmed a diagnosis of mononeuritis multiplex. This case highlights mononeuritis multiplex as a rarely described complication of LV, and suggests that early recognition of symptoms and a multidisciplinary approach are necessary for optimal management of this condition.

Successful Treatment of Painful Cutaneous Vasculopathy With Rivaroxaban in a Patient With Systemic Lupus Erythematosus.

Novel oral anticoagulant (NOAC) medications have revolutionized hematology and cardiology. Recently, NOACs have demonstrated additional promise in dermatology. Specifically, rivaroxaban, a direct factor Xa inhibitor NOAC, has been shown to be successful in the treatment of livedoid vasculopathy. Herein, we describe a patient with systemic lupus erythematosus who presented with painful cutaneous vasculopathy, demonstrated on biopsy with occlusive microvascular fibrin thrombi without evidence of concurrent vasculitis. Interestingly, imaging and laboratory studies did not show evidence of hypercoagulability, arterial disease, or embolic disease. The patient’s vasculopathy and pain progressed despite antiplatelet therapy, often considered first-line in cases of microvascular occlusive disease. However, with rivaroxaban therapy, the patient experienced complete regression of her painful lesions, thereby supporting a further role for NOACs in cutaneous vasculopathy treatment. J Drugs Dermatol. 2020;19(5) doi:10.36849/JDD.2020.4684.

Protocol for a randomized multicenter study for isolated skin vasculitis (ARAMIS) comparing the efficacy of three drugs: azathioprine, colchicine, and dapsone.

BACKGROUND: Skin-limited forms of vasculitis, while lacking systemic manifestations, can persist or recur indefinitely, cause pain, itch, or ulceration, and be complicated by infection or scarring. High-quality evidence on how to treat these conditions is lacking. The aim of this comparative effectiveness study is to determine the optimal management of patients with chronic skin-limited vasculitis. METHODS: ARAMIS is a multicenter, sequential, multiple assignment randomized trial with an enrichment design (SMARTER) aimed at comparing the efficacy of three drugs-azathioprine, colchicine, and dapsone-commonly used to treat various forms of isolated skin vasculitis. ARAMIS will enroll patients with isolated cutaneous small or medium vessel vasculitis, including cutaneous small vessel vasculitis, immunoglobulin A (IgA) vasculitis (skin-limited Henoch-Schönlein purpura), and cutaneous polyarteritis nodosa. Patients not responding to the initial assigned therapy will be re-randomized to one of the remaining two study drugs (Stage 2). Those with intolerance or contraindication to a study drug can be randomized directly into Stage 2. Target enrollment is 90 participants, recruited from international centers affiliated with the Vasculitis Clinical Research Consortium. The number of patients enrolled directly into Stage 2 of the study will be capped at 10% of the total recruitment target. The primary study endpoint is the proportion of participants from the pooled study stages with a response to therapy at month 6, according to the study definition. DISCUSSION: ARAMIS will help identify effective agents for skin-limited forms of vasculitis, an understudied group of diseases. The SMARTER design may serve as an example for future trials in rare diseases. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02939573. Registered on 18 October 2016.

Cutaneous findings of familial cerebral cavernous malformation syndrome due to the common Hispanic mutation.

Familial cerebral cavernous malformations due to the common Hispanic mutation (FCCM1-CHM) is an endemic condition among the Hispanic population of the Southwestern United States associated with significant morbidity and mortality. Cutaneous vascular malformations (CVMs) can be found in individuals with FCCM1-CHM, but their morphology, prevalence, and association with cerebral cavernous malformations (CCMs) has not been well characterized. A cross-sectional study of 140 individuals with confirmed FCCM1-CHM was performed with statistical analyses of CVM, CCM, and patient characteristics. We then compared these findings to other cohorts with Familial cerebral cavernous malformations (FCCM) due to other mutations. We observed a higher overall prevalence and a different predominant morphological subtype of CVM compared to previous FCCM cohorts. While the number of CVMs was not a reliable indicator of the number of CCMs present, each person with one or more CVMs had evidence of central nervous system (CNS) disease. Awareness of the morphology of these cutaneous lesions can aid in the diagnosis of individuals with FCCM-CHM in Hispanic patients or those with family history of CCM.

Efectividad del propranolol en el tratamiento de malformaciones vasculares cutáneas / Effectiveness of propranolol in treatment of cutaneous vascular malformations

Se realizó un estudio cuasi-experimental de series temporales para evaluar la efectividad del propranolol en el tratamiento de malformaciones vasculares cutáneas en 48 pacientes que asistieron a la consulta del Servicio de Dermatología del Hospital Central Universitario Dr. Antonio María Pineda durante el período febrero-julio 2018. Los resultados muestran que existen diferencias estadísticamente significativas (p <0.05; p0,0001) antes y después del primer mes de tratamiento con propranolol, las cuales se mantiene hasta los seis meses, con respecto al tamaño, color, consistencia y temperatura. Se espera que los resultados sirvan para proponer el uso de propranolol como una opción terapéutica no invasiva en el tratamiento de las malformaciones vasculares cutáneas(AU)

A quasi-experimental study of time series was carried out to evaluate the effectiveness of propranolol in the treatment of cutaneous vascular malformations in 48 patients attending the Dermatology Service of the Hospital Central Universitario Dr. Antonio Maria Pineda during the period February - July 2018. The results show that there are statistically significant differences (p <0.05; p0,0001) before and after treatment with propranolol starting one month post-treatment which are kept until six months, related to size, color, consistency and temperature of lesions. We hope that these results will encourage the use of propranolol as a non-invasive therapeutic option in the treatment of cutaneous vascular malformations(AU)

Vasculopatia livedoide tratada com rivaroxabana / Livedoid vasculopathy treated with rivaroxaban

A vasculopatia livedoide é uma doença rara caracterizada pela oclusão da microvasculatura da derme, originando lesões maculosas que, posteriormente, podem evoluir para úlceras e cicatrizes atróficas. Como um fenômeno vaso-oclusivo, o tratamento geralmente é realizado com antiplaquetários e fibrinolíticos. O presente relato descreve o caso de uma paciente refratária à terapia convencional, que obteve regressão da doença utilizando a rivaroxabana, um fármaco inibidor seletivo do fator Xa. (AU)

Livedoid vasculopathy is a rare disease characterized by occlusion of the dermis microvasculature, leading to spotted lesions that can later develop into ulcers and atrophic scars. As a vaso- occlusive phenomenon, treatment is usually performed with antiplatelet and fibrinolytic agents. The present report describes the case of a female patient refractory to conventional therapy who presented disease remission using rivaroxaban, a selective factor Xa inhibitor drug. (AU)