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Livedoid Vasculopathy; Peripheral Neuropathy; Globulins, Agood Producing Response in 6Patients

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Livedoid Vasculopathy; Peripheral Neuropathy; Globulins, Agood Producing Response in 6Patients 842 CLINICAL REPORT Livedoid Vasculopathy: A French Observational Study Including DV Therapeutic Options Emma GARDETTE1, Philippe MOGUELET2, Jean David BOUAZIZ3, Dan LIPSKER4, Olivier DEREURE5, François LE PELLETIER6, cta Catherine LOK7, Thierry MAISONOBE8, Didier BESSIS5, Jacqueline CONARD9, Camille FRANCES1 and Stéphane BARETE10,11 1 3 4 5 A Departments of Dermatology: CHU Tenon, APHP, CHU Saint Louis, APHP, Paris, CHU de Strasbourg, Strasbourg, CHU de Montpellier, Montpellier, 7CHU d’Amiens, Amiens, Departments of Histopathology: 2CHU Tenon, APHP and 6Groupe Hospitalier Pitié-Salpêtrière, APHP, 8Department of Neurophysiology, Groupe Hospitalier Pitié-Salpêtrière, APHP, Paris, 9Department of Hemostasis and Vascular Biology, CHU Cochin, APHP, 10Unit of Dermatology, Groupe Hospitalier Pitié-Salpêtrière, APHP, and 11Inflammation-Immunopathology-Biotherapy Department, Sorbonne Universités, UPMC Univ Paris, INSERM-UMRS 959, DHU i2B, Paris, France Livedoid vasculopathy is a rare thrombotic cutaneous SIGNIFICANCE disease. This observational study aimed to assess the clinical and biological features of livedoid vasculopa­ Livedoid vasculopathy is a chronic thrombotic disease of the thy and the efficacy of treatments. Patients enrolled skin microcirculation resulting in painful ulcers mainly af- enereologica had typical livedoid vasculopathy both clinically and fecting the lower legs. This study presents a French cohort V histologically. Investigation of thrombophilia was per­ of patients with livedoid vasculopathy. It describes clinical, formed. Electromyography was undertaken in the pre­ histological characteristics and outcome of patients. It no- sence of symptoms suggesting peripheral neuro pathy. tably shows a frequent thrombophilia background. Nerve damage can be associated with cutaneous manifestations. ermato- Eighteen women and 8 men were included, with a mean age of 35.5 years at onset. Twenty patients had These data also confirm that heparin or oral anticoagulants D at least one thrombophilia factor. Ten patients had a are able to achieve a complete response. Refractory cases can be treated with intravenous immunoglobulins. cta peripheral neuropathy with 2 of these patients demon­ A strating a specific thrombo-occlusive vasculopathy on muscle biopsy. Anticoagulation with low molecular weight heparin was the most prescribed therapy and associated with increased PAI-1 levels. Impaired fib- was associated with the best outcome (effective in 14 rinolysis through PAI-1 involvement was observed in patients). Eight patients had severe disease refractory several studies, related to increased levels of PAI-1 to anticoagulation and required intravenous immuno­ antigen (5), enhanced activity (6) or 4G polymorphism DV globulins, producing a good response in 6 patients. of the promoter gene (7). Recently, a few cases have reported peripheral neuro- cta Key words: livedoid vasculopathy; peripheral neuropathy; thrombosis of dermal vessels; thrombophilia; low molecular pathy in association with LV, most often mononeuritis A weight heparin; intravenous immunoglobulins. multiplex (8–15). Accepted May 4, 2018; Epub ahead of print May 8, 2018 Most treatments are based on anticoagulation (1, 3). Several retrospective studies and case reports have shown Acta Derm Venereol 2018; 98: 842–847. a good response to intravenous immunoglobulins (IVIG) Corr: Dr. Stéphane Barete, MD, PhD, Department of Dermatology, Hôpital in refractory patients (16–19). However, in the absence Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, FR-75013 Paris, France. E-mail: [email protected]. of large prospective controlled studies, there is no recom- mendation on the dose or duration of medication and as such the optimal therapeutic regimen is unknown. ivedoid vasculopathy (LV) is a chronic disease mani- We performed an observational multicenter study in Lfesting as recurrent necrotic and painful lower limb France reviewing the diagnosis and management of pa- ulcerations. These resolve leaving atrophic porcelain- tients with LV. We aimed to assess the clinical and histo- white scars with surrounding telangiectasias known logical features of LV, to identify related coagulopathies as atrophie blanche (AB). The estimated incidence is including plasma antigenic levels and 4G polymorphism 1:100,000 individuals, predominantly affecting young of PAI-1, neurological involvement, therapeutic mana- to middle-aged females, with a sex ratio of 3:1 (1, 2). gement and patient outcome. Histopathology reveals a vaso-occlusive disorder with intraluminal thrombosis of dermal vessels without leu- kocytoclastic vasculitis (1, 3). The exact mechanism of METHODS this entity is unknown but underlying thrombophilia with Study design and inclusion criteria abnormalities of coagulation or fibrinolysis, is observed in up to 50% of patients (2, 4). Plasminogen activator This observational study was conducted in 6 different French dermatology departments between 2006 and 2015. Patients inhibitor-1 (PAI-1) is a major inhibitor of fibrinolysis. included in the study presented with typical LV based on both dvances in dermatology and venereology The 4G/5G polymorphism of the PAI-1 promoter gene clinical symptoms (recurrent ulcers of the leg, livedo reticularis, A results in enhanced transcription and the 4G allele is AB) and histology (thrombosis of dermal vessels). The exclusion doi: 10.2340/00015555-2965 This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Acta Derm Venereol 2018; 98: 842–847 Journal Compilation © 2018 Acta Dermato-Venereologica. Livedoid vasculopathy: a French cohort study 843 criteria were severe venous insufficiency of the lower limbs do- with the possibility to switch to another treatment if pain relief cumented by Doppler ultrasound and vasculitis (leukocytoclasia) was not obtained. in skin biopsies. Data was collected according to a standardized Due to the multiplicity of treatments depending on practitioner’s case-report form (CRF) which included clinical, pathological and choice and the variable frequency of flares from one patient to DV biological parameters focusing on known characteristics of VL another, 3 groups were defined retrospectively in order to get a patients. Data regarding neurological abnormalities and electro- clearer picture of the different disease profiles: long-term remission cta myography where also included when performed. Patients were was defined as the absence of flare for a least 4 years, short-term informed about this observational study and written consent was remission defined as the absence of flare for at least 2 years and A obtained for all patients who underwent genetic investigations. active disease when a flare had occurred within the last 2 years. Twenty-one patients had prospective follow-up, 4 patients had data collected retrospectively and one patient was lost to follow-up. RESULTS Clinical and laboratory assessments Clinical characteristics Collected data included sex, age at onset of symptoms and at diag- nosis of LV, body mass index (BMI), previous oral medication for Eighteen women (70%) and 8 men (30%) were included. LV, clinical features and location of skin lesions. Assessment of 42% of patients were smokers. Comorbidities included pain with a visual analog scale (VAS) was not regularly reported systemic lupus erythematosus in one patient, familial enereologica in our patients. The impact on quality of life (QoL) was quantified hypertriglyceridemia in one patient, renal transplant V with the 36-item Short Form Survey (SF-36) as previously descri- bed by Polo Gascon et al. (20). Laboratory assessment included full in 3 patients (2 of whom were HIV positive). There blood count, fibrinogen level, protein electrophoresis, autoimmune was no history of deep vein thrombosis or pulmonary screen with antinuclear antibodies, antiphospholipid antibodies embolism. Median age at onset of LV was 35.5 years and lupus anticoagulant, antineutrophil cytoplasmic antibodies (range 6–67 years). The median time between first skin ermato- (ANCA), cryoglobulin and cryofibrinogen, homocysteine level, lesions and histological diagnosis was 3.4 years (range D antithrombin, protein C and S activity, prothrombin gene muta- tion, factor V (Leiden) mutation and methylenetetrahydrofolate 2.2 months–29.5 years). Median follow-up time was 5 cta reductase (MTHFR) mutation. years (range 1.2–9.4 years). Flares consisted of purpura A All skin biopsies were reviewed independently by two dermato- and necrotic ulcers in all cases and livedo reticularis in pathologists. The tissue was embedded in paraffin and stained with 85% cases. Sequelae consisted of hyperpigmentation and hematoxylin and eosin (HES). The slides were screened for dermal atrophie blanche in 80–100% of cases with peripheral te- vessel thrombosis (superficial, mid or deep dermis), endothelial proliferation, intravascular fibrin deposition, segmental hyaliniza- langiectasia in 62% of cases. Lesions were affecting both tion of the vessel wall, and extravasation of red blood cells. legs in all but one patient, located mainly on the ankle PAI-1 antigenic plasma level and genotype of the promoter (96%), shin (73%) and foot (dorsum 58%, sole 50%). DV (4G/5G or 4G/4G, 5G/5G) were assessed when the technologi- Mean duration of flares was 55 days and mean time cal equipment was available in the center’s laboratory. Patients between flares was 8 months (range 2–36 months). A cta with abnormal neurological examination or neuropathic pain underwent an electromyogram (EMG)
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