Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Acta DermVenereol 2018;98: 842–847 doi: 10.2340/00015555-2965 andthe4Galleleis inenhancedtranscription results The 4G/5Gpolymorphism of thePAI-1 promotergene fibrinolysis. of inhibitor major a (PAI-1)is inhibitor-1 in up to 50% of patients(2, 4). Plasminogen activator abnormalities of coagulation or fibrinolysis, is observed this entity is unknown but underlying thrombophilia with kocytoclastic vasculitis(1,3). The exactmechanismof L E-mail: [email protected]. Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, FR-75013 Paris, France. Corr: Dr. Stéphane Barete, MD, PhD, Department of Dermatology, Hôpital Acta DermVenereol 2018;98:842–847. Accepted May 4,2018;EpubaheadofprintMay 8,2018 weight heparin;intravenous immunoglobulins. throm­ Key words: livedoid vasculopathy; peripheral neuropathy; globulins, agood producing response in 6patients. to anticoagulation and required intravenous immuno­ Eight patientshadseverediseaserefractorypatients). was associatedwith the in14 bestoutcome (effective therapyand weight heparinwasthemostprescribed muscle biopsy. Anticoagulation with low molecular on vasculopathy thrombo-occlusive specific a strating peripheral neuropathy with 2of thesepatients demon at leastone thrombophilia factor. Tenpatients hada mean ageof35.5yearsat onset. Twentypatients had withEighteen womenand8menwereincluded, a peripheralneuro­ ofsymptoms suggesting sence formed. Electromyography wasundertakeninthepre histologically. Investigation of thrombophilia was per had typical livedoid vasculopathy both clinically and enrolled Patients treatments. of efficacy the and thy 842 clinical andbiological features of livedoid vasculopa disease. This observational study aimed to assess the Livedoid vasculopathy isararethrombotic cutaneous intraluminal thrombosisofdermalvesselswithoutleu to middle-agedfemales,withasexratioof3:1(1,2). 1:100,000 individuals,predominantlyaffecting young as atrophieblanche(AB). The estimatedincidenceis known telangiectasias surrounding with scars white ulcerations. leaving atrophicporcelain- resolve These CHU Cochin, APHP, Emma Therapeutic Options Livedoid Vasculopathy:AFrenchObservationalStudy Including 8 Departments of Dermatology: Montpellier, Department, Sorbonne Universités, UPMC Univ Paris, INSERM-UMRS 959, DHUi2B,Paris,France LOK Catherine Department of Neurophysiology, Groupe Hospitalier Pitié-Salpêtrière, APHP, Paris, Histopathology reveals a vaso-occlusive disorder with festing asrecurrentnecroticandpainfullowerlimb ivedoid vasculopathy (LV) is achronic disease mani bosis of dermal vessels;molecular thrombophilia;low GARDETTE 7 CHU d’Amiens, Amiens,DepartmentsofHistopathology: 7 , MAISONOBE Thierry 1 10 , Unit of Dermatology, Groupe Hospitalier Pitié-Salpêtrière, APHP, and Philippe MOGUELET 1 CHU Tenon, APHP, 8 , BESSISDidier 2 , Jean David BOUAZIZ 3 This isan open access article under the CC BY-NC license. www.medicaljournals.se/acta CHU Saint Louis, APHP, Paris, CLINICAL REPORT pathy. 5 , CONARD Jacqueline ­ ­ ­ ­ - - 3 2 , CHU Tenon,APHPand AB) andhistology(thrombosisof dermalvessels). The exclusion clinical symptoms(recurrentulcers oftheleg,livedoreticularis, included in the study presented with typical LV based on both dermatology departmentsbetween 2006and2015.Patients This observational study was conducted in 6 different French Study designandinclusioncriteria METHODS gement andpatientoutcome. of PAI-1, neurological involvement, therapeutic mana including plasmaantigeniclevelsand4Gpolymorphism logical featuresofLV, toidentifyrelatedcoagulopathies tients withLV. We aimedtoassesstheclinicalandhisto France reviewingthediagnosisand management ofpa such theoptimaltherapeuticregimenisunknown. mendation onthedoseordurationofmedicationandas of large prospective controlled studies, there is no recom in refractorypatients(16–19).However, intheabsence a goodresponse to intravenous immunoglobulins (IVIG) Several retrospectivestudiesandcasereportshaveshown multiplex (8–15). pathy inassociationwithLV, mostoftenmononeuritis of thepromotergene(7). antigen (5),enhancedactivity(6)or4Gpolymorphism several studies,relatedtoincreasedlevelsofPAI-1 rinolysis throughPAI-1 involvementwas observedin associated with increased PAI-1 levels. Impaired fib Impaired levels. PAI-1 increased with associated Dan LIPSKER can betreated withintravenous immunoglobulins. are able to achieve a complete response. Refractory cases These data also confirm that heparin or oral anticoagulants damage can be associated with cutaneous manifestations. tably shows a frequent thrombophilia background. Nerve histological characteristics and outcome of patients. It no of patients with livedoid vasculopathy. It describes clinical, fecting the lower legs. This study presents a French cohort skin microcirculation resulting in painful ulcers mainly af Livedoid vasculopathy isa chronic thromboticdisease of the SIGNIFICANCE We performed an observational multicenter study in Most treatmentsarebasedonanticoagulation(1,3). Recently, a few cases have reported peripheral neuro Journal Compilation ©2018ActaDermato-Venereologica. 4 CHU de Strasbourg, Strasbourg, 9 , 9 Department of Hemostasis and Vascular Biology, FRANCES Camille 4 , Olivier DEREURE 11 Inflammation-Immunopathology-Biotherapy 6 Groupe HospitalierPitié-Salpêtrière,APHP, 1

5 and Stéphane BARETE , François LEPELLETIER 5 CHU de Montpellier, 10,11 - - 6 ------, Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV (Innohep period, a first evaluation was done after one month of treatment, of month one after done was evaluation first a period, response [PR])ornoimprovement (noresponse [NR]). Within this response [CR]),improvement >50%compared tobaseline (partial after 3monthsasfollows:complete healingofulcers(complete evaluated was flare each for treatment to Response LVflare. a Patients wereenteredintotheobservationalstudyattime of Outcome andresponse totreatment (Lovenox Low molecularweightheparin(LMWH),enoxaparinsodium toire Sanofi-Aventis) 75 mg/day; Unfractionated heparin (UFH); latelet drugs, aspirin (Aspegic neuropathologist. biopsy ifindicated.Musclebiopsieswereanalyzedbythesame underwent anelectromyogram(EMG)andamusclenerve with abnormal neurological examination orneuropathic pain cal equipmentwasavailableinthecenter’s laboratory. Patients (4G/5G or4G/4G,5G/5G)wereassessedwhenthetechnologi tion ofthevesselwall,andextravasationredbloodcells. proliferation, intravascular fibrin deposition, segmental hyaliniza endothelial dermis), deep or mid (superficial, thrombosis vessel hematoxylin and eosin(HES). The slides werescreenedfor dermal pathologists. The tissue was embedded in paraffin and stained with reductase (MTHFR)mutation. tion, factor V (Leiden)mutationandmethylenetetrahydrofolate antithrombin, proteinCandSactivity, prothrombingenemuta level, homocysteine cryofibrinogen, and cryoglobulin (ANCA), and lupusanticoagulant,antineutrophilcytoplasmicantibodies screen withantinuclearantibodies,antiphospholipidantibodies blood count, fibrinogen level, protein electrophoresis, autoimmune bed byPoloGasconetal.(20).Laboratoryassessmentincludedfull with the36-itemShortFormSurvey(SF-36)aspreviouslydescri in our patients. The impact on quality of life (QoL) was quantified pain with a visualanalog scale (VAS) wasnot regularly reported LV, clinicalfeaturesandlocationofskinlesions. Assessment of nosis ofLV, bodymass index(BMI),previous oral medication for Collected data included sex, age at onset of symptoms and at diag Clinical andlaboratoryassessments collected retrospectivelyandonepatientwaslosttofollow-up. Twenty-one patientshadprospectivefollow-up,4data obtained forallpatientswhounderwentgeneticinvestigations. informed aboutthisobservationalstudyandwrittenconsentwas myography wherealsoincludedwhenperformed.Patientswere patients. Data regardingneurologicalabnormalitiesandelectro biological parameters focusing on known characteristics of VL case-report form(CRF)whichincludedclinical,pathologicaland in skinbiopsies.Datawascollectedaccordingtoastandardized cumented byDopplerultrasoundandvasculitis(leukocytoclasia) do limbs lower the of insufficiency venous severe were criteria (Coumadin Trading Ltd, Munich, Germany); Vitamin K antagonist, warfarin Factor Xainhibitor, fondaparinux (Arixtra and pentoxifylline. Paris, France) 75–100 mg/day or clopidogrel (Plavix (Plaquenil occasionally includingcolchicine,dapsone,hydroxychloroquine LWMHused (UFH, were medications Other fondaparinux). and per cycle. All anticoagulantagentswereusedatacurativedose target of 2–3; Pulsed intravenous immunoglobulins (IVIG) 2 g/kg The principal medications used in this cohort were: Antip PAI-1 antigenic plasma level and genotype of the promoter All skinbiopsieswerereviewedindependentlybytwodermato ® ® , Laboratoires LEO, Voisins-le-bretonneux,France); LEO, Laboratoires , ® , Laboratoire Sanofi-Aventis) or tinzaparin sodium tinzaparin or Sanofi-Aventis) Laboratoire , ® , Laboratoire Sanofi-Aventis), topical or oral steroids, , Bristol-Myers Squibb, New York,INR Squibb, with Bristol-Myers USA) , ® , Laboratoire Sanofi-Aventis, Laboratoire , ® , Aspen Pharma , Aspen ® , Labora ­ ------atrophie blanchein80–100%ofcaseswithperipheralte 85% cases.Sequelaeconsistedofhyperpigmentationand and necrotic ulcers in all cases and livedo reticularis in years (range1.2–9.4years).Flaresconsistedofpurpura 2.2 months–29.5 years). Median follow-up time was 5 lesions andhistologicaldiagnosiswas3.4years(range years). 6–67 (range skin first between time median The embolism. MedianageatonsetofLV was35.5years was nohistoryofdeepveinthrombosisorpulmonary in 3 patients (2 ofwhom were HIV positive). There hypertriglyceridemia inonepatient,renaltransplant systemic lupuserythematosusinonepatient,familial 42% ofpatientsweresmokers.Comorbiditiesincluded Eighteen women(70%)and8men(30%)wereincluded. Clinical characteristics RESULTS Table I.Histopathological oflivedoidvasculopathy characteristics biopsy specimens,mostlyinthepapillarydermis,but dicated in in are biopsies skin in findings histopathological The Histological characteristics (44/100) wasfortheperceptionofgeneralhealth. body painandphysicalfunctioningthelowestscore 52/100 andtheimpactwasmaximal(score> constant feature.MeanscoreofSF-36for7patientswas a was Pain exertion. physical by patient one and flares) (summer temperatures warm by triggered flares had considering all patientstogether. Fourteen patients (54%) period follow-up the during occurred flares 94 of total months). A 2–36 (range months 8 was flares between (96%), shin(73%)andfoot(dorsum58%,sole50%). legs inallbutonepatient,locatedmainlyontheankle langiectasia in62%ofcases.Lesionswereaffecting both active diseasewhenaflarehadoccurredwithinthelast2years. and 2 years least at for flare of absence the as defined remission was defined as the absence of flare for a least 4 years, short-term clearer picture of the different disease profiles: long-term a remission get to order in retrospectively defined were groups 3 another, to patient one from flares of frequency variable the and choice was notobtained. with thepossibilitytoswitchanothertreatmentifpainrelief Segmental hyalinization of the vessel wall Extravasation of red blood cells Endothelial proliferation Intravascular fibrin deposition Deep dermis Middermis Superficial dermis Intraluminal thrombosis Characteristics ofbiopsysamples Due tothemultiplicityoftreatmentsdependingonpractitioner’s Mean duration of flares was 55 days and mean time mean and days 55 was flares of duration Mean Table I. Dermal thrombosis was found in all Livedoid vasculopathy:aFrenchcohortstudy Acta DermVenereol 2018 50/100) for 50/100) for n (%) 8 (31) 14 (54) 16 (62) 16 (62) 5 (19) 23 (88) 24 (92) 26 (100) 843 - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV www.medicaljournals.se/acta (17%) other flares were treated with colchicine, dapsone, min K antagonist (VKA), antiplatelet agents or IVIG. 16 molecular weightheparin(LMWH),fondaparinux,vita the following drugs: unfractionated heparin (UFH), low with treated were (68%) 64 flares, 94 of total a Among Therapeutic management or pathologicaldeposits. There wasnosignofnecrotizingvasculitis,granuloma with endothelialcelldamageandnecrosisofcapillaries. sels oftheepineurium,alterationsendoneurium with vasculopathymadeofenlarged andthickenedves revealed aseverelossofmyelinatedaxonsassociated mononeuritis multiplexandoneaxonalneuropathy) Muscle-nerve biopsies were performed in 2patients (one drugs). neurotoxic deficiency, vitamin consumption, peripheral neuropathywereexcluded(diabetes,alcohol There were no cases of motor deficit. The main causes of tive symptomsbutanormalneurologicalexamination. patients had a sensory deficit and 7 patients had subjec neuropathy confirmed by fibre small with diagnosed was but EMG normal a had and 6casesofsensorypolyneuropathy. Onepatient mal EMG,including3casesofmononeuritismultiplex median time of 11.4 years. Nine patients had an abnor neuropathy rangedfrom6monthsto30yearswitha cutaneous manifestations of LV and the diagnosis of LV.to pathy, of attributed onset first the between Time gations wereavailable,10(50%)hadaperipheralneuro­ Of the20patientsinwhomneurophysiologicalinvesti Neurological involvement associated withhighlevelPAI-1. and 4G/5G(45%)genotypesamong9patientswerenot PAI-1 antigen, with a 5G/5G genotype. The 4G/4G (22%) ferent factors detected. Only onepatient had anincreased and aredetailedin patients in detected were factors thrombophilia Multiple Coagulation disorders in theadventitia. dermis-subcutis junction with perivascular inflammation in theintima,thrombosisofasmallarteryfrom nodosa” appearance with circumferential fibrin deposits litis. Onepatienthadacutaneous“pseudo-polyarteritis was presentin19patients(73%)withoutsignsofvascu junction. A scattered perivascular lymphocytic infiltrate also inthedeepdermisarounddermal-hypodermal 844 patient demonstrated 3 factors, and one patient had 5 dif (54%) hadonefactor, 4patients(15%)2factors,one patients 14 factor; thrombophilia positive one least at 1 https://www.medicaljournals.se/acta/content/abstract/10.2340/00015555-2965 E. Gardetteetal. Table SI laser-evoked potentials. Three 1 . Twenty patients(77%)had ------Fig. S1 ormore(Fig. treatment modalities was obtainedbut40%ofpatientsrequired3different or twotreatments were tried before an effective response gulation (UFH or LMWH). In a majority of patients, one prescribed first-line therapy was heparin-based anticoa fyllin. Fourteen flares (15%) were not treated. The most (PR) ornoresponse(NR). bararea) each in treated with different drugs; complete response (CR), partial response reported of flares (number flares for response of % livedoid vasculopathy flares. to 1. Evaluation according for treatment Fig. of response used taking over3months,andnoresponsetoconventional other 8patients(32%)hadseverediseasewithhealing toxifylline and hydroxychloroquine in one patient. The anticoagulation in3patientsandcombinationofpen to responded which flares regular had patients 4 sion, dual antiplatelettreatment(n antiplatelet agents:aspirin(n on based flare last the after treatment maintenance a ded to anticoagulation withLMWH andthey all received with the absence of flare for 2 years. All patients respon (n maintenance treatment for secondary prophylaxis: VKA mission afterrenaltransplantation.Fourpatientshada and 2patientswithend-stagerenalfailureachievedre 2 patientsachievedremissionaftersmokingcessation them, among treatment; maintenance no had patients and LV disappearedspontaneouslyin2patients.Five treated successfullywithanticoagulationfor7patients were flares Skin years. 6 was flare last the since time median The years. 4 least at for flares of absence the Nine patients(36%)achievedlong-termremissionwith Patient outcome least aPRin94%offlares. drugs. IVIGledtoCRin63%ofcasesandproducedat antiplatelet for 33% only and VKAfor 59% LMWH), 1), the mean CR for flares was 83% for heparin (UFH or treatment failures. According to the treatment used (Fig. nor wasIVIGwhichprescribedafter1to3other treatment, first-line a as used never was VKA drugs. was based onheparin anticoagulation orantiplatelet hydroxychloroquine, oral or topical steroids, or pentoxi topical steroids,or or oral hydroxychloroquine, % of response 100% Among the 12 other patients in short-term remis inshort-term the12otherpatients Among Four patients(16%)achievedshort-termremission = 10% 20% 30% 40% 50% 60% 70% 80% 90% 0% 2), aspirin(n Heparin 24 2 3 Fondaparinux = 1), aspirin+ VKA (n 3 Stacked graph bars represent the cumulated CR = 1). = VKA 4 1 2 2), clopidogrel(n PR

1 NR ). First-line therapy therapy ). First-line IVIG 10 = 1). 5 1 Antiplatelet drugs 1) or = 1) 4 3 2 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Hyperhomocysteinemia was frequent(50%ofpatients) in DiGiacomoetal.(2)and 50%inHairstonetal.(4). superior to previous studies: 64%in Tran et al. (22),52% coagulation factorsin77% ofourpatients,afrequency disease. Ourthrombophiliascreenrevealedabnormal derlying hypercoagulablestateisthecornerstoneof with signsofvasculitis. selection ofourpatientswasstrict,excludingallcases clinical symptomsofPAN. However, thehistological a pseudo-PAN appearancewithoutanyextracutaneous ported previously(21).Inourstudy, onlyonepatienthad vasculitis. The association ofLV andPAN hasbeenre thrombosis andruleoutPAN oranyothernecrotizing dermo-hypodermal junctiontoassesshypodermisvessel as itshouldbelarge anddeepenoughtoanalyzethe of diagnosis the confirm to biopsy punch a of stead LV, (1, 3). We recommendasurgical incisionalbiopsyin­ which isalocationscarcelyreportedinotherstudies We observedthrombosisinthedeepdermis19%, endothelial proliferationorredbloodcellextravasation. sociated withsegmentalhyalinizationofthevesselwall, as often was deposits fibrin intraluminal with vessels would beofbenefitinmonitoringthesepatients. diseases. The use of a specific LV-designed score of QoL higher impactwithLV comparedtoothercommonskin to 17.83 during active disease, confirming a significantly impact onQoL showingariseofmeanDLQIfrom11.37 scores. Similarly, Polo Gascon et al. (20) identified a high feature impactingonqualityoflifeasobservedbySF36 ral practitionersanddermatologists.Painisaconstant before diagnosis,LV remainsunderdiagnosedbygene entity. However, asevidencedbythedelayof3.4years (1, 3), confirming the typical clinical presentation of this tations ofLV weresimilartothosereportedpreviously In thismulticenterobservatorystudy, cutaneousmanifes DISCUSSION developed neutropenia. one wasdiagnosedwithasepticmeningitisandanother years. Two patients treated with IVIG had adverse events; one patient died of hemorrhagic stroke at the age of 56 one patientwashospitalizedforathighhematomaand Two seriousadverseeventsoccurredwithfondaparinux: Toxicity andadverseeventswithtreatments CR and5ofPR. of cases 10 success: with IVIG with treated were flares 15 of total a patients, 6 other the For infusion. first the stopped treatmentfollowinganadverseeventduring IVIG. Onepatientdidnotrespond,andafurther antiplatelet or anticoagulation drugs. They all received Pathophysiology isnotclearlyunderstoodbutanun In ourstudy, thromboticocclusionofsmalldermal - - - - - disturbance of hemostasis, fibrinolysis defect, autoim defect, fibrinolysis hemostasis, of disturbance factors forLV ateachstepofthecoagulationcascade: with LV inourpatients. region ofthePAI-1 genewasnotparticularly associated conclude thatthe4G/4Gpolymorphisminpromoter other studies (respectively 30%, 50%, 20%) (26, 27). We different tothecontrolsamplesinsamelaboratoryor 5G/5G genotypes(respectively22%,45%,33%)wasnot we found that the distribution of the 4G/4G; 4G/5G and 4G/4G homozygous genotype (7). In our LV population, thrombosis. InLV, one patienthasbeenreportedwith risk ofthrombosiswiththe4Ghomozygosity in venous (25) has concluded that there was a significantly higher polymorphism butarecentmeta-analysisby Wang etal. about theexactthromboticriskassociatedwith4G/5G with higher levels of PAI-1. Studies have been discordant shown to be more transcriptionally active and associated allele in the promoter region of the PAI-1 gene has been technological equipmentinsomelaboratories. The 4G for everypatientbecauseofthelackavailability (23, 24). Of note, we were not able to study PAI-1 antigen ceridemia. This associationhasbeenreportedpreviously signs of vasculitis, as previously documented in 2015 signs ofvasculitis,aspreviously documentedin2015 vasculopathy, without of findings similar identified sies 50% ofpatients.Intwopatients, muscleandnervebiop revealed astrikingincidence ofperipheralneuropathyin cutaneous manifestationofLV known.Ourstudy has recently reportedbyourteam(28). kidney transplantand2ofthem,HIV-infected, havebeen alone in2patients.Interestingly, 3patientsreceiveda noticed along-termremissionaftersmokingcessation National InstituteforEducationandHealth). We also 32 to35%ofsmokersinFrance(datafromtheFrench in the general French population:42%inLV patients vs king prevalenceratewashigherintheLV cohortthan the lowerlegsandheatasatriggerfactor. Ofnote,smo on location explaining occur, can insufficiency venous superficial Additional remission. of periods and flares vary overtime,explainingthechronicevolutionwith presence of these different hypercoagulablefactorscan to smallvesselthrombosisandskinulceration. The leading fibrinolysis, and coagulation between balance effect ofmultiplethrombophiliafactorsinducesan im abnormalities arenotalwayspathogenic. The combined mune conditionsandrheologicaldisorders. Alone, such 1 antigen and he also presented with severe hypertrigly (5–7). In our study, only one patient had an elevated PAI- PAI-1 hasbeenimplicatedinLV in3previousstudies (tissue plasminogenactivatortPA andurokinaseuPA). through theinhibitionofactivatorsplasminogen µmol/l). (> 50 but there were no cases of severe hyperhomocysteinemia In this observational study we identified different risk To date,peripheralneuropathy istheonlyknownextra- PAI-1 has a central role in the inhibition of fibrinolysis Livedoid vasculopathy:aFrenchcohortstudy Acta DermVenereol 2018 845 - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV www.medicaljournals.se/acta data were concordant with previous studies and justified Our improvement with63%going tocompleteremission. successfully treatedwithIVIG: 94%hadatleast> not respondingtoanticoagulants. These patients were both developedmajorhemorrhagicevents. only twopatientsweretreatedwiththismedicationand as fondaparinux, of efficacy the assess to difficult is It flares. for treatment first-line a as recommended be not appeared tobelesseffective inourcohortandshould tion promoted compliance. Antiplatelet drugs and VKA healing. The convenience ofasubcutaneousdailyinjec varying durationfrom15daysto3monthsuntilulcer to anticoagulants. Tinzaparin sodiumwasusedwitha Fourteen ofourpatients(56%)hadagoodresponse gulation byheparinwasthemostsuccessfultreatment. anticoa and therapy first-line a as used often most the 30% patientsrequiredLMWHasaback-uptreatment. tolerability forthisanticoagulant(34).Nevertheless, and efficacy good revealed has study 2 phase recent A(32–34). VKAthan manage to easier and heparin to alternative Rivaroxabanmightbeaninteresting let drugs. (54%), followedbyanabolicsteroids,IVIGandantiplate gulant therapiesrivaroxabanwasthemostprescribed was anticoagulation in98%ofcases. Among anticoa treatment prescribed most the that confirmed have (31) be theearliestsignofhealingprocess. might heal spontaneously. However, pain relief seems to complex because duration of flares can vary and patients or frequency of flares. Evaluation of treatment efficacyis no predictive clinical or biologic indicators for severity variable fromonepatienttoanother. To date,thereare Indeed, both responsetotreatmentsand outcome remain (30). achieve to difficult is consensus a and clinicians normal EMG,persistingafterulcerhealingofulcers. percentage ofpatientswithneuropathicpaindespitea is probablyunderestimatedandwouldexplainthehigh nerve biopsy) only explore large nerve fibres. This entity vestigations because the conventional techniques (EMG, fibre neuropathy associated with LV. It requires special in process. Interestingly, we describe the first case of small vessels ofthe skin and nerves, without any vasculitic confirms that the same thrombotic disease occurs in small details. This is concordant with an ischemic processand their cohort of70patients but without electromyographic al. (9)hasreported6casesofperipheralneuropathyin lymphocytic infiltrate, without signs of vasculitis. Gan et biopsies revealedthesameimagesofaxonallosswitha mononeuritis multiplex (8,10–15). Among them, 5nerve ganglionopathy, oneaxonalneuropathyand7casesof a totalof9detailedcasesintheliterature:onesensory (29). Peripheral neuropathy has been rarely described with 846 However,flares regular with disease severe had 32% In ourstudy, LMWH and antiplatelet agentswere A recentreviewofLV treatmentbyMicieli& Alavi Finding aneffective therapyisarealchallengefor E. Gardetteetal. 50% - - - - - recurrent flaresrespectively(FigsS2andS3 we managepatientswithLV forinitialdiagnosisand propose twotreatmentalgorithmsastoillustratetheway others agentshasnotbeenstudiedintheliterature. We treatment withanticoagulationorantiplateletdrugs maintenance for need The VKAdose-adjustment. with LVhad healed patients and 2 low was INR when flares treatment difficult to analyze. It is worth mentioning that of treatments,whichmadetheimpactamaintenance in aninter- andintra-individualwaylarge diversity spective data collection, variable frequency of flares both sample population, difficult follow-up with some retro several limitationstothisstudyofararedisease:small drugs or VKA as a long-term therapy. We acknowledge be corrected.Someofourpatientsreceivedantiplatelet sis (3). As faraspossible,thrombophiliafactorsshould venous stasisandedema,whichcanpromotethrombo compression, especially during summer time tolimit venous recommend We address. to difficult very was The question of a maintenance treatment to prevent flares Limitations cessful useofheparinanticoagulation(16–19). The authorshavenoconflicts of interest todeclare. therine HOrteufortheirkindproofreading. support andclinicalcases. We thank DrJessicaGaleandCa groups fromtheFrenchsociety ofdermatology(SFD)fortheir angiodermatologie)thematic (Groupe en dermatologie)andGAD We areindebtedtotheEMSED(Etudedesmaladiessystémiques ACKNOWLEDGEMENTS mended inthenearfuture. reported byseveralstudies,maybeincreasinglyrecom been well evaluated. Rivaroxaban, with a good efficacy maintenance therapyassecondarypreventionhasnot anticoagulation of benefit the study, size small this in native treatmentforthemostseverepatients.However, drugs arelesseffective. IVIGcanbeaninteresting alter antiplatelet whereas treatment, efficient most the be to gical disease.CurativeanticoagulationbyLMWHseems the use of IVIG as a second-line treatment after unsuc LV isnotonlyacutaneousbutalsoperipheralneurolo that confirming process, ischemic an revealed biopsies associated withLV withanincidenceof50%andnerve level ofPAI-1 inourcohort.Peripheralneuropathywas 4G/4G polymorphismwasnotassociatedwithahigh Interestingly, PAI-1 was exceptionally elevated and Patients shouldundergo fullthrombophiliascreening. surgical skinbiopsyfordiagnosis,toruleoutvasculitis. vasculopathy isararedisease,justifyinganincisional Our national observational study confirms that livedoid Conclusion 1 ). ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 17. 15. 13. 11. 16. 14. 12. 10. REFERENCES 4. 3. 7. 2. 9. 8. 6. 5. 1. 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