Rev. Bras. Reumatol. vol.56 número6

rev bras reumatol.2016;56(6):554–556

ww w . r e u m a t o l o g i a . c o m . b r

REVISTA

BRASILEIRA

DE

REUMATOLOGIA

Case

report

Livedoid

vasculopathy

夽

Vasculopatia

livedoide

José

Roberto

Provenza

_,

_Lucas

_Eduardo

_Pedri

,

Gabriel

Mesquita

Provenza

a_{PontifíciaUniversidadeCatólicadeCampinas,HospitaleMaternidadeCelsoPierro,Servic¸odeReumatologia,Campinas,SP,Brazil}

b_{PontifíciaUniversidadeCatólicadeCampinas,HospitaleMaternidadeCelsoPierro,Servic¸odeRadiologia,Campinas,SP,Brazil}

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Articlehistory:

Received18September2014 Accepted25September2015 Availableonline19March2016

Introduction

Livedoidvasculopathy(LV)isarecurrent,chronicandpainful skindisease,characterizedbylesionsthatariseaspunctateor lenticularpurple-coloredmaculesand/orpapulesoccurringin thelower limbs(lowerthirdofthelegsand ankles),which commonly progress to ulceration, and subsequently heal slowlyoverweeksormonths,givingrisetopearlyatrophic scars(whiteatrophy),punctatetelangiectasia,andbrownish pigmentation,accompaniedbyaracemouslivedo.1–3

Thedisease usuallysettles bilaterally inthe legs, often causingedemainthelowerthirdofthelimbs.Livedoid vascu-lopathymainlyaffectswomen(aboutthreewomenforevery man)between15and50(mean32)yearsold.2,3

Wereportacaseofafemalepatientwithlivedoid vascu-lopathy,withexcellenthealingoflowerlimbulcersafterusing ananti-TNFagent.

夽

StudyconductedatHospitalandMaternityCelsoPierro,PontifíciaUniversidadeCatólicadeCampinas,Campinas,SP,Brazil. ∗ _{Correspondingauthor.}

E-mail:lucaspedri@hotmail.com(L.E.Pedri).

Case

report

Femalepatient,60,married,tradeswoman.Twelveyearsago, thispatientbeganaclinicalpictureofbilateralulcersinher legs and feet,accompaniedbycolor changes,withintense worseningincoldweather.Initially,thesuperficialulcerswere fewinnumber,withagradualincreaseintheirnumberand depth.Thepatienthadnoothersystemicand/orjoint com-plaint,nocomorbidities,andnofamilyhistoryofrheumatic disease.

Onphysicalexamination,nochangeincardiac,pulmonary andmusculoskeletalsystemswasnoted.Thelowerlimbs(legs andfeet)presentedwithanintenselivedoracemosa(Fig.1), with multipleinfected, deepulcers showing destructionof subcutaneousfatandallowingmusclevisualization(Fig.1).

In 2010, the patient had already been treated with several doses of corticosteroids (20–60mg/day), with only

http://dx.doi.org/10.1016/j.rbre.2016.02.014

rev bras reumatol.2016;56(6):554–556

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Fig.1–LivedoRacemosaonaleftfoot,andulcerationinrightleg.

slightimprovementandalwayswithrecurrentlesionsafter decreasingthedose.Shehadalsobeentreatedwitha com-binationofaspirin200mg/dayandpentoxifylline800mg/day, withnoclinicalimprovement.In2011,thepatientwastreated withmethotrexate15mg/weekinassociationwith corticoste-roids,buttonoavail.

Her lab work showed no change in blood count, renal function,liverfunctionandurinarysediment. The comple-mentproteins(C3and C4)werenormal; ANA1/320with a finespeckledpattern.Anti-DNA,anti-RNP,anti-Sm,anti-RO, anticardiolipin antibodies (IgM and IgG), lupus anticoagu-lant,rheumatoidfactor,andcryoglobulinswerenegative;ESR: 25mm, and CRP: 2.4mg/dL.Anulcer biopsy wasobtained, andthepathologicalexaminationdescribedocclusionof der-malbloodvessels,causedbydepositionofintravascularfibrin; andthrombosisassociatedwithsegmentalhyalinizationand endothelial proliferation, with the presence of a discrete perivascular inflammatory infiltrate, suggestive of livedoid vasculopathy/Milian’swhiteatrophy.

In2012,afterthefailureofmultipletreatments,a combi-nationoftheanti-TNFagentadalimumabandcorticosteroids wasinstituted,withasubsequentdecreaseofcorticosteroids. Ayearafterthistherapeuticregimen,thepatientshoweda significantimprovementofherlowerlimbulcers(Fig.2).

Discussion

Livedoidvasculopathyisadiseasewhosepathophysiologyis notwell understood.Thisfact reflectsthe manysynonyms forthisdisease,suchasMilian’swhiteatrophy,livedo vasculi-tis,segmentalhyalinizingvasculitis,livedoidvasculitis,livedo reticulariswithsummerulcers,andPURPLE(Purpuricpainful ulcerswithReticularPatternoftheLowerExtremities).1

Thisvasculopathy may beprimary orsecondary. In the first type, this condition is not associated with any other disease. On the other hand, the secondary form is com-monlyrelated tothrombophilia (factor V Leidenmutation, proteinC and/orS deficiency, hyperhomocysteinemia, pro-thrombingenemutation),andtoconnectivetissuediseases (SLE,cryoglobulinemia,APS).Therefore,inthefaceofa sus-picion of this diagnosis, it is important to start a clinical

Fig.2–Improvementofulcersandlivedoracemosainright legandfoot.

investigationofthepatientand his/herfamily,with partic-ular emphasisonhypercoagulablestatesandinflammatory diseases.1,4 _{Wesuggestedthe exclusion ofall those}

condi-tionsthatmaydeterminepunch-like(“piecemeal”)reticulated ulcerationsanddifficult-tohealconditions;suchdisorderscan causestellate-likewhitishscars(i.e.,septicand leukocytoclas-ticvasculitides).2

Inadditiontoacompletephysicalexamination,the doc-torshouldrequestacompletebloodcount,coagulationtests, CRPlevels,fibrinogen,anti-nuclearfactor,anti-DNAantibody, rheumatoidfactor,antiphospholipidantibodies,and cryoglob-ulins.Inaddition,itisimportanttogetaDopplerultrasoundof lowerlimbs,withtheaimofdiscardingchronicvenousstasis.4

Withtheexceptionoffibrinogendosage,thepatientinthis studyobtainedresultsforalltestssuggested.

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primarilyinlatelesions,consistingofasecondaryevent.The thrombosisintothesevesselswouldoccurthroughmultiple changesinthecoagulationcascade–fromplatelet dysfunc-tion to a defect in the production of tissue plasminogen activator.1–5

Furthermore, the link between coagulation and inflam-mation has been investigated in cases of LV, taking into accountthatthrombinactivatesthosereceptorsactivatedby proteasetype1(which,ininflammatorycells,produce inflam-matorymediatorssuchasIL-6,IL-8,chemotacticsubstancesof monocytes,andadhesionmolecules)and,moreover,recruits leukocytestowardtheintravascularenvironment.1

Asnotedinthispatient’sbiopsy,inthehistological descrip-tion oflivedoidvasculopathyonecan observe occlusionof vesselsofthedermisthroughdepositionofintravascularfibrin andbyintraluminalthrombus,besidessegmental hyaliniza-tion and endothelial proliferation. The perivascular mixed inflammatory(neutrophilic atits onset,and then lympho-cytic)infiltratearisesataminimumdegree.Ingeneral,direct immunofluorescenceshowsdepositionofimmunoglobulins, fibrin,andcomponentsofcomplement.1–4

Largely duetoits uncertain pathogenesis,there isno a single effective treatment for this skin condition. Current treatmentoptionsarebasedonreportsofisolatedcases,or ofcaseseries.Mosttreatmentsaimtoimprovethephysical manifestationsandalleviatethepain.5

The therapeutic arsenal – described in the literature – consists of antiplatelet and anticoagulant agents, fib-rinolytic agents, vasodilators, phototherapy with PUVA, hyperbaric chamber, and immunosuppressants (corticoste-roids,cyclosporine,sulfasalazine,immunoglobulin).Allthese agentsare described in the literature,inattempts ofulcer treatment.5

Among antiplatelet drugs and hemorheologic agents, acetylsalicylicacidandpentoxifylline,respectively,havebeen successfullyusedinthetreatmentofLV,andtheirassociation isone ofthe mostcommonlyused therapeuticregimens.5

Yangetal.reportedthat13of27patientswithLVresponded to a combination of local care of wounds, rest, and low-doseaspirinincombinationwithdipiridamol.6_Acasereport

described the successful treatment of LV associated with sickle cell trait with ASA.7 _{Sams et al. reported the use}

of pentoxifylline in eight patients; in seven, a significant improvementofulcerationswasnoted.8_{Ourpatientdidnot}

benefitfromthecombinationofthesetwodrugs.

Immunosuppressiveagentsare generallyusedfor recur-rent cases, such as rescue therapy.9 _{However, the use of}

methotrexatewasnoteffectiveforourpatient.

Sheinbergetal.describedacaseofa38-yearoldfemale with LV refractory to treatment with anticoagulants and immunosuppressants, and who obtained a good response after the institution of rituximab. These authors reported that,inspiteofitsunknownetiology,LVcorrelatesstrongly

with immune complex diseases; and its histology shows consistentlyinflammatoryinfiltrates;itmaycomethatB lym-phocytes are involved inthe pathogenesisof this disease, butfurtherstudiesareneededtoclarifythispoint.10_Inthis

report, we have succeeded in healing our patient’s ulcers aftertheuse ofadalimumab.Toourknowledge,this isthe firstreportdescribingthetreatmentofLVwithananti-TNF agent.

Tumor necrosisfactor (TNF) contributesto the develop-mentofthrombosis,becauseTNFstimulatestheexpressionof tissuefactorbyendothelialcells(i.e.anactivatorofthe extrin-siccoagulationpathway) andofthrombomodulin(apotent inhibitorofcoagulation).11_{Thus,adalimumab,whichisafully}

humananti-tumornecrosisfactormonoclonalantibody,can reducetheformationofthrombiintodermalvessels,actively participatinginthepathophysiologyoflivedoidvasculopathy andprovidinganewperspectivetoitstreatment.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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CarvalhoJF,etal.Vasculopatialivedoide:umadoenc¸a cutâneaintrigante.AnBrasDermatol.2011;86:961–77. 3.ZaniniM,BertinoD,WulkanC,ItoL.Vasculiteou

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