Cutaneous vasculitis is an inflammatory processaffecting the vessel wall that leads to its damageand subsequent haemorrhagic features1. It may bea primary disorder or a presenting sign of primarysystemicvasculitissuchaspolyarteritisnodosa(PAN),Wegener’s granulomatosis (WG), Churg Strausssyndrome (CSS)or secondary todrugs, infectionsor

Anaetiological&clinicopathologicalstudyoncutaneousvasculitis

PoojaKhetan,GomathySethuraman,BinodK.Khaitan,VinodK.Sharma,RajeevaGupta*, AmitK.Dinda**,V.Sreenivas+ &ManojK.Singh**

Departments of Dermatology & Venereology, *Medicine, **Pathology & +Biostatistics, All India Institute of Medical Sciences, New Delhi, India

ReceivedAugsut4,2010

Background & objectives: Cutaneous vasculitis has protean clinical manifestations. It may be idiopathic or associated with a spectrum of conditions such as infections, drugs, etc. Skin is involved in both small vessel vasculitis (SVV) and medium vessel vasculitis (MVV). Overlapping features are seen between SVV and MVV. The histopathological features may not always relate with the clinical lesions. The aim of the present study was to evaluate the aetiological factors and clinicopathological association in patients with cutaneous vasculitis.Methods: In this cross-sectional study, detailed history and clinical examination were done on patients with biopsy proven cutaneous vasculitis. Two skin biopsies were taken from each patient for routine histopathology and direct immunofluorescence.Results: Of the 61 patients studied, hypersensitivity vasculitis (HSV) [23 (37.7%)] and Henoch Schonlein purpura (HSP) [16 (26.2%)] were the two most common forms. Systemic involvement was seen in 32 (52.45%) patients. Drugs were implicated in 12 (19.7%) cases, infections in 7 (11.4%) and connective tissue disorders in 4 (6.5%) cases. Histologically SVV was the most common pattern, seen in all the clinically diagnosed patients with SVV (47), and in 12 of the 14 clinically diagnosed patients with MVV. Direct immunofluorescence showed positivity for at least one immunoreactant in 62 per cent of the patients and the most common deposit was C3 followed by IgG, IgA and IgM. Interpretation & conclusions: Majority of our patients with cutaneous vasculitis were idiopathic. Histologically, SVV was seen in most of our patients. No association was seen between history of drug intake and tissue eosinophilia and also between histologically severe vasculitis and clinical severity. The presence of immunoreactant IgA was not specific for HSP.

Key wordsHenochSchonleinpurpura-hypersensitivityvasculitis-mediumvesselvasculitis-smallvesselvasculitis

systemic diseases such as connective tissue disease(CTD)andmalignancy2. Basedonthesizeofthevesselwallaffected,cutaneousvasculitisisclassified assmallvessel vasculitis (SVV), medium vessel vasculitis(MVV)andlargevesselvasculitis3.SkinisaffectedinbothSVVandMVV.PatientswithpredominantlySVVhavepalpablepurpura,urticaria,vesicobullouslesions

IndianJMedRes135,January2012,pp107-113

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andtargetoidlesionswhereasMVVischaracterizedbysubcutaneousnodules,livedoreticularis,ulcer,infarct,digitalpittedscarsandgangrene1,2.

Althoughthereisamultitudeofcausesofcutaneousvasculitis, yet most of the cases are idiopathic. Thefrequencyofeachof thecause isvariabledependingupontheepidemiologicaldifferenceandprevalenceofinfections.Fromapooleddata,cutaneousvasculitisisduetoinfectionsin22percent;drugsin20percent;CTDin12percent;HenochSchonleinpurpura(HSP)in10percentand<5percenteachduetomalignancy,primarysystemicvasculitisorsystemicinflammatorydisease such as sarcoidosis and cryoglobulinemia2. Histopathology can be significantly variable andseveral overlapping features are seen between SVVand MVV. The histopathological features may notshowanyassociationwiththeclinicallesions.

ThereareonlyfewstudiesfromIndiaoncutaneousvasculitis4,5. Henceweundertookthisstudytoevaluatethe aetiological factors and clinicopathologicalassociation with clinical lesions in patients withcutaneousvasculitisinatertiarycarehospitalinnorthIndia.

Material & Methods

Allconsecutivepatientswereselected.Nosamplesizewas fixed a priori. Patientswith biopsy provencutaneous vasculitis were recruited from the outpatient departments of Dermatology & VenereologyandMedicine,AllIndiaInstituteofMedicalSciences(AIIMS), New Delhi, between November 2006 toOctober2008.Patientswithbleedingdiatheses,thoseunwillingtogiveinformedwrittenconsentandpregnantfemaleswereexcluded.ThestudywasapprovedbytheInstitutionalEthicsCommittee.

The study protocol included detailed history andclinicalexamination.Thefollowinginvestigationsweredone: complete haemogram, renal and liver functiontests, urine analysis, antinuclear antibody (ANA),antineutrophilic cytoplasmic antibody (ANCA),Rheumatoid factor (RF), C-reactive protein (CRP),cryoglobulins,anti-cardiolipinantibody(IgGandIgM),lupusanticoagulant,HBsAg,antiHCVantibody,antistreptolysinO(ASO)titre,throatswabforcultureandsensitivity,ChestX-rayandMantouxtest.Othertestscarried out depending upon the clinical indicationsincluded stool for occult blood, 24 hour urinaryprotein,sputumforacidfastbacilli(AFB),HBVRNA,AntiHBcIgM,dsDNA,antiRo/antiLaantibody,IgA,IgG,IgM,C3,HIVserology,X-rayofwristandfeet,

nerveconductionstudies,arterialandvenousdoppler,ultrasonography (USG) abdomen, echocardiography,renalbiopsy,contrastenhancedcomputedtomographyof chest, digital subtraction angiography (DSA) andcontrast enhanced magnetic resonance angiography.Two skinbiopsies (punchbiopsy, 4mm)were takenin all cases, one each for routine histopathology anddirect immunoflourescence (DIF).All the laboratorytests were performed as per the standard guidelineswithintheAIIMSlaboratories.

All historical, clinical, histopathological andlaboratory features were evaluated. Patients wereclassifiedaccordingtothestandardcriterialaidbytheAmericanCollegeofRheumatology(ACR)6withsomemodifications.Modifications inACRcriteria: (i)AgefactorwasrelaxedinbothHypersensitivityvasculitisandHenochSchonleinpurpura(ii)Urticarialvasculitis,microscopic polyangitis, and vasculitis associatedwith connective tissue diseases were included asseparatecategoriesowing to theirdistinctiveclinico-pathological features (iii) patients who do not fulfilany of the entities were classified as unclassifiedvasculitis.

Statistical analysis:Theproportionofcutaneousvasculitiswitheachaetiologywasdeterminedalongwith95percentconfidenceinterval.Thequantitativevariablessuchasagewereexpressedasmean.Resultsofqualitativevariables were expressed as percentage. Associationof aetiology and diagnosis with immunoflourescencefeatures, drug history with histopathological featureswere examined by using Pearson’s Chi-square test.P<0.05wasconsideredsignificant.

Results

Of the 80 patients with clinically suspectedvasculitis screened, 61 had histological features ofvasculitis and were included in the study. Nineteenpatients were excluded (misdiagnosis-2; Non-confirmatoryhistopathology-3;Declined-5;losttofollow-up -9).Therewere 35males (57.4%) and 26females(42.6%)withanagerangeof7to64yr.Themean agewas 29.4±27 and 35.5±14.98 yr formalesand females, respectively. The maximum number ofpatients (n=20, 36%) was seen in the age group of 16-30 yr followed by 31-45 (n=20, 32.7%). Thedurationoftheillnessrangedfromasshortasonedayto10yr.Palpablepurpurawasthemostcommontypeofcutaneous lesion seen in43 (70.5%)patients.Theother cutaneous lesionswere crustedplaques,ulcers,wheals and haemorrhagic vesicles. Clinical presence

108 INDIANJMEDRES,JANUARy2012

of deep seated nodules/ulcers/gangrene (suggestiveofMVV)wasseenin14patients.Thirtytwo(52.4%)patientshadinvolvementofupperlimbs,trunkorfaceincombinationwithinvolvementoflowerlimbs.

Constitutionalfeatureswerepresentin24patients(39.3%)[arthralgiain19(31.1%);myalgiain11(18%);and fever in six (9.8%)]. Systemic symptoms wereseenin23patients(37.7%)andincludedarthritisin17(27.9%),abdominalpainandmelenain5(8.2%)eachandhaematuriainthree(4.9%)cases.Otherassociatedsymptoms were oral ulcers in four patients (6.5%),patchysensorylossoverfeetandpalpitationsinthree(5%)each,exertionaldyspnoeaandparesthesiaintwo(3.3%)each,dryeyesanddrymouth,uveitis,epistaxisin one (1.6%) each. After complete investigations,systemic involvement was found in 32 (52.45%)patientswithrenalinvolvementin19patients(31.1%),arthritisin17(27.9%),gastrointestinalinvolvementinfive(8.2%),neuropathyandpulmonaryinvolvementinone(1.6%)each.

Historyofchronicdrugintakewaspresentinsevenpatientsforhypertension,diabetesmellitus,rheumaticheartdisease,rheumatoidarthritisandhypothyroidism.Drugintakeuptoonemonthpriortoonsetofcutaneouslesionswasconsideredrelevant.Suchassociationwaspresent in 12 patients (19.7%). Non steroidal anti-inflammatory drugs (NSAIDs) were the commonestdrugs infive(41.6%)followedbyunknowndrugs infour, antihistaminics in three, antibiotics in two andothersinthreepatients.Theotheraetiologicalfactorsidentifiedwere infections in seven,CTD in four andcryoglobulinemiainonepatient.

The twomost common forms of vasculitiswerehypersensitivityvasculitis(HSV)(23patients,37.7%)(Fig. 1a) and HSP (16 patients, 26.2%). Thoughurticarialvasculitis(Fig.1b),microscopicpolyangiitis(MPA)andCTDwerenotpartoftheACRclassification,thepatientswereclassifiedintothesegroupsbecauseofdistinctiveclinicalfindingsandinvestigations.Tenpatients(16.3%)didnotqualifyforanygroupdespitehaving features of vasculitis, and were labelled asunclassifiedvasculitis.

The most common laboratory abnormality waselevatedESRfoundin38(62.2%)patients,11werepositiveforANAandallwereHIVnegative(TableI).Eighteenpatients(29.5%)hadurinaryabnormalitiesof which 12 had hematuria with proteinuria, 4had hematuria alone and 2 had proteinuria alone.The liver and renal function tests were normal in

all patients except for one who had unconjugatedhyperbilirubinaemia.

Histopathological features: Of the 61 patients, 53biopsy specimens of 52 patients were re-analyzed.SVVwasseenin51andMVVin2specimensonly(Table II). In the SVV group, leukocytoclasia was

Fig. 1 (a). Hypersensitivity vasculitis showing palpable purpura on the lower leg; (b). Urticarial vasculitis showing urticarial plaguesontheupperextremity.

(a)

(b)

KHETANet al:CLINICOPATHOLOGICALSTUDyONCUTANEOUSVASCULITIS 109

present in 45 biopsies (84.9%), endothelial cellswellingin44(83%),fibrinoidnecrosisin47(88.6%),RBCextravasationin48(90.5%)anddermaloedemain 45 (84.9%) (Fig. 2).Most of them showedmildto moderate vasculitis. DIF was performed in 40patients who had early active purpura. C3 was thecommonest (perivascular) immune-reactant seen in19(47.5%)patientsfollowedbyIgGin12(30%),IgAin11(27.5%),andIgMin10(25%).Thepositivityfor

IgAwasstatisticallyinsignificantfordifferentgroupsofvasculitisincludingHSP.

Clinicopathological association: In patients withHSV (n=23), leukocytoclastic vasculitis (SVV) wasseen in 20 biopsy specimens.Three patients showedlymphocytic vasculitis.DIFwas positive for at leastone immunoreactant in seven of 13 (53.84%) andnegative in six (46.1%) patients. C3was positive insix (46.1%), IgM in three (23%) and IgG and IgAin two (15.4%) each. SVV was seen in 16 patientswith HSP. DIF showed positivity for at least oneimmunoreactant in 10 patients (83.3%). The most

Table I.Laboratoryparametersofthepatients(n=61)Laboratoryparameters No.ofpatients(%)HaemogramRaisedESRAnaemiaLeukocytosiswithneutrophiliaEosinophiliaThrombocytosis

38(62.5)14(22.9)8(13.1)1(1.6)1(1.6)

ANAHomogenousSpeckledNucleolar

11(18)641

RF 5(8.1)P-ANCA(n=54) 1(1.8)Cryoglobulin(n=52) 1(1.9)Raisedanticardiolipinantibodies(n=52)IgGIgM

3(5.8)2(3.8)

ElevatedCRP(n=51) 7(13.7)HbsAg(n=53) 1(1.8)AntiHCV(n=53) 1(1.8)ASLOtitre(n=45) 3(6.6)Mantouxtest(n=49) 24(48.9)(>10mm)

6(12.2)(<10mm)HIVserology(n=12) NegativeinallSerumIgG(n=31) Increasedin6,

Decreasedin3,Normalin22

SerumIgA(n=31) Increasedin8,Decreasedin1,Normalin22

SerumIgM(n=31) Increasedin3,Decreasedin10,Normalin18

SerumC3(n=12) Increasedin7,Decreasedin1,Normalin4

ESR, erythrocyte sedimentation rate; ANA, antinuclearantibody; ANCA, antineutrophilic cyptoplasmic antibody;CRP, C-reactive protein; RF, rheumatoid factor; ASLO, antistreptolysin-O;C3,complement3

Table II. Classification based on size of blood vessel andcompositionofinflammatoryinfiltrate

No.ofspecimens

95%confidenceinterval

Small vessel vasculitisOnlyneutrophilic 10(19.6) 9.8-33.1NeutrophilicandeosinophilicPredominantlyneutrophilicPredominantlyeosinophilic

37(72.5)18(48.6)4(10.8)

58.3-84.131.9-65.63.0-25.4

Lymphocytic 4(7.8) 2.2-18.9Medium vessel vasculitisLymphocyticNeutrophilic

211

Valuesinparenthesesarepercentages

Fig. 2. Showinglecucytoclasticvasculatiswithfibrinoidnecrosis(showninarrows)(H&E,X200).

110 INDIANJMEDRES,JANUARy2012

commonimmunoreactantwasC3seenineight(66.6%)patients,followedbyIgAandIgGinfive(41.6%)eachandIgMinthree(25%)patients.InpatientswithCTD,predominantlyneutrophilicinfiltratewasseenadmixedwitheosinophils.DIFwasdoneinthreepatientsandallwerepositiveandshowedpositivityforIgGinallthreepatients,C3andIgAintwopatientseachandIgMinonepatient.PredominantlyeosinophilicvasculitiswasseenintwopatientswithurticarialvasculitisandtheDIFshowedpositivityforIgA,IgGandC3inoneandwas negative in the other.The comparison betweenclinical diagnosis, histological andDIF features (in52 patients the slides were re-analyzed and in theremaining nine only the reports were analyzed) isshowninTableIII.

Histologically severe vasculitis (characterized byextensive fibrinoid necrosis of the vessel wall withRBCextravasationanddermaloedema)wasseenin6

cases(HSP-2,HSV-1,andunclassified3).Theclinicalpresentationandthesystemicinvolvementdidnotshowany association with the severity of vasculitis (mild,moderate or severe). Forty seven (77%) of clinicallydiagnosed SVV cases, showed histologic features ofSVV.Butonlytwoofthefourteenpatients(14.3%)withclinicallydiagnosedMVVshowedhistologicalfeaturesofMVV.Theremaining12hadfeaturesofSVV.

Of the12patientswithprior drughistory, tissueeosinophiliawaspresentineightwhileintheremainingfour tissue eosinophilia was absent. In another 32patients with tissue eosinophilia, prior drug historywas absent and two patients had urticarial vasculitis.Peripheraleosinophiliawaspresentinonlyonepatient.

Discussion

In this cross-sectional study we report findingsin 61 consecutive patientswith cutaneous vasculitis.

Table III.Comparisonbetweenclinicaldiagnosis,histologicalandimmunoflourescencefeatures(n=61)Clinicaldiagnosis(No.) Histological diagnosis DIFHypersensitivityvasculitis(23) Leukocytoclasticvasculitis:20

Neutrophilic-7Neutrophilic+eosinophilic-13

N=13Neg(5),C3(2),IgG+C3(2)IgM(1)

Lymphocyticvasculitis-3 Neg(1),IgA+C3+IgM(2)HenochSchonleinpurpura:Classical(7) Leukocytoclasticvasculitis:7

Neutrophilic+eosinophilic:7N=5IgA,IgG,C3(1),C3(1),Neg(2),IgG,IgA,IgM,C3(1)

HenochSchonleinpurpuraAdult(9) Leukocytoclasticvasculitis:9Neutrophilic+eosinophilic:8(N>E)Neutrophilic-1

N=7Neg(1),IgA(1),IgA,IgG,C3(1),IgM,IgG,C3(1),IgG,C3(1),C3(1),IgA,IgM,C3(1)

Microscopicpolyangiitis(1) LeukocytoclasticvasculitisNeutrophilic+eosinophilic

--

Connectivetissuedisease(4)Rheumatoidarthritis(2)SLE(1)Sjogren’ssyndrome(1)

Leukocytoclasticvasculitis:4Neutrophilic+eosinophilic:4(N>E)

N=3IgG,C3(1),IgA,IgG(1),IgA,IgM,IgG,C3(1)

Urticarialvasculitis(4) Leukocytoclasticvasculitis:4Neutrophilic+eosinophilic:4

N=2Neg(1),IgA,IgM,C3(1)

Wegener’sgranulomatosis(1) LeukocytoclasticvasculitisofsmallvesselsNeutrophilic+eosinophilicwithgranuloma

--

Polyarteritisnodosa(1) LeukocytoclasticvasculitisofsmallvesselsLymphocytes>neutrophils

--

Takayasu’sarteritis(1) Vasculitisofsmallandmediumvesselswithlymphocytesandhistiocytes

IgM,IgA,IgG

Unclassifiedvasculitis(10)Smallvessel(9)

Mediumvessel(1)

Leukocytoclasticvasculitis:8Neutrophilic(4)Neutrophilic+eosinophilic(3)Lymphocytic(1)Neutrophilic(1)

N=6Neg(4),C3(1)

Neg(1)

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HSV (23) and HSP (16) represented the maximumnumberofpatients,whichissimilartoearlierstudies7. Palpable purpura was the most common cutaneouslesionseeninourpatientsasreportedbyothersalso7-10. Systemic involvementwas seen inmore thanhalfofourpatientsasalreadybeen reported8,9.Weobservedrenalinvolvementasthemostcommonfeaturewhichis in contrast tomusculoskeletal system involvementinotherseries8,9,11.Eightpercentofourpatientshadgastrointestinalinvolvementasreportedbyothers7,9. In arecentseriesfromIndia,22percentofthepatientshad GI involvement5. Consistent with the earlierstudies,elevatedESRwasthemostcommonlaboratoryabnormalityseeninnearlytwo-thirdsofourpatients4,9-11.

A causal agent or an underlying condition hasbeen reported in 20-85 per cent of the cases withvasculitis7,8,11-14. The aetiological association wasseenin40percentofourcases.InfectionsandCTDare the two most common associated conditions inEurope8,11,12. In our study, drugs were found to bethe commonest factor associated with vasculitis,as reported from Kuwait9. In Mexico, drugs wereimplicatedinlessthan2percentofthecases13.Themostcommonly implicateddrugs inour studywereNSAIDswhereasantibioticswerethemostcommoncause in other studies7,9,11,12. NSAIDs are easilyavailable over the counter which might explain itshigherfrequency.There isno testavailable thatcanexactly delineate drugs as the cause of vasculitisexceptforthetemporalcorrelation,effectofwithdrawlofdrugandrechallenge.Nodifferencewasobservedin the clinical outcome between these patients andthosewithoutdrughistory.Also,rechallangewasnotdoneinanyofourpatients.Therefore,thedefinitivecausal association could not be established. Theoverallfrequencyofinfectionwas11percentinourstudywhich is slightlyhigher than thatobserved inreports from Belgium (9.5%) and Mexico (6.8%)while higher frequency has also been reportedfrom Australia (26%), Spain (19.8%) and Kuwait (14%)7-9,12,13.

Histologically,weobservedSVV(96%)inmostofourpatientsandMVVinonly4percent.ThiswasincontrasttoSaiset al10whoreportedSVVandMVVin60and40percentrespectively.ThelowfrequencyofMVVinourstudymaybeduetothefactthatMVVisasegmentalandpatchyprocessandallthevesselsofthesamecalibermaynotbeaffectedandthusthebiopsymay not have picked up the involvedmedium sizedvesselleadingtosamplingbias.Multipleskinbiopsies

couldhavebeentakenatdifferenttimes.Theinfiltratewaslocalizedtoupperandmiddermisinmostcases,thoughlowerdermalandpanniculusinvolvementwasalsoseen.Panniculusinvolvementwasseeninpalpablepurpura,wheals,nodules,crustedplaquesandulcers.Infiltrate was mostly confined to perivascular andinterstitiallocationandwaspredominantlyneutrophilicin50percentascomparedto76percentbySaiset al10. Leukocytoclasia and fibrinoid necrosis were presentin85and89percent respectivelywhileothershavereported these changes in more than 95 per cent ofthe cases10,15.RBCextravasationwasseenin90.5percentofourcasesascomparedto100percentinotherstudies10,15.Most of the patients withHSV andHSPshowedSVVwithbothneutrophilicandeosinophilicinfiltrate. Three patients showed predominantlylymphocytic vasculitis which could be explained byadvancedageoflesionbiopsied.InpatientswithCTD,predominantlyneutrophilicinfiltratewasseenadmixedwitheosinophilswhich is similar to theobservationsreported earlier16. Tissue eosinophilia was found tobeareliableindicatorofdruginducedvasculitis17 but we did not find any significant difference for tissueeosinophilia in those patientswith andwithout drughistory.

DIFanalysis revealedpresenceofat leastoneoftheimmunoreactantsin62percentofpatients.OtherstudieshavereportedDIFpositivityin55-92percentof cases12,15,18.Consistentwith the previous reports19,themost common immune depositwasC3 followedby IgG, IgA and IgM.However, therewas variationinthepositivityofdifferentimmunoreactantsbetweendifferent studies. Grunwald et al20 found C3 and IgGas themost common,while IgAaspredominantimmunoreactant in a study from Kuwait9. Sanchez et al18foundIgM,C3andfibrinasthemostcommonimmunoreactants. Inconcordancewithotherreports12,no specific patterns of DIF results were found invasculitiswiththedifferentaetiologiesandtypes.

In conclusion, the two most common forms ofcutaneous vasculitis were HSV and HSP. Possibleaetiological association was seen in 39.6 per centof cases. Drugs were probably the most commoncause (historically) seen.Majority of the caseswereidiopathic.Histologically,SVVwasthemostcommonpattern. No associationwas seen between history ofdrugintakeandtissueeosinophilia,andalsobetweenhistologically severe vasculitis and clinical severity.ThepresenceofimmunoreactantIgAwasnotspecificforHSP.

112 INDIANJMEDRES,JANUARy2012

Based on our data, work-up for patients withcutaneous vasculitis including clinical historyand examination, skin biopsy, haemogram, ANA,routinebiochemicalprofile,andurineexamination isrecommended.

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Reprint requests: DrG.Sethuraman,AdditionalProfessor,DepartmentofDermatology&Venereology,AllIndiaInstituteof MedicalSciences,AnsariNagar,NewDelhi110029,India

e-mail:kgsethu@yahoo.com,aiimsgsr@gmail.com

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