Associationbetweenhidradenitissuppurativaandmetabolicsyndrome:SystematicReviewandMeta-analysisMiltonJoseMaxRodríguez-ZuñigaMD.DermatologyDepartmentHospitalNacionalDanielAlcidesCarrion,Callao,Peru.UniversidadNacionalMayordeSanMarcos,Lima,Peru.HerneyAndrésGarcía-PerdomoMDMScEdDPhDAssistantprofessorUniversidaddelValleandUniversidadLibre,Cali,Colombia.DirectorAssociateCochraneGroupandUrogiv.AlexOrtega-Loayza,MDAssistantprofessorOregonHealthandScienceUniversity,Portland,Oregon,USA.

1. Introduction

a. ProblemDescriptionMetabolicSyndrome(MS)isaburdenpublichealthproblemworldwideduetotheincreaseprevalenceofobesity.Furthermore,obesityistheresultofinadequatelifestylesanddiet,andlackofexerciseroutinesinceyoungages,withaprevalenceinLatinAmericaaround17%,evenhigherinmaincities,around21%(1).SeveralstudieshaveshownthatMSisariskfactorfordevelopingcardiovasculardisease(CVD).Ameta-analysisthatincluded172,573individualsshowedthatMSpatientshaveincreasedalmosttwiceriskofCVDanddeath(OR1.78,95%CI1.58-2.00).ItisalsoknownthatpatientwhomeetthecriteriaforSM,havesix-foldincreaserisktodevelopDiabetesMellitus(DM)(2).Hidradenitissuppurativa(HS)isachronic,inflammatory,debilitatingskindisease,andrecentstudieshaveshownitsassociationwithMS.Inameta-analysisconductedbyTzelloseta(3),authorsshowedthatpatientswithHShadtwiceofrisktodevelopMS(OR2.22,95%CI1.62-3.06,P<0.001)thancontrols.Thisassociationisevenhigherinhospitalpopulation,thaningeneralpopulation(3).ThefirststudythatreportedthisassociationwascarriedoutinGermany(4).TheyfoundthattheprevalenceofMSintheHSgroupwas40.0%versus13.0%inthecontrolgroup(OR4.46,95%CI2.02-9.96;p<0.001).However,theydidnotadjustedtheyresultforcovariates.Ontheotherhand,Shalometal.(5)showedthatafteradjustmentforseveralcovariates(age,sex,diabetes,hypertension,hyperlipidaemia,obesityandsmokingstatus)thisassociationwasnotashigherasthefirst,butsignificant(OR1.61,95%CI1.36-1.89).Thus,totheextentthatHSisassociatedwithMS,thesepatientswillhaveincreasedriskofdevelopingCVDandDM.However,dataisbiasedasadjustedandadjustedstudieswereincludedinobservationalstudiesandmeta-analyses.Therefore,westilllackofinformationoftherealdimensionoftheassociationbetweenHSandMS,afteradjustingforseveralcovariates.

b. ProblemformulationIsthereanassociationbetweenHidradenitissuppurativaandMetabolicSyndrome?

c. JustificationTherearestudiesreportinganassociationbetweenHSandMS,withprevalencerangingfrom35%to50%inHScohorts.However,westilllackofstudieswithadjustedORsonly,asthelastmeta-analysisincludedmixadjustedandunadjustedOR.Therefore,itjustifiestheconductofthisstudy.

Resultsareofgreatinterestsincetheyserveasbasisforhypothesesandstudiesofgreatercomplexity,whichareneededtofurtherinvestigateefficienttreatmentsbasedonimprovingtheMS.

d. Goals• Maingoal

• ToevaluatetheassociationbetweenHSandMSinobservationalstudieswithadjustedresults.

• Secondarygoals• ToevaluatetheassociationbetweenHSandMSin

observationalstudieswithcruderesults.• TocomparetheresultsofadjustedORsvs.resultswith

crudeORsinordertoseethedifferencesofdegreeofassociation.

• Toconductaregionalanalysisbysubgroup,groupingstudieshavebeenconductedinLatinAmerican,NorthAmerican,European,AsianandAfricanpopulation,withbothcrudeandadjustedORswhenpossible.

• Toconductasubgroupanalysis,accordingtoseveralcharacteristicsastypeofpopulation(hospitalvs.general),typeofMScriteria(IDFvs.NCEP-IIIvs.AHA),etc.,withbothcrudeandadjustedORswhenpossible.

• TodescribeobservationalstudiesofHSandMS.

e. Hypothesis• NuleHypothesis(H0)

HSisnotassociatedwithMSinobservationalstudies.

• AlternativeHypothesis(H1)

HSisassociatedwithMSinobservationalstudies.

2. Theoreticalframework

a. Background

Arecentmeta-analysisfoundasignificantassociationbetweenHSandMS.Theyincludedfivestudieswith3888patientswithHSand21585controls.AsignificantassociationwithMSwasdetectedwithapooledORof2.22(95%CI162–306,P<0001).Noevidenceofpublicationbiaswasdetected.Heterogeneitywassignificant(I2=77%).SensitivityanalysisfororiginofpatientswithHS(generalpopulationorhospital-based)didnotchangetheresultsandtheassociationscontinuedtobesignificantforbothpopulations.ForpatientswithHSfromthegeneralpopulationthepooledORwas1.59(95%CI140–180).TheassociationforpatientswithHSfrom

dermatologyclinicswasmuchhigherat3.20(95%CI207–496).However,authorsusedadjustedandunadjustedORwhilepoolingtheresults.2.2. Definitions2.2.1. HidradenitissuppurativaHidradenitissuppurativa/acneinversa(HS)isachronic,inflammatory,recurrent,debilitatingskindiseaseofthehairfolliclethatusuallypresentsafterpubertywithpainful,deep-seated,inflamedlesionsintheapocrinegland-bearingareasofthebody,mostcommonlytheaxillae,inguinalandanogenitalregions(6).Prevalencesarereportedaslowas0.00033%andashighas4.1%(7).ThepathogenesisofHSisnotcompletelyunderstood.Recentresearchhasledtogreaterinsightintothemechanismsinvolvedinthedisease.TheprimarydefectinHSpathophysiologyrestswiththehairfollicle.Follicularocclusion,followedbyfollicularrupture,andaforeignbody-typeimmuneresponsearenecessaryconditionsforthedevelopmentofclinicalHS.Aspecificgeneticsignatureandenvironmentalfactors,suchascigarettesmoking,microbialcolonization,andadiposity,allcontributetotheHSphenotype(8).OcclusionofthefollicularinfundibuluminHSpathogenesisisacertainty.Regardlessofdiseaseduration,follicularocclusionisanearlyfeatureinthepathogenesis,asaresultofhyperkeratosisandhyperplasiaoftheepithelialliningofterminalfollicles(9).Follicularocclusionleadstodilatationofthehairfolliclefollowedbyruptureanddischargeofcontents,includingkeratinandbacteriaintothesurroundingdermis.Therefore,vigorousinflammatoryresponsethatrecruitsneutrophils,lymphocytes,andhistiocytes(10).Ithasbeenpostulatedthatdeficienciesinthefollicularskinimmunesystemmayresultinmicrobialovergrowth,whileanothertheorysuggeststhatanoveractiveimmunesystemmayresultinaninflammatoryresponsetonormal,harmlessflora(8).HSisepidemiologicallyassociatedwithsmoking.Tobaccosmokeiscomposedofthousandsofchemicalsthatactivatekeratinocytes,fibroblasts,andimmunocytesviaatleast2typesofreceptors:nicotinicacetylcholinereceptorsandarylhydrocarbonreceptors.Inkeratinocytes,thisleadstoacanthosis,infundibularepithelialhyperplasia,andexcessivecornification.TobaccosmokealsoinducesproinflammatorycytokineslikeTNF-a,interleukins(ILs)-1a,-1b,and-8,leadingtoneutrophilchemotaxisandTH17cellinduction(8,11).Hormonesmayinducefollicularocclusionviaincreasedproliferationoffollicularkeratinocytes,leadingtointrafollicularacanthosis,keratosis,andpluggingofthefollicle.However,anormalandrogenprofileisfoundinmostofHSpatients.ObesitymayaggravateHSviaincreasedskineskinandskineclothingfriction.26MechanicalstressisassociatedwithworseningofHSbyincreasingfollicularocclusion

andfollicularrupture.Mechanicalcompression,friction,orshearforcesaresensedbyseveralmechanotransducersinhumanskin.Thesesignalsaltogetherresultintheactivationoftranscriptionfactorsthattranslocatetothenucleusandactivatemechanoresponsivegenes.Activationofthesegenesmaycontributetolocalskinirritation,sweatretention,intrafollicularacanthosis,andkeratinization.Inaddition,theproinflammatorystate,whichiscommoninobeseindividuals,maysynergizewithproinflammatorycytokinesfoundinlesionalHSskin,contributingtooverallinflammation.ThecytokinesandimmunepathwaysthatdriveinflammationinHScontinuetobeinvestigated.TNF-a,aproinflammatorycytokineproducedbyinnateandadaptiveimmunecells,hasacriticalroleinseveralautoinflammatorydiseases.SomestudieshavenotedthepresenceofTNF-aatthemRNAandproteinlevelsinHSskin.Thisisconsistentwiththeclinicalimprovementthatisusuallyobservedwithinfliximabandadalimumabtherapy.ForthediagnosisofHS,3criteriamustbepresent.First,typicallesionsmustbepresent(ie,deep-seatedpainfulnodules).Theseareoftendescribedas‘‘blindboils’’intheearlylesions.Otherlesionsareabscesses,drainingsinus(inflamedtunnels),bridgedscars,andpostinflammatory‘‘tombstone’’double-endedpseudocomedones.Mostoften,multipleelementsarepresentsimultaneously.Itis,however,importanttoavoidconfusionwithnondiagnosticelements,suchassimplefolliculitis,whenmakingthediagnosis.Second,theseelementsmainlyoccurinoneoftheareasforwhichHShasapredilection:theaxillae,groin,perinealregion,buttocks,andinfraandintermammaryfolds.Lesionsmayappearectopically,buttheymustinvolvetheareasforwhichthediseasehasapredilectiontomeetthediagnosis.Third,theremustbeaclearhistoryofchronicityandrecurrence.LesionsinitiallyrecurintheareasforwhichHShasapredilection,onlytoturnchroniclateroninthecourseofthedisease.Arbitrarily,2recurrencesoveraperiodof6monthshavebeenusedasaqualifierforadiagnosis.All3criteriamustbepresentforthedefinitivediagnosis,andbecauseofthediagnosticrequirementforrecurrence/chronicity,anobservationperiodmaybenecessarybeforethedefinitivediagnosisismade.Therehasbeendescribedseveralclinicaltypes:

• TheregulartypeofHSfulfillsallofthediagnosticcriteria.Thisisprobablythemostcommontype,andallHSpatientswholackotherspecificcharacteristicsbelonginthiscategory.

• Frictionalfuruncletype.Thesepatientsareusuallyoverweight;inadditiontoregularHS,theyarecharacterizedbythepresentationofmultipledeepnodulesandabscessesonsitesexposedtoenhancedfriction,suchastheabdomen,thighs,andbuttocks.Theformationoftunnelsandfistulasintheseareasisunusual.

• Scarringfolliculitistype.PatientswiththescarringfolliculitistypeofHShave,inadditiontoregularHS,pustules,cysts,superficialnodules,depressedcribriformscarring,anddouble-endedcomedones.Theselesionsarefrequentlyseenonthebuttocks,inguinalregion,andpubicregion.Theformationofsinustractsandfistulasinthesesitesmaybeunusual,and

althoughtheinflammatorylesionsaresmallandsuperficial(HurleystageI),scarringtypicallyoccurs.Thesepatientsarealsofrequentlyoverweightandoftensmoke.

• Conglobatatype.Thesepatientsarecharacter-izedbycystformationandacneconglobatalesionsonthebackespecially,butalsotheface.HSusuallyrunsinthefamilyinthistype,andismoderatetosevere,HurleystagesIItoIII.Patientsareusuallymenandarenotoverweight.TheChinesecasesinwhomtheinitialfindingofgamma-secretasemutationswerefoundmaybelongtothisputativegroup.15

• Syndromictype.PatientswithsyndromictypeHSarecharacterizedbyconcomitantmanifestations,suchaspyodermagangrenosumandarthritis,inthesyndromicconstellationrecognizedaspyodermagangrenosum,acne,andsuppurativehidradenitissyndromeorpyogenicarthritis,pyodermagangrenosum,acne,andhidradenitissuppurativasyndrome.

• Ectopictype.Theexistenceofanectopictypeinvolvingthefacehasbeenproposed.

Ontheotherhand,Hurleyetal.firstdescribedaseverityclassificationforHS.

• StageI—Abscessformation,singleormultiple,withoutsinustractsandcicatrization.

• StageII—Recurrentabscesseswithtractformationandcicatrization,singleormultiple,andwidelyseparatedlesions

• StageIII—Diffuseornear-diffuseinvolvementormultipleinterconnectedtractsandabscessesacrosstheentirearea

StageIdiseaseismostcommon,affecting68%ofpatients,whilestageIIoccursin28%ofpatients,and4%ofHSpatientsdevelopstageIII.TheHurleyclassificationisusefulforrapidclassificationofHSseverity,butithasseriouslimitations.First,itcannotbeconsideredasurgicalclassificationbecauseitdoesnotincorporateinflammatoryfeatures,suchaserythemaanddischarge.Itisbasedonstaticdiseasecharacteristics,suchasscarringandfistulas,whichareonlytreatablewithsurgery.Itisthereforestaticandnotusefultomonitortheefficacyofmedicaltherapy.Second,becausescarringisakeyfeatureofstageIIandIIIpatientsandirreversible,thescorecanneverfallbelowII,evenifthediseaseisincompleteremission.Third,theclassification,withjust3stages,isnotaprecisemonitoringtoolintheclinicaltrialsetting.2.2.2. MetabolicsyndromeMSisagroupofmetabolicriskfactors,whichdirectlypromotethedevelopmentofatheroscleroticcardiovasculardisease(12).Themostwidelyrecognizedmetabolicriskfactorsareatherogenicdyslipidemia,elevatedbloodpressureandelevatedplasmaglucosebaseline.Individualswiththesecharacteristicscommonlymanifestprothromboticstatesandaproinflammatorystate(13).Thisconstellationofmetabolic

riskfactorsisstronglyassociatedwithtype2diabetesorelevatedriskforthiscondition(14).ItiscurrentlyunclearwhethertheMShasasinglecauseorisprecipitatedbymultipleunderlyingriskfactors.TheunderlyingriskfactorsarethosethatwouldbeassociatedwithMSandthoseseemtobethepredominantareabdominalobesityandinsulinresistance(15).Otherconditionsmaybeassociatedwithphysicalinactivity,age,hormonalimbalance,geneticorethnicpredisposition.WhileanatherogenicdietcanaccentuatetheriskfordevelopingCVDinpeoplewiththissyndrome,itisstillconsideredaspecificunderlyingriskfactorforthiscondition(16).Itisfurthercontemplatedthatnon-obesepeoplemayhaveinsulinresistanceandhaveabnormallevelsofmetabolicriskfactors.Althoughindividualswithinsulinresistancearenotrequiredtobeobese,oftenhaveabnormalbodyfatdistribution,beingpredominantlyupperbody.Adiposetissueexhibitsincreasedproductionofinflammatorycytokinesandadiponectinreduction,aprotectiveadipokine(17).Ontheotherhand,theAHA/NHLBIindicatesthatMSisassociatedwithastateofchroniclow-gradeinflammation,havingreportedthatinflammatorycytokinescaninduceinsulinresistancebothinadiposetissueandmuscle(18).Theseconcepts,chronicityandlow-gradeinflammation,althoughtheyarereportedinthestudiesarenotyetstrictlydefinedbytheauthors.ToevaluatetheprevalenceofMSindifferentpopulationsisdifficultdespiteattemptstoreachanagreementonthedefinitionofthissyndrome.InWesternEuropeitisestimatedthattheprevalenceofthesyndromewouldrangebetween15and35%(19).TheyfounddifferencesintheprevalenceofMSinrelationtosex,beinghigherinwomen.Inthosestudiesinvolvingpeopleaged20-25years,theprevalenceinurbanpopulationsbetween8%(India)and24%(USA)inmales;and7%(France)and43%(Iran)inwomen(20).Molleretal.reportedthatabout25%ofUSadultsmetcriteriaforMS(21).Theprevalenceislowerindevelopingcountriesbutwithnumbersincreasing.Fordetal.(21)suggestedthatethnicityhaseffectsonthepresenceofMS.IntheUSA,MSislessprevalentinnon-HispanicwhitesthaninMexicanAmericans;andMSisevenlowerinAfricanAmericanmalesascomparedwithnon-HispanicwhiteandMexican-Americanmales.AnotherimportantfactisthattheprevalenceofMSishighlydependentonage.USAreportedMSof7%inthoseaged20-29years,44%ofthosebetween60-69yearsand42%in70yearsorolder.AccordingtohistoricalreviewsofMS(22,23),itwasfirstdescribed80yearsagobyKilyn,aSwedishdoctorwhodefinedtheassociationbetweenhypertension,hyperglycemiaandgout.In1947,Vaguepublishedanarticledescribingthephenotypeofandroidobesityanditsassociationwithmetabolicalterationsobservedinpatientswithtype2diabetesandcoronaryheartdisease.Subsequently,Avogarodocumentedthesimultaneousoccurrenceofobesity,hyperinsulinemia,hypertriglyceridemiaand

hypertension.In1988,theclinicalsignificanceoftheassociationofmetabolicdisorderswashighlightedagainbyReaventhatconsidersinsulinresistanceasacommonpathophysiologicalfeature,callingthispicture"SyndromeX",butsurprisinglydidnotincludeobesity.Laterin1998,theWorldHealthOrganization(WHO)(24)publishedthefirstofficialdefinitionofMS,andproposedinsulinresistanceasafactorofgreaterunderlyingriskandrequiredhispresenceforthediagnosisofMS.Patientswithdiabetesmellitus2wereincludedinthisdefinition.Thefollowingyear,theEuropeanGroupfortheStudyofInsulinResistance(EGIR)(25),usedtheterm"syndromeinsulinresistance",requiringmorethantwodiagnosticcriteriabesideselevatedinsulinlevels.TheyperformedamodifiedversionfromtheWHOforthediagnosisofMS,introducingwaistcircumferenceasameasureofadiposity.Itexcludedpatientswithdiabetesmellitussyndromesinceinsulinresistancewasconsideredasariskfactorfordiabetesmellitus.Twoyearslater,theNationalCholesterolEducationProgram(NCEP)introducedthedefinitionATPIII(AdultTreatmentPanelIII)(26),keepingasaparameterofobesity,waistcircumferencebutwithhigherthresholdsthanthoseusedintheEGIRdefinition.Thisdefinitionachievedgreatpopularitybecauseofitssimplicity,givenequallytoallMScomponents,withoutrequiringspecificquantificationofinsulinsensitivityasthetwopreviousdefinitions.AbdominalobesitywasnotconsideredaprerequisitebecausecertainethnicgroupsappeartobesusceptibletothedevelopmentofMSwithlowerabdominalcircumferences.TheATPIIIalsonotedthatsomeindividualshavingothercriteriaofthesyndromeseemedtohaveinsulinresistanceevenwhentheabdominalcircumferencewasbelowthethresholdvalues.Thesyndromealsoincludedpatientswithdiabetesmellitus.Then,in2003,theAmericanAssociationofClinicalEndocrinologists(AACE)madeanamendmenttotheATPIIIdefinition,consideringagainthatresistancetoinsulinwasthebasicproblem(12).TheAACEcollectedfouridentifiableabnormalitiessyndrome:highbloodpressure,hightriglycerides,impairedtolerancetoglucoseandreducedHDLcholesterol.Theyexcludedobesityasabasiccomponent.Otherfactorsweretakenintoaccounttoassesstheclinicalcriteriasuchasfamilyhistoryofcardiovasculardiseaseordiabetesmellitus,polycysticovarysyndromeandhyperuricemia.In2005,theInternationalDiabetesFederation(IDF)issuedanewdefinitionofthemetabolicsyndromeconsideringcentralobesityasamandatoryrequirement(23).Thesameyear,theAHA/NHLBI,publishedanupdateofthedefinitionofATP-III(27)maintainingthesamecriteriaofATPIIIconsideringthataresimpletouseandhavetheadvantageofnotrelyingonasinglecriterion.Thevalueforimpairedfastingglucosedecreasedfrom110to100mg/dl,accordingtotheamendmentissuedbytheAmericanDiabetesAssociation(ADA).AsdescribedintheversionofATPIII,some

individualsofnon-Asianorigin(white,black,Hispanic),havingonlytwocriteriaofmetabolicsyndrome,appeartobeinsulinresistantevenwithonlymarginalincreasesinabdominalcircumference(94-101cminmenand80-87cminwomen).Therefore,thecriteriacurrentlyincludeatleastthreeofthefollowingfiveconditions:glucosegreaterthanorequalfasting100mg/dl(ortreatmentforhyperglycemiapresent);bloodpressuregreaterthanorequalto130/85mmHg(orpresenceoftreatmentforhypertension(HBP),triglycerides(orpresenceoftreatmentforhypertriglyceridemia),greaterthanorequalto150mg/dl;HDL(highdensitylipoprotein)under40mg/dlinmenorlessthan50mg/dlinwomen(orpresenceoflowHDLcholesteroltreatment),andfinallyanabdominalcircumferencegreaterorequalto102cminmenorgreaterorequalto88cminwomen.AmongthecharacteristicsthatcouldpredisposetoinsulinresistanceanddevelopmentofMSinsuchindividuals,theauthorsconsider:1.Type2diabetesmellitusinfirst-degreerelativesbefore60years.2.Polycysticovarydisease.3.Fattyliver.4.CRP>3mg/dl,ifquantifiable.5.microalbuminuria,ifdetected.6.impairedglucosetolerance.7.TotalapolipoproteinBhigh.Accordingtothisdefinition,theseindividualsshouldbehandledasthosewhomeetthreecriteriaofMS.Inaddition,theauthorsdescribesomepopulationswouldbepredisposedtothedevelopmentofinsulinresistance,metabolicsyndromeanddiabetesmellitus2withonlymoderateincreasesinabdominalcircumference(populationsofSouthAsia,China,JapanandotherAsiancountries)bywhattheyconsiderappropriatetoreducethevalueoftheabdominalcircumferencediagnosticcriteriontoconsiderinthesepopulations.Thesedefinitionshavenotonlypresenteddifferencesintheproposedcomponentsbutalsointhevaluesusedtodefineeachofthecomponents,allofwhichhasgeneratedconsiderableconfusion.Thisconfusionhasnotonlyreducedtheusefulnessofdefinitionsintheclinicalsetting,butalsodifficulttocomparetheprevalenceofMSindifferentpopulationgroups.2.2.3. MetabolicsyndromeandhidradenitissuppurativaIncreasingevidencefurthermoreproposesHStobeassociatedwiththemetabolicsyndrome.Becausethemetabolicsyndromeisaclusterofcardiovascularriskfactorsincludingdiabetes/insulinresistance,hypertension,dyslipidemia,andobesity,thereisaclearoverlapbetweenthiscomorbidityandtheriskfactorsobesityandsmoking.PossiblepathophysiologicmechanismsbehindthesupposedassociationofHSandthemetabolicsyndromeintroduceahypothesisconcerningthelong-termeffectsofthechronicinflammatorystateofHS,thesedentarylifestyle(i.e.,overeating,lackofphysicalexercise)thatmayaccompanyHSpatientsasaconsequenceofpsychologicalstigmatization,inflammation-inducedneuropsychologicalfactorsaffectingappetiteandcortisonelevels,andconcomitantpharmacotherapywithsubsequentincreasedcardiovascularrisk(7).

AssystemicinflammationmightbeafactorrelatedtoMS,someauthorssuggestedmeasuringneutrophiltolymphocyteratioasamarkerofsystemicinflammation.Studiesofpsoriasispatientshavefoundtheirneutrophiltolymphocyteratiotobeincreased.Bloodsamplescollectedduringcontrolvisitsfrom50HSpatientswereexamined,andcomparedtoroutinebloodsamplesfrom250age-andsex-matcheddermatologicaloutpatients.TheneutrophiltolymphocyteratiowasnotsignificantlyincreasedinHSpatientsasseeninpsoriasispatients,butCRPwasfoundtobehigherinHSpatients,indicatingsystemicinflammation.However,N/LratiowaspositivelycorrelatedtoHurleystage(p<0.006)(10).ThepathogenesisofHSispostulatedtobeginwithhairfollicleocclusionleadingtolymphohistiocyticinflammation,withtheinvolvementofpro-inflammatorycytokinesIL-1beta,IL-10,IL-12,IL-23,andTNF-alpha,andoveractivationofthemammaliantargetofrapamycincomplex-1(mTORC1)signalling.Over-activatedmTORC1increasesandrogenhormonalsecretionandcontributestowardsdrivingtheproliferationofsebaceousfollicles.Hence,thedisease,atleastasfarastheinitialpluggingofthefollicularepitheliumisconcerned,isdrivenbyintracellularmechanismsthatareinturndrivenby,amongstotherfactors,diet.Indeed,thedietthatisresponsibleforMScontainsthesamemetabolicdriversleadingtotheandrogen-drivenoverproductionofsebumandovergrowthoftheintra-ductalkeratinocytes(28).Similartootherchronicsystemicinflammatoryconditions,suchasrheumatoidarthritisandpsoriasisthatareassociatedwiththeMS,HSincontrastisamorelocalizedinflammationoftheskin.Asizablebodyofliteraturedemonstratesobesityasaparamountriskfactor.Recently,across-sectionalhospital-andpopulation-basedstudycomparing32hospital-basedHSsubjects,326population-basedHSsubjects,and14,851controls(non-HSsubjects)foundanORforobesity(bodymassindex>30kg/m2)of6.38(95%CI,2.99–13.62)and2.56(95%CI,2.00–3.28)forhospital-andpopulation-basedHSsubjects,respectively,whencomparedwithcontrols.Correspondingly,thisstudyfoundanORforabdominalobesityof3.62(95%CI,1.73–7.60)and2.24(95%CI,1.78–2.82)forthehospital-andpopulation-basedHSsubjects,respectively.Overall,theORswerehigherfortheHSpatientsfromthehospitalgroupthanfromthepopulationgroup(29).AnIsraelicross-sectionalstudy(5)whichincluded3,207patientswithHSand6,412controls,showedthatHSwassignificantlyassociatedwithMS,withanORof1.61,andwiththeindividualriskfactorsofdiabetesmellitus(OR1.41),obesity(OR1.71),hyperlipidemia(OR1.14)andhypertension(OR1.19).Sabatetal.(4)andGoldetal.(30)performedhospital-basedstudiesof80and366HSpatients,respectively,andfoundtheMStobeacomorbidityofHS.Sabatetal.(4)thatexamined80hidradenitissuppurativapatientshospitalizedforsurgicaltreatmentand100controls,whichshowedanincreasedprevalenceofmetabolicsyndrome,withan

adjustedORof4.46.Thetrendwassimilar,inthattheHSgroupwere4.09timesmorelikelytohavehyperglycemia,5.88timesmorelikelytohavecentralobesity,2.24timesmorelikelytohavehypertriglyceridemia,and4.56timesmorelikelytohavelowHDLlevels.Goldetal.(30)foundthat50.6%ofHSpatientscomparedwith30.2%ofthecontrolssufferedfromtheMS(P<.001).ApossiblereasonobesityisstronglyassociatedwiththeprevalenceofchronicinflammatoryconditionsincludingpsoriasisandpossiblyHSmaybebecauseadiposetissueactivelyproducespro-inflammatoryadipocytokines,includingIL-6,andTNF-alpha(31).TheprevalenceofMSinpatientswithHSmaybeevenhigherthaninpatientswithpsoriasis,withanORofapproximately6.00comparedto2.0012.Surprisingly,thereisalackofassociationbetweendiseasedurationandseverity(bySartoriusscore)andthedevelopmentofMSinpatientswithHScomparedtopsoriasis.Inaddition,theMSaffectsmuchyoungerHSpatients.ThisissignificantasthecardiovascularconsequencesofMSarelikelytoafflicttheseyoungerpatientsearlier,leadingtodecreasedlifeexpectancy.WhilethereisnocleargeneticcausalitybetweenHSandmetabolicsyndrome,theassociationmaybeexplainedbythesystemiceffectsofchronicinflammation,withcommonpro-inflammatorycytokinessuchasIL-1andTNF-alphaupregulatedincardiovasculardisease(32),commonlifestylehabitsofpoordietarycontrol,lackofexercise,andtobaccosmoking(33).Inparticular,ahighglycemicandhighdairyproteindietincreasesinsulinandIGF-1signalingatthecellularlevel.FoxO1andmTORC1areinvolvedinthedetectionofnutritionalstatusandsubsequentandrogensignalingtodrivetheregulationofproteinandlipidsynthesis,andcelldifferentiationincludingtheproliferationofsebaceousglandsandkeratinocytes(34).ThismayformthecommonbasisforMS,inparticular,obesityandinsulinresistance,andtheinitialtriggersforthepluggingofthefollicularcomponentofthefolliculo-pilo-sebaceousunitinHS.ThetreatmentofHSischallengingduetoitschroniccourseandfrequentrelapses.Thereisnooneoverwhelminglysuperiortreatmentoveranother,withtheuseofvarioustreatmentoptionsdirectedbytheseverityofthedisease.Thefirstlineoftreatmentformilddiseaseisoftentopicalororalantibiotics,withthesecondlineconsistingofsystemicretinoidasacitretin.Third-lineoptionsoradjunctivetherapyincludeanti-androgens(cyproteroneacetate-ethinylestradiol)andmetformin(35).Inmoderatedisease,biologicssuchasinfliximab,etanercept,andadalimumabhavebeentriedinadditiontosurgicalandlaseroptions.Anakinrahasbeensuccessfullyusedinthetreatmentofseveredisease.Theinsulinsensitizermetformin,withitsrangeofbeneficialeffectsonMSbeyondimprovingglycemiccontrol,hasbeenshowntocontrolHSwithminimalsideeffects.DysfunctionalmTORC1signaling,and,therefore,dysfunctionalcellproliferationandmetabolism,havebeenimplicatedinconditionssuchasobesity,diabetesmellitus,andcancer.MetforminhasbeenfoundtoinhibitmTORC1throughvariousmechanisms,

resultinginthereductionofhyperandrogenismandlipidlevels,whichexplainstheimprovementintheskincondition(36).MetforminhelpscontrolHSwithminimalsideeffectsandgoodpatientcompliance.Inastudyof25patientswithHStreatedwithMetforminoveraperiodof24weeks,18patientsclinicallyimprovedwithasignificantaveragereductionintheirSartoriusscoreof12.7andnumberofmonthlyworkdayslostreducedfrom1.5to0.4.Dermatologylifequalityindex(DLQI)alsoshowedasignificantimprovementin16cases,withadropinDLQIscoreof7.6(35).Lastly,lifestylemodificationsinconjunctionwithmedicaltherapyshouldbeemphasizedinthemanagementofHS.Manyencouragingstudieshavedemonstratedresolutionoftheskinconditionafterweightlosseitherthroughdietarymeasuresalone(37)orwiththeaidofbariatricsurgery(38).Inparticular,weightlossofmorethan15%resultsinasignificantimprovementintheseverityoftheskincondition.Inarecentstudy,authorsfoundusingquestionnairesthatthenumberofpatientsreportingHSsymptomsafterweightlossdecreasedby35%andthemeannumberofinvolvedsiteswasreducedfrom1.93to1.22followingweightloss(p = 0.003).TheprevalenceofHSappearedhigherintheobesethaninthebackgroundpopulation,andaweightlossofmorethan15%wasassociatedwithasignificantreductionofdiseaseseverity(39).Latestinsightsintohowtheover-activityofdiet-relatedmTORC1signalingmayformthetriggerfortheinitialfollicularpluggingeventinHSprovideabasisfordietaryintervention,whichshouldaimtoreducetheintakeofhyperglycemiccarbohydratesandinsulinotropicdairyproteins.TobaccosmokershavebeenfoundtosufferfrommoresevereHS,likelysecondarytotheeffectofnicotineonpromotinginfundibularepithelialhyperplasiaandthusfollicularplugging.WhiletherearenostudiesexaminingwhethersmokingcessationdirectlyimprovesoutcomesinHS,itappearstoreducethedevelopmentoftheMS(40).3. MethodologyDesignAsystematicreviewandmeta-analysisofobservationalstudiesthatexaminetherelationshipbetweenHSandMSwillbeconducted.Theobservationsstudieswillbecohortstudy,case-controlorcross-sectional.Studiesmusthaveagroupofpsoriaticpatientsandacontrolgroup.WewillanalyzethenumberofpatientswithMSineacharminordertoobtainapooled-OR.StudiesthathaveadjustedtheirORforvariousvariables,suchasage,sex,etc.,willbeanalyzedseparatelyfromthosewithcrudedata.Inaddition,wewillperformasubgroupanalysisbyregion:LatinAmerica,NorthAmerica,Europe,Africa,MiddleEastandAsia;accordingtodesign,typeofparticipants,andMScriteriaused(ATP-III,IDF,AHA).

TypeofstudiesThestudiesareobservational,cross-sectional,cohort,case-control,inadultsolderthan18yearsold,whohave2armsofthestudy:agrouphavingHSandanothercontrolgroup.TheymusthavebeenpublishedfrominceptionuntilMarch2017(3).Ifthereisduplicationofpublication,populationoranestedpopulation,theonethatcontainsthemostcompleteinformationoronethatcontainsthelargestpopulationwillbeincluded.Finally,studiesthathaveadjustedresultsbysomevariablesuchassex,age,orconditionassociatedwithMSwillbeincludedasmainoutcome.StudieswithcrudeORswillbealsoincludedandwillbeanalyzedseparately.ThestudyshouldbeclearreportingthenumberofpatientswhohavemetthecriteriaforMSineachgroup,HSandControl.Similarly,studiesshouldbecleartoreporttheprevalenceofeachconditionassociatedwithMSineachgroupHSandControl.TypeofparticipantsStudiescanincludedbothchildrenandadultpopulation.HSpatientsincludedwillbegroupedaccordingtoseverityanddurationofdisease,typeoftreatment,casedefinition,originofcontrolsubjects(generalpopulationordermatologypatients).TypeofinterventionStudiesshouldstudytheOddRatioofhavingMSinHSandcontrolgroups.MSdiagnosticcriteriahavechangedastheyearshavepassed,andthecriteriadefinedbytheAHA/NHLBIandATP-III(17,26)arecurrentlyaccepted.However,meta-analysisstudieshavedefinedthecriteriaSMavailablewhenpublishedwillbeacceptedinthepresent.TypeofmeasuredresultsPrimaryoutcome:thepooled-ORofMSinHSgroupcomparedwiththecontrolgroup,usingstudiesthathaveadjustedtheirORintheiranalysis.Secondaryoutcomes:wewillmeasureandcomparestudieswithcrudeOR;furtheranalysiswillbeperformedbygroupingstudiesbyregion:LatinAmerica,NorthAmerica,Asia,Europe,AfricaandMiddleEast;bydatacollectionprocess(prospectiveorretrospective);bydesign(case-control,cross-sectional);casedefinition(ATP-III,AHA,IDF),typeofpopulation(hospital,general),HSseverity(mild,severe),agegroup(onlyadultvs.adultandchildren);instrument(electronicdatabasevs.hospitalcharts).SearchstrategyFirst,wewillconductasystematicreviewofobservationalstudiespublishedinMEDLINE,SCOPUS(IncludingEmbase),SCIELO,GOOGLESCHOLAR,SCIENCEDIRECTandLILACSfrominceptiontoMarch2017.Forunpublishedstudieswewillreviewopengrayliteratureandauthorsandexpertsonthetopicopinion.Inaddition,wewillscanbibliographiesofpublishedstudiesforunpublishedstudiesbyamanualsearchoftheliterature,searchinginvirtuallibrariesofuniversitiesandthesiswork,andrequestingauthorsforpaperspresentedatconferencesandcongresses.Wewilllook

foradditionalstudiessearchingpublishedreviewsonhidradenitissuppurativaandmetabolicsyndrome.Wewillsearchforabstractsofstudiesinthefieldpresentedininternationalcongressesofdermatologysocieties.Alsowewillfollowreferencesinthearticlesthatwefoundinthemainsearch.LanguagesrestrictedtoSpanishandEnglishforthisreview.SearchstrategywillbeaccordingtotheNCBIMESHterms:Thesearchstrategywillbespecificforeachdatabaseaccordingtothemedicalsubjectheadings(MeSH)andfreetexttermsforthekeyconcepts.Thesearchtermswillbecombinedasfollows:"hidradenitissuppurativa"[MeSHTerms]AND"metabolicsyndrome"[MeSHTerms]AND“ObservationalStudy[PublicationType]”[MeSHTerms].

1. Medline: ((hidradenitis suppurativa) OR (acne inversa)) and ((metabolic syndrome) OR (syndrome x) OR (metabolic syndrome X) OR (Syndrome X, Metabolic)) AND ((case-control) OR (cohort) OR (observational) OR (nested) OR (cross-sectional) OR (transversal)) . Publication dates: to 2017/03/31 URL: https://www.ncbi.nlm.nih.gov/pubmed/?term=((hidradenitis+suppurativa)+OR+(acne+inversa))+and+((metabolic+syndrome)+OR+(syndrome+x)+OR+(metabolic+syndrome+X)+OR+(Syndrome+X%2C+Metabolic))+AND+((+observational+)+OR+(+cross-sectional+)+OR+(+case-control+)+OR+(+cohort+)+OR+(+transversal+))

2. SCOPUS (Including Embase): ((hidradenitis suppurativa) OR (acne inversa)) AND ( ( metabolic syndrome ) OR ( metabolic syndrome x ) OR ( syndrome x, metabolic ) ) AND ( ( observational ) OR ( cross-sectional ) OR ( case-control ) OR ( cohort ) OR ( transversal ) OR (observational) OR (nested) ) AND ( LIMIT-TO ( DOCTYPE , "ar" ) ) AND ( LIMIT-TO ( SUBJAREA , "MEDI" ) ) Date of search: April 1st 2017.

3. ScienceDirect: Search results: 254 results found for ((hidradenitis suppurativa) OR (acne inversa)) and (((metabolic syndrome) OR (syndrome X metabolic)) and ((cross-sectional) OR (case-control) OR (nested) OR (observational))). Date of search: April 1st 2017.

4. Google Scholar: ("hidradenitis suppurativa" OR "acne inversa") ("syndrome x" OR "metabolic syndrome" OR "metabolic syndrome X OR "Syndrome X, Metabolic") ("observational" OR "cross-sectional" OR "case-control" OR "cohort" OR "transversal") customerange-2017. English and Spanish. Date of search: April 1st 2017. URL: https://scholar.google.com/scholar?start=103&q=((hidradenitis+suppurativa)+OR+(acne+inversa))+AND+((metabolic+syndrome)+OR+(syndrome+X+metabolic))+AND+((cross-sectional)+OR+(case-control)+OR+(nested)+OR+(observational)+OR+(transversal))+)+&hl=es&as_sdt=0,21

5. Scielo: ((hidradenitis suppurativa) OR (acne inversa)) AND ((metabolic syndrome) OR (syndrome x) OR (metabolic syndrome x) OR (syndrome x, metabolic)) Date of search: April 1st 2017.

6. Lilacs: (tw:((hidradenitis suppurativa) OR (acne inversa))) AND (tw:((metabolic syndrome) OR (syndrome x metabolic) OR (syndrome X))) AND (tw:((case control) OR (cross sectional) OR (observational) OR (nested) OR (cohort))) Date of search: April 1st 2017. URL: http://pesquisa.bvsalud.org/portal/?lang=es&q=%28tw%3A%28%28tw%3A%28%28hidradenitis+suppurativa%29+OR+%28acne+inversa%29%29%29+AND+%28tw%3A%28%28metabolic+syndrome%29+OR+%28syndrome+x+metabolic%29+OR+%28syndrome+X%29%29%29+AND+%28%28%28case+control%29++OR+%28cross+sectional%29+OR+%28observational%29+OR+%28nested%29+OR+%28cohort%29%29%29%29%29

Some databases do not allow performing exact date searching; therefore, those were carried out on the date April 1st 2017. SelectioncriteriaTheselectioncriteriaforthissystematicreviewandmeta-analysisare:1. Inclusion• Studiesshouldbeobservationalcohorttype,case-control,cross-sectionalandnestedcase-control;theymuststudytheassociationbetweenHSandMSwithtwostudyarms:onegroupofcasesandcontrol;withintheperiodfrominceptiontoMarch31st,2017.• Studypopulationcouldbechildrenoradult.• StudiesshouldcontaininformationontheORofhavingMSinpatientswithHSandcontrolgroup,usingmethodsfordiagnosis:physicalexamination,laboratoryanalysisandreviewofcharts,orbyinternationalcodesstories,retrospectivelyorprospectively.• Studiesmusthaveadjustedtheirresultsbysomevariablesuchassex,age,orconditionassociatedwithMS.• StudiesthatreportcrudeORwillbeincludedinaseparatedanalysis.• StudieswillbeincludedinEnglishandSpanish.• ClinicaldiagnosticcriteriaforHSandMSdefinedbytheauthorsthemselvesavailableforpublicationdatewillbeused.2. Exclusion• StudiesthatdidnotreporttheincidenceorprevalenceofMSinanyofthestudyarms,neitherinthecaseorcontrolgroups,willbeexcluded.• Studiesthatduplicatethestudypopulationareexcluded,andbechosenaboveallthosethatmeetthecriteriaforinclusionandpresentthelargestpopulationincluded.• StudiesthatreportasimilarconditionorassociatedwithMS(e.g.cardiovascularriskfactorssuchassmoking,hyperhomocysteinemia,etc.),butnotMSitself;orthosethathavenotacleardistinctionofcasesofMSwillbeexcluded.

Datacollectionandanalysis1. SelectionofstudiesInitially,aftersearchinginmentioneddatabases,potentialstudieswillbeobtained.Theauthorsindependentlywillreviewalltitlesandabstractsobtainedbyapplyingthecriteriaofinclusionandexclusion.Thenameoftheauthorsandtheirinstitutions,thenameofthejournalanditssponsorsandfundingwillbeblinded.Ifanydisagreementonthechoiceofanarticlearises,authorswillbediscussedreasons.Finally,wewillhavetoreachtoanagreementandafinaldecision.2. DataExtractionOfalleligiblestudies,therelevantdataisextractedinduplicate,usingastandarddatasheetonMicrosoftExcel2010.Anauthorwillreviewthecompletefillingofthedatasheetforeachselectedstudyatleasttwice.Thevariablesareasfollows: Variables of Articles Coding Variable Decoding Type of

variable Definition

A1 Author Wells Qualitative nominal

Family name of the study first author.

A2 País Canada Qualitative nominal

Country where the study was conducted.

A3 Language Spanish Qualitative nominal

Language in which the study was made.

A4 Year 2010 Numeral Discrete

Year when the study was made.

Variable of design Coding Variable Decoding Type of

variable Definition

T1 Size of groups 230 Numeral discrete

Number of subjects in the study.

T2 Patients in HS 115 Numeral discrete

Number of patients having HS.

T3 Patients in Control

115 Numeral discrete

Number of patients that do not have HS.

T4 Type of study by design

0= transversal 1= case-control 2 = cohort

Nominal categorical

Type of study according to its design

T5 Type of study 0= retrospective Nominal Type of study

by temporality 1= prospective

categorical according to temporality.

Variables of participants

Name Label Decoding Variable type Definition P1 Average age 14.3 Numeric

continua The average of age of the participants in the study.

P2 Sex 0= female. 1= male. 2= both.

Nominal categorical

Phenotypical sex of the participants in the study.

P3 Number of female patient

110 Discrete numerical

Number of female participants in the study.

P4 Number of male patient

120 Discrete numerical

Number of male participants in the study.

P5 Patients with MS in HS group

1095 Discrete numerical

Number of patients with MS in patients with HS.

P6 Patients with MS in Control group

1095 Discrete numerical

Number of patients with MS in patients with out HS.

P8 Crude OR 2.5 Discrete numerical

Odd Ratio of MS between HS and control

P9 Adjusted OR 2.5 Discrete numerical

Odd Ratio of MS between HS and control that has been adjusted for covariates

P10 Adjusted covariates

Sex, age, smoking status

Nominal List of covariates adjusted for OR.

QualityassessmentofstudiesAfterobtainingthestudiestobeincludedinthemainanalysis,wewillperformqualityassessmentofeachstudybasedonamodifiedversionoftheCochraneriskofbiastable.Twogroupsofstudyqualitywillbedefined:high,andlow.Subgroupanalysiswillbeperformedaccordingly.Missingdata

OnlystudiescontaininginformationonpatientspresentingwithMSonboththeHSandthecontrolgroupwillbeincluded;orinanycase,thatshowtheOddRatio,whetheradjustedorunadjustedforvariables.Ifthisstudydonotshowsuchdatawillnotbeincludedintheanalysis.HeterogeneityHeterogeneitybetweentrialswillbeassessedbytheI2statistic,whichindicatesthepercentageofvariationintheeffect-sizeestimateattributabletoheterogeneityratherthansamplingerror.Itprovidesameasureofthedegreeheterogeneityinthestudies'results.AvalueequaltozeroofI2meansnoheterogeneity,andlargermeansthatheterogeneityisincreasing.I2wouldbedescribedaslow,moderate,andhighaccordingtoitscorrespondingvalue(I2valuesof25%,50%,and75%)(41). FinallyifI2hasavaluegreaterthan50%,itwillbeconsideredasheterogeneouswhichmeansthatwewilluserandom-effectsmodelformeta-analysis.EvaluationofpublicationbiasThepossibilityofpublicationbiaswillbeassessedbymeanofaFunnelplot;itisagraphoftreatmenteffectagainstameasureofstudysize:inthiscase,asymmetricinvertedfunnelmeansthatpublicationbiasisunlikely.Ontheotherhandanasymmetricfunnelmeansthatthepossibilityofpublicationbiasorasystematicdifferencebetweensmallerandlargerstudies.DatasynthesisOddRatio(OR)withpatientshavingMSforboththeHSgroupversusthecontrolgroupwithaconfidenceinterval(CI)of95%foreachstudywillbeobtained.Thepooled-ORisobtainedwitharandomeffectsmodel(Random-effectModel)ifheterogeneityishigh;otherwise,ifheterogeneityislow,aFixed-effectModelwillbeused(47).ItwillbepresentedbyForestPlotgraphsshowingtheeffectsizeofeachstudywithitscorrespondingCI.RevMan5fordataanalysisandgraphicproductionwillbeused.SubgroupanalysisSubgroupanalyseswillbeperformed,withtestsforheterogeneityandobtainingapooled-ORineachsubgroup.Eachsubgroupcorrespondstotheanalysisofstudiesshowinganadjusted-ORvs.thosewithcrudeOR.Also,studiesgroupedbyregion:LatinAmerica,NorthAmerica,Asia,Europe,AfricaandMiddleEast;bydatacollectionprocess(prospectiveorretrospective);bydesign(case-control,cohort);casedefinition(ATP-III,AHA,IDF),typeofpopulation(hospital,general),HSseverity(mild,severe),agegroup(onlyadultvs.adultandchildren);instrument(electronicdatabasevs.hospitalcharts);withbothcrudeandadjustedORswhenpossible.SensitivityanalysisSensitivityanalysisisaninformalwaytoprovethattheresultshaveahighdegreeofcertainty.Theprocedureinvolvestheremovalofarepresentativestudyandthencomparestheresultofthenewpooled-ORobtainedwiththeoriginalresult.Iftheyaresimilar,thentheresultshaveahighdegreeofcertainty.Iftheresultsvary

considerably,thentheseshouldbeinterpretedcautiously.Wewillexhausteffortstoobtainadditionalinformationonthesestudiestotrytoexplainthisdifference.Sensitivityanalysiswillbepresentedinasummarytablewithstudiesexcludedinacolumn,andthenewpooled-ORobtainedinthenextcolumn.

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