ETAS_04 general

General Dermatology 73

4 General DermatologyPriya Swamy Zeikus, MD

Bruce E. Strober, MD, PhD

Katherine L. White, MD

C o n t e n t s

4.1 Acne Vulgaris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .76

4.2 Rosacea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .79

4.3 Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

4.4 Psoriatic Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .86

4.5 Reiter’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .86

4.6 SAPHO Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

4.7 Sneddon-Wilkinson Disease . . . . . . . . . . . . . . . . . . . . . .88

4.8 Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .88

4.9 Atopic Dermatitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .92

4.10 Alopecia Areata . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .95

4.11 Alopecia: Other Forms . . . . . . . . . . . . . . . . . . . . . . . . . . .96

4.12 Vitiligo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .98

4.13 Pityriasis Rubra Pilaris . . . . . . . . . . . . . . . . . . . . . . . . . . .99

4.14 Lichen Sclerosus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .99

4.15 Granuloma Annulare . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

4.16 Hirsutism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

4.17 Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

4.18 Calciphylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

4.19 Angioedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

4.20 Carcinoid Syndrome and Flushing Disorders . . . . . 106

4.21 Lupus Erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

4.22 Scleroderma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

(Continued on next page)

74 2011/2012 Dermatology In-Review l Committed to Your Future

4.23 Dermatomyositis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .113

4.24 Sjogren’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . .115

4.25 Connective Tissue Disease: Serology . . . . . . . . . . . . .115

4.26 Relapsing Polychondritis . . . . . . . . . . . . . . . . . . . . . . . . .117

4.27 Behçet’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .118

4.28 Livedo Reticularis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119

4.29 Leukocytoclastic Vasculitis. . . . . . . . . . . . . . . . . . . . . . .119

4.30 Cryoglobulinemia and Cryofibrinogenemia. . . . . . . 122

4.31 Acanthosis Nigricans . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

4.32 Lipodystrophy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

4.33 Hyperlipoproteinemias. . . . . . . . . . . . . . . . . . . . . . . . . . 125

4.34 Xanthomatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

4.35 Vitamin Deficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

4.36 Diabetes and Skin Disease . . . . . . . . . . . . . . . . . . . . . . 130

4.37 Langerhans Cell Histiocytosis . . . . . . . . . . . . . . . . . . . 132

4.38 Cutaneous T-cell Lymphoma . . . . . . . . . . . . . . . . . . . . 133

4.39 Pyoderma Gangrenosum . . . . . . . . . . . . . . . . . . . . . . . . 136

4.40 Sweet’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

4.41 Erythema Annulare Centrifugum . . . . . . . . . . . . . . . . 138

4.42 Erythema Elevatum Diutinum . . . . . . . . . . . . . . . . . . . 138

4.43 Erythema Nodosum . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

4.44 Mastocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140

4.45 Cutaneous Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . 142

4.46 Perforating Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . 144

4.47 Elastosis Perforans Serpiginosa. . . . . . . . . . . . . . . . . . 144

4.48 Reactive Perforating Collagenosis . . . . . . . . . . . . . . . 145

4.49 Cutaneous Features and Disorders of Pregnancy . . 145

4.50 Pruritus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

4.51 Scleredema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

4.52 Nephrogenic Fibrosing Dermopathy/

Nephrogenic Systemic Fibrosis . . . . . . . . . . . . . . . . . . 149

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4.1 ACNE VULGARISKey Pathogenic Factors

• Abnormalkeratinization(follicularretentionhyperkeratosis)• Inflammation• PresenceofPropionibacterium Acnes (P. acnes)insebum• Sebumproduction,underhormonalcontrol,startingatadrenarche

Pathogenesis Overview• Precursorlesionofcomedonalandinflammatoryacneisthemicrocomedo• Humansebumisrichintriglycerides.1 P. acnes makesanenzymaticlipasewhichcleavestriglyceridesintofreefattyacids

• Inflammationistriggeredbyfollicularwallruptureandsubsequentimmuneresponse.P. acnes itselfispro-inflammatory;itcanactivatecomplement,andneutrophilchemotaxisandactivity

• IL-1,apro-inflammatorycytokine,maypromotefollicularpluggingandmicrocomedoformation2

• Toll-likereceptors(TLR’s)→alargegroupofreceptorsthatrecognizecertainbacterialpatterns.TLR-2activationbyP. acnes leadstointracellularsignaltransductionandupregulationoftheimmuneresponsebystimulatingpro-inflammatorycytokines.3 Certain topicalretinoidshavebeenshowntodownregulateTLR-2expression4

Clinical VariantsAcne Vulgaris• Noninflammatorylesionsarethemicrocomedoandthecomedo(openandclosed)• Inflammatorylesionsarepapules,pustulesandnodules

Acne Conglobata• Aseverevariantcharacterizedbylarge,oftenmultiplecomedones,abscesseswithsinusformation,andinflammatorynodules

• Seenmostfrequentlyinyoungmalepatients• Follicularocclusiontriadconsistsofacneconglobata,hidradenitissuppurativa,anddissectingcellulitisofthescalp.Treatmentiswithhighdoseisotretinoin

Acne Fulminans• Arare,explosiveformofseverecysticacneaffectingyoungmales• Markedbyacute,suppuratingnodulesandplaquesthatulcerateandformblackisheschar• Thetrunkisaffectedmoreseverelythantheface• Patientsmaybesystemicallyill,withleukocytosis,fever,arthralgias,andmyalgias.Lytic

changes, indicative of a sterile osteomyelitis, can be seen on x-ray and bone scans. The sternoclavicular joint and the chest wall are most frequently affected

• Treatmentiswithoralprednisone,intralesionalsteroids,antibiotics,andisotretinoinMiscellaneous Acne VariantsIndustrial Acne

• Chloracneisaformofindustrialacnetriggeredbyworkplaceexposuretochlorinated compounds

• Themalarcheeksandpostauricularscalp,aswellasthescrotum,areaffected.Thelesionsarecharacterized bylargecomedonesaswellasinflammatorypapules,pustules,andcysts

• Insolublecuttingoilsarethemostfrequentcauseofindustrialacne


• Dioxin(2,3,7,8tetrachlorobenzodioxin)isawell-known,potenttriggerofacneiformeruptions5

Acneiform Eruptions • Numerousoralagentshavebeenassociatedwithacneiformeruptions,includingthehalogensbromideandiodide,androgenetichormonessuchastestosterone,ACTH,corticosteroids,isoniazid(INH),lithium,erbitux,phenytoin,cyclosporine,andVitaminsB2,B6,andB126

Treatment of Acne Vulgaris

Topical Retinoids • Tretinoin(alltrans-retinoicacid),adapalene,andtazaroteneareeffectivecomedolyticagentswhichnormalizefollicularepithelialdifferentiation

• Retinoidactivityismediatedbyretinoidreceptors.Twogroupsexist:RAreceptors(RAR)andRXreceptors(RXR).Eachhasthreereceptorsubtypes:α,β,γ.RAR-γisthemostimportantmediatorofretinoidactivityintheskin

• TretinoinandadapalenearepregnancycategoryCdrugs; tazarotene is category X.TretinionactivatesRARreceptorsα,β,γ.BexaroteneselectivelybindsretinoidXreceptors.AdapaleneactivatesRARβ and γ.TazoracbindsRARα,β,γbutshowsselectivelyforRARβ and RARγ

Topical Antibiotics (Erythromycinandclindamycin)• DecreasethepopulationofP. acnes ontheskin• Increasingantibioticresistancehasdiscouragedtheiruseasmonotherapy

Benzoyl Peroxide(BPO)• Bactericidalagentwithdirectoxidizingeffects,andthusnopotentialforresistance• Irritation,dryness,andbleachingofclothingorhairmayoccur

Combination Products (ClindamycinorErythromycinandBPO)• Synergisticefficacyanddecreasedpotentialforantibacterialresistance• Maycauseirritation

Azelaic Acid • DicarboxylicacidthathasweakactivityagainstP. acnes• Inhibitstyrosinase,andcanbehelpfulinreducingpost-inflammatorypigmentalteration.Itching,burningordrynessattheinitiationoftreatmentisnotuncommon

• PregnancycategoryB

Oral AntibioticsTetracyclines• Tetracycline,doxycycline,andminocycline• InhibitRNA-dependentproteinsynthesisbybindingthebacterial30sribosomalsubunit• Tetracyclineisbestabsorbedonanemptystomach,anditsabsorptionisinhibitedbychelationwithbi-andtrivalentcations(e.g.,calcium,bismuth,iron)

• Tetracyclinecancausepermanentbrowndiscolorationoftheteethinchildren,andisnotusedroutinelyforchildrenundertheageofeight

• RiskofphotosensitivityDemecycline>Doxycycline>Tetracycline>Minocyline• Photo-onycholysishasbeenreportedwithTetracycline• Unlikeothertetracyclines,doxycyclineisexcretedviatheGItractratherthanthekidneys,andthusisthetetracyclineofchoiceinrenallycompromisedpatients8


• MinocyclinehasbeenassociatedwithCNSsymptoms,includingvertigoandheadache,autoimmunehepatitis,drug-inducedanti-histoneAbpositiveSLE-likesyndrome,andhyperpigmentation

• Minocyclinecancausehyperpigmentationoftheskin.Threetypesaregenerallydescribed:

-Blue-BlackDiscoloration:Appearinginareasofpriorskininjury,suchasacnescars -Blue-GrayDiscoloration:Oftenattheloweranteriorlegsandforearms -MuddyBrownDiscoloration:Foundonsun-exposedareas.Theleastcommontypeofhyperpigmentation

•Thefirsttwotypesshowstainingforbothironandmelanin[FontanaMassonstainsmelaninblack;Perlsstainstainsiron(hemosiderin)blue].Thethirdtypeshowsincreasedmelaninatthebasallayerandwithinmacrophages

• Dosesoftetracyclinesbelowtheminimuminhibitoryconcentration(MIC)caninhibitneutrophilchemotaxis,pro-inflammatorycytokinecascades,andreduceP. acnes productionoflipase

Macrolides• Includeerythromycinandazithromycin• InhibitRNA-dependentproteinsynthesisbybindingthe50sribosomalsubunit• Erythromycincancausegastrointestinaldistressandpotentiallysignificantdruginteractions

• ErythromycininhibitsthehepaticcytochromeP450systemandcanincreaseserumlevelsandpotentialtoxicitiesofcarbamazepine,theophylline,warfarin,digoxin,methylprednisolone

Trimethoprim-sulfamethoxazole (TMP-SMX) • Consideredsecond-linetherapyforacne,duetoincreasedriskofseriousadversereactions,includinghypersensitivityreactions

• TMP-SMXinhibitsbacterialfolicacidsynthesis• Drughypersensitivitysyndromeischaracterizedbyfever,skineruptionandinternalorgan

involvementIsotretinoin

• Goldstandardfortreatingnodularacneandrecalcitrantacne• Reducessebumproductionbyreducingsebaceousglandsize,normalizesfollicularkeratinization,andindirectlyreducesP. acnes anditsinflammatorysequelae

• Apotentteratogen• Half-lifeofisotretinoinis10-20hours13 • Dosesrangefrom0.5-2.0mg/kg/dayfor4to6months(or120-150mg/kgtotaldose)• Patientsaremonitoredmonthlyforchangesintheplasmalipids,liverfunctiontestsandcompletebloodcounts.Monthlypregnancytestsforwomenarealsorequired.Themostcommonlaboratoryabnormalitiesareincreasedtriglycerides,followedbyelevationofALTandAST;decreasedbloodcountsarerare;increasedexercisecancauseelevationofcreatininephosphokinase

• Almostallpatientsexperiencecheilitis,xerosis,drynasalmucosa,dryeyes• Other,lesscommonsideeffects:hairthinning(usuallyreversible),skininfection,petechiae,abdominalpain,cornealopacities,boneandjointpain,headache,diffuseidiopathicskeletalhyperostosis(DISH)


• Screenforpapilledemaifheadache,nausea,andvomitingoccurs

• Recentreportsofseriouspsychiatriceventspossiblyrelatedtoisotretinoinhavedrawnconsiderableattention.Alargepopulationbasedstudywithcontrolgroupsfailedtoshowanincreasedriskofdepression,suicideattemptandsuicideamongisotretinointreatedpatients14

Hormonal Therapies • Maybeanimportantcomponentofacnetreatmentinthefemalepatient,especiallyforadultwomenwithapredominanceofacneatthelowerface

• Mostcommonendocrinopathyassociatedwithacneispolycysticovarysyndrome(PCOS),characterizedbyacne,obesity,hirsutism,amenorrheaandglucoseintolerance

• Congenitaladrenalhyperplasia(CAH)isalsoassociatedwithacne• Althoughrare,veryhighlevelsofDHEA-Smaysuggestanadrenalandrogen-secreting

tumor • Apatientwhoseacnefailstorespondtoconventionaltherapy,whoseacneflarescyclically,withhirsutism,alopeciaorirregularmenseswarrantsanendocrinework-up,includingfreeandtotaltestosterone,LH,FSH,andDHEA-S

• Benefitfromhormonally-basedtherapies,suchasoralcontraceptives(OCPs)• Usuallyethinylestradiol.OCP’sleadtoadecreaseinfreetestosteronelevelsbyincreasingtheadrenalproductionofsexhormonebindingglobulin(SHBG)

• Spironolactone,commonlydosedbetween50to200mg/day→blocksandrogenreceptorsandadrenalandrogensynthesis.Sideeffectsincludemenstrualirregularities,breasttenderness,andintestinalsymptoms,whichcanbemitigatedbyconcomitantOCPuse.Hyperkalemiaismorelikelyinthesettingofrenalfailure.SpironolactoneisnotFDA-approvedforthetreatmentofacne.ItispregnancycategoryX

4.2 RoSACEA• Papulesandpapulopustulesincentralregionoffaceagainstavividbackgroundoftelangiectases.Later,diffusehyperplasiaofconnectivetissuewithenlargedsebaceousglands

• Localizedtonose,cheeks,chin,forehead,glabella;lesscommonlyaffectedareasincludetheretroauricular,V-shapedchestarea,neck,back,scalp

• FlushingandblushingevokedbyUV,heat,cold,chemicalirritation,strongemotions,alcoholicbeverages,hotdrinks,andspices

Variants of RosaceaPersistent Edema of Rosacea (RosaceaLymphedemaorMorbihan’sDisease)• Hard,nonpittingedema• Oftenmisdiagnosedascellulitis

Ophthalmic Rosacea• Blepharitis,conjunctivitis,iritis,keratitis(inflammationofcornea)• Thetreatmentofchoiceforocularrosaceaisoralantibiotics

uTIPa�Pseudotumor cerebri occurs

more often with co-adminis-tration of a tetracycline


Granulomatous Rosacea• Dozensofbrown-redpapulesornodulesondiffuselyreddenedskin,frequentlyinvolvinglowereyelids

• Histopathology:perifollicularandperivascularnoncaseatingepithelioidgranulomas• Chronicandunremitting

Steroid Rosacea• Rosacearesultingfromsteroiduse• Steroidatrophywithresultanttelangiectases• Flamingred,scaling,papule-coveredface• Severepain,discomfort• Withdrawalofsteroidaccompaniedbyexacerbationofdisease• Slowtaperingofsteroidovermonthsisrequired

Rosacea Fulminans (PyodermaFaciale)• Occursalmostexclusivelyinpost-adolescentwomen;lotsofflushingandblushing• Largecoalescentnodulesandconfluentdrainingsinusoccupymostoftheface• Prognosisisexcellent,andrecurrencesrare

Perioral Dermatitis• Maybetriggeredorexacerbatedbytopicalsteroiduse• Generallyrespondswelltotopicaland/ororalantibiotictreatment

TreatmentTopical• Antibiotics–ofteneffective– Topicalclindamycinanderythromycin– Topicalmetronidazoleactiveagainstpapulesandpustules,butnottelangiectasiaandflushing

– Topicalsulfur-basedpreparations• Azelaicacid• Sunscreens• Green-tintedmakeupconcealercanneutralizeredness

Systemic• Antibiotics–generallyrespondswell– Tetracyclines– Erythromycin

• Isotretinoin–indicatedinphymas;butrosaceaoftenrapidlyrecursafterdiscontinuationofisotretinoin

Treatment for Rosacea Fulminans • Oralglucocorticoids,1.0mg/kgperdayfor7-10days,addisotretinoin,withslowtaperingofsteroid,for3-4monthsuntilallinflammatorylesionsdisappear

• Donotincisedrainingabscesses• Topicalsteroids(potent)forfirsttwoweeks


Phymas

Rhinophyma• Occursalmostexclusivelyinmen1.) Gnathophyma–chinswelling2.)Metophyma–foreheadandnosesaddle3.)Otophyma–earlobes4.)Blepharophyma–eyelids

4.3 PSoRIASISPsoriasisisanimmunedysregulatorydiseaseresultingfrompersistentT-cellactivationand

theresultantreleaseofTH1-basedcytokinessuchasTNF-αandIL-2.Thesecytokinescausekera-tinocyticproliferation(acanthosis),andincreasedrecruitmentofinflammatorycellsintothepsori-aticskin.

Epidemiology• Affectsapproximately2%ofpopulationofU.S.• Usuallybeginsin3rddecadeoflife.Bimodalincidence:peaksatages29and55• Anearlyonsetpredictsmoreseveredisease.Also,earlyonsetmorelikelywithpositivefamilyhistory

Inheritance• Increasedincidenceinoffspringofparentsinwhichoneorbothaffected• MonozygotictwinconcordanceHLAassociationwith• HLA-B13• HLA-B17(earlieronsetandmoreseriousdisease)• HLA-Bw57• HLA-Cw6(mostdefinitiveassociatedHLAtype)–relativerisk9-15timesnormal• PsoriaticarthritisindisequilibriumwithHLA-B27,especiallyifspondylitispresent

Clinical FeaturesSkin Lesions• Sharplydemarcatedpapulesandplaques• Non-coherentsilveryscales• Auspitzsign→bleedinguponremovalofscale• Koebnerizationseenin20%• WoronoffRing:Areaofblanchingaroundpsoriaticplaquessecondarytodecreaseinprostaglandin,PGE2

Clinical PatternsChronic Stationary/Psoriasis Vulgaris• Mostfrequent• Red,scalylesionspersistforyears• Littlealterationinshape/distributionofplaques• Areasofpredilection:elbows,knees,scalp,retroauricularregion,lumbar,umbilicus• Whenlocalizedinthemajorskinfolds,scalingisabsent


Guttate (Eruptive) Psoriasis• Small(0.5to1.5cm)lesionsoveruppertrunkandproximalextremities• Earlyageofonset/youngadults

•StreptococcalthroatinfectionfrequentlyprecedeseruptionPsoriatic Erythroderma• Affectsallbodysites• Erythemaismostprominentfeature,scalinglessprominent

Generalized Pustular Psoriasis

•VonZumbuschtype;acutevariant• Usuallynootherformsonskinatsametime

•Fever,lastingseveraldays,witheruptionofsterilepustules2-3mmdiameterparalleling thefever

• Distribution:Trunk,extremitiesincludingnailbeds,palms,andsoles• Pustulesariseonhighlyerythematousskin• Fingertipsmaybecomeanonychicandatrophic

•Hypocalcemia,hypoalbuminemia,leukocytosisLocalized Pustular Psoriasis• Systemicsymptomsabsent• Twodistinctconditions1.)Pustulosispalmarisetplantaris2.)AcrodermatitiscontinuaofHallopeau

Psoriatic Nail Disease • Maybeofnailmatrixornailbedorigin• Fingernailsinvolvedin50%,toenailsin35%• Nailchangesmorefrequent(80-90%)inpatientswitharthritis

•Psoriaticnailchangesofmatrix→pits(themostcommonnailchangeofpsoriasisandrepresentingfocalpsoriasisoftheproximalmatrix)andleuconychia

• Pitsinpsoriasisaregenerallymorerandomlydistributedthantheregularrowsofpitsseeninalopeciaareata

• Psoriaticnailschangesofnailbedorigininclude:salmonspots,“oilspots,”onycholysis,subungualhyperkeratosis,andsplinterhemorrhages16

Psoriatic Arthritis• Asymmetricoligoarthritis,smalljointsofhands• Associatedonycholysis

Trigger Factors• Warmerweatherandsunlightreportedtobebeneficial

• Physicaltrauma–Koebnerreaction• Infection– 50%ofchildrenexacerbateexistingpsoriasisduring2-3weekintervalafterURI

– Acuteguttatepsoriasisfrequentlyfollowsanacutestreptococcalinfectionby1-2weeks(56-85%)andstreptococcalinfectionsmayplayaroleinexacerbatingotherformsofpsoriasis

uTIPa�Drugs

– Steroids – withdrawal of systemic and possibly topical) corticosteroids can result in severe flares

– Lithium – Beta-blockers – Interferons – ACE inhibitors – Granulocyte-colony stimulating factors17

a�Antimalarials and NSAIDS are not elieved to truly exacerbate psoriasis in most patients


– InfectionwithHIVmayrepresentanothertriggerfactor• Stress–psoriasismadeworsebystressin30-40%ofcases

Systemic Associations• Psoriaticarthritis• Crohn’sdiseaseandulcerativecolitis• HTN,obesity,diabetes,andchronicoropharyngealinfectionsfoundmorefrequentlyinpsoriaticpatients

• PustularpsoriasisassociatedwithHLA-B27,andarthropathyiscommon• Increasedriskoflymphoma

Keratinocyte Proliferation• 8-foldshorteningofepidermalcellcycle(36hrsvs.311hrsfornormal)

TreatmentAnthralin (topical)• Advantage:lackslong-termsideeffects• Possessesantiproliferativeactivityonhumankeratinocytes• Also,stronganti-inflammatoryeffectsbyinhibitingPMNsandmonocytes• Irritantreactions,especiallyafterincreasingconcentrationtoofast• Canstainhairtopurple• Brownishdiscolorationofsurroundingskin—reversible

Vitamin D3 Analogues• Calcipotriol,tacalciol,calcitriol• Inhibitkeratinocyteproliferationandinduceterminaldifferentiation• Anti-inflammatory• Usedforplaque-typepsoriasisQDorBID• Calcipotriolinactivatedbysalicylicacidorlacticacid(Lac-hydrin)• ShouldbeusedafterUV-light(calcipotriolabsorbsUV)• Localirritation

Tazarotene• Retinoid• Reducesscalingandplaquethickness,withlittleeffectivenessonerythema• Maybebeneficialincombinationwithphototherapy

Tar• Unknownactivity• 2-5%tarinvariousbaseseffectiveinchronicplaque-typepsoriasis

Topical Glucocorticoids

PUVA• Oralingestionofapotentphotosensitizersuchas8-methoxypsoralen(8-MOP)ortrimethoxypsoralen(0.6mg/kg)andvariabledosesofUVA,2hoursafteringestion

• TreatmentsgivenTIWorQIW• Clearingusuallyoccursafter19to25treatments• Overdosingresultsinsunburn,24-48hourpost-treatment• Psoralens→intercalatewithDNA,withenergyofUVAcovalentlycross-linknucleicacidsbetweenopposingstrandsofduplexregions,leadstoirreversiblephoto-inhibitionofDNAsynthesisandmitosis


• Nausea,dizziness,headache• Photosensitivityduringthe8-12hafteringestionofpsoralen,protectiveeyewearneeded• Higherfrequencyofsquamouscellcarcinomas,andperhapsmalignantmelanomarisk,increasesafter250treatments

Methotrexate• Syntheticanalogoffolicacidthatcompetitivelyinhibitsdihydrofolatereductase• InhibitsSphaseofcellcycle(likehydroxyurea)• 10-30mgonceperweekPOorIM• Nausea,anorexia,fatigue,headaches,alopecia,stomatitis• Leukopeniaandthrombocytopeniaindicateoverdose→leucovorinrescuerequired• Carefulinkidneydysfunction→renalexcretion• Acuteinterstitialpneumonitis(rare)• Hepatotoxicity;excludethosewithliverdiseaseoralcoholabuse;aboveacumulativedoseof1.5g,liverbiopsyisoftenrecommendedbeforecontinuingwiththerapy

• Alsoeffectiveintreatingpsoriaticarthritis

Cyclosporine• Inhibitsreleaseofcytokines,specificallyIL-2,bybindinganddeactivatingcalcineurin• Effectiveinerythrodermicandgeneralizedpustularpsoriasis• Startat2.5to4mg/kgperday,andcangoashighas5.5mg/kgperday• Renalimpairment(oftenreversible)→reducedosageby25%ifcreatinineincreasesto30%orgreaterofbaseline

• Hypertension(TreatwithACE-inhibitors)• Elevatedtriglycerides• Hyperkalemia• Hypomagnesemia• Hepatotoxicity• Hypertrichosis(common),gingivalhyperplasia,trichomegaly,nausea,vomiting,diarrhea,arthralgia,myalgia,tremor,acne,sebaceoushyperplasia,andfatiguemayoccur

• Long-termriskofmalignancy• MetabolizedbyP450,thuserythromycinorketoconazolewillincreasedruglevels

Retinoids → Acitretin• VitaminAderivatives• Effectiveinpustularandpalmoplantarformsofpsoriasis• Acitretinismostcommonlyused,givenat25mgperdayinitially• Restrictuseinwomenofchildbearingage• Regulategrowthandterminaldifferentiationofkeratinocytes;modulatetranscriptionofspecificgenesthroughretinoidresponseelements

• Showlowerresponseratesthanothersystemicmodalitiesfortreatmentofplaque-typepsoriasis→oftenineffectiveasmonotherapyforplaque-typepsoriasis

• Effectivewhencombinedwithultravioletphototherapy(eitherUVBorPUVA)• Treatmentover3-4monthsnecessary• Doserelatedadverseeffects:cheilitis,siccasymptomsofeyesandmouth,generalizedpruritus,dryskin,lossofstratumcorneumofpalmsandsoles,hairloss

• Muscleandjointpain• Elevationinserumlipids,andalsoLFTs• Monitorliverandkidneyfunction,bloodglucose,lipidprofile


Biologic Agents (seeTable4.1)• Etanercept• Efalizumab• Alefacept• Infliximab• Adalimumab• Ustekinumab

Table4-1.BiologicsDrug Mechanism Labs Pregnancy

ClassOther

Etanercept RecombinantfusionproteintoTNFreceptor;bindssolubleTNF-alpha

50mgSCinjectionstwiceweekly

B

Efaluzimab HumanizedantibodythatbindsCD11acomponentofLFA1whichbindstoICAM1onAPCandendothelialcells

WeeklySCinjections

C

Adalumimab AntibodytowardshumanTNF-alpha SelfadministeredIMinjectionqoweek

B

Alefacept ProteinthatblockstheinteractionofLFA3andFchumanIgG,LFA3isthereceptorforCD2andincreasedin CD45RoTcells

IMinjectionsonceweeklyoronceweeklyIVbolus

CD4 counts

B

Infliximab MonoclonalantibodieswhichinhibitTNF-alpha

IVinjections,firstdosefollowedbydoseatweeks2,6,thendosed8weeks

B ContraindicatedinCHF,maycausedruginducedSLE

Ustekinumab HumanantibodythatblocksIL-12andIL-23

SCinjectionsonce,thenin4weeksthenin12weeks

PPD B

Systemic Glucocorticoids• Systemicsteroidsareveryrarelyusedinthetreatmentofpsoriasisasmanybetteralternativetherapiesexist

• Severereboundpsoriasiscanoccurafterdiscontinuation• Chronicuseleadstowell-characterizedsideeffectsofsystemiccorticosteroiduse

Combination Therapies• Oftendesirable,ascombinationscanlimitthetoxicitiesofindividualtherapies;examples:– TopicalsteroidswithUVBorPUVA– RetinoidswithPUVAornarrowbandUVB– VitaminDanalogueswithUVB– Ingrammethod:coaltarbaths,UVB,anthralin– MethotrexatewithUVB–Methotrexatewithcyclosporine– Etanerceptwithmethotrexate

Phototherapy,conventionalsystemicagents,andbiologicagentstreatingpsoriasisaredis-cussedelsewhereinthistext.


4.4 PSoRIAtIC ARthRItISFeatures

• 20-40%ofpsoriaticpatients;higherfrequencyfoundinmoderatetoseverepsoriasispatients

• Ageofonset:18–50years• Usually(80%)rheumatoidfactornegative(seronegative)• Synovial,serumandlesionallevelsofTNF-αareincreasedinpsoriasisandpsoriaticarthritis18

Types of Psoriatic Arthritis • Asymmetricoligoarthritisorpolyarthritis(mostcommon)• Symmetricpolyarthritis(RA-like)• Spondylitis(axial)• Distalinterphalangealjoint(DIP)disease• Arthritismutilans(leastcommon)• Enthesopathy(inflammationofligamentsandtendonsatinsertionpointonbones)19

Clinical• Morningstiffnessofjointslastingmorethan60minutes• InflammationofDIPjoints→oftenwithnailinvolvement(~80%)• Dactylitis:“sausagedigits”• Enthesitis/Enthesopathy→Inflammationoftendonsorligamentsoratsitesoftendoninsertionintobone

• Spondylitis/sacroiliitisandaxialdisease• Reducedrangeofmotionofshoulders,neck,andlowerback• 80%ofpatientspresentwithskindiseasefirst

Radiographic Features of Psoriatic Arthritis• “Sausagedigits”• Largeeccentricerosions• Pencil-in-cupdeformities—erosivechangesofthejoint:phalangealdistraltipispencilonanerodedcuplikejointspace

• Tuftresorption:(acroostcolysis)• Periostitis:inflammationoftheperiosteum• Sacroileitis

Therapy for Psoriatic Arthritis• NSAIDs• Sulfasalazine• Methotrexate• Etanercept(FDA-approvedtherapy)• Ustekinumab(awaitingFDAapproval)

4.5 REItER’S SyNDRomEChronicinflammatorydiseasesimilartopsoriasiswithpsoriaticarthritis.•Urethritis• Conjunctivitis• Arthritis


Fewpatientspresentwithclassictriad,thuscanbediagnosedwith• Peripheralarthritis>1monthduration• Associatedurethritis(orcervicitis)

OccursinyoungmenofHLA-B27genotype.Rarelyoccursinwomen.

Clinical• Anyoneoftriad• Fever,weakness,andweightloss• Nonbacterialurethritiswithpainfulandbloodyurinationandpyuria• Mayinvolvegastroenteritis• Cystitis,prostatitis,seminalvesiculitis• Keratitismayleadtocornealulceration• Iritiscommon• Arthritisisasymmetric• Endocarditis,pericarditis,myocarditis,aorticinsufficiency• Erythemanodosum

Skin Lesions• Multiplesmall,yellowishvesiclesthatbreak,becomeconfluent,andformsuperficialerosions→ frequentlyongenitalsandpalms

• Crusted,hyperkeratoticpapulesandplaquesonplantarsurfaces→keratodermablennorrhagicum• Penilelesions:Perimeatalbalanitis;circinatelesions;similarlesionsseenonvaginalmucosaofaffectedwomen

• Buccal,palatal,andlingualmucosamayshowpainless,shallow,rederosions,andseverestomatitis

• Nailsbecomethickandbrittlewithheavysubungualhyperkeratoticdeposits

Etiology• Chlamydia trachomatisassociatedwithcasesinvolvinginfectionofGUtract• HLA-B27in80%ofcases

Treatment• Topicalsteroids• NSAIDs• Methotrexate• Acitretin• Cyclosporine• TNF-inhibitingbiologicssuchasetanercept• Courseofdiseasemarkedbyexacerbationandremission.Achronicdeformingarthritisoccursin20%

4.6 SAPho SyNDRomE• Synovitis• Acne(Acnefulminansorconglobata)• Pustulosis(pustularpsoriasis)• Hyperostosis• Osteomyelitis

uTIPa�

Shigella flexneri (most common) of nonurethral form of Reiters, Salmonella spp., Yersinia spp., Ureaplasma urealyticum, Borrelia burgdorferi, Cryptosporidia, Campylobacter fetus


4.7 SNEDDoN-WILkINSoN DISEASE• Subcornealpustulardermatosis• Middle-agedwomen• Superficialpustulesinannularandserpiginouspatterns• Abdomen,axillae,groin• Pustulesaresterile

Histology• Pustulesformbelowstratumcorneumwithoutacantholysis• Containsmanyneutrophils

Treatment• Dapsone• Acitretin• NarrowbandUVBChroniccondition,possiblyrelatedtopsoriasis,withremissionsofvariableduration.

4.8 LIChEN PLANUSInflammatorydisorderthataffectstheskin,mucousmembranes,nails,andhair.• Purple,polygonal,pruritic,papule,planar• Scalingisnotasprominentasotherpapulosquamousdiseases• Prevalence:<1%,noracialpreference• 2/3casesbetweenagesof30and60

Etiology and PathogenesisClassification Scheme• Idiopathic(classic)• Drugassociated• Associatedwithotherdiseases(UlcerativeColitis,AlopeciaAreata,Vitiligo,Dermatomyositis,MyastheniaGravis)

Role of Infection• HepatitisCimplicatedintriggeringLP• Associationwithsyphilis,HSV2,HIV,amebiasisandchronicbladderinfections

Clinical Manfiestations• Erythematoustoviolaceous,flat-topped,polygonalpapule,withoccasionalsmallcentralumbilication

• Thin,transparent,adherentscaleatopthelesion• Wickham’sstriae–fine,whitishreticulatednetworksonsurfaceofwell-developedplaques• LPbeginsaserythematousmaculesthatevolveoverweeks;initiallesionsalwaysappearontheextremities

• Generalizederuptiondevelopsoveronetofourmonths• Symmetricallyinvolvesflexuralareasofwrists,arms,legs;also,oralmucosaandgenitalia• InverseLP:Axillae,groin,inframammaryareas• LPisusuallypruritic;oralinvolvementgenerallyasymptomatic,unlesserosive→ extremely painful

• Koebnerization(isomorphicresponse)occurs

uTIPa AssociationwithIgAmonoclonal

gammopathy


Clinical VariantsConfigurationAnnular LP• Blacksmorecommonlyaffected• Onpenisandscrotum• Also,largerlesionsreach2-3cmindiameterandbecomehyperpigmentedwithraised

outer rimLinear LP• Secondarytotrauma,often

Hypertrophic LP • Shins,interphalangealjoints• Mostpruritic• Healswithscarformationandhyper/hypopigmentation

Atrophic LP• Rare• White,bluishpapulesorplaqueswithcentralsuperficialatrophy• Mostcommonlowerextremitiesandtrunk• Resembleslichensclerosusetatrophicus

Vesiculobullous LP• Rare• VesiclesandbullaewithinlesionsofLP• BullaearisefrompapulesofLP,notnormalskin• Subepidermalseparation

Erosive Ulcerative LP• Chronicandpainfulbullaeandulcerationsonfeet• UsuallyassociatedwithmoretypicalLPlesionsofnails,mucosalsurfacesandskin• Lossoftoenailsandalopeciacommon• SCCmaydevelopinlesionsofulcerativeLP,thereforebiopsymaybeindicated

• InoralLP,oralmucosa,gingivaandtonguemaybeaffected.Desquamativegingivitismayoccur

• HistologyofmucosalLPdiffersfromLPoftheskininthatparakeratosisratherthanorthokeratosisisseen,secondarytothelackofgranularlayeronmucosalsurfaces21

Follicular LP (lichen planopilaris)• Individualkeratoticandfollicularpapulesandstuddedplaques• Trunkandmedialaspectsofproximalextremities• Affectsscalp–cicatricialalopecia• Graham-Little-Piccardi-Lassueur syndrome: triad of

1.) Follicular LP of skin and/or scalp2.) Multifocal cicatricial alopecia of scalp3.) Nonscarring alopecia of axillary and pubic areas

Lichen Planus Pigmentosus• Uncommon• Hyperpigmented,darkbrownmaculesinsun-exposedareasandflexuralfolds• Occursindarker-pigmentedpeople• Similartoerythemadyschromicumperstans

uTIPa

Erosive mucous membrane disease more common in patients with Hepatitis C infection


Actinic LP• MorecommoninMiddleEasterncountriesinspring/summer• Affectssun-exposedareas• TypicalLPmaybeseenoverextremities• Pruritusandscalingminimal

Sites of InvolvementLP of the Scalp• LichenplanopilarisorfollicularLP:individualkeratoticpapulesthatcoalesceandmergetoformpatches

• Women>men• Uni-ormultifocalhairloss• End-stage:scarringalopecia• PseudopeladeofBrocq:scarringalopeciaandfibrosis;endstageoffollicularfibrosiscausedbyprimaryinflammatorydermatosissuchasLP,LE,pustularscarringformsoffolliculitis,favus,scleroderma,andsarcoidosis

Mucosal LP• Affectsmouth,vagina,esophagus,conjunctiva,urethra,anus,nose,andlarynx• 60-70%patientswithLP• OnlymanifestationofLPin20-30%• Forms:reticular,plaque-like,atrophic,papular,erosive-ulcerative,andbullousforms• Malegenitalia:25%ofcases,glanspenismostcommonsite(annularlesions,frequently)• Femalegenitalia:leukoplakia/erythroplakia,erosive,orgeneralizeddesquamativevaginitis• VulvarandgingivalLPcanexisttogether–erythemaanderosionsofgingivaeandtongueandwhitereticulatedplaques

• ConjunctivalLP:cicatricialconjunctivitis

LP of the Nails• 10-15%ofcases• UsuallyincombinationwithotherLPlesionsonskin• 20-naildystrophy(trachyonychia)canbeseen,buttrachyonychiaisnotdiagnosticofLP• Thinning,longitudinalridging,anddistalsplittingofnailplate(onychoschizia)• Also,oncholysis,longitudinalstriation(onychorrhexis),subungualhyperkeratosis,oranonychia

• Classicfinding:dorsalpterygiumorforwardgrowthoftheeponychiumwithadherenceofproximalnailplate;also“tenting”signasnailplateelevatedwithlongitudinalsplitting

• Pitscommon

Inverse LP• Rare• Occursinflexuralareassuchasaxilla,underbreast,groin• Reddish-brown,discretepapules

Palmoplantar LP• Yellowish,compactkeratoticpapulesandpapulonodulesonlateralmarginsoffingersandhandsurfaces


Special Forms of LP/Lichenoid EruptionDrug-induced LP• MaybetypicaloratypicalforclassicLP,localizedorgeneralized• Typicallymanifestpostinflammatoryhyperpigmentation,alopecia,withoutWickham’sstriae

• Symmetriceruptionontrunkandextremities—photodistributioncommonwiththesedrugs:5-FU,carbamazepine,chlorpromazine,diazoxide,ethambutol,quinine/quinidine,tetracyclines,thiazidesandfurosemide

• Mucousmembraneinvolvementoftenassociatedwithspecificdrugsandchemicals—amalgamcontainingmercury;goldmorecommon

LP–Lupus Overlap• ClassiclesionsofLPnotusuallyseen• Photosensitivity,pruritus,follicularpluggingalsouncommon• Lesionsonextremities,commonly:atrophicplaquesandpatcheswithhypopigmentationandalividred-to-bluevioletcolorwithtelangiectasiaandminimalscaling;bullaemaydevelop

• MayprogresstoSLE• Prolongedcourse• Histo:LichenoidreactionandhistologicfeaturesofLEseeninsamebiopsy

Lichen Planus Pemphigoides• TenseblistersatoplesionsofLP,ordevelopmentofvesicledenovoonuninvolvedskin

• DifferentiatefrombullousLP,whereblistersinlesionsoflongstandingLPasaresultofintenselichenoidinflammationandextensiveliquefactiondegenerationofbasalkeratinocytes

• HistologicallylikeLP,withlineardepositionofIgGandC3atDEjunction

• CirculatingIgGautoantibodiesreactto180/200kDaantigenwithinBMzone

Keratosis Lichenoides Chronica (NekamDisease)• Violaceouspapularandnodularlesions;hyperpigmentedandhyperkeratotic,coveredwithgrayscales

• Often,linearandreticulatepatternonthedorsalhandsandfeet,extremitiesandbuttocks• Veryrefractorytotreatment

LP and Malignant Transformation• Riskisverylowtononeatall• Riskincreasedbylongstandingdisease,erosiveoratrophictypesofLP,andtobaccouse• Mostcommonsitesformalignanttransformationaretongue,gingivaandbuccalmucosa• MostpatientsdevelopingSCCincutaneousLPhadahistoryofeitherarsenicorX-rayexposure

Lichenoid Keratosis (LichenPlanus-likeKeratosis)• Browntoredscalingpapuleorplaquefoundonsun-exposedskinofextremities• HistologicalfeaturesofLPwithadditionalfindingofparakeratosis• Frequentlyoccurwithsolarlentigo,seborrheickeratosis,andactinickeratosis

uTIPa Lichenoid drug eruptions have

been associated with β-blockers, antimalarials, captopril, gold, peni-cillamine, HCTZ, NSAIDs

uTIPa Lichenoid contact dermatitis

– color film developers, dental restorative materials, musk ambrette, nickel, aminoglyco-sides, gold


Associated Conditions• Autoimmunechronicactivehepatitis• Primarybiliarycirrhosis• Postviralchronicactivehepatitis• HCVinsomepopulations

Treatment• Spontaneousremissionsandexacerbations• Oral/MucosalLP–replacementofgoldoramalgamdentalrestorations• Topicalhighpotencysteroidsformucosalandlimitedcutaneousdisease• Topicalimmunomodulatorssuchastacrolimusointmentfororal/genitaldisease• Topicalanestheticsfororalpain• IntralesionalTAC• Systemicsteroidsforrefractorycases• PUVAphotochemotherapysuccessfulingeneralizedLP• Oralretinoids

Course and Prognosis• Typicallypersists1-2years• Mayfollowchronic,relapsingcourse• Spontaneousremissiononaverageafter15months• Lichenplanopilarismostchronicandprogressivewithlittlepotentialforhairregrowth• HypertrophicLPfollowsprotractedunremittingcourse• OralLPdoesnotusuallyspontaneouslyregress

4.9 AtoPIC DERmAtItISClinical Features

Major• Pruritus• Facialandextensorinvolvementininfantsandchildren• Flexurallichenificationinadults• Chronicorrelapsingdermatitis• Personal/familyhistoryofatopy

Associated Features• Xerosis• Cutaneousinfection• Nonspecificdermatitisofhands/feet• Ichthyosis,palmarhyperlinearity,keratosispilaris• Pityriasisalba• Nippleeczema• Whitedermatographismanddelayedblanchresponse• Anteriorsubcapsularcataracts,keratoconus• ElevatedserumIgElevels• Positiveimmediate-typeallergyskintests• Earlyageofonset• Dennie-Morganinfraorbitalfolds


• Orbitaldarkening• Facialerythemaorpallor• Perifollicularaccentuation• Courseinfluencedbyenvironmentaland/oremotionalfactors

Genetics• Strongercorrelationbetweensiblingsthanbetweensiblingsandparents• Exposuretoenvironmentalfactorsduringchildhoodislikelytobethemajorfactor• Seeninfamilieswithatopicdermatitis,asthma,andallergicrhinitis•Filaggringenemutationsareknownriskfactor

Clinical Manifestations• Typicallybeginsininfancy→50%infirstyearoflife,andanadditional30%between1and5years

• MostchildrenwithADeventuallydevelopallergicrhinitisorasthmalaterinchildhood

Infancy • ADgenerallymoreacuteandprimarilyinvolvestheface,scalp,andtheextensorsurfacesoftheextremities

• Diaperareaspared

Older Children• PatientdevelopsthechronicformofADwithlichenificationandlocalizationoftherashtotheflexuralfoldsoftheextremities

• Subsidesaspatientgrowsolder,leavingadultwithskinthatispronetoitchingandinflammation

• ChronichandeczemamaybetheprimarymanifestationofadultswithAD

ComplicationsOcular Problems• Eyeliddermatitisandblepharitis• Atopickeratoconjunctivitis• Keratoconus:conicaldeformityofcornea• Cataracts

Infections• Frequentlycomplicatedbyrecurrentskininfections:– Kaposi’svaricelliformeruption→ herpessimplex→resultsineczemaherpeticum→ incubationof5-12days,multiple,itchy,vesiculopustularlesionseruptinadisseminatedpattern→ oftenbecomehemorrhagicandcrusted

–Molluscumcontagiosum– HPV– Superficialfungalinfections—Trichophyton rubrum and

Pityrosporum ovale– S. aureus–foundinover90%ofADskinlesions.Honeycoloredcrusting,folliculitis,andpyodermaareindicatorsofsecondarybacterialskininfection.Regionallymphadenopathycommon.Deep-seatedS. aureusinfectionsmayindicatehyper-IgEsyndrome

uTIPa Innate antimicrobial peptides

include human β-defensin (HBD) and cathelicidins, such as LL 37. Ong et al found a deficiency of HBD-2 and LL 37 in lesions from patients with atopic dermatitis com-pared to those with psoriasis. This decreased expression of innate antimicrobial peptides may explain the increased sus-ceptibility to colonization and skin infection with S. aureus in patients with atopic dermatitis4


Foods• FoodallergensexacerbateskinrashesinatleastasubsetofpatientswithAD,particularlyinfantsandyoungchildren

• Eggs,milk,peanuts,soybeans,treenuts,fish,andwheatarethemostcommonallergensimplicatedinAD

• FollowingpositiveoralfoodchallengesinchildrenwithAD,histamineconcentrationincreasesintheplasma

• MostADpatientsdoNOThavefoodallergy

Immunohistochemistry• LymphocytesareCD3+,CD4+,andCD45RO+memoryThelpercells• LangerhanscellsandmacrophagesinfiltratingintoADskinlesionshavesurface-boundIgE• ActivatedeosinophilsarepresentinsignificantlygreaternumbersinchronicascomparedtoacuteADlesions

Immunologic Abnormalities in AD• IncreasedsynthesisofIgE• IncreasedexpressionofCD23(lowaffinityIgEreceptor)onBcellsandmonocytes• Increasedbasophilhistaminerelease• ImpairedDTHresponse• DecreasedCD8suppressor/cytotoxicT-cellnumberandfunction• IncreasedsecretionofIL-4andIL-5byTH2cells• DecreasedsecretionIFN-gammabyTH1cells

An Immunologic Aside• TH1cells→produceIL-2,IFN-γ,andTNF-β,associatedwithcell-mediatedimmunity• TH2cells→produceIL-4,IL-5,IL-6,IL-10,andIL-13,associatedwithantibodymediatedimmuneresponses

Management

Allergens• Dustmites,molds,animaldander,pollens• Avoidanceoftriggeringfoods• Infantsandyoungchildrenmorelikelytohavefoodallergies;olderchildrenandadultssensitivetoenvironmentalaeroallergens

Infectious Agents• Anti-staphylococcalantibioticshelpfulinthosecolonized• HSV:Antiviraltreatmentveryimportanttopreventdisseminateddisease;IVtreatmentmaybenecessaryfordisseminatedeczemaherpeticum

• Molluscumcontagiosum→topicalimiquimod,liquidnitrogen,topicalsalicylicacid,ornotherapy

Pruritus• Antihistamines→usesedatingantihistamineatnight

Systemic Glucocorticoids• Rarelyindicated,andriskofreboundflareafterdiscontinuation• Shortcoursescanbedonewhileothermodalitiesarestarted,andtaperingdosageiscritical


UV Phototherapy• UVBusefuladjuncttotreatmentofchronicrecalcitrantAD• HighintensityUVAcanbefast-actingandeffectivewithacuteexacerbationsofAD

Systemic Cyclosporine or Tacrolimus• OralcyclosporineortacrolimuscanhelpsevereADthatisrefractorytotopicalsteroids• Discontinuationoftreatmentmayresultinrapidrelapseofskindisease

Probiotics• Theutilityofprobioticsinprimarypreventionofatopicdermatitishasbeenstudied• LactobacillusGGculturesweregiventopregnantwomenwithahistoryofatopytoassesstheeffectofpotentiallybeneficialgutfloraonthepreventionofatopicdiseaseintheirchildren

• Frequencyofatopicdermatitisintheprobioticgroupwashalfthatintheplacebogroupattwoyearsoflife

Prognosis• Diseasemoresevereandpersistentinyoungchildren• Periodsofremissiongrowlongeraspatientages• Milddiseaseatinfancy:Spontaneousresolutionoccursin40%ofpatientsafterage5• Poorprognosticfactors–WidespreadADinchildhood– Associatedallergicrhinitisorasthma– FamilyhistoryofAD– Earlyageofonset

4.10 ALoPECIA AREAtAGenetics

• Highfrequencyoffamilyhistory,especiallyinpatientswithearlyonset(37%)• Twinconcordance=55%(identicaltwins)

Immunologic Factors• Majorassociations:Vitiligoandthyroiddisease(10%),withincreasedprevalenceofantithyroidantibodiesandthyroidmicrosomalantibodiesinAA

• Otherautoimmunediseasesshowntobeassociated:perniciousanemia,diabetes,LE,myastheniagravis,RA,polymyalgiarheumatica,ulcerativecolitis

Emotional Stress• Maybeprecipitatingfactorinsomecases

Clinical Features• Prevalence:0.1-0.2%,withlifetimeriskof1.7%• Affectsmenandwomenequally• 60%presentbeforeage20• Pulltestmaybepositiveatmargins,indicatingearlydisease

• Usuallyasymptomatic,butsomepatientsperceivepruritus,tenderness,burning,orpainprecedinghairloss

• Areata–partiallossofscalphair

uTIPa PATTERNS of alopecia areata: patchy (most common);

reticulated; ophiasis (parietal/temporal/occipital); ophiasis inversus (sisapho – bandlike pattern in fronto parietotemporal scalp); diffuse


• Totalis–totallossofscalphair• Universalis–100%lossonscalp,eyebrows,eyelashes,andrestofbody• Initialregrowthiswhite,followedbyrepigmentation• Naildystrophy(10-66%),seeninone,some,orallnails,preceding,coinciding,oroccurringafterhairdisease→ pittingwithirregularpatternorinorganizedrows;trachyonychia:longitudinalstriationsresultinginsandpaperappearance;Beau’slines;onychorrhexis;thinningorthickening;koilonychia;red-spottedlunula;punctateortransverseleukonychia

Prognosis• Unpredictablecourseandpattern• Mostpatientsseecompleteregrowthwithinoneyearwithouttreatment• 10%developseverechronicform• Predictorsforpoorprognosis:atopicdermatitis,childhoodonset,widespreadinvolvement,ophiasis,durationforlongerthanfiveyears,onychodystrophy

Treatment• Alllocaltreatmentshelptreatedareas,butdonotpreventfurtherspread• Spontaneousrecoveryisextremelycommon,withmostshowingregrowthwithin1year• Firstline:ILsteroidsconcentrationof5mg/ccmaximumof3ccpervisit→ 0.1ccpersite,approximately1cmapart;after6monthsandnoresponse,d/c

• Topicalsteroidsasmonotherapygenerallyineffective• Minoxidil5%:stimulatesfollicularDNAsynthesisandregulateshairphysiologyindependentlyofbloodflowinfluences;effectivewithalopeciaareatainvolving20-99%involvementin25-50%ofpatients→ initialhairregrowthin12weeks

• Anthralin0.25-1.0%• SquaricaciddibutylorDNCBorDPCP(diphenylcyclopropenone)–aimistomaintainlow-gradetolerableerythema,scaling,andpruritus,withweeklyapplications

• PUVA,witheithertopicalorsystemicpsoralentherapy;relapseafterdiscontinuationoccurs• Cyclosporineworks,butsystemicuseassociatedwithadverseeffectsandhighrecurrence

rate

4.11 ALoPECIA: othER FoRmSTrichotillomania

• Practiceofpluckingorbreakinghairfromthescalporeyelashes• Areasofalopeciacharacteristicallycontainhairsofvaryinglength• Girlsunderageof10• Treatwithpsychotherapyandantidepressant

Hot Comb Alopecia• AfricanAmericanwomenwhostraightenedtheirhairwithhotcombs• Characteristicallyonthecrownandspreadsperipherallytoformalargeovalareaofpartialhairloss

• Thermaldamagetofolliclebyhotpetrolatum,leadingtodestructionofhairfollicleandfollicularscar

• Maybesameasfolliculardegenerationsyndrome/centralcentrifugalscarringalopecia

uTIP a Biopsy shows high

number of catagen hairs, pigmentary defects and casts, trichomalacia, and hemorrhage


Pseudopelade of Brocq• Scarringalopeciawheredestructionofthehairfollicleproducesmultipleround,oval,orirregularlyshapedcicatricialpatchesofvaryingsizes

• Nopustules,crusts,orbroken-offhairsarepresent• Onsetisinsidious• Female:male=3:1• Alopeciapermanent• Noinflammationwithdecreasedorabsentsebaceousglands,normaloratrophicepidermis

Traction Alopecia• Prolongedtensiononthehairfrombraiding,ponytails,rollingcurlers,twistingwithfingers

Pressure Alopecia• Occipitalareasofbabieslyingontheirbacks• Inadults,prolongedpressureonthescalpduringgeneralanesthesiaorafterprolongedbedrest

• Peoplewithchronicillnessafterprolongedbedrestinoneposition• Likelyrelatedtopressure-inducedischemia

Loose Anagen Syndrome• Anagenhairspulledfromthescalpwithlittleeffort• Blondegirls• Usuallyimproveswithage

Follicular Mucinosis• Depositionofmucinintheouterrootsheathandsebaceousglands• Mostcommonlyonscalpandbeardarea• SecondarytypeassociatedwithCTCLwithwidespreadandchroniclesions,andpatients

are older

Meralgia Paresthetica• Mayhavealopeciaoftheanestheticareaoftheouterthigh

Hypothyroidism• Haircoarse,dry,brittle,andsparse• Telogenhairs3xmoreprevalent

Hyperthyroidism• Hairbecomesextremelyfineandsparse

Alopecia Neoplastica• Hairlossfrommetastatictumors• Usuallybreastcarcinoma


4.12 VItILIGo• Halfofallcasesbeginbeforeage20• Depigmentedwhitepatchessurroundedbynormalorhyperpigmentedborder• Trichromevitiligo:intermediatetanzoneshalfwaybetweenthenormalskincolorandthe

depigmentation• Hairsinvitiliginousareasbecomewhite

Four Types1.)Localizedorfocal(includessegmental)2.) Generalized(mostcommon)3.) Universal4.) Acrofacial

Generalized• Symmetrical• Face,upperchest,dorsalhands,axillae,groin• Skinaroundallorifices• Areasoftrauma(kneesandelbows)

Focal• Asymmetric• Treatmentresistant• 5%ofadult,20%ofchildhoodcasesofvitiligo

Universal• Entirebodysurfacedepigmented

Associations• Insulin-dependentdiabetes• Perniciousanemia• Hashimoto’sthyroiditis• Grave’sdisease• Addison’sdisease• Alopeciaareata

Genetics• Multifactorial• 30%ofvitiligopatientshaveanaffectedrelative

Treatment• Topicalcorticosteroids• Ultravioletphototherapy(NarrowbandUVBandPsoralenwithUVA)• Laser(308nmexcimer)• Topicaltacrolimus• Re-pigmentedsurgerywithpunchminigrafts,dermoscopicdermalgrafts


4.13 PItyRIASIS RUbRA PILARIS • Smallfollicularpapules→ salmon-orangetoreddish-browncolor,pinheadsize,andtoppedwithscalyplug

• Yellowishpinkscalingpatches,oftenbeginsonscalp• Solidconfluentpalmoplantarhyperkeratosis

Progresses to: • Sidesoftheneckandtrunk• Extensorsurfacesoftheextremities• Anyportionofthebodycanbeaffected

Clinical Features• Involvementgenerallysymmetricalanddiffuse,withcharacteristicsmallislandsofnormalskinwithintheaffectedareas

• Palmsandsoleswillbehyperkeratoticwithfissuring• Nails:dull,rough,thickened,brittle,andstriated;maycrackandbreak;nopitting

Treatment• Topicalkeratolytics• Systemicretinoids• VitaminA500,000unitsdaily• Systemicsteroidsforshorttermmanagement• Methotrexate• Azathioprine• Cyclosporine

4.14 LIChEN SCLERoSUS• Presentsfromchildhoodtooldage,andoccursinallraces• Femalespredominateatallages

Clinical• White,polygonal,andflat-toppedpapulesorplaquessurroundedbyerythematoustoviolaceoushalo

• Later,lesionscoalesceintolargeatrophicpatches,becomingsmooth,slightlywrinkled,andwhite

• Bullaemayariseinpatches• Prurituscanbesevere,especiallyinanogenitalarea,whereerosionsandfissuringcanoccur• Inwomen,normalanatomicstructuresmaybeobliterated• Balanitisxeroticaobliterans→ maleinvolvementoftheglanspenis;hemorrhageiscommonintheglans

• Extragenitallesionsmostfrequentontheupperback,chest,andbreasts,andareusuallyasymptomatic

• +Koebnerization

Cancer Risk• IncreasedriskofgenitalSCCinbothmenandwomen• Lifetimeriskforwomenlessthan5%


Etiology• Autoimmunephenomenon,likely• 20%ofbothmenandwomenhaveatleastoneautoimmunedisease(vitiligo,alopeciaareata,orthyroiddisease),andalargerproportionhavecirculatingantibodies

• Traumacaninducelesions,andboysdobetteraftercircumcision

Childhood LS• Onsetinchildhoodin10-15%ofcases• Girlsoutnumberboys10:1• Genitaldiseaserepresents90%ofchildhoodLS• Ingirls:Symptomsincludedifficultywithdefecation,dysuria,perinealpruritus,andperinealskinlesions

• Inboys:Phimosisismostcommonpresentingsign• Mayresolvespontaneously,especiallyaroundpuberty(50%ofgirls,aftercircumcisioninboys)

Treatment• Superpotenttopicalsteroidstwicedailytobetaperedineitherstrengthorfrequencyover

time• Topicaltacrolimusointmentorpimecrolimuscream,sometimeseffective• Oralretinoidsmayworkwithanogenitallichensclerosusinbothmenandwomen

4.15 GRANULomA ANNULARELocalized GA

• Youngadults• Lateralordorsalsurfacesoffingers,hands,elbows,feet,ankles• White,pink,flat-toppedpapulesthatspreadperipherally• Neverulcerateandhealwithoutscarring• 75%clearwithin2years

Generalized GA• Diabetesin20%• Diffusepapules• Maybepruriticorasymptomatic• Laststhreemonthstofouryears

Macular GA• Flatorslightlypalpablelesionsoverfeet,ankles,anduppermedialthighs• Smallpapulescanbefeltinsomecases

Subcutaneous GA• Mostcommoninchildren• Oftenahistoryoftraumatoarea• Multiplelesionsmaybepresent• Generallyasymptomatic

Perforating GA• Dorsumofhands


• PapuleswithcentralkeratoticcorerepresentingtransepidermaleliminationofthedegeneratedmaterialinthecenterofGAlesions

4.16 hIRSUtISmAndrogens in Women

• Dehydroepiandrosterone(DHEA),adrenal• Androstenedione–adrenal,ovary• Testosterone–ovary,adrenal,extraglandularconversionof androstenedioneanddehydroepiandrosterone– Adrenalandrogenregulatedbyadrenocorticotropin– Ovarianandrogenregulatedbyluteinizinghormone– Thehairfolliclerequiresconversionoftestosteroneto dihydrotestosteroneforexpressionofandrogenaction

Tumors → Rapid Onset of Hair Growth with or without Accompanying Virilization• Adrenaladenomasandcarcinomas• Arrhenoblastoma• Kruckenbergtumorsofovary

Polycystic Ovarian Disease• Mostcommoncauseofovarianhyperandrogenism• Manifestations:Hirsutism,amenorrhea,virilization

Congenital Adrenal Hyperplasia Congenitaladrenalhyperplasia(defectsinadrenalsteroidogenesis)canoccuratanypoint

inlife.• 21-hydroxylasedeficiency• 11β-hydroxylasedeficiency• 3β-hydroxysteroiddehydrogenaseisomerasedeficiency(3β-hsd)

Idiopathic Hirsutism• Womenwithevidenceofandrogenexcessbutwithnormalmenses,normal-sizedovaries,noevidenceoftumorsofadrenalorovary,andnormaladrenalfunction

• Slightelevationsofplasmaandrostenedioneandtestosteronecommon

Signs of VirilizationSignsofvirilization→ correlateswithandrogenoverproduction• Deepeningofthevoice• Temporalbalding• Clitoromegaly• Increasedmusclemassinthelimbgirdles

Signs of Cortisol Excess• Plethora• Centralobesity• Striae• Dorsocervical/supraclavicularfatpads

uTIPa�Drugs → Hirsutism without

Virilization/Defeminization

• Phenytoin • Minoxidil • Diazoxide • Cyclosporine • Hexachlorobenzene


Work-up• Pelvicexam:Searchforpalpableovarianmasses• Radiographicimagingofthepelvis/adrenalglands• Laboratoryexam:DHEA>8000ng/mlorserumtestosterone>2ng/mlsuggestneoplasm• Plasmatestosteronelevelsinthenormalrangearedifficulttointerpret→ doesnotnecessarilyreflectthefreeorunboundlevelsofhormoneunderconditionswhentestosterone-bindingglobulinlevelsareeitherincreasedordecreased

• Cushingsyndrome,ifsuspected,shouldbeevaluatedwithanovernightdexamethasonesuppressiontest

• Polycysticovariandisease:Diagnosisfromhistoryandphysicalexam• Delayedonsetadrenalhyperplasia:ShortACTHstimulationtestandmeasurementofplasma17-hydroxy-progesterone

4.17 AmyLoIDoSIS• Beta-pleatedsheetformsofvarioushost-synthesizedmolecules

Classification1.)Primary(oftenhasskinfindings)2.) Secondary(rareskinmanifestations)3.) Primarylocalized4.) Secondarycutaneousortumorassociated5.) Familialsyndromes

Pathology• PASpositiveanddiastaseresistant• Congo-redpositive• Purplewithcrystalviolet• PositivewiththioflavinT• Secondarysystemicamyloid(aa)losesitsbirefringenceaftertreatmentwithpotassiumpermanganate,butprimaryandlocalizedformsdonot

Primary Systemic Amyloidosis• Involvestongue,heart,GItract,andskin• Involvesskinin40%• Includesmyeloma-associatedamyloidosis

Clinical• Shiny,smooth,firm,flat-toppedpapulesofwaxycolorthatcoalesceintonodulesorplaques• Commonlyaroundnose,eyes,mouth,andmucocutaneousjunctions

• Purpuriclesionsresultfromamyloidinfiltrationofbloodvessels;occursaftertrauma(pinch purpura)

• Glossitis→ mayleadtodysphagia;lateralaspectsoftongueshowsindentationsfromteeth• Bullousamyloidosis→ subepidermalhemorrhagicbullaeatareasoftrauma

• Carpaltunnelsyndrome• RA-likearthropathy

• Shoulderpadsign → enlargeddeltoids

• CardiacarrythmiasandCHFcausedeath •Prognosispoor

uTIPa�Protein AL → derived from Ig

light chains (lambda subtype); AL also found in nodular amyloidosis produced by a plasmacytoma


Secondary Systemic Amyloidosis• Amyloidintheadrenals,liver,spleen,andkidneyasaresultofsomechronicdisease,suchasTB,leprosy,Hodgkin’s,Behçet’s,rheumatoidarthritis,ulcerativecolitis,schistosomiasis,orsyphilis

• Skinnotinvolved

Primary Cutaneous Amyloidosis• Keratinistheproteincomponent• Noamyloidaroundthebloodvessels

Macular Amyloidosis• Moderatelypruritic,brown,rippledmaculesininterscapularregionoftheback

• Mayhaveassociatednotalgiaparesthetica

Lichen Amyloidosis• Bilateralshins• TypeIIaMEN• Small,brown,discrete,scalypapules• Treatbyreducingfriction,occlusion,ilsteroids

Nodular Amyloidosis• Singleormultiplenodulesonextremities,trunk,genitals,orface• Overlyingepidermismayappearatrophic• Numerousplasmacells• ALtype

Secondary Cutaneous Amyloidosis• SeenfollowingPUVAtherapyandinbenignandmalignantneoplasms:nonmelanomaskincancers,seborrheickeratoses,trichoepitheliomas

• Also,keratin-derivedamyloid

Familial Syndromes Associated with Amyloidosis• FamilialMediterraneanfeverandMuckel-Wellssyndrome→ showAAprotein• MENIIa→ keratin-derivedamyloid

Familial Amyloidotic Polyneuropathy (fap)• FapIandfapII→ mutationsintransthyretin• FapIII→ apolipoprotein a-1• FapIV→ gelsolinmutation

uTIPa�AA amyloid fibrils → derived from SAA protein, an

acute phase reactant

a�AA also seen in Muckle-Wells (renal amyloidosis, rti-caria, fevers, limb pains, and deafness) and familial Mediterranean fever

a�Dialysis-related amyloidosis: beta 2-microglobulin is the protein component altered by uremia → carpal tunnel syndrome, bone cysts, and spondyloarthropathy


Table4-2.Amyloidosis

Types Fibril Protein Other Features

Systemic

Primary

AL(lambdaλchain) Involvestongue,heart,GItract,andskin.Petechiae,purpura,waxyskincoloredpapules,alopecia,car-paltunnelsyndrome,neuropathy,arthropath

Secondary AA Resultofchronicdisease:TB,leprosy,Hodgkin’s,RA,Reiter’s,syphilisNoSkininvolementAmyloidintheadrenals,liver,spleen,andkidney

Localized Cutaneous

Macular AlteredKeratin Rippledbrownmaculesininterscapularregiononback,notalgiaparesthetica

Lichen AlteredKeratin Brown,scalypapulesonbilateralshins

Nodular ALchains Singleormultiplenodulesonextremities,genitals,trunk,orface

Hereditary

Familial MediterraneanFever

AA AR,intermittentfevers,renalamyloidosis,peritonitis,pleurisyMEFVgene;marenostrin/pyrinprotein

MuckleWells AA AD,periodicattacksofurticaria,fever,deafness,renalamyloidosis

HemodialysisAssoication

β2microglobulin

Senile Bamyloidprotein Senileorneuriticplaques,Alzheimer’sdisease

4.18 CALCIPhyLAxIS• Painfulviolaceouseschar-likeplaquesassociatedwithsofttissuenecrosis• Metastaticcutaneouscalcificationfromincreasedparathyroidhormone(andincreasedcalciumphosphateproduct)secondarytorenalfailure

• Treatment:Phosphatebindingagents,parathyroidectomy


4.19 ANGIoEDEmAReview of the Complement System

Classic Pathway• C1bindstoFcfragmentofIgMorIgGinimmunecomplexes• C1qdoesthebindingtoimmunoglobulin• C1sfragmentdigestsC4andC2,activatingthemintoaC4b,2acomplex,creatingC3convertase,thatactivatesC5convertase→ membraneattackcomplex

Alternative Aathway• Lessclear,butC3activatedbyaC3-convertasecomplexconsistingofC3b,bb• Duringinflammation,lowlevelsofC3bbindfactorb,thatundergoescleavagebyfactordtogenerateC3b,bb→ actsasaC3convertase

C1 Esterase Inhibitor• Proteaseinhibitor• Inhibitsthecatalyticsubunitsoffirstcomponentsofclassicalpathway(C1randC1s),kallikrein,plasmin

• InabsenceofC1esteraseinhibitor,activatedC1andplasmingenerateactivatedC2kinin• C2kininmediatesangioedema

AngioedemaTypeI:

•Occursinsettingoflymphoproliferativedisease(low-gradelymphoma,CLL,monoclonalgammopathyofundeterminedsignificance,systemicamyloidosis)orrheumatologicillness,whereidiotype/anti-idiotypeimmunecomplexesconsume availableC1q,andfunctionallyandquantitativelylowertheamountsofC1esteraseinhibitor• CanalsooccurinsettingofautoimmunitydirectedagainsttheC1esteraseprotein

• Importantpoint:inboththeinheritedandacquiredformslevelsofC2andC4aredecreasedbecauseoftheuncontrolledactionsofC1s

Clinical Presentation• Swellingofhead,neck,andextremities• Abdominalsymptoms• Upperairwaysymptoms• Recurrentsymptoms,withinterveningtimeofweekstomonths

Treatment• Androgentherapy:danazolorstanozolol→ bringaboutdramaticdecreasesinfrequencyandseverityofattacks

• Glucocorticoids,buttaperingresultsinrelapseofsymptoms• Therapyforunderlyingdisease• Pretreatmentwithandrogenspriortosurgicalprocedures

uTIPa Inherited (Quincke’s edema) (Normal C1q levels)

• Detectedinthefirstorseconddecadeof life • Autosomaldominantpatternofinheriance • SerumC1qnormalininheritedform • Defectinsynthesisand/orfunctionofC1

esterase inhibitor • TypeI:LowamountsofnormalC1sterase

inhibitor • TypeII:NormalamountsofdysfuncionalC1

esterase inhibor

aAcquired(LowC1q)

• Affectsadultorelderlywithnofamilyhistory

• SerumC1qdecreasedinacquiredform


Diagnosis• ScreenwithC3andC4levels→ C4low,C3normalinangioedema• C1qlevellowinacquired,butnormalinhereditary

4.20 CARCINoID SyNDRomE AND FLUShING DISoRDERS

Menopausal Flushing • Perimenstrualflushingwhenestrogenlevelslow• Hotbeveragesandemotioncanexacerbate• Pharmocologicmenopausecausedbydrugs:danazol,tamoxifen,clomophenecitrate,decapeptyl,leuprolide,and4-hydroxyandrostenedione

• Tuballigationoranysurgicallossofovarianfunction• Clinicalmanifestationsincludedrenchingperspiration,wakingepisodesduringthenight,prodromalsensationofoverheatingbeforetheonsetofflushingandsweating

• Treatwithoralestrogenreplacementorclonidinehydrochloride0.05mgbid

Emotional Flushing• Cantreatwithbiofeedback,hypnosis,andnadolol(40-80mgqd)

Foods• Monosodiumglutamate• Scombroidgroupoffish(tunaandmackerel)• Spicyfoods

Mastocytosis•Seeseparatesectionlaterinthischapter

Medications• Nicotinamide,disulfiram,metronidazole

Carcinoid Syndrome• <4%withabdominalcarcinoidtumorshavethecarcinoidsyndrome• Presenceofsyndromeimplieshepaticmetastases,extraabdominalcarcinoidtumor,orlargeenoughtumorburdensuchthatthelivercannotdegradetheincreasedlevelofhormone

• Tumorsderivedfromenterochromaffin(Kulchitsky)cells• Appendixismostcommonsite,followedbytheileum• Ilealtumorsarethemostcommonsourceoftheclassiccarcinoidsyndrome,andthesetumorsmetastasizemostfrequently

Clinical• Pellagra-likelesionscausedbyexcessiveutilizationoftryptophan→ hyperkeratosis,xerosis,scalingoflegs,forearms,andtrunk,angularcheilitis,andglossitis

• Rosaceastigmata• Yellow-brownorbrown-graypatchesontheforehead,back,andwrists• Pruritus• Chronicwaterydiarrheain85%• Abdominalpain,constipation,nausea,vomiting,malabsorption,anorexia,weightloss,smallbowelobstruction,andrectalbleeding

• Respiratorysymptomsofwheezing,stridor,dyspnea,coughing,andbronchospasm


• Arthritis,psychiatricsymptoms,osteoblasticbonelesions• Fibroticreactionsaffectingthevalvesoftheheart

Diagnosis• Serotoninoverproduction• Elevatedurinary5-HIAA• Foodsanddrugscanaffecttheurinaryexcretionof5-HIAA

4.21 LUPUS ERythEmAtoSUSClassification

Chronic Cutaneous LE• Discoid• Verrucous(hypertrophic)• LE-LPoverlap• Chilblain• LupusPanniculitis

Subacute Cutaneous LE• Papulosquamous• Annular• Neonatal• Complementdeficiencysyndromes

Acute Cutaneous LE• SystemicLEwithskinlesions→ localizedorgeneralizederythemawithbullae

Discoid Lupus• Youngadults,women:men2:1• Dullredmaculeswithadherentscalesextendingintopatulousfollicles• Pluggedfollicles• Patcheshealwithatrophy,scarring,dyspigmentation,andtelangiectasiaLocalized• Aboveneck:scalp,nose,malar,lips,ears• Pruritusandtendernesscommon• Mucosalinvolvementofmouth,nose,eyes,vulvacommon

Generalized• Lesscommonthanlocalized• Thoraxandupperextremities,inadditiontousualsitesabovetheneck• ElevatedESR,positiveANA,orleukopeniamorecommon

Course• 95%ofcasesconfinedtotheskinatoutsetwillremainso• AbnormallabssuchasANA,leukopenia,hematuria,oralbuminuriaidentifythosewhoprogress;also,rashaboveandbelowtheneck

• Relapsesarecommon• BCCorSCCoccurinscars,andafavoredsiteisthelowerlip


Treatment• Sunavoidance• Avoidexposuretoheat,cold,trauma• Topicalcorticosteroids(potent)withorwithoutocclusion• ILsteroids

Antimalarials• Firsthydroxychloroquine(Plaquenil),thenchloroquine,oraddquinacrine• Sideeffects:erythemamultiforme,purpura,urticaria,ocularrisksareverysmall,nausea,vomiting,tinnitus,abducensnerveparalysis,toxicpsychoses,leukopenia,andthrombocytopenia

• ExacerbatePCT• Bleachhair• Quinacrineyellowshairandconjunctivaebecomeyellow

Other Forms of Cutaneous LEVerrucous LE (Hypertrophic)• Non-pruritic,papulo-nodularlesionsonarmsandhands• ResemblesKA’sorLP• TreatwithILTAC

LE-LP Overlap Syndrome• SeeLPsection

Chilblain Lupus Erythematosus• Chronic,unremittingformwithlesionsonfingertips,ears,calves,andheels• Lesionsareduetocold• TreatmentisthesameasLE

LE Panniculitis• Deepdermalandsubcutaneousnodules,rubbery-firm,sharplydefined,andnontender• Head,face,upperarms,chest,buttocks,thighs• Chronic,inwomen20-45yearsold• DLEatothersites,commonly• Healswithatrophyanddeepdepressions• Treatwithantimalarialsformanymonths

Subacute Cutaneous Lupus• Scalypapulesthatevolveintoeitherpsoriasiformorpolycyclicannularlesions(morecommonly)

• Telangiectasiaanddyspigmentationalwayspresent• Nofollicularinvolvement• Noscarring• Occursonsun-exposedsurfacesoffaceandneck,innerarms,axillaeandflanks• Sparesknuckles• Photosensitivityin40%• Hardpalateinvolvedin40%• ConcomitantDLEin20%• AtleasthalfofthepatientsmeetARAcriteriaofSLE (usuallyhavearthralgia,arthritis,leukopenia,positiveANA)

• Diseaserunsamildcourse

uTIPa Majority positive for anti-Ro

a Drugs that may induce: HCTZ, enicillamine, glyburide, griseofulvin, piroxicam, spironolactone, diltiazem, ACE inhibitors, terbinafine


Neonatal LE• AnnularscalingerythematousmaculesandplaquesonheadandextremitieswithinthefirstfewmonthsoflifeinbabiesborntomotherswithLE,rheumaticdisease,orotherconnectivetissuedisorders

• 50%mothersasymptomaticatdelivery• Lesionsresolvespontaneouslyby6months,healingwithoutscarring• Photosensitivitymaybeprominent• 75%ofcasesinvolvegirls• Thrombocytopeniaandhepaticdiseaseasfrequentascardiacdisease

Complement Deficiency Syndromes• MostcommonlyC2andC4• Photosensitivity• AnnularSCLElesions• Roantibodyformation

Systemic LECriteria: 4 Needed• Malarerythema• DiscoidLE• Photosensitivity• Oralulcers• Nonerosivearthritis• Serositis(carditisorpleurisy)• Nephropathy• CNSdisorder(seizureorpsychosis)• Hematologicdisorder• Immunologicdisorder(positiveLEcellpreparation,anti-DNAorSm,false-positiveRPR)• PositiveANA

Cutaneousmanifestations •Butterflyfacialerythema,maybeassociatedwithedema→ lastsdaystoweeksandhealswithoutscarring

•Bullouslesions,sun-exposedareas→ histologicallylikeEBAwithantibodiesagainstcollagenTypeVII,butrespondstodapsone(EBAdoesnot)

•Fingertipsandtoetipsshowpuffyerythema,telangiectasias •Periungualtelangiectasias •Redlunulae •Erythematoustopurplishpalmsandsoles •Telangiectasiasonfaceorelsewhere •Diffusenonscarringhairlosswithshort,broken-offhairsinfrontalregion •Multiple(>15)dermatofibromas •Vasculitissecondarytoantiphospholipidantibody •Cryoglobulinemia,livedoreticularis,thrombophlebitis,cutaneousinfarction •Erythemamultiforme-likelesions(Rowell’ssyndrome) •Calcinosiscutis •Plaque-likedepositionsofmucin

uTIPa 50%havecongenitalheart

block,whichispermanent(thismaybetheonlymanifestationofdisease)


Pregnancy and SLE• Miscarriagesoccurwithgreaterfrequency• LEmayworsen,orgointoremissionduringpregnancy• Fetaldeathriskincreasedwithanti-cardiolipinoranti-Roantibodies• Postpartumperiodshowsthehighestrisktothepatient

Drug-induced LE• Usuallybenigncourse• Hydralazine→ 14%,withslowacetylators(HLA-DR4)

more prone• Procainamide→ 50%oftreatedpatients• Anti-histoneantibodycloselyassociatedwithsymptomaticdisease

• Penicillamineinducesnativedisease,withanti-dsDNAAb’s• HCTZinducesSCLE

4.22 SCLERoDERmAChronicdiseaseofunknownetiologyaffectingthemicrovasculatureandlooseconnectivetissue.

ClassificationLocalized Scleroderma• Morphea→ mostcommontype• Generalizedmorphea→ morphea,symmetricandbilaterallesions;butabsenceofRaynaud’s,acrosclerosis,andorganinvolvementdifferentiatesfromSSc

• Guttatemorphea(LS&A)• Nodularmorphea• Subcutaneousmorphea(morpheaprofunda)• Linearscleroderma→ bandlikelesionsthatmayinvolvethedeeperlayersoftheskin

Systemic Sclerosis• Limited(lSSc):60%,includesCRESTsyndrome;70-80%haveanti-centromereantibodiesandsystemicinvolvementmaynotappearforyears;patientsareolderthandSScandmanyoutlivethedisease;bettersurvivalrate(50%at12years)

• Diffuse(dSSc):AbruptonsetofswellingofthehandsandfeetwithRaynaud’sandhideboundchangesintheskin;polyarticularsymmetricsynovitis,tenosynovitisandtendonfrictionrubsoftenpresent;nailfoldcapillarydilatationanddestruction

• Earlyonsetofinternalorganinvolvement;anti-topoisomerase1antibodies(SCL-70)in30%;worsesurvivalrate(15%at12years)

EpidemiologyLocalized Scleroderma• Women:men3:1• Morecommoninwhites

Systemic Sclerosis• Women:men4:1• Morecommoninblackwomen,withdiffusediseasemorelikelytoaffectblackwomen• 7-yearsurvival75%

uTIPa Hydralazine, procainamide, sulfon-

amides, penicillin, anticonvulsants, minocycline, and INH

a Drug-induced LE not usually associated with skin, renal, and CNS manifestations


Scleroderma-like Disorders •Bleomycin:PulmonaryFibrosis,Raynaud’s,andcutaneous

changesindistinguishablefromSSc(reversibleupondiscontinuationofdrug)

•Scleroderma-likeskinchangesseeninscleromyxedema,PCT,GVHD

ClinicalLocalized Morphea• Circumscribedscleroticplaqueswithivory-coloredcentersandviolaceousborders(ifdiseaseactive)

• Plaquesmaybeelevatedordepressed,areinduratedbutnotboundtothedeeperstructures

• Mayoccurafterradiationtherapy• Allformsoflocalizedmorpheahavegoodprognosiswithdiseasebecominginactiveinthreetofiveyears

Generalized Morphea• Widespreadinvolvement• Multipleinduratedplaquesandhyperpigmentation• Uppertrunk,abdomen,buttocks,andlegs• Notassociatedwithsystemicdisease

Guttate Morphea (LS&A)• Multiplesmallchalk-whitelesionsthatlackthefirmcharacterofmorphea

Nodular Morphea• Lesionsresemblekeloids• Maycoexistwithmoretypicallesionsofmorphea

Morphea Profunda(SubcutaneousMorphea)• Deep,bound-down,scleroticplaques

Atrophoderma Pierini and Pasini• Idiopathicatrophyoftheskincharacterizedbysingleorseveraldepressedareasofskin• Lesionsarewell-definedwitha“cliffdrop”border

Linear Scleroderma• Single,unilaterallinearband• Lowerextremitiesaremostfrequentsite• Upperextremities,frontalhead(coup de sabre),thoraxalsoinvolved• Differentiatefrommorpheabyinvolvementofdeeperlayersofskinwithfixationtounderlyingstructures

• Maycauseseveredeformity• Maybeassociatedwithspinabifidaocculta

Melorheostosis• Linear,dense,corticalhyperostosis• Affectsaninvolvedlimbusually,butmaybewidespread

Parry-Romberg Syndrome• Facialhemiatrophy;maybeformoflinearscleroderma• Hyperpigmentationfollowedbyatrophyofthedermis,subcutaneousfat,muscle,andsometimesthebone

uTIPa Polyvinylchloride → scleroderma

withhepaticandpulmonaryfibrosis


Systemic Sclerosis• InitialcomplaintsrelatedtoRaynauld’sorchronicnonpittingedemaofthehandsandfingers

• Painandstiffnessofthefingersandknees• Firstmanifestationmaybemigratorypolyarthritis• Usually,skinchangesprecedevisceralinvolvementbyseveralyears• Diseaseextendstoupperextremities,trunk,face,andfinallythelowerextremities• Periorbitaledemamayoccurintheearlyedematousphase• Facebecomesmask-like• Lipsthin,andopeningofthemouthbecomesconstricted(microstomia)• Painfulindurationofthegumsandtongue• Matliketelangiectases• Thinningorcompletelossofhairandanhidrosis• Generalizedhyperpigmentationwithoutadrenalinsufficiency• Focalhyper/hypopigmentation• PeriungualtelangiectasiaoccurslikeinSLEandDM;75%ofthosewithsschaveenlarged,dilatednailfoldcapillariesforminggiantloops

• Recurrentpainfululcerationofthefingertipsandslow-healingulcersoftheknuckles• Boneresorptioncausingdissolutionoftheterminalphalanges• Cutaneouscalcificationoverfingertipsandoverbonyprominences→ mayulcerate

Systemic Involvement in SSC• Esophagealdysfunctionismostcommon(>90%)• Dysphagiafromdecreasedperistalsis,andmayoccurbeforeskinfindingsseen• Heartburn• Smallintestineinvolvementgivesrisetoconstipation,diarrhea,bloating,andmalabsorption• PulmonaryFibrosis• Earlypulmonaryinvolvementwithlowereddiffusingcapacityofthealveolocapillarymembranecorrelateswithchangesofthenailfoldcapillaries

• Cardiacconductiondefects,heartfailure,pericarditiswitheffusion;myocardialfibrosisseenin50-70%ofSSc

• Renaldiseasewithslowlyprogressiveuremia

CREST Syndrome• Telangiectasiasonface,uppertrunk,hands• Developslaterinlife• Esophagealdysfunctionisidenticaltothatofthemoresevereformsofthedisease• Anti-centromereantibodiesin50-96%,butonly12-25%inthosewithdSSc• Mixedconnectivetissuedisease:combinedfeaturesofscleroderma,LE,andmyositis→ hightiterstoribonucleoprotein

PathogenesisThreeprocessesoccur• Damagetovascularendothelium• Immunologicandinflammatoryactivation• Dysregulatedextracellularmatrixmetabolism

Course• Morpheaandlinearscleroderma→ fewmonthstomanyyears• 50%ofpatientswithlesionsthatdisappearareleftwithareasofhypo-ordepigmentation


• Coup de sabrelesionsmayremainunchangedorbecomemoreextensive• LimitedSScrarelyprogressestodSSc• VisceralinvolvementultimatelydevelopsindSSc• 5yearmortalityfordSScisabout50%→ pulmonaryfibrosisandrenalhypertensivecrisisindSSc;pulmonaryhypertensioninlSSc

ManagementLocalized Scleroderma• Generallyself-limited,sonotreatmentnecessary• HighpotencytopicalsteroidstolesionsaugmentedbyILsteroids• Antimalarials,phenytoin,colchicine,andsystemicsteroidshavelittlebenefitingeneralizedmorphea

• D-penicillaminemaysoftenskin,allowtheresumptionofskingrowth,andthecessationofnewlesions

• HighdoseUVA1(340-450nm)formorphea

Systemic Sclerosis• Azathioprine,chlorambucil,methotrexate,cyclophosphamidevariablysuccessful• Systemicsteroidsdonotaltertheoveralldiseasecourse• Cyclosporinemayresultindecreaseinskinthickness,butpulmonaryfunctionremainsunchangedandrenalfunctionmayworsen

• Extracorporealphotophoresisverycontroversial• D-penicillaminemaybeeffectiveifusedinearlydisease,withimprovedsurvivalcurvesinpatientsbecauseoflowerincidenceofrenaldisease;sideeffectslimitlong-termuse:autoimmunelupus/polymyositis,pemphigus,nephroticsyndrome,myastheniagravis,andGoodpasturesyndrome

• ACE-inhibitorsmarkedlyimprovesurvivalbytreatingrenaldisease• Peripheralvasospasmtreatedwithdiltiazem• Calcinosistreatedwithcalciumchannelblockers• Refluxesophagitiswithproton-pumpinhibitors• Physicaltherapy• CessationofsmokingdecreasesmorbidityinthosepatientswithdocumentedRaynaud’s

4.23 DERmAtomyoSItISWithorwithoutskinlesions,weaknessofproximalmusclegroupsistheprominentfeature.

Cutaneous Findings• Heliotroperash:Violaceouserythemaandswellingofperiorbitalskin• Gottron’spapules:Flat-topped,violaceouspapulesoverMCP,PIP,DIPjoints• Periungualtelangiectasiaswithfrayedcuticles• Erythematousorurticarialpatchesandplaquesonupperportionoffaceandextremities• Photosensitivity• Hyperkeratosis,scaling,fissuring,andhyperpigmentationoverthefingertips,sidesofthumb,andfingers

• “Mechanic’shands”• Raynaud’sphenomenon• Poikilodermaofchestorback(Shawlsing),Oronlateralthighs(Holstersign)• Calcinosiscutis:MoreofteninkidswithDermatomyositis


Muscle Changes• Symmetricweaknesswithswellingandpain,involvingshoulder• Difficultyswallowing,talking,orbreathing• Cardiacdiseaselateindisease• Skineruptionprecedesmusclesymptomsbytwotothreemonths• Amyopathicdermatomyositis:lackofmuscleinflammationafterayearorlonger

Associated Diseases• Sclerodermatouschanges→ sclerodermatomyositis(anti-KUantibodies)• Othercollagenvasculardiseases• Presenceofanti-Jo-1antibody,aswellasanti-PL-7,anti-PL-12(anti-synthetaseantibodies)correlateswellwithpulmonarydisease

Neoplastic Risk• Cancercanprecede,occursimultaneouslyas,orfollowDM• Malignancyusuallyin5thor6thdecadeoflife,andmorecommoninwomen

Incidence• Twiceasprevalentinwomen• Bimodalpeak:Smallpeakinchildrenandlargepeakinadultsbetween40and65

Laboratory Findings• Creatininekinase,aldolase,LDH,andtransaminaseelevations(AST>ALT)

• PerformEMGandMRItofinddiseaseactivity• Pulmonaryfunctiontests• Bariumswallowforesophagealdysmotility

Myositis Specific Antibodies(MSAS)• PositiveANAin60-80%ofpatients• Anti-Mi-2• Anti-p-155(linkedtocancerassociatedmyositisandamyopathicdermatomyositis)• Anti-Jo-1• Anti-CADM-140(inpatientswithamyopathicDM)• Anti-Ku,Anti-Srp

Treatment• Systemiccorticosteroids• Azathioprine• Methotrexate• Sunscreens• Antimalarials• Mycophenolatemofehl• Cyclophosphamide• Treatcalcinosiswithaluminumhydroxide,diphosphonates,diltiazem,colchicine,lowdosewarfarin

uTIPaOvarian cancer is overrepresented

uTIpaChildhood DM

• BrunstingType:morecommon,slowcourse,progressiveweakness,calcinosis,teroidresponsive

• BankerType:vasculitisofmusclesandGItract,rapidonsetofsevereweakness,steroidunresponsive,anddeath

uTIpa�Anti-Mi-2 AB’s correlate with shawl

sign, cuticular changes, and good prognosis

a�Anti-Jo-1 AB’s correlate with pulmonary fibrosis, Raynaud’s, polyarthritis

a�Anti-SRP AB’s correlate with cardiac disease and poor rognosis

a�Anti-Ku AB’s correlate with sclerodermatomyositis


Course• Majorcausesofdeatharecancer,ischemicheartdisease,andlungdisease

4.24 SjoGREN’S SyNDRomETriad

• Keratoconjunctivitissicca• Xerostomia• Rheumatoidarthritis• Morethan90%women• Vasculitis→ palpablepurpura• PatientsdeveloplymphoreticularmalignancysuchasNHL

Laboratory• Labialsalivaryglandbiopsy• SchirmerTestforxerostomiadetectsdiminishedglandularsecretion• RFpositive• Positivecryoglobulins• Anti-Ro• Anti-La• Antibodiestofodrin(93%specific)

4.25 CoNNECtIVE tISSUE DISEASE: SERoLoGy

Double-Stranded DNA Antibodies (dsDNA)• ELISAusedmorethanIF• PerformedonCrithidiaeLuciliae→ possessesgiantmitochondrionwithnossDNA• PositivityhighlycharacteristicofSLE→ highlycorrelativewithpositiveDIFinpatient’snormalskin(lupusband),lowcomplementlevels,renaldisease,andpoorprognosis

• HighlypositivelevelsconfirmdiagnosisofSLE;lowlevelsfoundinRA,Hashimoto’s,Grave’s,Waldenstrom’s,MCTD,SSc,Sjogren’s,autoimmuneliverdisease

• NegativetestdoesnotexcludeSLE(50-83%sensitive)

Single-stranded Antibodies• Verylowdiagnosticvalue→ detectedinLEandotherCTD’s(DM,morphea,Sjogren’s,andlinearmorpheaofchildren)

RNP Antibodies• Smallribonucleoproteins(SRNP)• SS-A(Ro),SS-B(La),SM,andU1RNP

Anti-Ro Antibodies• FoundinLE(varyingpercentagesbasedonsubsetofLE)andSjogren’s(50%)

• Stronglyassociatedwithphotosensitivity(especiallyinSCLE)

Anti-La Antibodies• Morethan90%withpositiveanti-Laalsopositiveforanti-Ro• Associateddiseasessimilartothoseassociatedwithanti-Ro

uTIPaHistoneAntibodies

• Characteristicofdrug-induced

SLE → >90%ofpatients • 30%ofpatientswithidiopathic

SLEhaveanti-histoneAb’s

uTIPa 100%ofpatientswithMCTD


Ro and La Helpful in Workup of Photosensitivity• ConfirmclinicaldiagnosisofSCLE,Sjogren’s,orneonatalLE• Patientswithchronicidiopathicvasculitis• UsefulintestingANAnegativepatientswithclinicalmanifestationsofsleorscle

Anti-U1RNP • 30%ofpatientswithSLE;patientswithSLEandanti-U1RNPalsohaveotherpositiveserologies

• MajorityofpatientswithpositiveU1RNPhaveSLEratherthanMCTD• Presenceassociatedwithsclerodactyly,Raynaud’s,esophagealdysmotility

Anti-Sm• DiagnosticofSLE,andnotreportedinpatientswithotherCTD’s• Foundin15-40%ofpatientswithSLE• Mostpatientswithanti-SMalsohaveantibodiestoU1RNP(converseisnottrue)

ANAsubstrate → humanHep-2cells;aserumnegativeonanimalsubstratemaybepositiveonhumancellsTiter→ negative or low in young andhealthypersons;highinthosewithsystemicCTD;lessthan1:80hasnodiagnosticvalue.

Patterns– Peripheral→ SLE → stainingnativeDNA(mostspecificpatternforSLE)– Homogeneous→ SLE → stainingnativeDNA,histones– Nucleolar→ SSc,SLE → stainingnucleolarRNA– Centromere→ CREST → stainingkinetochore– Speckled→ MCTD,SLE,SSc,Sjogren’s→ stainingribonucleoproteins

• ANA-negativeSLE → determinedoftenonanimalsubstrates,yetlaterfoundtobepositiveonhumancells,orifpatientonlymakesantibodiestossDNA(notdetectedbymosttests)

• AlmostallpatientswithSLEhavepositiveANAs• ANA:highnegativepredictivevalue,lowpositivepredictivevalue

Antiphospholipid Antibodies• Alsocalledthelupusanticoagulantandanticardiolipinantibodies• Associatedwiththrombosis(notbleeding)• MostprevalentinSLEpatients• Seeninpatientstakingcertaindrugs(cocaine,IFN-α,procainamide,hydralazine,quinine,quinidine,phenytoin,fansidar,phenothiazines),chronicinfections

• Indicationsfortesting– Livedoreticularis– Purpuraandnecrosis– Ulcers– Internalorganthrombosis– Recurrentmiscarriages– ScreeninginpatientswithSLE

uTIPaOther Antibodies

• Scl-70 (anti-topoisomerase) → characteristic of SSc, and defines presence of systemic involvement

• Anti-centromere → marker for creSt syndrome • Anti–jO-1 (histidyl trnA synthetase) seen in minority

of patients with dm and polymyositis → associated with pulmonary involvement and mechanic’s hand skin lesions


Table4-3.AntinuclearAntibodyPatterns

Pattern Associated Antibody Associated Disorder

Homogenous anti-histone SLEfalse+,DruginducedLE,SLE

Rim(peripheral) anti-dsDNA SLEnephritis

Speckled(finespeckled) anti-SmantiRoandLa(SSA/B)anti-U1RNPanti-Kuanti-topoisomerase(Scl-70)

SLESLE,SjogrenssyndromeSLE,MCTDSLE,scleroderma,myositisScleroderma,SLE

Centromere(discretespeckled) anti-kinetochore CREST

Nucleolaranti-RNApolymeraseanti-PM-Scl

anti-U1RNP Scleroderma,SLE

4.26 RELAPSING PoLyChoNDRItIS• Intermittentepisodesofinflammationofthearticularandnonarticularcartilage• Resultsinchondrolysis,dystrophy,andatrophyofthecartilage• Bothsexesequallyaffected• Onsetin4thto5thdecade

Clinical• Beefyredinvolvementoftheearsconfinedtothecartilaginousportion• Oftenunilateral• Acuteflareofinflammationlasts1-2weeks• 85-90%ofpatientsdevelopauricularchondritis• Conductivedeafnessbecauseofswollencartilage• Recurrentepisodesofchondritisresultindestructionofnormalcartilaginousstructuresandtheirfibroticreplacement→floppyorcauliflowerears

• Nasalseptalcartilageinflamed(50-70%)→rhinitis,crusting,bleeding,andsaddle-nosedeformity

• Involvementofbronchiresultsinhoarseness,coughing,anddyspnea• Migratoryarthralgiaseenin50-80%• Oculardisease:conjunctivitis,scleritis,iritis(anypartoftheeyemaybeaffected)• Cardiovascular:aorticregurgitationandaorticaneurysm• 1/3haveassociatedrheumaticorautoimmunediseaseandmanyhaveLCV

Laboratory• ElevatedESR

MAGIC Syndrome• Behçet’sandrelapsingpolychondritissimultaneously(mouthandgenitalulcerswithinflamedcartilage)


Pathophysiology• Autoimmunity:IgGanti-typeIIcollagenantibodieswithtiterscorrespondingtodiseaseactivity→foundinupto50%ofpatientswithrelapsingpolychondritis(inonly15%inthosewithRA)

• AntibodiesdirectedagainstnativeandnotdenaturedcollagenII• TypeIIcollagenrestrictedtocartilage

Course• Unpredictable;chronicandvariablewithepisodicflares(usually1-4weeks)andspontaneousremissions

• Peripheralarthritispredictsaworsecourse• Causesdeathin1/3ofpatientssecondarytoairwaycollapse,cardiovascularcomplications,andinfection(secondarytosystemicsteroids)

Treatment• Dapsone100mgQDtoBIDwithmaintenancedosefor4-6months→butmaybeineffectiveincontrollingscleralinflammation

• Systemicsteroids• Cyclosporine• NSAIDs• TNF-alphainhibitors

4.27 bEhCEt’S DISEASERecurrent Oral Ulceration

• Recurredatleast3timesin12monthperiod

Plus 2 of the Following:• Recurrentgenitalulceration• Eyelesions(posterioruveitis)• Skinlesions(erythemanodosum,pseudofolliculitis,papulopustularlesions,oracneiformnodules)

• Positivepathergytest

Clinical Features• Lesionsarepainful• CNSlesionsoccurandgivepictureofmultiplesclerosis• Thrombophlebitis• Thrombosisofthesuperiorvenacava• Asymmetric,non-erosivepolyarthritis• AssociatedwithHLA-B51

Treatment• Sucralfate• Colchicine• Dapsone• Thalidomide• TNF-inhibitingagentssuchasinfliximabandetanercept


4.28 LIVEDo REtICULARISPhysiologic

• Cutismarmorata

Intravascular Obstruction• Stasis• Cardiacfailure• Emboli• Cryoglobulinemia• Anticardiolipinsyndrome• Hyperoxaluria• Arteriosclerosis• Hyperparathyroidism• Arteritis(PAN,rheumatoidarteritis,LE,DM,syphilis,TB,pancreatitis)

Drugs• Amantadine,quinine,quinidine

4.29 LEUkoCytoCLAStIC VASCULItISDiversegroupofdisorders:combinesegmentalinflammationwithnecrosisofbloodvessels.

Maybeprimary,afeatureofasystemicdisorder,oridiopathic.

Pathogenesis• Postulatedthatcirculatingimmunecomplexesarelocallydeposited.Thecomplexesactivatecomplement,andthusattractneutrophils,whichreleaselysosomalenzymesanddamagetissue

• ANCAs,antineutrophilicautoantibodies– C-ANCAs(cytoplasmic)—specificforproteinase3– P-ANCAs(perinuclear)—specificformyeloperoxidase

• SeenwithhepatitisCinfection.ANCAsproducenecrotizingvasculitisbyactivatingcirculatingPMNsandmonocytes,whichthenadheretobloodvessels,degranulate,andreleasetoxicoxygenmetabolitestocausevascularinjury

Clinical Manifestations• Palpablepurpura–non-blanchingerythematouspapules• Papules,urticaria,angioedema,pustules,vesicles,ulcers,necrosis,andlivedoreticularis• Usuallyoccursonlowerextremitiesoroverdependentareassuchasthebackandglutealregions.Uncommononface,palms,soles,andmucousmembranes

• Palpablepurpurapersists1-4weeks,resolvingoftenwithtransienthyperpigmentationand/oratrophy

• Symptoms:pruritus,burning,andpainlesscommonly.Episodeassociatedwithfever,malaise,arthralgias,andmyalgias

Associated Chronic Disorders• Rheumatoidarthritis• Sjogren’ssyndrome• SLE


• Dermatomyositis• Hypergammaglobulinemicpurpura• Mixedconnectivetissuedisease,relapsingpolychondritis,andscleroderma• Paraneoplasticvasculitis• AssociatedmalignanciessuchasHodgkin’s,lymphosarcoma,adultT-cellleukemia,mycosisfungoides,myelofibrosis,AML,CML,IgAmyeloma,diffuselargecellleukemia,hairycellleukemia,squamouscellbronchiogeniccarcinoma,prostatecancer,renalcellcarcinoma,andcoloncarcinoma

• Cryoglobulinemia• ParticularlymixedtypesIIandIII• OccurinidiopathicLCV• AssociatedwithhepatitisA,B,andC• Cysticfibrosis• IBDofthecolon• Behçet’sdisease

ANCA’s• SeenwithhepatitisCinfection• Palpablepurpura

Antiphospholipid Antibodies• Livedoreticularisismostcommonfinding

Precipitating Infections• GroupAβhemolyticstreptococci• Staphylococcus aureus• Mycobacterium leprae–erythemanodosumleprosum,cutaneousnodularlesionsofleprosy,involvescapillaries,venules,arterioles,veins,andsmalltomediumsizedarteries

• HepatitisB• HIV• N. meningitidis • RockyMountainspottedfever• Catheterinfections

Precipitating Drugs• Penicillin• Sulfonamides• Thiazides• Allopurinol• Phenytoins• NSAIDs• PTUandhydralazineinassociationwithancas• Streptokinase• Radiocontrastmedia• Monoclonalantibodies• G-CSF


Idiopathic DisordersHenoch-Schonlein Syndrome• Mostwidelyrecognizedsubgroup• Mostlychildren• RecentURIin75%• Involvesskin,synovia,GItract,kidneys• Skinlesionsofadultsshowblistersandnecrosis• Long-termmorbidityfromkidneydisease,whichispredictedbythespreadofpurpuratotheuppertrunk

Acute Hemorrhagic Edema of Childhood• Affectschildrenandinfants<2yearsofage• Painful,edematouspetechiaeandecchymosesonheadanddistalextremities• Triggeringfactors:Infection,drugs,immunization• LackssystemicfeaturesofHSP,andresolveswithin1-3weekswithoutsequelae

Urticarial Vasculitis• Episodesofrecurrenturticariaandangioedema• Occurswithserumsickness,connectivetissuedisorders,infections(HepBandC,infectiousmononucleosis),physicalurticarias,coloncarcinoma,administrationofpotassiumiodide,fluoxetine,NSAIDs,andasanidiopathicdisorder

• Lesionsoftenpersistfrom3-5days,andusuallyhealwithoutresidua.Episodesarechronic,rangeindurationfrommonthstoyears

• 70%afflictedarewomen• Generalfeatures:Fever,malaise,andmyalgia,withpossiblelymphadenopathyandhepatosplenomegaly

• Episodicarthralgias• Renal:DiffuseGNorglomerulitis• GI:Diarrhea,nausea,vomiting• Pulm:Laryngealedema• Eye:Conjunctivitis,uveitis,episcleritis• CNS:Headaches,pseudotumorcerebri

Nodular Vasculitis• Recurrent,tender,red,subcutaneousnodulesoverlowerextremities,especiallythecalves;lesionscanoccuronthighs,buttocks,trunk,andarms

• Nosystemicmanifestations• Womenbetween30and40• Erythemainduratum:formofnodularvasculitisassociatedwithM. tuberculosis

Livedoid Vasculitis (AtrophieBlanche)• Recurrentpainfululcersoflowerextremitiesinassociationwithpersistentlivedoreticularis;oftendeeppurpleincolor

• Atrophieblanche:Healedlesionsresultinscleroticpaleareassurroundedbytelangiectases• Associatedwitharteriosclerosisorstasis• Pathogenesismaybesecondarytofibrinthrombiinlumensofsuperficialvessels• Sneddon’ssyndrome:Livedoreticularisandlivedoidvasculitisassociatedwithischemiccerebrovascularlesions,hypotension,andextracerebralarterialandvenousthromboses

uTIPa

Schnitzler’s syndrome: episodes of urticarial vasculitis that occur in association with monoclonal IgM M component. Fever, lymphadenopathy, hepatosplenomegaly, bone pain, and sensorimotor neuropathy


Genetic Domplement Deficiencies• C2,C4aandC4bseeninsomepatients

Eosinophilic Vasculitis• Idiopathicsyndromewithrecurrentpruritic,purpuric,papularskinlesionswithangioedema• Also,urticarialplaquesandpalpablepurpurapresent• Infiltrateofeosinophils

LCV Treatment• H1antihistaminesusedwithpalpablepurpuratoalleviatelesionalsymptoms• H1blockerswithNSAIDs• Colchicineorhydroxychloroquinecanbeaddedtoorsubstitutedfortheseagents;nobenefit,thenusedapsone

• Systemicsteroids,azathioprine,cyclophosphamide,plasmapheresis,cyclosporine• IFN-alphaclearslesionsinHepC

Urticarial Vasculitis• H1blockers,indomethacin,colchicine• Systemicsteroidsalleviatesurticariaandsystemicproblems

Erythema Elevatum Diutinum• Dapsone

Nodular Vasculitis• NSAIDs,colchicine,systemicsteroids

Erythema Nodosum Leprosum• Thalidomide

Livedoid Vasculitis• Aspirin,dipyridamole,colchicine,low-doseheparin,systemicglucocorticoids,andlowmolecularweightdextran,nifedipine,pentoxyfylline

4.30 CRyoGLobULINEmIA AND CRyoFIbRINoGENEmIACryoglobulinemia

Circulatingimmunoglobulinscomplexedwithotherimmunoglobulinsorproteinsthatrevers-iblyprecipitateinthecold.

Type I• Singlemonoclonalimmunoglobulin,usuallyIgGorIgM• Usuallyanunderlyingβ-cellmalignancysuchasmyelomaorlymphoma• AssociatedalsowithCLLandWaldenstrom’smacroglobulinemia• Purpura,acrocyanosis,retinalhemorrhage,Raynaud’sphenomenon,andarterialthrombosis

Type II (MixedCryoglobulinemia)• MonoclonalIgMrheumatoidfactorcomplexedwithpolyclonalIgG• Multiplemyeloma,Waldenstrom’s,CLL,rheumatoidarthritis,Sjogren’s,HepatitisC• LCVwithpalpablepurpura,arthritis/arthralgias,andvascularpurpura


Type III (MixedCryoglobulinemia)• RheumatoidfactorsthatarepolyclonalIgMandIgG,complexedwitheachotherorwithanotherprotein

• Oftencomplementactivatedandcomplementlevelsarelower• SLE,RA,Sjogren’s,infectiousmononucleosis,CMVinfection,primarybiliarycirrhosis,HepatitisB,HepatitisC

• LCVwithpalpablepurpura,arthritis/arthralgias,andvascularpurpura

Essential Mixed Cryoglobulinemia• Cryoglobulinsandthemanifestationofsymptomswithoutanidentifiableconnectivetissue,neoplastic,orinfectiousprocess

• OftenHCVinfectioncoincides

Clinical Features• Purpura,livedo,Raynaud’s,distalulcerations• Affectedorgansareskin,kidneys,liver,musculoskeletal,andnervoussystems

Cryofibrinogenemia• Cryoproteinsinanticoagulatedbloodorplasmathatreversiblyprecipitateinthecold• Composedoffibrinogen• Cutaneousmanifestations:purpura,ecchymoses,gangrene,ulcers• Associatedwithmalignancy,thromoembolicdisease,diabetes,pregnancy,oralcontraception,andpseudotumorcerebri

4.31 ACANthoSIS NIGRICANSCutaneousmarkerofeitherinsulinresistance,malignancyorobesity.

Clinical• Grayish-brown,velvetyplaques,hyperpigmentation,papillomatous• Mostcommontoleastcommonareas:axillae,neck,externalgenitalia,groin,face,innerthighs,antecubitalandpoplitealfossae,umbilicus,perianalarea

• Achrochordons• Tylosis:Palmoplantarhyperkeratosiswithacanthosispalmarisorpachydermatoglyphy(exaggerationoffingerprints,ortripepalms)

• Mucosalinvolvementconsistingofthickeningandpapillomatosiswithminimalhyperpigmentation

Associated Conditions• Insulinresistance,associatedwithobesity,withpositivecorrelationbetweendegreeofANandseverityofobesity

• Lipodystrophies(Lawrence-Seipsyndrome)• Leprechaunism–elfinappearanceofface,thickenedskin,absenceofsubcutaneousfat,andhirsutism

• TypeAsyndrome:Severeacanthosisnigricans,hirsutism,clitoromegaly,andmasculinehabitus• TypeBsyndrome:ANafterteenageyearswithlessextensiveinvolvement,withoftenunderlyingSLE(anti-insulinreceptorauto-antibodies)

• Malignancy:Moreextensiveandinvolvesmucosalsurfaces;usuallyadenocarcinomas(gastric)• Drugs:testosterone,nicotinicacid,diethylstilbestrol,oralcontraceptives,triazinate,glucocorticoids,topicalapplicationoffusidicacid


4.32 LIPoDyStRoPhy

Partial Lipodystrophy• Etiologyunknown• Lossofsubcutaneousfatinclearlydemarcated,generallysymmetricareas• Beginsonface,spreadsdownward,stoppingatanylevel→facebecomecachectic,withdisappearanceofbuccalfatpads;prematureagedexpression;sunkeneyes;easyvisualizationofveins

• Lowerpartofbodymaybeaffectedwithoutupperpartbeingaffected• Excessfatdepositionoverhipsandthighsfrequentlyinwomen• 80%female,andusuallybeginsbeforeage15

Laboratory• Hypertriglyceridemiaandinsulinresistance• Clinicallyapparentdiabetesin20%• Decreasedserumcomplement(C3)• IncreasedC3nephriticfactor→immunoglobulinthatbindsFactorH,aninhibitorofC3,allowinguncontrolledC3activation

• Glomerulonephritis(unknownfrequency)

Treatment• Noeffectivetherapy

Generalized Lipodystrophy• Etiologyunknown• Lackbothsubcutaneousfatandextracutaneousadiposetissue• Congenital(Seip-Lawrencesyndrome)• Acquired(Berardinelli-Seipsyndrome)• Often,acanthosisnigricans,hypertrichosis,generalizedhyperpigmentation,andthick,curlyscalphair

• Patientshavevoraciousappetites,perspireexcessively,andmaybeheat-intolerantdespitenormalthyroidfunction(elevatedbasicmetabolicrate)

• Muscles,genitaliaappearhypertrophic• Mentalretardationiscommon

Laboratory and Internal Disease• Glucoseintolerance(lipoatrophicdiabetes);insulinresistancedetectedearlierthandiabetes• Hepatomegalyresultingfromincreasedfat;cirrhosismaydevelop• Renal,retinal,andneuropathicdiabeticchanges• CTandultrasoundshowreducedfataroundviscera• Eruptivexanthomasmayappear

Treatment• Noeffectivetreatment


4.33 hyPERLIPoPRotEINEmIASType I

• Familiallipoproteinlipasedeficiency(AR)orapoproteinCIIdeficiency• Increasedchylomicrons• Eruptivexanthomas,lipemiaretinalis• Associatedwithhepatomegaly,pancreatitis,abdominalpain(“horrible,screamingpain”)

Type IIa• Familialhypercholesterolemia,commonhypercholesterolemia(AD)• IncreasedLDL• Tendinous,tuberous,xanthelasma,arcusjuvenilis,planar,eruptive• Secondarilycausedbyhepatoma,obstructivebiliarydisease,porphyria,hypothyroidism,anorexia,nephroticsyndrome,Cushing’s

• Atherosclerosis

Type IIb• Familialhypercholesterolemia(AD)• IncreasedLDLandVLDL• Tendinous,tuberous,xanthelasma,arcusjuvinilis,planar• SecondarilycausedbynephroticsyndromeandCushing’ssyndrome• Atherosclerosis

Type III• FamilialDysbetalipoproteinemia(AR)• IncreasedIDL• Palmar,planar,tendinous,tuberous,eruptive,intertriginousxanthomas• Secondarilycausedbyparaproteinemia• Atherosclerosis• Associatedwithdiabetes,gout,andobesity

Type IV• Familialhypertriglyceridemia(AD)• IncreasedVLDL• Eruptive,tendinous,tuberous• Secondarilycausedbydiabetes,uremia,paraproteinemia,alcoholism,lipodystrophy,obesity• Atherosclerosis

Type V• FamilialtypeVhyperlipoproteinemia,familiallipoproteinlipasedeficiency(AD)• IncreasedchylomicronsandVLDL• Eruptive,lipemiaretinalis• Secondarilycausedbydiabetes,obesity,andpancreatitis• Associatedwithhepatomegaly


4.34 xANthomAtoSISClinical Types and Associations

Tuberous Xanthoma• Flatorelevated,rounded,grouped,yellowish,ororangenodulesoverjoints(particularlyelbowsandknees)

• TypesII,III,andIV• Biliarycirrhosis

Tendinous Xanthoma• Papulesornodulesovertendons(extensortendonsondorsumofhands,feet,andachilles)• TypesII,III

Eruptive Xanthoma• Smallyellow/orange/redpapulesappearingincropsoverentirebody→buttocks,flexorsurfaces,arms,thighs,knees,oralmucosaandmaykoebnerize

• Associatedwithmarkedlyelevatedorabruptincreaseintriglycerides(elevatedchylomicrons)

• TypesI,III,IV,andV• Diabetes,obesity,pancreatitis,chronicrenalfailure,hypothyroidism,estrogentherapy,corticosteroids,isotretinoin,acitretin

Planar Xanthoma• Flatmaculesorslightlyelevatedplaqueswithyellow/tancolor,spreaddiffuselyoverlargeareas

• Frequentlyassociatedwithbiliarycirrhosis,biliaryatresia,myeloma,HDL-deficiency,monoclonalgammopathy,lymphoma,leukemia,serumlipoproteindeficiency,xanthomasfollowingerythroderma,RA,acquired C1esterasedeficiency

• Characteristicallyaroundeyelids,neck,trunk,shoulders,oraxillae• TypesII,III

Palmar Xanthoma• Nodulesandirregularplaquesonpalmsandflexuralsurfacesoffingers• TypeIII

Xanthelasma• Mostcommontypeofxanthoma• Eyelids,2-30mminlength• Frequentsymmetry• Usuallypresentwithoutanyotherdisease,butmayoccurconcomitantlywithotherxanthomas;canoccurintypesIIandIII,particularly

• Commonamongwomenwithhepaticorbiliarydisorders,alsoseeninmyxedema,diabetes,andphytosterolemia

• Besttreatedwithsurgicalexcision

4.35 VItAmIN DEFICIENCIESAlcoholismisthemaincauseofnutritionaldiseaseindevelopednations.Otherconditions:• Postoperativepatients• Psychiatricpatients• Unusualdiets• Inflammatoryboweldisease

uTIPa�Xanthomastriatapalmaris:diagnosticoftypeIII

dysbetalipoprotinemia(broadbetadisease)


• Cysticfibrosis• Surgicalboweldysfunction• Inbornerrorsofmetabolism

Vitamin APhrynoderma (HypovitaminosisA)• Diseasesoffatmalabsorption:Crohn’s,celiacdisease,CF,cholestaticliverdisease• Requiredfornormalkeratinization• Deficiencyleadstoinflammatorydiseaseofgutandlung• Supplementationrequiredinrubeola(200,000IU/dayfor2d)

Clinical• Phrynoderma→toadskin,keratoticpapulesoverextremitiesandshoulderssurroundingpilosebaceousfollicles

• Spreadstoinvolveabdomen,back,buttocks• Wholeskindrynessandfinescaling• Nightblindness• Xerophthalmia• Keratomalacia

Hypervitaminosis A• Similartosideeffectsofsyntheticretinoidtherapy• Proneindividuals:Children,hepaticdisease,dialysispatients• AllVitaminAsupplementationshouldbestoppedifpatienttakingaretinoid

ClinicalChildren

• Lossofhairandcoarsenessofremaininghair• Lossofeyebrows• Exfoliativecheilitis• Generalizedexfoliationandpigmentationofskin• Clubbingoffingers• Bonegrowthretardation• Pseudotumorcerebri(bulgingfontanellesininfants)

Adults• Drynessoflips• Anorexia• Jointandbonepains• Follicularhyperkeratosis• Desquamationofskin• Fissuringofcornersofmouthandnostrils• Lossofscalphairandeyebrows• Naildystrophy

Vitamin D• Deficiency:Alopeciaonlyskinmanifestation• Elderly:Resultsfromdecreasedsunexposureandpoorintake• Thosetakinganticonvulsants• Fatmalabsorption• ExtensivesunprotectionandsunscreendoesnotleadtoVitaminDdeficiency• Excess:Hypercalcemiaandgeneralizedcalcinosis


Vitamin K• Doesnotoccurinadults(synthesizedbybacteriaingut)• Deficienciesoccurbecauseofmalabsorptioncausedbybiliarydisease,malabsorptionsyndromes,CF,anorexianervosa,liverdiseaseofallcauses

• Drugssuchascoumadin,salicylates,cholestyramine,cephalosporins• Cutaneousmanifestations:purpura,hemorrhage,ecchymosis

Vitamin B2 Deficiency (Riboflavin)• Mostofteninalcoholics• Oral-ocular-genitalsyndrome• Angularcheilitis• Atrophictonguethatismagenta• Seborrheic-likedermatitisaroundnose• Genitaldermatitis→scrotaldermatitissparingmidlineandextendingtothighs• Photophobiaandblepharitis

Vitamin B6 Deficiency (Pyridoxine)• Causedbyuremiaandcirrhosis;pharmacologicagents• Seborrheicdermatitis-likeeruption• Atrophicglossitiswithulceration• Angularcheilitis• Conjunctivitis• Intertrigo• Neurologicsymptoms:somnolence,confusion,neuropathy

Vitamin B12 Deficiency• Deficiencyofintrinsicfactor,achlorhydria,ilealdisease,congenitalabsenceoftranscobalaminII

• Occurs3-6yearsafterGIabnormalities• Glossitis→brightred,atrophictongue• Hyperpigmentation→resemblesAddison’sdisease• Canities• Neurologicfindings

Folic Acid Deficiency• Hyperpigmentation,glossitis,cheilitis,andmegaloblasticanemia,identicaltoVitaminB12deficiency

Vitamin C Deficiency (Scurvy)• Malealcoholicsandpsychiatricpatients• Hemorrhagicsigns,hyperkeratosisofthehairfollicles,hypochondriasis,andhematologicabnormalities

• Perifollicularpetechiae• Subperiostealhemorrhageleadingtopseudoparalysis• Subungual,subconjunctival,intramuscular,andintraarticularhemorrhage• Hemorrhagicgingivitis• Epistaxis• Delayedwoundhealing


Niacin Deficiency (Pellagra)• Canresultfromdeficiencyinniacin(VitaminB3ornicotinicacid)oritsprecursortryptophan

• Alcoholics• Carcinoidtumors• Hartnupdisease(impairedabsorptionoftryptophan)• GIdisorders• ProlongedIVsupplementation• Anorexianervosa• Medications:INH,azathioprine,5-FU

Clinical• Photosensitiveeruptiononface,neck,andupperchest(Casal’snecklace);maybevesiculobullous

• Thickeningandpigmentationoverbonyprominences• Seborrheicdermatitis-likeeruptionontheface• Diarrhea,depression,abdominalpain,dementia,coma• Patientsdieinfourtofiveyearsifuntreated

Pathology• Mostcharacteristic→pallorandvacuolarchangesofkeratinocytesintheupperlayersofthestratummalphighii,justbelowthegranularlayer;acleftmaydevelopinupperepidermis

Biotin Deficiency• Patientswithshortgutormalabsorption• Ingestionofavidin(raweggwhites)bindsbiotincausingdeficiency• Multiplecarboxylasedeficiency• HolocarboxylasesynthetasedeficiencyClinical• Dermatitisissimilartozincdeficiency→periorificialandmarkedbypatchy,red,erodedlesionsoffaceandgroin

• Conjunctivitis• Alopecia

Zinc Deficiency• Inheritedabnormality,oracquired• Presentationininfancymostcommon→especiallyprematureinfants• Humanbreastmilkhasadequatezinc,andweaningprecipitatesdeficiencyinprematureinfantsandthosewithacrodermatitisenteropathica

• Lowmaternalbreastmilkzinclevelsorhigherinfantrequirementscanprecipitatedeficiencyinfull-terminfants

• Zincrequirementsincreaseduringmetabolicstress(infection)

Clinical• Pustularandbullouslesionsinanacralandperiorificialdistribution• Patchy,red,dryscalingwithexudationandcrusting• Angularcheilitisandstomatitis• Periungualerythema,scaling,andpustules• Patientsareirritableandemotionallylabile


Labs• Lowserumzinclevels• Lowalkalinephosphatase(azinc-dependentenzyme)

Essential Fatty Acid Deficiency• Infantswithlowbirthweight• GIanomalies• Inflammatoryboweldisease• Intestinalsurgery• Parenteralnutrition(prolonged)

Clinical• Similardermatitistothatofzincandbiotindeficiency• Widespreaderythemaandintertriginousweepingeruption• Diffusealopecia• Ratioofeicosatrienoicacidtoarachidonicmorethan0.4diagnosticofEFAdeficiency

Iron Deficiency• Koilonychia,glossitis,angularcheilitis,pruritus,andtelogeneffluvium• Plummer-Vinson:Microcyticanemia,dysphagia,andglossitisseennearlyentirelyinmiddle-agedwomen;lipsarethinandopeningofmouthissmallandinelastic

Marasmus• Prolongeddeficiencyofbothproteinandcalories• Children60%oftheiridealbodyweight• Noedemaorhypoproteinemia• Skinisdry,wrinkled,andloose

Carotenemia• Excessiveingestionofcarrots,oranges,squash,spinach,yellowcornandbeans,butter,eggs,rutabagas,pumpkins,yellowturnips,sweetpotatoes,orpapayaleadingtoyellowishdiscolorationofskin

• Prominentonpalms,soles,andcentralface

Lycopenemia• Excessiveingestionofredfoodsliketomatoes,beets,chilibeans,andvariousfruitsleadstoreddishdiscolorationofskin

4.36 DIAbEtES AND SkIN DISEASEInfections

• Staphpyodermas• Candidiasis• Erythrasma• Epidermophytosis

Xanthomatosis• Chylomicronemiawithxanthomas• Regressionwhendiabetesbroughtundercontrol

uTIPaKwashiorkor

• Proteindeficiencybutadequatecaloricintake

• Edemaandpotbelly

• Hypopigmentedhair →reddish yellowtograyorwhite

• “Flagsign” → hairgrownduringperiodsofpoornutritionispale


• Xanthelasma:Occursinhyperlipidemicstates(includingdiabetes)andmayoccurwithoutdemonstrableabnormalityofplasmalipids

Diabetic Dermopathy• Asymptomatic,irregularlyshapedpatchesoveranteriorlowerlegs• Depressedandbrownsurfaces• Oftenaccompaniedbysignificantmicroangiopathyelsewhereinbody

Bullous Lesions/Bullous Diabeticorum• Spontaneousbullaeonextremities,especiallyofthefeet• Healwithoutscarringwithinweeks• Bullaeoccurinplaneofbasementmembraneabovebasallamina

Thickened Skin and Stiff Joints• 1/3ofpatientshavetight,thickenedandwaxyskinoverdorsaofthehands• Multiple,minute,flesh-coloredpapulesondorsumoffingers,knucklepads,andperiungualareas

• Contracturesofhands• Scleredemaadultorum

Cutaneous Neuropathy• Autonomicdisturbancesthataccompanyneuropathyincludinganhidrosis

Necrobiosis Lipoidica• 0.3%ofdiabetics• 3:1female:male• OnlyaminorityofthosewithNLDactuallyhavediabetes• Anteriorandlateralsurfacesoflowerlegs,usually(alsoface,arms,andtrunk)• Beginsassmall,dusky-redelevatednodulewithsharplycircumscribedborder,enlargingtoanatrophicplaque

• Brownish-yellowcenter,redborder• Extremelychronicandindolent• Diabetesmayprecede(80%)oroccursubsequenttodevelopmentoflesions(10%);resthavenoglucoseintolerance;mosthaveabnormalglucosetoleranceinresponsetoglucocorticoids

Granuloma Annulare• GeneralizedformmorecommoninDM

Vitiligo• GreaterthanexpectedincidenceinpatientswithDMType1• Mayprecedeclinicallyevidentdiabetes

Acanthosis Nigricans• Seeseparatediscussion


4.37 LANGERhANS CELL hIStIoCytoSISHistiocytosis X

• ProliferationofdendriticorLangerhanshistiocytes

Morphology• Rose-coloredpapules,somescaling,crusting,andulceration• Mergingoflesionsonscalpgivesseborrheicdermatitisappearance• Nailchanges:Paronychia,nailfolddestruction,onycholysis,subungualhyperkeratosis(poorprognosticsigns)

Systemic Manifestations• Extremelyvariable• Pulmonaryinvolvementin>50%→lungsshowhoneycombappearance;dyspnea,cyanosis,andpneumothorax

• Hepatosplenomegaly:Nevertheinitialsignofdisease• Bonelesions(60%)• Hematopoieticinvolvement(rare)• Fever

ClassificationLetterer-Siwe Disease• Acute,disseminatedLCH• Firstyearoflife• Cutaneousdiseasemorecommoninthisentity(80%),andusuallyinitialsign• Fever,anemia,thrombocytopenia,enlargementofliverandspleen(neverpresentingsign)• Potentiallyfatalvisceralinvolvement• Onlyosteolyticlesionisinmastoidbone(lookslikeotitismedia)

Hand-Schuller-Christian Disease• Earlychildhood• Lessextensivevisceralinvolvement• Chronic,multifocaldisease• Cutaneousdiseaseinonly30%• Osseouslesions,especiallyofcranium(80%)• Exophthalmos(10-30%)• Cancausediabetesinsipidus(50%),causedbygranulomatousinfiltrationofposterior

pituitary gland

Eosinophilic Granuloma• Olderchildrenandadults• Benign• Oneorafewbonelesions• Affectsskull,ribs,andvertebraemostfrequently• Canaffectmucosa

Hashimoto-Pritzker Disease (Congenital,Self-healingReticulohistiocytosis)• Presentatbirth,usually• Nomucousmembranelesions• Systemicsignsabsent• Rapidspontaneousregression


Course and Prognosis• Skinandboneinvolvementgoodsigns,andorganinvolvementbad• 10%withmultifocaldiseasedie,60%havechroniccourse,30%showcompleteremission

ManagementTreatmentbasedonage,extentofdisease,andlocationoflesions

Children• Nonaggressivemanagement• Observation• Topicalnitrogenmustardforpersistentlesions

Adults• Topicalnitrogenmustard• PUVA• CO2laser• Thalidomide• Isotretinoin

Bone Involvement• Surgicalexcision• Glucocorticoidinjections• Radiotherapyinadults• Monochemotherapyformultiplebonelesions

4.38 CUtANEoUS t-CELL LymPhomA

Clinical TypesPatch and Plaque Stage• Flatlesionsassociatedwithinflammationandpruritus,thatcanpersistforyearsorresolvespontaneously

• Patchstagecanlastformonthstoyearsbeforeprogressing• Plaquescanarisede novo

Hypopigmented MF• Darker-skinnedpatients• Patientsrespondtotherapybyregainingpigment

Pigmented Purpura• Capillaritis

Granulomatous CTCL and Slack Skin• Primarilyinfemales• Largeregionsofslackskinaccompaniedbyfibroticbands

Pagetoid Reticulosis (Woringer-KoloppDiseaseorAcralMF)• Typicallypresentsasasolitaryplaque(localized)• Longduration,slowgrowing• Benign;longdurationwithoutprogression• Pronouncedepidermotropism• FollicularMF


Alopecia Mucinosa• Follicularmucinosis• Groupedfollicularpapulesorred,raised,boggy,occasionallynodularplaques• Alopeciamaybepresentingsign• Histology:Sebaceousglandsandouterrootsheathsdisruptedwithincreasedmucindeposition

• CTCLmaybepresentbeforedevelopmentofalopeciamucinosa

Erythrodermas• De novo orasaprogressionfrompre-existingCTCLlesions• Mayleadtoleoninefacies• Alopecia,ectropion,naildystrophy,ankleedema• Sezarysyndromemaycause

Tumor Stage MF• Predilectionforfaceandbodyfolds• Mayoccurinpre-existingplaquesandpatchesofCTCL• Neoplasticcellsmoremalignantbiologically• Nodulesmayulcerate• Mayspontaneouslyresolve,butprognosisispoor• Infiltratedenserthanplaquestage,andextendstosubcutaneousfat• Epidermotropismisnotaprominentfeature,andgrenzzonemayappear

Diagnosis• Diagnosismadebybiopsy• Multiplepunchbiopsiesat3monthintervalsmaybeneeded• Anypatientwithchronic,refractorydermatosis(ACD,AD,psoriasis,PRP)shouldbebiopsiedtoruleoutCTCL

• Clonalityassistsindiagnosis,butisnotpathognomonic

Peripheral Blood• MalignantclonalT-cellpopulationsrecirculatefromskintolymphnodes,andthentoblood,eveninpatchstagedisease,CD4+/CD7-

• ElevatedCD4/CD8ratioindicatesdiseaseexpansionintoblood• Flowcytometrymustbeacomponentinthestagingprocess(CD4/CD8),CD3,CD45RO• MemorycellmarkerCD45ROiselevatedoftenincasesofperipheralbloodinvolvementbyCTCL

Sezary Cells• Hyperchromaticandhyperconvolutednuclei• RepresentanactivatedT-cell• Canbeseenininflammatorydermatoses,andinDilantin(phenytoin)hypersensitivitysyndrome• 100cellscountedtoassesspercentage,and>5%associatedwithpoorprognosis

Prognosis• Involvementof10%orlesswithpatchdisease:mediansurvivalof12years• Tumors,erythroderma,ornodeinvolvement:mediansurvival2-3years• Sezarysyndrome:2-3years


Topical Chemotherapy• Nitrogenmustard(bis-chloronitrosurea,BCNU);mechlorethamine(10mgin50mltapwaterasinitialdose)

• Ointment-basedmechlorethaminehaslongershelflife• Sideeffects:Hypersensitivity,primaryirritation,secondcutaneousmalignancies,hypoandhyperpigmentation

• Dailywhole-bodyapplicationrequireduntilremission,afterwhichfrequentmaintenancetherapyused

Radiotherapy• Electronspenetrateonlytoupperdermis• Wholebodyirradiationinducescompleteremissionin>80%;withrelapseratehigherinlaterstagesofCTCL

• Mostrelapsesoccurwithinfirstyearaftercessationoftreatment• Localsideeffects:Alopecia,atrophyofsweatglandsandskin,radiodermatitis,andedema;fractionatingdosereducessideeffects

• SCCincidenceincreased• 2ndand3rdcoursesacceptableifneeded

Photochemotherapy• PUVA• Inducesremissionevenintumorstages

Extracorporeal Photochemotherapy• Photoinactivationofaportionofthepatient’slymphocytecompartmentwith8-methoxypsoralen+UVA,followedbyreinfusion

• Twoconsecutivedayseveryfourweeks• Effectiveforerythroderma• Requires4-12monthsforresponse

Alpha and Gamma Interferon• 10-27%completeresponsewithin6monthsusingmonotherapy• 3millionunits3x/week,andcanbeincreasedto20millionunitsperdayastolerated• Maintenancedoseof1millionunitsdaily• Toxicities:Flu-likesymptomsfirstweek.Sideeffects:chronicfatigue;long-termneurologictoxicitymayoccur,andautoimmunephenomenasuchasproteinuria,thrombocytopenia,and anemia

DAB-IL-2 Toxin/Denileukin Diftitox• DiphtheriatoxinfusedtoIL-2,bindingtoreceptor,killingcells• InfiltratesmustcontainhighlevelsofIL-2receptor-positivecells• Maycausefluidretention,diffuseerythema,andliverabnormalities,whichareallreversible

Systemic High-Dose Chemo• Palliative• Glucocorticoids,adriamycin,CHOPtherapy


4.39 PyoDERmA GANGRENoSUmFour Types

Ulcerative• Inflammatorypustulewithsurroundinghalo• Enlargesoverdaysandulcerates• Manylesionsbeginatsitesoftrauma(pathergy)• Distinctrollededgesandshowsatelliteviolaceouspapulesthatbreakdownandfusewithcentralulcer

• Painful• Adults40-60yearsoldonlowerextremitiesandtrunk• Healwiththin,atrophicscars

Pustular• Describestheprimarypustularlesionsthatmayormaynotprogressontoulcerativelesions

• OftenseenassociatedwithIBD• Associatedwithpyostomatitisvegetansandsubcornealpustulardermatosis

Bullous• Lessdestructive,moresuperficial• OverlapwithatypicalSweet’s• Patientswithleukemiaorpolycythemiavera• Redinflammatoryplaquesthatbecomeduskyanddevelopsuperficialerosionoftheepidermis

• Lesspainfulthanulcerative

Vegetative• Leastaggressiveform• Cribiformchronicsuperficialulcerationsonthetrunk,usually• Notpainful• Notoftenassociatedwithsystemicdisease

Clinical Associations• 1.5-5%ofpatientswithIBDdevelopPG• Diseasesrunseparatecourses• Associatedwithleukemia,myeloma,monoclonalgammopathy(IgA),polycythemia,chronicactivehepatitis,HCV,HIV,SLE,pregnancy,andTakayasu’sArteritis

• AssociatedwithPAPAsyndrome→pyogenicarthritis,pyodermagangrenosum,severecysticacne

• 33%havearthritis→asymmetrical,seronegative,monoarticulararthritisofthelargejoints• Childrenwithcongenitaldeficiencyofleukocyte-adherenceglycoproteins

Histology• Massivedermaledemawithepidermalneutrophilicabscessesattheviolaceousunderminedborder

Treatment• Iflesionspustular,seekandtreatforunderlyingIBD• Aggressivenessoftreatmentdeterminedbyseverityofdisease

uTIPa50% have associated disease, most commonly is IBD (UC > Crohn’s)


• Localtreatment:Compressesorwhirlpoolbathswithuseofointmentocclusivedressings• PotenttopicalsteroidsorILsteroids• Topicaltacrolimus• Systemicsteroids,andifnotresponding,pulsemethylprednisolone• Sulfapyridine,sulfasalzine,anddapsone• Clofazamine200-400mgqd• Cyclosporineisthenextchoice,with85%ofreportedcasesrespondingdramatically:startat5mg/kg

• Infliximab• Otheragents:thalidomide,SSKI,azathioprine,cyclophosphamide,chlorambucil

4.40 SWEEt’S SyNDRomEAcute Febrile Neutrophilic Dermatosis

• Recurrentpainfulplaque-forminginflammatorypapules,fever,peripheralleukocytosis,adiffusedermalinfiltrate,andpromptresolutionofsymptomsandlesionswithglucocorticoidtherapy

ClinicalSkin • Suddeneruptionoftenderredorbluishredpapulesornodulesoverface,neck,upperextremities

• Coalescetoformirregularsharplyborderedplaques(“reliefofamountainrange”)

• Transparentvesicularappearance,thoughsolid(“illusionofvesiculation”)• Eventuallyresolvewithoutscarringafterweeksormonths

Systemic• Fever,leukocytosis,withpatientsappearingdramaticallyill• Headache,arthralgia,myalgia,andgeneralmalaise,conjunctivitis,andepiscleritis• Bone:Sterileosteomyelitis• Neuro: Asepticmeningitis,neurologicandpsychiatricsymptoms,withneutrophilsintheCSF

• Renal:Proteinuria,hematuria,glomerulonephritis• Hepatic:InfiltrationofportaltriadandtractswithelevatedLFT’s• Pulmonary:Culture-negativeinfiltrates

Laboratory• ElevatedESR• Peripheralleukocytosiswithneutrophilia• Malignancy-associatedSweet’s:anemia,normalorlowneutrophilcountandabnormalplateletcount

• Proteinuriaifrenalinvolvement

Etiology• Noknowncause.Thoughttobeahypersensitivityreaction• Majorityofpatientshaveafebrileupperrespiratorytractinfection,tonsillitis,orinfluenza-likeillnessthatprecedestheirskinlesionsby1-3weeks

• CanbeassociatedwithintestinalinfectionwithYersiniaenterocolitica

uTIPa Face, upper extremities, and

neck, most commonly

uTIPaCan be drug-induced (GCSF)


Pathology• Edemaofthedermalpapillaeanddenseinfiltratecomposedlargelyofneutrophils,withsomelymphocytesandhistiocytes,andoccasionaleosinophils

• Infiltrateisbandlikeinpapillarydermis(“Seaofneutrophils”)• Leukocytoclasiacommon

Associated DiseasesProbable Association• Infection:UsuallyupperrespiratorytractandGItract• Inflammatoryboweldisease• Medications:G-CSF–anemiacommonlyassociated,andTMP-SFX

• PregnancyTreatment• Corticosteroids• PotassiumIodide

4.41 ERythEmA ANNULARE CENtRIFUGUm• Polycyclicerythematouslesionsthatgroweccentricallyandslowly• Oftenrecurrent• Characteristictrailingscaleatinnerborder• Characteristiclymphocyticcoatsleevingofvascular/adnexaeonpathology

Associations• Idiopathic• Malignancy• Dermatophyte(feetandgroin) Butnoextensiveworkupnecessary

4.42 ERythEmA ELEVAtUm DIUtINUmClinical Features and Course

Morphology• Multiplelesions:Papulesplaquesornodules• Earlylesionsoftenpinkoryellow.Olderlesionsareredorpurpleandharder.Lesionsmayberoundoroval,andsurfaceissmoothwithoccasionalscale.Also,freelymovablefromunderlyingtissues

Distribution• Symmetriconextensorsurfaces,especiallyskinoverlyingjoints,especiallyonhandsandknees.Alsoinvolvethebuttocksandskinoverlyingtheachillestendon

Symptoms• Asymptomatictoverypainful

Associated Symptoms and Conditions• Arthralgia(mostcommon)• Recurrentpharyngealandsinopulmonaryinfection,usuallystreptococcal• Inflammatoryboweldisease

uTIPa

Malignancy, most commonly hematologic (AML); lesions may precede diagnosis of leukemia


Course• Variable,butoftenprogressiveover5-10years,withlong-termremissionpossible• Periodsofwaxingandwaning

Laboratory Findings• ElevationinESR

Treatment• Dapsoneorsulfapyridine–withexacerbationafterthedrug’swithdrawal• Glucocorticoidsnoteffectivesystemically,butintralesionalandtopicalhighpotencysteroidsmaydecreasethesizeoflesions

4.43 ERythEmA NoDoSUmExtensorsurfaces,lowerextremities:inflammatory,spontaneously

regressing,tender,nodularlesions.

Clinical• Erythematous,tendernodulesonanteriorshins;alsoseenonthighs,lateralaspectsoflowerlegs,arms,andface

• Onsetofnewlesionsoftenaccompaniedbyfever,chills,malaise,andleukocytosis

• Oftenprogressesintoaviolaceousbluecolor• 70%haveassociatedarthropathythatmaypersistafterdisappearanceoferuption

• Occursatanyage,butmostprevalentbetween20and30yearsofage• Resultsfromimmunologicreactiontriggeredbydrugs,benignandmalignantsystemicillness,bacterial,viral,andfungalinfections

Infections• Streptococcal,betahemolytic:cutaneouslesionsdevelopwithinthreeweeksofinfection• Tuberculosis:Associatedwithprimaryinfection• Yersinia• Blastomycosis,coccidioidomycois,histoplasmosis;dermatophytes,particularlythosecausingtineacapitiswithkerionformation

• Oftenoccursafteracuterespiratoryillnessthatisnonstreptococcalforwhichnoagentidentified

• Viruses:paravaccinia,infectiousmononucleosis,lymphogranulomavenereum,cat-scratchdisease,psittacosis,HepatitisB

Sarcoidosis• Maybepresentingsignalongwithhilaradenopathy• Lofgren’ssyndrome:sarcoidosis,erythemanodosum(goodprognosis)

Drugs• Sulfonamides• Bromides• Oralcontraceptives

uTIPaIgA (mainly) or IgG or IgM monoclonal gammopathies or even myeloma

MNEMONIC Erythema Nodosum

SHOUT BCG

Sarcoid,Sulfa,Strep Histoplasmosis Oralcontraceptives Ulcerativecolitis TB

Bechet’s Crohns GI(Yersinia)


Enteropathies• UlcerativecolitismorefrequentlythanCrohn’sdisease

Miscellaneous Causes• Behçet’ssyndrome• Malignancy:Lymphoma,leukemia,cervicalcancer• Onsetofradiationtherapyforcancer

Treatment• Spontaneousresolutionusuallyoccurswithinthreetosixweekswithoutscarring• NSAIDssuchasindomethacinornaproxen• Systemicsteroidseffectiveinseverecasesandcanbedangerousifinfectionisetiology• Potassiumiodide400to900mgdaily

4.44 mAStoCytoSIS• Mastcellhyperplasiainthebonemarrow,liver,spleen,lymphnodes,GItract,andskin• Clinical:Pruritus,flushing,urtication,abdominalpain,nausea,vomiting,diarrhea,bonepain,vascularinstability,headache,andneuropsychiatricdifficulties

Etiology and Pathogenesis• Originatefrompluripotent(CD34+)bonemarrowcells→circulatethroughblood→ mature intofullygranulatedcells

• Mutationsinc-kit→associatedwithenhancedreceptorfunction• Increasedproductionofmastcellmediators: –Histamine –Heparin –Tryptase –Leukotrienes –ProstaglandinD2 –Plateletactivatingfactor –Cytokines–growthenhancingandproinflammator

Clinical• Featuresareduetoexcessproductionofmastcell-dependentmediators• Patientsineverycategoryofmastocytosissometimesexperienceflushingorvascularcollapse→provokedbyalcohol,aspirin,narcotics,contrastagents(iodinated),insectstings,exercise,orinfections

Major Types of Mastocytosis •Urticariapigmentosa –Mostcommonskinmanifestationinchildrenandadults –90%ofthosewithindolentmastocytosis –Small,yellow-tantoreddish-brownmaculesorslightlyraisedpapules –Darier’ssign:Trauma/rubbingoflesionscausesurticationanderythema –Associatedwithpruritusexacerbatedbychangesintemperature,frictiononskin, ingestionofhotbeveragesorspicyfoods,ethanol,andcertaindrugs

•Diffusecutaneousmastocytosis –Diffusemastcellinfiltrationwithoutdiscretelesions


–Usuallyoccursbeforeageofthree –Entireskininvolved –Skinnormaltoyellow-brownandthickened •Solitarymastocytomas –Rare –Onsetbeforesixmonthsofage –Involutespontaneously,usually •Bullouseruptionswithhemorrhage –Neonates –Blistersmayeruptspontaneously •Telangiectasiamaculariseruptivaperstans –<1%ofpatients –Tan-to-brownmaculesandpatchyerythema –Telangiectasiasobserved –Exclusivelyinadults

Systemic Features

Gastrointestinal Disease •Gastrichypersecretionsecondarytoelevatedhistamine→gastritiswithpepticulcerdisease •Diarrheaandabdominalpain •Malabsorption •LFT’sabnormalinhalfofpatients→alkalinephosphataseelevated

Splenomegaly •50%ofpatients •Mastcellinfiltrateswithfibrosis •Extramedullaryhematopoiesis

Bone Marrow •Radiographicallydetectablelesionsinmajorityofpatients→proximallongbonesmost oftenaffected;pathologicfracturesmayoccur

•Anemia,leukopenia,thrombocytopeniaandeosinophiliamayoccur

Neuropsychiatric •Decreasedattentionspan •Memoryimpairment •Irritability

Mastocytic Leukemia • Rarestformandhasmostfulminantbehavior;peripheralbloodshowsnumerousimmaturemastcells

Work Up 1.)Skinexam–grossandmicroscopic 2.)Bonemarrowbiopsy 3.)24hoururine• Suspicionshouldpromptabonemarrowbiopsyandaspiratefordiagnosisandcategorizationofthetypeofmastocytosis

• Obtain24hoururinefor5-hydroxyindoleaceticacid(5-HIAA)andurinarymetanephrinestoruleoutcarcinoidtumororpheochromocytoma


Treatment •H1blockersreducepruritus,flushing,tachycardia •H2blockersadded •Cromolynsodium,particularlyforGIcomplaints •Ketotifenandazelastine,antihistaminesthatstabilizemastcells •Epinephrineforvascularcollapse(patientsshouldbepreparedtoself-administer) •PUVA(withmethoxsalen)relievespruritusandwhealingafter1-2months,butrecursafter 3-6months

•Topicalglucocorticoidsunderocclusionfor8hoursperdayover8-12weekscanbeused forextensiveUP;lesionsrecurafterdiscontinuation

•Radiotherapyforbonepain

Survival •50%ofchildrenwithUPresolvebyadulthood •AdultswithUPusuallyprogressgraduallytosystemicdiseaseandrarelydevelop hematologicdisease

•Diffusecutaneousmastocytosisisusuallyassociatedwithindolentsystemicdisease •Mastcellleukemia:survivallessthansixmonths •Lymphadenopathicmastocytosiswitheosinophilia:twotofouryearswithouttherapy

4.45 CUtANEoUS SARCoIDoSIS• Skinlesionsoccurin25%ofpatientswithsarcoidosis

Lupus Pernio• Middleagedfemales,increasedinAfricanAmericans• Chronic,violaceous,induratedplaques• Predilectionfornose,ears,lips,andface• Persistentsarcoidosischaracterizedbyextensivepulmonaryinfiltrationandfibrosis,chronicuveitis,andbonelesions

• Noselesionaccompaniedbygranulomatousinfiltrationofnasalmucosaandupperrespiratorytract,andbonynasalseptummaybedestroyed

• Bulbousorsausage-shapedfingerinapatientwithlupuspernioindicatespresenceofunderlyingbonelesion

Plaques• Violaceous,elevated,indurated• Limbs,face,back,andbuttocks• Distributionissymmetric• InAfricanAmericans,hypopigmentedappearance:“hypomelanoticumbrella”• Sarcoidlesionsmayappearpsoriatic

Papular Eruptions• MostcommonskinmanifestationsinAfricanAmericans• Waxy,translucent,flattop,2-6mm• Occuronface,lids,aroundorbits,neck,upperback


Subcutaneous Nodules/Darier Roussy Sarcoidosis• Oval,firm,painless• Arisedeepindermisandsubcutis• Foundontrunkandextremities• Rarely,ulcerate

Erythema Nodosum• Mostcommonnonspecificcutaneousmanifestationofsarcoidosis(Lofgren’ssyndrome)• Hallmarkofacutesarcoidosis,predominantlyofwomenofchildbearingage• Maybeassociatedwithfever,malaise,polyarthralgia• Associatedwithgoodprognosisinsarcoidosis

Laboratory Investigations• Hypercalcemia:duetoincreasedintestinalabsorptionsecondarytoactiveformofVitaminD3overproduction(inlungs)

• ACElevel:raisedin60%,higherinpatientswithhilaradenopathyandpulmonaryinfiltration(stageII)andpositiveinpatientswithextrathoracicsarcoidosis;ACEderivedfromepithelioidcellsofgranulomasandthusreflectsgranulomaloadinthebody

• ACEusedformonitoringclinicalcourse,notfordiagnosis(60%sensitive,and90%specific)

ImmunologyCutaneous Anergy• DepressionofDTHreactions;negativePPDin66%• Anergydoesnotcorrelatewithdiseaseactivity—persistsevenduringrecovery

Humoral Responses• Exaggeratedcirculatingantibody• Hypergammaglobulinemiaoccursinhalfthepatients

Kveim Test• Intradermalinjectionofhomogenizedtissuefromsarcoidosispatient• Requiresfourtosixweeksfornoduletodevelop

TreatmentGlucocorticoids• Prednisone,20-40mgqd,istreatmentofchoice• Doseisreducedgraduallyto10mgdaily• After4-6weeksofdailytreatment,dosecanbereducedto10-20mgeveryotherday• ILtriamcinolonetodisfiguringlesions• Topicalglucocorticoidstoindividuallesions

Antimalarials• Chloroquine• Hydroxychloroquine

Immunosuppressive Drugs• Methotrexate• Infliximab

Surgery• Excisionofsmalllesions• Graftingofextensivesarcoidulcers


4.46 PERFoRAtING DISoRDERS

Perforating Folliculitis

Pathogenesis• Lesionsmayberelatedtosuperficialtrauma

Clinical• Keratoticfollicularpapulesoverextensorsurfaces• Associationwithchronicrenalfailure

Reactive Perforating Collagenosis

Pathogenesis• Lesionsprecipitatedbysuperficialtraumaalteringcollageninthedermalpapillae

Clinical• Pinheadkeratoticpapulesthatgrowto6-10mmindiameter• Centeroflesionbecomesumbilicatedcontainingtightlyadherentplug• Firstlesionsusuallyappearininfancyafterminortraumaorarthropodbite

Kyrle’s Disease (Hyperkeratosisfolliculitis)

Pathogenesis• Absenceofcollagen• Follicularpluginanepidermalinvagination

Clinical• Scalyfolliculo-centricpapules

Elastosis Perforans Serpiginosum (EPS)

Pathogenesis• Alteredelasticfibersindermisandconcomitantalterationofcollagenfibers

• Elasticfibersactasaforeignbodyandareeliminatedthroughtransepidermalchannels

Clinical• PatientswithMADPORES:Marfans,Acrogeria,Downsyndrome,Penicillamine,OsteogenesisImperfecta,EhlersDanlos

• Fleshcoloredtoerythematousumbilicatedpapules2-3mmarrangedinarcuateserpiginousorgroundedfashion

• Napeandsidesofneck,upperextremities

Treatment• Cryotherapy

4.47 ELAStoSIS PERFoRANS SERPIGINoSA

Pathogenesis• Alteredelasticfibersindermisandconcomitantalterationsofcollagenfibers• Elasticfibersactasaforeignbodyandareeliminatedthroughtransepidermalchannels

MNEMONIC

MAD PORES Marfan’s Acrogeria Down’s

Penicillamine OsteogenesisImperfecta Rothmund-Thomson EhlersDanlos Scleroderma


Patients• Idiopathic• PatientswithDown’ssyndrome,heritableconnectivetissuedisorders(Ehlers-DanlosTypeIV,osteogenesisimperfecta,Marfan’ssyndrome,Rothmund-Thomson,scleroderma,andacrogeria),penicillamine

Clinical• 2nddecadeoflife• Flesh-coloredtoerythematousumbilicatedpapule2-3mm,withcentral,tightlyadheringplugthatbleedswhenremoved

• Napeandsidesofneck,upperextremities• Arcuate,serpiginous,grouped,scattered,discrete• Regressionleavesatrophic,wrinkled,andhypopigmentedscars

Treatment• Cryotherapy• Avoidelectrocautery,dermabrasion,andsurgery

4.48 REACtIVE PERFoRAtING CoLLAGENoSIS

Pathogenesis• Perhapsgeneticpredisposition• Developmentoflesionslikelyprecipitatedbyminorsuperficialtraumaalteringcollageninthedermalpapillae

• Noassociatedmetabolicdisorders

Clinical• Lesionsstartaspinhead-sizedkeratoticpapulesandgrowto6-10mmindiameteroveronemonth

• Centeroflesionbecomesumbilicatedcontainingatightlyadherentleatheryplugthatifremovedleavesableedingcrater

• Healswithaminorscarofhypopigmentedmacule• Firstlesionsusuallyappearininfancyafterminortraumaorarthropodbite• Asymptomatic

Treatment• Noconsistentlysuccessfultherapy• Maybephototherapy

4.49 CUtANEoUS FEAtURES AND DISoRDERS oF PREGNANCy

Pemphigoid Gestationis• Seenonlyinpregnancyorwithtrophoblastictumors• Beginsin2ndor3rdtrimester• Urticarialorpapulovesicularlesionsontrunk;spreadsrapidlyandmayinvolvefaceandpalms/soles,evolvingintobulla

• Pruritusmayprecedelesions• Mayremitpriortodelivery,but75%flarepost-partum• Recurswithpregnancy,OCP’s,ormenses


Laboratory• Severitymaycorrelatewitheosinophilia• Increasedanti-thyroidantibodies

Immunofluorescence• Direct:C3inhomogeneous,linearbandatBMZ(perilesionalandlesionalskin);IgGin30-40%

• Indirect:ComplementfixationatBMZ;HGfactor=complementfixingIgGantibody;almostallpatientsshowIgG1againstBMZ

Pathophysiology• IgGagainst180kdBPantigen;→extracellulardomain• Theory:CrossreactionofantibodiesdirectedagainstamnioticBMZ• Pregnanciescanskipdisease

Treatment and Course• Prednisone0.5mg/kg/day(topicalsteroidsoftenineffective)• Increasedriskforsmallforgestationalageinfantandprematurity• Mother:IncreasedlifetimeriskofGrave’sdisease

Cholestasis of Pregnancy• Thesameasprurigogravidarum+/-jaundice• Cholestaticjaundiceofpregnancy=abnormalLFT’s• Prurigogravidarum=pruritusandabnormalbileacidswithoutjaundiceClinical• Usually3rdtrimester• 50%associatedwithUTI• <50%developjaundice• Intenseprurituswithoutlesions• Resolveswithin2dayspost-partum

Laboratory• Bileacidselevated3-1000xnormal• Directbilirubinnotmorethan2-5mg/dl• Hepaticultrasoundisnormal

Course and Prognosis• Mother:LowVitaminK→post-partumhemorrhage• Mayrecurwithfuturepregnancy• Increasedriskofcholelithiasis

•Fetus:Prematurelabor(common),fetaldistress,perinataldeath

Treatment• UVBphototherapyforsymptoms• CholestyraminegivenwithVitaminK• Restandlowfatdiet• UrsodeoxycholicacidorUDCA(16mg/kg/day)→reducesriskofprematuredeliveryandpruritus

• Dexamethasone12mg/dayx7days→decreaseslababnormalitiesandpruritus,usedinconjunctionwithUDCA

• Deliverat38weeksorearlier


Polymorphous Eruption of Pregnancy (orPUPPP)

Clinical• Papulesbegininstriaeandspreadtotrunkandextremities

• Usuallyin3rdtrimester• Resolves15dayspost-partum,sometimespriortodelivery

Laboratory• Normal

Treatment and Course• Topicalsteroids• Antihistamines• Systemicsteroids• Nomaternalorfetalmorbidity

Pustular Psoriasis of Pregnancy• Alsocalled“impetigoherpetiformis”

Clinical• Late1sttrimesterto3rdtrimester• Oftenbeginsinintertriginousregionsandspreadstotrunkandextremities• Sparesface,palms,andsoles• Erythematousplaquewithringofpustules,thatenlargesatperipheryanderodesorcrustsatperiphery

• Mucosacanbeinvolved• Onycholysis• Nopruritus• Malaise,anorexia,fever,chills,nausea,vomiting,diarrhea

Course• Remitsquicklypost-partum• Recurswithsubsequentpregnancies,mensesandOCP’s• Fetusatriskforplacentalinsufficiency

Laboratory• Hypocalcemia• Leukocytosis• ElevatedESR• Pustuleculturenegative

Treatment• Prednisolone80mg/d→decreasesmortalityriskformother• Treathypocalcemia• Mayrequireearlydelivery

4.50 PRURItUSPathophysiology

• Theonlyperipheraltissuefromwhichitchevokedisskin,withtheexceptionofthecornea• TheCandAdeltafibersintheuppermostskinuniqueintheirabilitytoproduceitch• HistamineproducesitchviatheH1receptor

uTIPa Primigravidas, increased with maternal

obesity and twin gestation


• Othersubstancesthatproduceitch:papain,trypsin,serotonin,bradykinin,kallidin,kallikrein,substancePandVIP

• Prostaglandinsexaggerateexistingitch• Opiateshavebothcentralandperipheralitch-producingaction

Conditions that Cause PruritisChronic Renal Disease• Affects80%ofthoseondialysis• Dialysiscausestemporaryrelief• Emollients,antihistaminesineffective• Antihistaminesrarelywork• Secondaryhyperparathyroidismisanoccasionalcauseofuremicpruritus• Increasedpopulationofmastcellsinskin• UVphototherapymaybenefit

Cholestasis• Highlevelofbilesalts,andcholestyraminecausessymptomaticimprovement

Endocrine Disease• Thyrotoxicosis–oftenduetoincreasedskinbloodflowwhichraisesskintemperature• Hypothyroidism–pruritussecondarytothedryskinofmyxedema• Postmenopausalpruritusmaybegeneralizedorlocalized,usuallyinanogenitalarea

Malignancy• Mostcommonassociation:Hodgkin’sdiseaseandpolycythemiavera

Polycythemia Vera• 50%havewater-inducedpruritus;referredtoas“bathitch”oraquagenicpruritus

• MayprecededevelopmentofPVbyyears• Itchisindependentoftemperatureofwater

HIV Infection• Increaseditchingsecondarytoscabies,pediculosis,candidiasis,orseborrheicdermatitis,orrenal/hepaticdysfunction

• Eosinophilicfolliculitis• PruritusofHIV• MayrespondtoUVB,PUVA,ordapsone

Workup of Generalized Pruritus• Physicalexam,includingpelvicandrectal• CBC• StoolforO&P,occultblood• CXR• Thyroid,renal,andliverfunctiontests• Drughistory

4.51 SCLEREDEmAClinical Manifestations

• Skininvolvementmaybeprecededbyprodromeoflow-gradefever,malaise,myalgia,arthralgia

• 65%developinfectionusuallyofstreptococcaloriginafewdaysto6weeksbeforeonset


• Marked,nonpitting,symmetricindurationoftheskin• Affectsposteriorandlateralaspectsofneck,spreadstoface,shoulders,back,arms,andthorax

• Indurationiswaxywhiteorshiny,anddiffusewithoutsharpdemarcationbetweeninvolvedanduninvolvedareas

Laboratory Findings• IncreaseinASOtiterinsomepatients• Glucosetolerancetestmaybewarranted• Hyperinsulinemiamaybepresent

Pathogenesis• Unknown• Syndromeoflongduration,obesity,adultonset,andlatentorovertdiabetesassociatedwithcardiovasculardiseasenoted

• Dermismarkedlyincreasedinsizewithincreaseinhydroxyprolineandhexosamines• Associationwithmonoclonalgammopathy,IgGtype

Treatment• None

Course and Prognosis• Spontaneouslyresolvesin6monthsto2years• 25%shownoresolution,especiallyinthosewithDM

Table4-4.MonoclonalGammopathyandDiseaseAssociations

Type Disease

IgA EED,pyodermaganrenosum,subcornealpustulardermatosis,IgApemphigus,POEMS,Sweet’ssyndrome

IgM Schnitzlersyndrome,Waldenstrommacroglobulinemia

IgG NXG(IgG κ),scleredema(IgG κ > λ),scleromyxedema(IgG λ > κ)

4.52 NEPhRoGENIC FIbRoSING DERmoPAthy (NFD)/ NEPhRoGENIC SyStEmIC FIbRoSIS (NSF)Pathogenesis

• OccursinpatientswithrenalinsufficiencywhohavehadimagingstudieswithgadoliniumClinical Manifestations

• Induration,thickening,hardeningofskinwithbrawnyhyperpigmenting• Flexioncontractures,stiffeningofthehands• Pain,prurituscommon• Extremitiesmostcommonlyinvolved,thentrunk• Affectedskinisshiny,withpeaud’orangeappearance

Treatment• Extracorporealpholophoresis• Limitedoptions• Increasedmorbidily/mortalitybecauseofcontractures,mobilityproblems,falls,andfractures• Prognosis


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NOTES


NOTES

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