...—.—.__...._._._..._._j.............__...._._u....__.--—.
`
`FITZPATRICK’S
`
`DERMATOLOGY
`IN GENERAL
`MEDICINE
`
`SIXTH EDITION
`
`EDITORS
`
`IRWIN M. FREEDBERG, MD
`
`ARTHUR 2. EISEN, MD
`
`KLAUS WOLFF, MD, FRCP
`
`K. FRANK AUSTEN, MD
`
`LOWELL A. GOLDSMITH, MD
`
`STEPHEN I. KATZ, MD, PhD
`
`VOLUME 1
`
`M C C R A W - H I L L
`
`Medical F'ub|i5hing Division
`
`Lnabun
`San FI'aI1('i:“.Lr'I
`C|1iI;.1gcJ
`New York
`London Matlricl
`I'\a1E'><i::0 City Mllgan New Delhi
`San J|.J£'II'l
`Senui Smgapore
`S\_.='(Iney Toronto
`
`UNILEVER EXHIBIT 1051
`UNILEVER VS. PROCTOR & GAMBLE
`IPR2013-00505
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`UN T.|-'.V|-ZR I-ZXH H ‘I 1051
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`UNILEVER VS .
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`PROCTOR & GAMBLE
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`Note: DI‘. SIu:p|1t':n K:1I2'$ work an editor and £JUl|'10!'\|L-'il!i pe|'f01'Inet'i outside the scope
`ur'hi.~aen11pluy|11cnI :1:-. al LLS. _gUvr.'rnI'neI1{r:n1piDycr:. T]‘lihW(J1'k I'&[JI'I'.'SClllhhi\ |JCfSLIIlil]
`and prufe.ss'mI1.1| views and nul ne.<::::~;s;urily those of the Us. goveI'I1n1enL
`
`
`
`
`FITZPATRICICS DERMATOLOGY IN GENERAL MEDICINE
`
`Sixth Eililiull
`
`i‘)7I by T:|'n' M:.'G:'rnu'—.-’1’t'N
`C0p_vrig|1t-L’- 3003. I999. I993. I937. 197‘).
`('m::,rm:::'e.v. [ma All rights rmuzrved. Printcd in [he Llnited Slates nI'Ame1'ic;1.
`Exuepl us. peI'I1IiI1e!(J L|I1L1:-|'thcLIniIL=d Sulrm CnpyI'ighI Act n|' I976. nu p:I1'l
`ul't|1i.- pL1b|iL':1ti0n may hr: I't:pI'uu.|1:.;cd m'L|islrii‘mlczJ in any f'L‘r|'111 m'l1_v;1I1y
`mc:m~;. or .-unreal in ;u|ul:1b;1se or |'r:l1‘i'cv:1i s_\-stcn1. willmut the prior written
`pa-|1ni5siun of lhc publisher.
`
`I ?.345(1'a"89(J KGPKGP 09876543
`
`SCI: ISBN 0—O'I'—|38{I7fi-1'}
`Vnlumr I‘. ISBN U‘-07—| 380(36—3
`Voimnc ll: ISBN 0-{)7-|33U(1T— I
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`This lmrrk was‘. set 1l'I TiI'I'lE‘.S Roman-1 by Tcciiflnoks. Inc. The cdimrx ware
`Darlene Cooke. Susam R. Noujau'm. Lisa Silverm:u1. and Peter J. Boyle: the
`pI'(.K|1.!t.‘liU]'I blI[JI:l'\«'i!{0T'W1lS Rit.‘h2'll‘(| RLIz_w:k:I;l|1e cLw:3|'LicsigI1r3I' was Elizabeth
`PisaCI‘El:t'. B£tI‘h:1I‘:l Li1t|::w0od pnttpatred lllv: iI1dt:.\'. QuI.:bccU|' Wurld Kin gspurl.
`
`This bunk is printed on m:i(|—I'rce paper.
`
`Library 0|‘ Congress CaraIogiug-iu—Publicaliun Data
`Filzp:1lrick's :'lermato|:.>gy in general meu.Iic1'nc.—6t|'| z:L|.!
`Irwin M. Freecllwerg . __ [at u!.]
`p.
`; cm.
`Im.'|l1{Jes bibliogmphiczfi :'e|'ercnces and index.
`ISBN (1-tT:'~l38[l‘z'{1-U
`
`3. C|.H.1lJII.‘LIUb u:21uil'c5t;1l'IOI15
`2. S|;'tl1-Diseilses.
`I. DeI'1‘nil10|0gy.
`1. FiiZ[):lII'iCk. Thmmua I3. {Thnn1:|sa Bermwd). I919-
`oI'gcI1c.-ral diseases.
`”. Freetlberg. Irwin M.
`EDNLM: J.Skin Diseases.
`2003]
`RL? I D46
`6 I (1.fI—L1L'2 I
`
`20030.’! I933\
`
`000002
`000002
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`3. Skin M:1nifesiuli-3:15. WR I4(}F5fi93
`
`3003
`
`

`
`.___.___“-jag.
`
`
`
`-A.f'l-|J""\.Il.||u-t'-“"
`
`This material may be protected by Copyright law (Title 17 US. Code}
`
`SECTION ‘SIXTEEN
`-l I Cutaneous Changes in Disorders of Altered Reactivity
`
`
`
`I») '4-\
`
`E-J_D'\
`
`Cunninghttm MJ et .Il: Circulttrittg '.tctivaIer.l lDR—pusitivet T l}'F|‘lPl1L'lC_\|'l-C5
`in a patient with atItoeczem:IIizuliott. J mil Amt!’ .t)tv-timml‘ 14' III“). 1986
`Goldberg DJ et al: Bttllotlspemphtgoitl:tn1'il:torIies: l‘ll.l1]lill'l skin as at sub-
`strate for indirect iniinllnofitimescettce :tsstt_v. Flirt: Um-umtr:.' I21: I
`l_‘li'.
`I935
`
`3?. Ackcntttttt AB: Hi.rtrtirJ_r;:1- Diu_gn.-:.l.'.-'.t' rff .-‘rrfl'mrttlmlni'lt- .S‘.l'rl‘u D:'.ti:m.w.' /-In
`.-llgui'i'timrr'r:
`ilritvlim.’ fl'rr.t:'cimi Fttru‘t‘r:l Amrl’r.t‘r'.i'. 1nd ed Bttllimore. MD.
`Willittims S; Wilkins. I997
`28. Alntatwi WY eta]: Regttltttiunolcjrtolunetuiti t-ytokiliel'eeeptore.xpresl.ion
`by gtucocortieoids. J Le‘!-‘J'mr.' Biol’ 60:553. I996
`Paul (..' er til: Mctrntyciitsl Promising ttgenls for the lrenlt1Ientol‘inli:trtt—
`|'l'l'tI[EIt')t' skirt tlisenses. .-Erperr 0pl'ir irtt'e.rlig Drrt_t;.r 9:e9. 201.10
`30. Dutrtont F]: FKSDG. tin ltl’lI'l1LII10SIJ|J])F&‘.'iS£t|‘|l targeting calcineurin function.
`Curr M‘-:rti Client 1:13 I. 1000
`
`29.
`
`CHAPTER 122
`
`Donald Y.M. Leung
`Lawrence F. Eichenfielcl
`
`Mark Boguniewicz
`
`Atopic Dermatitis
`(Atopic Eczema)
`
`Ample tlenmttitis tAD} is :1 chronically relttpsing skin tliscuse that oc-
`curs most Cl'!l1‘l.lTt0l1ly dtt|‘ln,'; early inl':tnc_v and L‘lIllt'_ll10tl(].
`It
`is fre-
`quently associattetl with elevtttetl scrtttn IgE levels and u [Jr.‘|'.*iI.!|ltill or
`fuinily l1l.'%lUI'y of AD. allergic rhinitis. ant|i'or asthma. There is no sin-
`gle (Jistirtgtlishing fettture of AD or :1 ditigttttstic lal‘not':Ilo1'y lest. Tltttxu
`the diilgrttnis is btisecl on the constellation ofclinicttl lilttlings listetl in
`Table |22—|.
`
`HISTORICAL ASPECTS
`
`ll'l I803. we
`This CllSO1'(lt'.‘l'W:'lS probably first reporterl hy RnhertWill:tn.'
`at pr'rtri_r.{o—lil\'e condition. The term o'i.t.rr.'rtl."rtrrt€(l
`rtertrade.-'rrttrti'ri.r was
`proposed by Brocq tsndlacquet. in l8'9|. to etitphausize that the disorder
`was emotionally l:la.~:ed. in 1892. Besnier delitteuted the prttrigo groupnf
`diseases and described the t.lri.‘i.(‘JCli'lllt‘J|'I oflttiy Fevet'ut1d axtlttttrt with AD.
`He sttggested that these Llisorcle-rs tendetl to be Iltmilial and ttCI.'LlITt’.'tl
`in the eonstittttmnally predisposed. Besnier also believed ll'l:l[pt1.JI'l[u}i
`played fl]JI'll1‘l:lt'y role in the pztlltogeitesis oFAD;tt1d called the disorclel‘
`pl'tri-igr: tW(iii'l€.Yi{ftt(‘. a term that was-: soon chtmgerl to Be.\anier‘s prurigtr.
`in l923. Court and atssocizttes-' introduced the term (tltlp_\‘ for lnotal-
`pl:1ce[top}—|tet:sly)] to det-K:I'ilJe some of the I.‘llI‘!l(.':1l
`i't'l.'l|lll‘eSl.'1[l0l1S of
`ltumalt |1y[)t:t':tett.~:ilivity llttll t:|Ii1t'aL‘teI‘izerJ atstltttttl and hay l'r:ver_ Coca
`and Cooke latter ltlCll.lt.lI.'.‘(J patients with "the prtiritic rush" in this group.
`In the 19303. SttIzbei'ger and associattes’ suggested the term rttrrpit‘
`tt‘e.='uri:rtilt'.r to be l.I.'$I:l;i
`in place ul'Llis5eI1tittalet| nr:tIt'odei‘t‘nzttiti.~t. The
`term AD luis the advantage of" eonnoting :1 close relalion.~:hip among
`skin m'.tI'til'e.st:ttions. ttsthmtt. and allergic rhinitis in patients with an
`atopic tlittthesis.
`
`EPIDEMIOLOGY
`
`Becztuse there are no precise clinical tlelittilions of AD. epidemiologic
`studies must bt:l2ill't?f1.1lly intei13reted :15 they can be plagued by problems
`of bias ascertiiitttttertt. Despite these limitation S. severttl \vell—desigt1ed
`
`studies sttggesl that there l1tIS been zit least it I.wo~ to threefold increase
`in the prevalent-e ol‘ AD du:'inr_1l|re past tlrrer-. r|ec:1r|e<atn:viewetl in Ref.
`4). Indeed. the ITICISII'CL‘Cl'IlE:illl'l‘IillC!ill'lLllCil1l:Tl'Iiltf\DlS :1 major public
`health pruhlern worlcl\v|de_ Will] a prevatlence l|'I children of ID to 20 per
`cent in the l..'niI'et| States. northern and western Europe. urban Alricat
`Japan. Australia. and other indu.-stri:ilizl:t'l count:-less‘ The pnevztlence ol
`AD in .'ltl.lll[S is ztpproxiinately I
`to 3 percent. interestingly. the previ-
`lenee oi" AD is niueh lower in ugt'ictl|lur:il countries such ats China and
`in enslertt Europe. I‘lI1‘:1l Africa. and Cetttntl Asia. There is tllsoa l'et'i12ilt.
`pl'K:|)t)I‘lI:l€I‘itI‘tL‘e
`for AD. with an overall fetnttlefnttile ratio of |.3:l.
`The bastis for this increased prevalence of AD is not well under-
`stood. However. wide varizttions in prevalence have been observe---'
`within countries inhabitetl by sirnilar ethnic grottps. stiggestilig that
`
`TABLE l22—l
`
`Clinical Features of Atopic Dermatitis
`
`Major features
`-
`l’l'tlrlh.ts
`- Facial and e.-(tensor eczerna in infants and cnilrlren
`- Flexural eczema |l'I adults
`- Chronic or relttpsing tlermatilis
`- Personal or family history of atopic rlisease
`Associated features
`I Xe-rosis
`- Cutalieotts infections
`- Nottstlettiiic tlet'n1:Ililis oi the hancls or reel
`- Ichtliyosis, palmar hyperliitearity, keralosir. pilari-.
`- Pll‘fl'lZ|Sl5 allaa
`- Nipple eczerna
`- White {lE‘l'I'l'l.‘it(J§_‘,l'E.fJl'IlE'lT| and Llelayecl hlanch response
`- Attlr_~.'int- subcapsular calar:tet5, l<E'l‘Ell0('Clt‘ILt5
`- Flravalr-=rl serum lg? level-.
`- Positive imntc-rliate type allergy skin tests
`- E.-tllv age ul onset
`- Llennre-Morgan infrnorlaital folds. orbital clarkenrng,
`-
`l-atcial ervthema or ttallor
`- Perilolltcular accentttation
`- Course ii1FIut-mcetl by environmental ancllor emotional l'at:tors
`
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`
`l"-actors are critical in tltltcrtttinlng disease exptessiott.
`gnuimrttttertt:tl
`joint of the polentiai risk factors that have received attention as be~
`irrg associated with the rise in atopic tlisense include small faintly size.
`iircteasetl income and crltrcation both irt whites and blacks. rnigration
`trurn rural to urban envirortrttertts. and increased use of antibiotics. that
`is. the so—called West't:t'tt lifestyle." This has restrltetl in the "ltygietre
`n_vpotl1esis." lirst proposed by Str':tchan. that allergic diseases migltt be
`prevettted by “infectiort in early ehildltond transntitted by unhygienie
`L'0l]iE'It.‘[ with older siblings.” This lrypotltesis is supported by recent
`-.-ttrdies tlentonslrating that allergic responses are driven hy T helper
`type IT”) 2 imrttttne responses wlrereas infections are induced by THI
`Lrnmurte t'espor1ses.* '1]. I
`I't.’NpI.iI1.'a't:s antagurritce the developmerrt ul'TH2
`Cells. There t'ot'e. .'.I tlecteased nunrber oi" in leetiotts durittg early Cl‘Iild-
`ltootl could pt‘edi.<.pose to ettlittnced 'l”..2 allergic t'espr_inses
`
`ETIOLOGY AND PATHOG ENESIS
`
`Complex irrlet'actiotts antortg genetic. El1\r'll'(JI1tl“l61‘1I:tl. skirt barrier‘. phar-
`macologie. anti imtntrnoltrgic |‘actot'.s‘ contribute to tlte patltogeitesis of
`AD. The development of new techniques lot‘ the study of naturally
`occtrrring and experirnentally induced skin lesions have provided valu-
`able new ittsights into the patitogettesis of AD. The concept that AD
`ltas an itiitnttrttilogic basis is suppot'ted by the cibservtrtiott that patients
`with pr‘imar'_\-' T cell itnrittrnodeliciettcy tli.\ordet's t'r'eqr.rcrttly have ele-
`\'tliti(J set'ttrtt lgli levels and et:7.eIitattiit'.l skirt lesiotis itidistirtgttisltttitlc
`front AD. in patients with Wi.-:ltott—./\ldt‘ic|1 sytttlrmtte. clearing til‘ Ilir:
`skin raslt ocr.'ttt.~.
`liollowirtg. correction: oi’ their imtnttnologir.‘ defect by
`.~arecessI'ul hone rnarrow transplantatiort." These data suggest that AD
`is not caused by it constitutive skin tlclirct but is tttcu.linter.| by yr hone
`tt'tat'tuw—derived celllfil.
`
`The Systemic Response (Table 122-3}
`
`Most patients with AD|1:iveperip|'iet'ttl blood C[}Sll10pl'1lliEIitI'It.lil‘iCrCflSCt:.l
`serurti lgE levels (reviewed in Rel". Itll. Nearly 80 percent of children
`with Al) develop allergic rlrinitis or asthrna. suggesting that respiratory
`allergy and AD have tiC()I‘I't1‘I'It_‘tl1 systemic link. Because serurrr l_r_:E. levels
`rue strongly associzrtetl with the prevalence oi’ astltrna. it suggests that
`ttlleI'_'_.!t:tt settsitizatiort tltrottgh the ski rt predisposes to respirtrtorjr disease
`due to its elliects on the systetrticttlletgic r'espoI1Se {reviewed tn Ref. l 1‘).
`|nr.|eet.'l. when mice are sensitized epictttaneously with protein rrritigert.
`it irrduces allergic dermatitis. elevated serunt |gE. airway ensinophilirr,
`and |iypei'te.sponsivet1ess to tnetlitrclioline. sttggesting tltatepicttttrlteotts
`exposure to :rl|er'gert
`in AD may enhance the tleveloprrterrt ofallergic
`:tstht'n:.t."'
`
`TABLE l22—2
`
`Systemic ltrtrnune Abnormalities in Atopic Dermatitis
`
`lncrensetl synthesis at |_t{E
`lncreasetl specific IgE to multiple allergerts. including foods.
`aeroallergens, r1ticr'oort;ar'risms. l3.1CiE‘l'IElllCI5(II1S,?ILIlI)(lllEl"gEI‘l5
`Increase-;| expression or CD23 llow--altinity lgE receptor} on B cells
`and mortocytes
`increased basoplril Itistamine release
`impaired clelayecl—tvt'Je lrvpersettsilivitv response
`Eosirroplrilia
`Increased secretion of IL-4, lL-S, and lL-13 by THE cells
`Decr'r-east-.r:l secretion of lFl\l—}r
`lJy TH] cells
`lttcreased 5t3iL|lJli? IL-2 receptor levels
`Elevatecl levels or’ monocvle CAMP-phospliodiesterase Will! increasecl
`lL— ll} r‘lI‘lf.lprt)!-l?lglFIr1fiiI'l-l1_g
`
`CHAPTER 122
`ll8l
`Mnpic Uermalilis tstnpie Eczema)
`
`Peripheral blood monorttrclear cells IPBMCI from AD patients have
`a decreased capacity to produce interferomgarttma t IFN— )1 ). lFN—}« gen-
`Cl‘itti(JI1t3x vivo is inversely correlated with serum [gE cortcentnttiuns in
`AD. There are also a tttrtnberol'studies den1onstr'atirr_r>: an increased fre-
`quency olallergen-specificT cells producirtg increased interleukin {IL}-
`'~l_ IL-5. and lL-l 3. but little IFN-tr. itt tlit: pet'ipltct‘itl blood of patients
`with .-\D."‘ These irntnuttologic alterations are important because IL-4
`and IL- I3 are the only cyloitities that induce germ-line It':tt1st':riptlot'I at
`the C5 eson. thereby prontotittg isotype switcltittg to lgll. IL-4 and IL- 1 3
`also induce the expressiott of vascular adhesion molecules such as vas-
`cular cell adltesiott molecule tV(".'AMl-l itwnived in eosit1(‘tpl1ilit1filtr:1—
`lion and dowrtrcgu|atcTHl cell functiort. lt1 contrast. lFN—y inhibits lgE
`syrttltesis as well as the proliferattion of THE cells and expression of the
`IL-4 receptor on T cells. Peripheral blood tn-onocytes froth AD patients
`are also ttctivated. how: an t‘1bI‘t0t'n‘I'.1il)t low irteidenco of spontaneous
`apoptosis. and are ttnrespctttsive to [L4 induced apoptosis following
`stimttlation. The likely eatrse ol'this ittltihition olapoptosis is increased
`[3I'DdttEllUl1OFGlVl—CSF by oircttlating tmtnocytes ol‘ AD p:.-ttiettts.”
`
`Immunologic Triggers
`FOODS Well-cnntrolletl strrtlies. detrrunstrrrte that food allergetis in-
`duce skirt rashes lI‘l cltildrett with AD {reviewed in Rel‘.
`l~’ll. Based
`on dottble-hlintl. placebo-cot1tt‘o|lerl footl cltallenges. :tppt'oxitt'tately
`-ill trercettt oflI‘tl't1nts and young children with moderate to sevetc AD
`lttive lood allergy. Allliorrgh the LlL'I'l‘i'l:tlL)l0gy |iter'ature has l'reqLrerttl_v
`not srrppui-tr-cl a role for foorl-4 in AD. a stutJ_v by Eigennt:inn ct Lil.”
`r'epor'ted that 37 percent oftirtselected children with moderate to severe
`Al) lollowed at a university deritttttology clinic had Food atlletgy. Food
`allergies in AD patiertts may rnduee eczetnatous dermatitis in sortie
`patients. while in ot|1ersttrticat'ial rear.‘tiorts. contact l.lt'ilCt1l‘li|. or other
`nortctrtaneous syrttptonts are elicited. in rt study oi‘ 250 cltildrert with
`AD. Gttillet and Gulllet” Fnt.trrd that ittcreased severity ofAD syrrrptotns
`and younger age olpritierrts was correlated directly with the presence of
`food allergy. Removal or food allergens hunt the palient's rJiett::ur lead
`to sigrtitieant elinir.-:1! impr'ovr:ment but teqtrires :i great deal ofedueation
`because most oftlie eorttrnoa allergens (e._e.. egg. milk. wheat. soy. and
`peanut) currtatttinate many I1:-ods and are tltetefone dil"licult to avoid."
`Labor:ttor'y studies support a role for lood allergy in AU. Inlattts
`and young chilclrett with moderate to severe AD gctterttlly have posi-
`tive immediate sltin tests or sertttn lgE directed to various loorls lever:
`in the lace ol normal total serum IgE levels). Positive food cltallettges
`rire aecontprrnied by signilicanl increases in plasrrta histamine levels
`and eosittopltil activatiott. Childtten with AD who are cht'0ttie:tll_~,'
`in-
`gesting foods to which they are allergic have increased sporttatteotts bat-
`sophil ltistatnine release compared with t.‘l1ildI‘<iIl without food arlIer'g'y.
`in mouse models of AD. oral setisitizatiott with foods results in the
`elicitation ofeczctnntutrs skirt lesions on repeat oral fond clrallerrges.”
`in patients, however. irnrnediate skin tests to specific t‘tllct‘gI:tts do not
`always indicate clirtical sensitivity. Tltetefore, clinically relevant food
`allergy must be verified by corrtrollcd food challenges or cat'et'ull_v in-
`vestigtrtittg the effects of a foorl elimination diet that is being done lit
`the absence 0l‘0ll'let' esttt:er'brttittg i':tctors.
`
`|ttipot'turtt|y. food allergen-spccll'ic T cells have been cloned l'mtrr the
`skirt lestottsrdpatiettts with AD.” In strpport ofa role for roud:tllet'gert—
`specific T cells in AD. patients with food-rtrdueed AD have been stud-
`ied to analyze the relationship pctwcctt tissue specificity of at clittical
`reaction to an allergen and exp1essiortol'the skin homing receptor cuta-
`neous lyntphoid aatigett t C LA) on T cells activated in vitro by the rele-
`vant aller'g.ert.3" C:1.'iein—t'euciive Tcells front patients with rnill<—indtrced
`eczema were fourrd to have significantly higher levels of CLA than
`Crrmlidrr trllricrrrr.r—:'eactive T cells from the same patients. casein— or
`
`000004
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`
`.urn-g_;-tun.__iu--
`
`SECTION SIXTEEN
`l 1 Cutaneous Changes in Disorders of Altered Reactivity
`
`
`
`C. olbt'cmi.s'-reactive T cells fnoni nonatopit: controls. or noneczeinatous
`controls with inilk—induced gasttoenteropathy. Overall.
`these studies
`provide strong scientific evidence that footlscnit play it note in the patho-
`genesis of AD in young children. Most food allergic cliildreri.hovveve1'.
`outgrow their food liypersensitivity in the Ilrst Few years of life. so food
`allergy is not a comiuori trigger factor in older patients with AD.
`
`in I918, that several of his pa-
`AEROALLERGENS Walker t'e.pot‘tt:d.
`tients had cxacerbtition of AD following exposure to horse dander.
`timothy grass. or ragweed pollen." In the 1950s. Ttift :Il1Il co-worket‘s
`reported that in patients with AD. pturitus and eczciiiatoid skin lesions
`developed after iiitraiiasal irthalation challenge with either Alternziria or
`ragweed pollen. but not placebo. More recently. tlotible-blind. placebo-
`controllccl challeiiges have tlen1oristr'ated that inhzilation of house (last
`miles by bronchial challenge can result in new AD skin lesions and
`exacerbation of :1 previous skin rasli.” Epicutaneotis applictitiori of
`tteioitliergeiis by patch test tecliniques on tiiiinvolvecl utopic skin elicits
`eczeniatoid neactions in 30 to 50 percent of patients with AD trcviewcd
`in Rel". 23}. Positive reactions have been observed to \-'iIl'lI.‘il.IS aeru:i|-
`|ei'gens. including dust mite. weeds. oiiiinril cl:inders. and molds.
`In
`contrast. patients with tt:spii‘:tt0I‘y allergy arid healthy voltiiitcers i':1i'cl_v
`have positive allergen patch tests.
`Several studies have examined whether avoidance of zierozillergens
`results in clinical improvement of AI). Most of these reports have in-
`volved uncontrolled trrals in which patients were placed in mite-|'i-er:
`eiivii'oiinteiil's. such as hospital riiottis. tlirough the use of at::tt‘tL‘idcs or
`impcrnieable mattresses covers. Such inctliotls have invariably led to
`irnprovcnierit in AD. One double-blind, placebocoittrolled study using
`a comb ination of effect ive mite- red uction l1'tE:lSLll'eS. as compared to no
`treattneiit, in the home showed that a reduction in house dust mites is
`associated with sigiiiiicaitt iniptovenient in AD.-"'
`Laboi':itor_v data stippoititig a role for iiilialaiits include the rinding
`of lgfi ttittibotly to specific iithalaitt itllergens in most patients with
`AD. Indeed. a recent study to-uiid that 95 percent of seru t'i'oni AD
`patients continuetl IgE to house dust miles as conipttrecl lo 43 percent
`of asthmatic subjects.” The degree of sensitization to aeroallergens
`is directly associated with the severity 0|’ AD.“ The isoltttiori from
`AD skin lesions and allergen patch test sites of T cells that selectively
`respond to Dei'irmtripii(igoi'rle5 ’.'1ft.’.'r’tJT_\I.lI.1‘llJlli.§' and other -'IE‘Ff'tilllt:l‘gt.’.I'lS
`provides further evidence that the inimurie response in AD skin can be
`clicited by aeroallergeiis.”
`
`MICROBIAL PRODUCTS Ptiticiits with AD have an l|‘|t'.'|‘r)£ISed ten-
`
`dency to develop bacterial. viral, and Ftiitgal skin infections. lininune
`responses to the products of 5ti:rpli_vlococ'cir.i'
`t‘lli‘.".-'_’t‘t.S‘ have provided irt~
`sights into mechanisins underlying skin iiiflatminntion in AD. S.
`t.1‘trt't’ti‘.F
`is found in more than 90 percent of AD skin lesions.” In contrast.
`only 5 perceitt of itoriiial subjects l1ai'boi' this organistn. The density of
`S. (l'm'€1tS on inflamed AD lesions without clinical stiperinfectioii can
`reach tip to 10’ colotiy-formitig units per cm3 on lcsional skin. The
`importance of S.
`tI.‘ttl"e'tt.§' is supported by the observation that even AD
`patients without overt infection show a greater reduction in severit_v
`of skin disease when treated with ti coiiiliitiatioii of aritisttipliylococcal
`antibiotics and topical C0l’l.lCOSl€l‘(JlClS as coinpirred to topical eor'tico-
`steroids alone."
`tit.-i'ert.\' exacerbates oi‘ iitaintniiis skirt
`One strategy by which 3.
`uirlainmation in AD is by secreting :1 group of toxins known to
`act as stiperziiiligens that stiniulttte iiiarked activation of T cells niicl
`rmicrophages. The skin lcsions of over half of AD patients contain
`5. rtiririrs that secrete siipcrantigens such as eiiteiotoxitis A and B. and
`toxic shock syndrome toxiu- I 33'3" An analysis of the peripheral blood
`skin liotiiing CLA-+ T cells t“r'oin these patients. as well as T cells in their
`
`skin lesions. reveals that they have undergone a T cell receptor tTCRl
`Vfl expansion consistent with supetantigeriic stirnulutiuri.'““" Most AD
`patients iriake specific LEE antibodies directed against the staphylococ-
`cal superantigens found on their slr:iii.3“" Basopliils from patients with
`IgE antibodies tlirected to super‘-antigens relettse liista mine on exposure
`to the relevant strpt:i'antigen. btit not in response to superaittigerrs to
`which they halve no specific lgE.*‘ll This raises the interesting pt‘iss‘ibil—
`‘try tl‘r:tt superaiitigens induce specific lgE in AD pttticttts and mast cell
`dcgr':1i'tu|ation ]l'l vivo when the superuniigetis peiietrtite the disrupted
`epidei-inal hat-rier. This promotes the rtch—scr:itch cycle critical to the
`evolution of skin rashes in AD.
`
`A correlation has also been found between the presence of IgE
`iinti-stipeiaritigeiis and severity of AD.” Using it
`l‘ll.1I‘I‘l€tt'tlZt:(l
`inurinc
`model of skin inflznnination. the combination ofS. {tiii"t*ti.$'SLl|JCI'ttn[lge11
`plus allergen has been shown to have an additive effect in inducing
`skin iniiaii1inatioii."3 Stipcrtintigens also augment ttllergen-specific [gE
`syiitliesis and induce corticosteroid resisnriice suggesting that several
`inecliziiiisrns exist by vvliicli superantigeris could aggravate the severity
`of AD:""'” Fulfillinit Koch's postulates. application til‘ the superantigeii
`SEE to the skin can induce skin cltttriges oferytheiiiti and iiidi.ri'atioti :'rt'~
`coirrpaiiietl |.r_v tlte itrliltratioii o|'T cells that ate selectively cxptiiitied in
`icspoitse to SEB."""" Furtlierrnore, in a prospective study ofpiitieiits re-
`covering l'r'om toxic shock s_vnt.lrome. it wits Ilitirrtl that I-liilfalt pitlictils
`developed cliroi'tic eczciiiiittiid tlci'iiiotitis. whereas no patients rccovcr-
`"mg horn gi‘:iin—ncgati\'c sepsis developed ec:z.enia.'" These lI‘lvC.*ill!_£:.|lOl'S
`concluded that stipci':iiitigeiis niary induce an ample process in the skin.
`It is thcrcfoI'c of interest that !~'lJ]'.)El'iII1l.lgt'l‘lliI have beeti tlciniotistiatecl ts‘-
`intluce T cell expression til‘ the skin homing 1'eceptt.u' via stiintalaiioti or‘
`lL—| 3 prodtrctioii.-‘”
`strtphylocticci can protltice ot'l‘ter' tos-
`Aside lrotti Sll|'.l€l‘t'lnIlgI3llS,
`ins that
`likely contribtite to skin iriflaitirnatiori.-“' AD 3. m.iretis iso-
`lates that do not secrete stipcritiitigeiiic toxins produce alpliti-toxiit. AI.
`stiipliylococcal strains also e.'tpi'ess sttipliylococcnl protein A. There ttI'E‘
`sl_|__!t'ttllCt1tll dilf::i'eiices in the action ol‘ these toxins on keiatiiiucytes.
`Sripei'uni'igenic ioitins as well as protein A do not induce sigtiiticarii cy
`totoxic damage on lt.ei‘atiitocytes but cause the delayed release oftuntor
`iiecrosis l‘iicttii'l'l'l‘lF)-ix. In Ct'Jl'Ill'iI.‘il. ill[Jll.il-lDXl'll iiicluccs profotiiid ker
`tttinocyte cytotoxicity and itnrnetlitrte release of TNF~o. Ke1‘tttiiioc_viv
`cytoloiticity itnlncetl by EIlpl’i£I~lflXlll cleiiionstrtttes the iiioipliologic zititl
`fuitctioiittl characteristics of necrosis. but not apoptosis.
`increased binding of S.
`ritiiei.-.r
`to AD skirt
`is likely related In
`tinderlying atopic skin iritlzriiiimttioii. This concept
`is stippot'tei;l l.
`several lines of investigatioii. First.
`it has been found that ireatirient
`with topical corticosteroids or tacroliinus will reduce S.
`tttU"(’lt5 count.»
`on atopic skin although the_v have no antibiotic actioiis.‘““" Secori-5
`acute inflzininiatory lesions have more 3. CItiI'c'l't.5‘
`than chronic Al)
`skirt lesions or iturmaldooking atopit: skin. Scratching likely Cllllllllt.
`5'. riitrer.-.i' binding by disturbing the skin barrier and exposing extra-
`celltilttr tiiatriit iiiolecules ktiowit to act as iiclhesins for S. rrtii‘eir.r.
`in-I‘
`
`tirrnw-:
`in studies :3!‘ 5.
`exaniplc. fihroiiectin and collagens. Finally.
`bindiiitt to skin lesions of mice tiiidergoing TH I verstrs THE intl:tnuii.i-
`tuiy responses. bacterial binding was ugnilicantly greater at skin sl.’
`with TH2—rnediated inflrnninatioii." Iinportantly. this iiicncnsed bacte-
`rial bintling did not occur in IL-4 gene knockout mice, iitdicatiiig tr. -1
`|l_.4 plays it crticitil role in the enhanceiiieiit of S. mm-'.-rs‘ hindin:.' "3
`skin. IL-4 appears to enhance S. ritiietrr binding to the skin by inducnls’
`the syritliesis of libronectiii. an iinpoitarit 5'.
`t'lttl'{?li'.\' odhesiii. Interr '-
`iitgly in siirtlies nflirrriiirn AD. a role for Iihritiogen in the bindin,J “ll
`S.
`tn‘l'I.l‘é‘l'i‘.\' to atopic skin has been fotind.” Bccuusc acute €)(|.I(l:,tll\'L
`'
`sions likely have iircr'eused plasnia-derived fibriirogen. tliis n'i:t_v |Jl'tt\ idc
`it
`!Tlt3L‘l‘I:ll‘ll.‘Sll1 for‘ further binding ot‘.S‘. riiii'eti.r to acute AD lesions.
`
`hi the l‘)3fls. several irivesrigiittris repurtetl that
`AUTDALLERGENS
`huniati skin dander could trigger immediate liypersensilivity react: ~il-‘i
`in the skin of potlerits with severe AD suggesting that they inarle [RE
`
`000005
`000005
`
`.5“
`
`

`
`against aiitoantigeirs in the sl:in.““ The potential molecular basis for
`these observations was recently ClCIl'l('I't1.‘iIl'itl.El'J by Vrilcnta et til. {re-
`viewed in Ref. 45) who reportircl that thc inajority of sera lroin patients
`with severe AD contain lgElnirtibodies directed zigiiinst ll.Llltt.‘1n proteins.
`One ofthcsc lgE—ri:activc £1Lllt}i'II'lligCl'lS has been cloned from it human
`epithelial CDNA expression library and desigitatcd Him: 5 i’, which is
`:1 55-kDa cytoplasmic protein in skin kcratit1ocytes.“' Such antibod-
`ies were not detected in patterns with chronic ui'tic:1rin. systcnric lupus
`erytlrcntatostis tSLE). graft verstis host disease (GVHDJ. or healthy
`controls. Although the utitoallergens cl1ai'acterizcd to date have tnairrly
`been i1'1trttcellul:.ti' proteins. they have beeir detected in lgE inmrtiire
`complexes of AD serzr, suggestiirg that release ol" these £1ttl'0E1llt3l'g8I13
`from damaged tissues could trigger IgE- or T cell—medi:tte(| responses.
`These data Sttggest that While igE irnmuiie t‘esp-oirses are irtitiatecl by
`enviroinitciitul ullergeiis, allergic inflammation can be mriiiitaiirecl by
`human endogenous ttntigens. particularly in severe AD.
`
`Immune Response in AD Skin
`
`ROLE OF CYTOKINES TH2- and TH Hype cytokincs contribute to
`the pathogenesis ofskiit itrllzltnirration in AD. As CU|'|‘lpL‘tl‘t:'{l with the Sl(ll‘t
`of normal controls, unaffected skin of AD putierrts have an increased
`number til" cells expressiiig IL-4 and IL-13. but not IL-5, IL-12. or
`lFN—}-', I'nRl‘«lA.”"l3 Acute ttntl cl1I'oi1ic skin lesions, when compared
`to normal skin or uninvolved skin of AD patients. have sigiiilicairtly
`greater nutnbeis of cells that are positive for lL——l. IL-5. and lL-I3
`IIIRNA.
`l-ltrtvevet; ncttte AD does not coirttiin signilicttitt tnirnbers of
`IFN—}’ or lL—l3 n‘lRNA i:.=tp:'t:s.siIr_r._‘. cells.
`Chronic AD skin lesions have significantly fewer’ IL-4 and IL-13
`ritRNA—expt'essiirg cells. but l1‘ICl‘t2:lSE(l numbers of IL-3. _i_:r':intrlocyte-
`lltflCl'0t'Jllflg.C coloiry-slimtilatirrg l'ai.‘tnt' ("GM-CSF}. IL—|2, and IFN-r
`mRNA-expressiti-_.2 cells than does acute AD. Thus. acute T cell inlil-
`tration in AD is associtlteil with it pi'e(|c-nritrtiircc of l'l.—'-l unil ll.-H
`expression. whcreiis It't;llt'llCl‘tflI‘l.L‘.t: of chronic iiifiirninraition is associ-
`:ttc:i.| with increased IL-5. GM-CSF. lL- I 2. and IFN-)2 expression. and
`is ai.'i:oinp;tttied by the ll'|l'll[l't1llUl'I oicosittopltils and trrztctophitgcs. The
`lllCI13IlSC{llJKPl'CS5lLlIl0fll_.'l2 in clrroriic AD Skirt lesions is of iirterest
`in thttt cytokiire plays at key role in TH! cell developrncni and its ex-
`pression in eosiitopltils undilor rnaictoplrages nray initiate the switch to
`THI or THO cell development in chronic AD.
`This bipliasic pattern of T cell activation has also been demon-
`strated nt'tei'epicr.itaiieous application of acro:i|lci'gcIrs using patch—tcst
`teclririqttes (reviewed in Ref. 49). Twettly-|'otir‘ ho1.1i‘.s after allergcir ap-
`pliczttitrli to the skit}. ittcncrisetl expr'i:ssioit of IL-4 tnRNA and protein
`is Ol'JSCt‘\rC(l, after which IL-4 expression declines to baseline levels. In
`corrtrast, lFN—y mRNA exprcssiorr is not detected in 1-'-l»—h pitlclr-lest
`lesions. bill is strongly expressed at the 43- to 73-I1 time points. Fur-
`thcrrnore, T cell clones obtained from early time points oi‘ evotvitrg
`:rlle.i-gen patch test sites secrete TH2-type cytnkiires. 'Wl'Ili!|'E:iR the mri_ior-
`ity of allergen-spccitic T cell clones derived from later pittch-tcst sites
`(3-48 h) exhibit :1 TH l- or THl]—typc cytokinc profile. Interestiirgly. the
`itlCl‘t3LtSl:t'J expression of IFN-y mRNA in atopic patch tcst lesions is
`preceded by at peak of lL— I2 ertpression coinciding with the inliltrution
`of iniicropliages and eosinophils.
`Activated T cells itrliltratiiig the slrin til" AD patients have also been
`found to induce keratiiiocyte apoptosis conti'ibuting to the spongiotic
`process found in AD skin lCSlC|l‘tS.5” This process is incdiuteil by IFN-y
`released from activated T cells that upregulutes Fas on keratinircytes.
`The lethal hit is delivered to keratinoeytes by Fas-ligand exptessetl on
`the surface oI"l' cells that ltIV£tLlt.' tlic cpnleinris and soluble Fzis—lig.aiid
`released from T cells.
`
`for
`it clrcmoattractaiit
`ll.-lb.
`CHEMOATTRACTANT FACTORS
`CD4+ T cells.
`is more highly expressed in acute than chronic AD
`skin lesicrirs.“ Tlte C74.“ clrcmokines. RANTFS (regulated on activa-
`
`CHAPTER122
`
`Atopic Dermatitis Mtupic Eczerrtal
`
`1183
`
`trroirocyte chemotactic
`lion, normal T cell expressed and secreted].
`prriteitt-4. fll1Ll eotztxin are also it'icre:r.sed in AD skirt lesions and likely
`contribute to the chcniotaxis of cosinoplrils and THE lynrphocytes into
`the Slill1.fl'“ Recent studies suggest a role for cutaneous T cell at-
`trrictnnt cliemokine (CTACKICCLZT) in the preferential attraction of
`CLA+ T cells to the sl~;it'i."“ The chcinokine receptor CCR3. which is
`found on eosinophils and TH2ly1nphtrcytes and can mediate the action
`of eotuxin. RANTES. and MCP--1. has been reported to be increttsetl in
`iiotrlesioiial and lesioruil skin of patients with AD.” Sclcctive recruit-
`merit ofCCR-l expressing TH2 cells into AD skin may also be mediated
`by the chenrokiires MDC and TARC. whiclr are increased in AD.“
`
`PERSISTENT SKIN INFLAMMATION C'hi'onic AD is linked to the
`
`prolonged survival of cosinophils and nronocyte—iiiacropl1agi:s in atopic
`skin.
`lL.-5 expression during chronic AD likely plays a role in pro-
`longing cosiiroplril survival and enlrancement of‘ their Function.
`in
`chronic AD.tl1cincrcascd GM—CSF cripression plays an important role
`in inaintttining the survival and function of monocytes, Langerhans‘
`cells aird eosinophils." Epidermal kemtinocytes from AD patients ex-
`press sigtrilicantly higher levels trfRANTES followiirg stitnulation with
`Tl‘-‘F--or and IFN—}: than keiatirrocytes ftoin psoriasis patients.“ This
`may serve as one mechanism by which the TNF-at and IFN-iv pro-
`duction dut'in_:_: chronic AD enltttnces the chronicity and severity of"
`ecxcmat. Mechanical trauinn can also intluce the release of TNF-oi and
`many other prtrirrl1ainniatot'y cytokines front epidermal lceratinocytes.
`Thus. clirnnic scratching plays it role in the perpetuation ttrrdclicitation
`til skin iiillriiiitttution in AD.
`
`Factors Controlling TH2 Cell Development
`
`A number of dctcrrninaiits support TH2 cell development early in the
`atopic skin process arid provide opportunities for thempettlic interven-
`tion. These include the cytokinc rnilieti in which T cell development is
`taking placing. the host's genetic propensity to produce TH2-type cy-
`tokines. phairiracologie factors. the costirnulatory signals used during
`T cell activation. the aiiiiigcn-pitsiziiiirig cell. and skin barriizr function
`(reviewed in Ref. Ill).
`
`ROLE OF CYTOKINES lI_.-4 promot