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Erythema MultiformePeter Fritsch Ramon Ruiz-Maldonado

The erythema multiforme group of diseases encompasses a number of acute self-limited

exanthematic intolerance reactions that share at least two characteristic features: targetlesions stable circular erythemas or urticarial pla!ues with areas of blistering" necrosis"

and#or resolution in a concentric array$ and" histologically" satellite-cell or more

widespread$ necrosis of the epidermis% These features are the expression of an archetypicpolyetiologic reaction pattern of the s&in i%e%" a cytotoxic immunologic attac& on

&eratinocytes expressing non-self antigens$% 'ntigens in(ol(ed are predominantly

microbes (iruses$ or drugs%

't present" two main subsets are recognized: )$ erythema multiforme*a fairly common"

usually mild and relapsing eruption that is most often triggered by recurrent herpes

simplex (irus +,$ infection. and /$ the ,te(ens-0ohnson syndrome1toxic epidermalnecrolysis complex ,0,1TE2$*an infre!uent se(ere mucocutaneous intolerance

reaction that is most often elicited by drugs% Entities that may be grouped (ery close to

the erythema multiforme spectrum are the acute graft-(ersus-host disease" fixed drugeruption" and erythema multiforme1li&e disseminated allergic contact dermatitis% The

exact relationship among these entities is still a matter of contro(ersy" as are aspects of

therapy and management% The pathogenesis is only incompletely understood%

34',,5F53'T562 '27 +5,T6R8

2o generally accepted classification of the erythema multiforme spectrum exists%Morphology remains the predominant basis for disease definitions" which ha(e been the

arena of terminologic disputes for more than a century% 4umping and splitting of entities"

introduction of new terms" continued use of discarded ones" and too liberal usage of theterm erythema multiforme for ill-defined cutaneous eruptions ha(e led to terminologic

and conceptual confusion that lea(es most of the traditional terms without an une!ui(ocal

meaning and 9eopardizes the accessibility of the erythema multiforme literature% The

confusion can be disentangled only through a re(iew of the historical de(elopment%

7escriptions of erythema multiforme date bac& to anti!uity 3elsus$% ateman first

described the target lesion in );)s description exactly

fits the appearance of what is now &nown as +,-associated erythema multiforme"except that he made no reference to oral mucosal in(ol(ement% ,te(ens and 0ohnson

described a se(ere mucosal disease with ?purplish cutaneous macules and necroticcenters@ in )A//% 5n )ABC" Thomas proposed that erythema multiforme and the ,te(ens-

0ohnson syndrome ,0,$ were (ariants of the same pathologic process" differing only in

se(erity" and that they should be termed erythema multiforme minor and erythema

multiforme ma9or" respecti(ely% 'lthough this suggestion was broadly accepted" the term

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,te(ens-0ohnson syndrome continued to be used as a synonym for erythema multiforme

ma9or%

5n )AB=" 4yell described TE2" again as a separate clinical entity 4yell>s syndrome$" as a

life-threatening" rapidly e(ol(ing mucocutaneous reaction characterized by erythemas"

necrosis" and bullous detachment of the epidermis resembling scalding% ) 4yell>s seriesincluded not only patients suffering from what would still be called TE2 today" but also

others with staphylococcal scalded-s&in syndrome and generalized fixed drug eruption. /

thus" the series fueled terminologic disputes for many years% 5n the following decades" thenotion gained ground that" in most or e(en in all instances" TE2 was e!ui(alent to ,0, of

maximal se(erity% 4yell himself suggested that the term toxic epidermal necrolysis be

abandoned" D but its use has been retained%

3learly" the erythema multiforme spectrum has for decades been considered to include

the mild ?minor@ and the less common" but more se(ere" ?ma9or@ types of the disorder*

the distincti(e mar& being the presence of mucous membrane in(ol(ement*surmounted

by the rare de(astating TE2% 'll these categories were interpreted as polyetiologic" withan almost unlimited number of potential causati(e factors held responsible% 5t was

thought that the milder forms were caused more often by infections. the more se(ereones" by drugs% These prototypes were theoretically well defined" but their distinction

often pro(ed difficult in practice because of their o(erlapping features%

5mportant recent ad(ances ha(e" paradoxically" added to the confusion% 5t has become

clear that mild erythema multiforme is strongly lin&ed to +, infection% < +owe(er"

+,-related erythema multiforme cannot simply be e!uated with ?erythema multiforme

minor"@ because it fre!uently in(ol(es mucosal sites most often oral$ that ha(epre(iously been attributed to ?erythema multiforme ma9or%@ 4abeling such cases

erythema multiforme ma9or is again confusing" B " = because ?erythema multiforme

ma9or@ is firmly engrained as a synonym for ,0,%

3linical and histopathologic obser(ations" mostly by a team of French in(estigators" ha(e

suggested that there are two main morphologic patterns within the erythema multiformespectrum% The in(estigators proposed that these patterns be considered different disorders

with distinct causes B " = and Table B;-)$: +,-related erythema multiforme"

characterized by target lesions and a predominantly inflammatory histopathologic pattern"

and the primarily drug-related ,0,-TE2 complex" characterized by atypical or no targetlesions at all and a predominantly necrotic histopathologic pattern% ,te(ens-0ohnson

syndrome and TE2 were ta&en to differ only in the body surface area ,'$ in(ol(ed

and the se(erity%

3onsensus papers ha(e pro(ided clinical criteria for the entities of the erythema

multiforme spectrum that ha(e been widely used in subse!uent publications% The basis ofthe proposed definitions for ,0,-TE2 is !uantitati(e: B " ,0, represents cases of less

than )C percent ,' in(ol(ement. TE2 indicates more than DC percent. and those in

between are labeled ,0,-TE2 ?o(erlap%@ 'lthough somewhat artificial and not

particularly simple" this classification is definitely useful for epidemiologic purposes

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,' is a prognostic factor in ,0,1TE2$ and permits the determination of medication

ris&s% 'lso" it corresponds to a classification proposed earlier by one of us R%R%M%$% ;

,e(eral problems remain to be clarified: )$ the issue of o(erlapping features has not been

resol(ed. /$ the !uestion of whether all instances of erythema multiforme that are not

,0,-TE2 by clinical criteria are +,-related has not been properly addressed. D$ it hasnot been pro(en that all instances of extensi(e TE2" in fact" represent (ariants of ,0,

e%g%" what has been called ?TE2 without spots@ B $. and

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E(idence lin&ing +, to erythema multiforme is best for recurrent erythema multiforme"

as clinical lesions of recurrent +, infection precede an outbrea& of erythema

multiforme in about ;C percent of patients% )/ 5n situ hybridization and the polymerasechain reaction ha(e demonstrated +,-72' in the epidermal cells not in the dermis$ of

erythema multiforme lesions in up to AC percent of patients" )D " )< e(en in indi(iduals

without ob(ious preceding +, infection% )B 5n addition" immunofluorescence andimmune histochemistry ha(e demonstrated +,-specific antigens in lesional s&in% Most

patients with recurrent erythema multiforme are seropositi(e for +," and it is

occasionally possible to reco(er +, from circulating immune complexes% )= Peripheralblood mononuclear cells from patients with +, infection and those with +,-related

erythema multiforme exhibit a similarly s&ewed T cell receptor response on stimulation

with +, antigen" indicating a specific immune response against +, in both

conditions% ) Proof for the pathogenetic rele(ance of +, infection deri(es from thefact that the prophylactic administration of acyclo(ir can effecti(ely pre(ent recurrent

+,-associated erythema multiforme. ); this is also true for many patients with no

clinical e(idence of +, infection% There are no data at present" howe(er" to pro(e that

nonrecurring erythema multiforme is as strongly related to +, as recurring erythemamultiforme%

5t is a matter of terminology and therefore contro(ersy$ whether cases should be

classified as erythema multiforme if they fulfill the clinical criteria" but do not show

e(idence of preceding +, infection% There is little doubt that such eruptions exist" but itis unclear how fre!uent they are. they may occur more often in nonrecurrent erythema

multiforme% The e(idence for causati(e factors other than +, infection is only

circumstantial% Published reports implicate hepatitis and 3 (irus" as well as other (iral

infections% )A " /C Progesterone may elicit chronic recurrent erythema multiforme thatresponds to tamoxifen treatment /) and oophorectomy% 7rugs are a rare cause of

erythema multiforme with mucous membrane lesions% 5t may" of course" be argued

whether these eruptions were truly erythema multiforme or mere imitators. moreo(er"subclinical +, infection generally cannot be ruled out% 6ther problems are idiopathic

cases" in which neither +, infection nor any other cause can be unco(ered% ,uch cases

are fairly common under routine circumstances" but are e(en found in studies thatspecifically loo&ed for +, infection% /) Many such cases respond to prophylactic

acyclo(ir treatment and are thus li&ely to ha(e been triggered by subclinical +,

infection. some" howe(er" are resistent% /)

Erythema multiforme1li&e dermatitic eruptions result from contact sensitization to

sulfonamides" antihistamines" dinitrochlorobenzene 723$" diphencyprone 7P3P$"

rosewood" Rhus" primula" tea tree oil" cutting oils" cinnamon" and other substances. theserashes should be (iewed as only imitators of erythema multiforme" despite clinical and

histopathologic similarities% //

PathogenesisThe current belief is that erythema multiforme is a cell-mediated immune reaction

leading to the destruction of &eratinocytes expressing +, antigens% +owe(er" manyaspects of the underlying pathomechanisms are not &nown%

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'lthough erythema multiforme lesions can exhibit (iral antigens and 72'" attempts at

(iral cultures almost in(ariably fail" and electron microscopy cannot detect intact (irions%

Therefore" erythema multiforme lesions are not sites of regular +, replication" as canbe suspected from their histopathologic appearance% This paradox has been partially

resol(ed: )< no (iable +, particles are present in epidermal &eratinocytes. there are

only 72' fragments" most often encoding (iral 72' polymerase% Fragments of 72'persisted for ) to D months in the epidermis after healing as in acute +, lesions$. (iral

polymerase R2'" howe(er" was identified only in fresh" not in healed erythema

multiforme lesions% These data suggest that transcription and translation are limited" andthat the de(elopment of erythema multiforme lesions may be associated with the

expression of (iral polymerase and#or additional antigens$" stimulating a specific

immune response%

6b(iously" +,-72' reaches distant cutaneous locations from a site of acti(e replication

(ia the bloodstream% 5mmune complexes may mediate hematogenous transport. )= more

importantly" howe(er" peripheral blood mononuclear cells" which contained +,-72' in

more than =C percent of patients during acute erythema multiforme episodes" may be thetransport (ehicle% )D The use of this (ehicle may explain (iral 72' fragmentation:

monocytes are nonpermissi(e for +, replication" which may lead to 72' damage% )s syndrome@$% DA 5t may sometimes be difficult to distinguish

mucosal lesions from pemphigus (ulgaris and herpetic gingi(ostomatitis% 7isseminated

contact dermatitis may exhibit lesions that mimic target lesions closely" both clinically

and histologically% //

Treatment5n most cases" erythema multiforme causes little discomfort and regresses spontaneously

within about / wee&s% ,ymptomatic treatment with sha&e lotions" topical steroids"analgesics" and antihistamines has little impact on the course" but may reduce sub9ecti(e

symptoms% 4i!uid antacids" topical glucocorticoids" and local anesthetics relie(esymptoms of painful mouth erosions% The systemic administration of glucocorticoids is

unnecessary and may e(en ha(e worsened some cases%

5n recurrent erythema multiforme" early treatment of +, infection with oral acyclo(ir

/CC mg fi(e times per day for B days$ or its deri(ati(es with better bioa(ailability e%g%"

(alacyclo(ir or pencyclo(ir$ may pre(ent erythema multiforme" but often it comes too

late% 5n such cases" continuous administration of low-dose acyclo(ir