7
Reactive PA RT
Erythemas
Chapter 43 :: Erythema Multiforme
:: Jean-Claude Roujeau &
Maja Mockenhaupt
AT-A-GLANCE
■ Erythema multiforme is a rare cutaneous or
mucocutaneous eruption characterized by “target”
lesions, predominantly on the face and extremities.
■ The highest incidence was found in male children
and young adults.
■ It has a benign course but frequent recurrences,
possible ocular complications.
■ Most cases are related to infections (herpes
simplex virus [HSV] and Mycoplasma pneumoniae).
Medications are not a common cause, in contrast to
the spectrum of drug-induced epidermal necrolysis
(see Chap. 44) that are different diseases.
■ Herpes-induced recurrences can be prevented
by long-term use of anti-HSV medications.
Thalidomide, mycophenolate mofetil, or both may
be considered in recalcitrant, recurrent cases.
INTRODUCTION
DEFINITIONS
Erythema multiforme (EM) is an acute mucocutaneous
syndrome originally described by von Hebra in 1860
as erythema exudativum multiforme. It is defined by a
distinctive clinical pattern (with consistent histopathol-
ogy when done). The course is usually mild and self-
limited but carries a risk of relapse. Based on the degree
of mucous membrane involvement, EM is separated
into EM minus (EMm, also called EM minor) if only
the skin and lips are involved and EM majus (EMM,
also called EM major) when mucous membranes are
affected. Subtypes of EM are described in Table 43-1.
Kang_CH043_p0723-0732.indd 723
Historically, a variety of factors have contributed to a
confusing nosology, especially with the concept of a so-
called “EM spectrum” from EMm to Stevens-Johnson
syndrome (SJS) and toxic epidermal necrolysis (TEN).
The definition of EM in this chapter is based on the
classification proposed 25 years ago by Bastuji-Garin
and colleagues.1 The principle of the classification was
to consider SJS and TEN as severity variants of a pro-
cess termed epithelial necrolysis (EN; see Chap. 44) and
to separate them from EM. The validity of that classi-
fication has been established by several studies, espe-
cially the prospective international Severe Cutaneous
Adverse Reactions study2 and by recent series3,4 show-
ing that compared with SJS and TEN, EM cases have
different demographic features, clinical presentation,
severity, and causes.
The consensus classification was improved by
German investigators by separation of EMM into
typical EMM (typical targets on the extremities) and
atypical EMM with more extensive distribution of
atypical, larger targets, occasionally involving the skin
around the mouth and the eyes, resulting in clown-
like facies. The relevance of that subclassification was
supported by the demonstration of younger age and
more frequent association with Mycoplasma pneumoniae
infection in cases of atypical EMM.5
Cases of mucosal disease with target lesions on the
trunk are often diagnosed as SJS or M. pneumoniae–
associated SJS, especially in the pediatric realm. How-
ever, we consider these cases EMM caused by M.
pneumoniae. Other authors have proposed that muco-
cutaneous eruptions associated with M. pneumoniae
are a distinct entity, termed M. pneumoniae-induced
rash and mucositis (MIRM).4 It is certainly true that
EMM and the range of presentations of EN have to
be differentiated, no matter what the cause. It is also
true that typical EMM associated with herpes simplex
virus (HSV) presents differently than atypical EMM
07/12/18 2:05 pm
 7 TABLE 43-1
EM occurs in patients of all ages but is most preva-
lent in adolescents and young adults. There is a male
Erythema Multiforme (EM) Subtypes preponderance (male:female ratio of 2 to 3:1). Recur-
rence happens in about 10% of patients with EMM and
ASSOCIATED up to 30% in EMm, more frequently, but not exclu-
SUBTYPE CLINICAL FEATURES ETIOLOGY
sively, in HSV-associated cases.
EM minus Typical targets HSV, other There are no established associations of underlying
(EMm) Acral skin and lip involvement infections disease with risk for EM. HIV infection and collagen
No mucosal erosions vascular disorders increase the risk of SJS and TEN but
EM majus Typical targets HSV, other not EM. Cases may occur in clusters, which supports a
(EMM) Acral skin involvement infections role for infectious agents. The incidence does not vary
Mucosal erosions with ethnicity or geographic location.
Atypical EMM Giant targets Mycoplasma Predisposing genes have been reported. A total of
Central distribution pneumoniae, 66% of EM patients have HLA-DQB1∗0301 allele com-
Part 7

Prominent mucosal erosions HSV pared with 31% of control participants.9 However, this
Mucosal EMM No or minimal skin lesions M. pneumoniae association has not translated into a meaningful clini-
Prominent mucosal erosions cal test or intervention.
::

Continuous or Typical targets HSV, idiopathic

persistent EM Acral skin involvement
Reactive Erythemas

Few mucosal erosions

Overlapping recurrences CLINICAL FEATURES
HISTORY
HSV, herpes simplex virus.

associated with M. pneumoniae, but we do not consider
atypical EMM a distinct entity.
Atypical EMM may present in a variety of forms,
sometimes predominantly affecting the skin and some-
times predominantly affecting two or more mucosal
sites. If only the mucous membranes are involved,
making the correct diagnosis may be a challenge. In
1878, the ophthalmologist Fuchs described a patient
with erosions of the eyes and mouth and a transient
skin eruption. The term Fuchs syndrome (also called
ectodermosis pluriorificialis) has been applied to such
cases that share demographic and etiologic features
with atypical EMM. The term mucosal EMM, a subset
of atypical EMM, is now preferred.
Unfortunately, the International Classification of
Diseases 10th Revision (ICD-10) did not incorporate
these advances and uses the same code, L51.1, for SJS
and bullous EM, and classifies TEN as L51.2 under
the heading of EM (L51). Nonspecific codes maintain
the confusion of a so-called “EM spectrum” despite the
accumulation of evidence of different mechanisms,
clinical presentations, severity, and causes of EM ver-
sus SJS-TEN.2-4
Prodromal symptoms are absent in most cases. If pres-
ent, they are usually mild, suggesting an upper respira-
tory infection (cough, rhinitis, low-grade fever). In EMM,
fever higher than 38.5°C (101.3°F) is present in one third
of cases.2 Prior occurrences are reported in up to one
third of patients and help make the correct diagnosis.
The events of the preceding 3 weeks should be reviewed
for clinical evidence of any precipitating agent, with a
special focus on signs and symptoms of HSV and symp-
toms of respiratory infection or influenza-like illness.
In more than 70% of patients with recurrent EM,
an episode of recurrent HSV infection precedes the
skin lesions. The association with herpes labialis pre-
dominates over that with genital herpes or herpes in
other locations. EM usually follows recurrent herpes
but may also occur after primary HSV infection. The
average interval is 7 days (range, 2–17 days). The dura-
tion of the lag period appears to be specific for indi-
vidual patients. In a small number of patients, HSV
recrudescence and EM may occur simultaneously. Not
all episodes of EM are preceded by clinically evident
HSV, and not all HSV episodes are followed by EM.
Episodes of recurrent HSV infection may precede the
development of HSV-related EM by years.

EPIDEMIOLOGY
EM is considered relatively common, but the true inci-
dence is unknown. There is selection bias for severe
cases requiring hospitalization in the medical litera-
ture; such cases are rare and occur in the range of 0.5
to 1 per million per year.6 EMm is likely more frequent
than EMM. Another obstacle to proper evaluation of
incidence is the misdiagnosis of EM in patients with
annular or figurate eruptions, including annular urti-
caria, serum sickness–like eruption, polymorphous
724 maculopapular eruptions,7 subacute cutaneous lupus
erythematosus,8 and even SJS or TEN.7
CUTANEOUS FEATURES
The skin eruption arises abruptly. In most patients,
all lesions appear within 3 days, but in some, several
crops follow each other during a single episode of
EM. Often there are a limited number of lesions, but
up to hundreds may form. Most occur in a symmetric,
distribution on the extensor surfaces of the extremi-
ties (hands, feet, elbows, and knees), face, and neck
and less frequently on the thighs, buttocks, and trunk.
Lesions often first appear distally and then spread in

Kang_CH043_p0723-0732.indd 724 07/12/18 2:05 pm

 7

Chapter 43 :: Erythema Multiforme

Figure 43-1 Mixture of typical targets and papules in a
case of erythema multiforme.

a centripetal manner. Mechanical factors (Koebner

phenomenon) and actinic factors (predilection for sun-
exposed sites) appear to influence the distribution of
lesions. Although patients occasionally report burning
and itching, the eruption is usually asymptomatic.
The diversity in clinical pattern implied by the
name multiforme is mainly related to the features of
single lesions. Most lesions are usually very similar in a
given patient at a given time. The typical target lesion Figure 43-3 Typical targets around the knee.
is a highly regular, circular, wheal-like erythematous
papule or plaque that persists for 1 week or longer
(Fig. 43-1). It measures from a few millimeters to and dark; inflammatory activity may regress or relapse
approximately 3 cm and may expand slightly over 24 in the center, which gives rise to concentric rings of
to 48 hours. Although the periphery remains erythem- color (see Figs. 43-1 to 43-4). Often, the center turns
atous and edematous, the center becomes violaceous

Figure 43-4 Disseminated targets on the trunk (atypical 725

Figure 43-2 Typical target lesions on the palm. erythema multiforme majus).

Kang_CH043_p0723-0732.indd 725 07/12/18 2:05 pm

 7

Figure 43-5 Giant targets on the arm (atypical erythema

multiforme majus).

purpuric or necrotic or transforms into a tense vesicle Figure 43-6 Involvement of the lips with a target pattern
Part 7

or bulla. The result is the classic target or iris lesion. in erythema multiforme majus.
According to the current classification,1,5 typi-
cal target lesions consist of at least three concentric
frequent and more severe in M. pneumoniae–associated
::

components: (1) a dusky central disk or blister; (2)

more peripherally, an infiltrated pale ring; and (3) cases.10 The nasal, urethral, and anal mucosae also may
Reactive Erythemas

an erythematous halo. Not all lesions of EM are typi-
cal; some display two rings only (raised atypical tar-
gets). However, all are infiltrated papules, in contrast
to macules, which are the typical lesions in EN (SJS
and TEN). In some patients with EM, most lesions are
violaceous vesicles overlying a just slightly darker
central portion, encircled by an erythematous margin
(see Figs. 43-2 to 43-4). Larger lesions (Fig. 43-5) may
have a central bulla and a marginal ring of vesicles
(herpes iris of Bateman).
In most cases, EM affects well under 10% of the body
surface area. In 88 hospital cases of EMM prospectively
included in the Severe Cutaneous Adverse Reactions
study, the median involvement was 1% of the body
surface area.2 The duration of an individual lesion
is shorter than 2 weeks, but residual discoloration
may remain for months. There is no scarring unless
mechanical manipulation takes place.
be inflamed and eroded.
RELATED PHYSICAL
FINDINGS
Fever and other constitutional symptoms are usu-
ally absent in EMm, and the noncutaneous physi-
cal examination is normal. Fever higher than 38.5°C
(101.3°F) is present in one third of EMM cases. Mouth
erosions may be painful enough to impair alimenta-
tion. The patient may be unable to close the mouth
and constantly drools blood-stained saliva. Cervical
lymphadenopathy is usually present in these patients.
The pain of genital erosions may lead to reflex uri-
nary retention. Cough and hypoxia may occur in
M. pneumoniae–related cases.

NONCUTANEOUS COMPLICATIONS
FEATURES In contrast to SJS, in which cutaneous lesions may
progress to extensive detachment of the epidermis,
Mucosal lesions are present in up to 70% of patients, there is no risk of “skin failure” or visceral involvement
most often limited to the oral cavity.
Predilection sites are the lips, on both the cutane-
ous and mucosal sides, nonattached gingivae, and the
ventral side of the tongue. The hard palate is usually
spared, as are the attached gingivae. On the cutane-
ous part of the lips, identifiable target lesions may be
discernible (Fig. 43-6). In children and adolescents, lips
and oral mucosa are often affected very severely both
in cases caused by M. pneumoniae or by respiratory
infections caused by unspecified infectious agents. On
the mucosa proper, there are erosions with fibrinous
deposits, and occasionally intact vesicles and bullae
can be seen (Fig. 43-7). The process may rarely extend
to the throat, larynx, and even the trachea and bronchi.
Eye involvement begins with pain and bilateral con-
726 junctivitis in which vesicles and erosions can occur
(Fig. 43-8). In children, ocular lesions appear to be more Figure 43-7 Oral erosions in erythema multiforme majus.

Kang_CH043_p0723-0732.indd 726 07/12/18 2:05 pm


Figure 43-8 Conjunctivitis with erosions in erythema mul-
tiforme majus.
to establish. Clinical and radiologic signs of atypical
pneumonia can be mild, and M. pneumoniae is usu-
7
ally not directly detected. Polymerase chain reaction
(PCR) testing of throat swabs, or bronchopulmonary
lavage if performed, for M. pneumoniae is the most
sensitive technique for diagnostic confirmation.
Serologic results are considered diagnostic in the
presence of IgM or IgA antibodies to M. pneumoniae
in the acute phase or a more than twofold increase in
IgG antibodies in paired serum samples obtained at
onset and after 2 or 3 weeks. M. pneumoniae–related
EM can recur.
Many other infections have been reported as causes
of EM in individual cases or small series, but the evi-

Chapter 43 :: Erythema Multiforme

dence for causality of these other agents is only circum-
stantial. Published reports have implicated infection
in EMM. Mouth erosions may impair oral alimenta-
with EBV, Orf virus, varicella zoster virus, parvovirus
tion. Reflex anuria from periurethral erosions rarely
B19, hepatitis B and C viruses, and a variety of other
needs bladder catheterization. Severe ocular lesions
bacterial or viral infections. Immunization has been
leading to sequelae are rare but can occur, and ocu-
also implicated as a cause in children, but a spurious
lar symptoms must be checked by an ophthalmolo-
association can be suspected.
gist in the acute phase of the disease and followed
Drugs are also a reported cause of EM, although
appropriately.10
a true association is unlikely. Most reports of drug-
associated EM actually deal with imitators,7 for
ETIOLOGY AND example, annular urticaria (also called urticaria mul-
tiforme)15 or disseminated maculopapular eruptions
PATHOGENESIS with some lesions resembling targets (Fig. 43-9).
EM-like dermatitis may also result from contact sen-
Most cases of EM are related to infections (Table 43-2). sitization. These eruptions should be viewed as imita-
HSV is the most common cause, principally in recurrent tors of EM despite some clinical and histopathologic
cases. Proof of causality of HSV is firmly established
from clinical experience, epidemiology,2 detection of
HSV DNA in the lesions of EM,11,12 and prevention of
EM by suppression of HSV recurrences.13 Clinically, a
link with HSV can often be made. EM eruptions begin
on average 7 days after HSV eruptions. The delay can
be substantially shorter, especially with more recur-
rences. Not all symptomatic HSV recurrences are fol-
lowed by EM, and asymptomatic ones can induce EM.
Therefore, the causal link can be overlooked by both
the patient and physician. HSV-1 is usually the cause,
but HSV-2 can also induce EM.
M. pneumoniae is the second major cause of EM
overall and the first in children.5,14 In cases related
to M. pneumoniae, the clinical presentation is often
atypical (giant targets, clown-like facial distribution)
and more severe than in cases associated with HSV.
The relationship to M. pneumoniae is often difficult

TABLE 43-2
Conditions Commonly Associated with
Erythema Multiforme
Herpes simplex virus
Mycoplasma pneumoniae
Epstein-Barr virus
Orf
Varicella zoster virus
Parvovirus B19
Figure 43-9 Figurate erythema in a case of “drug erup-
Hepatitis B
tion” to amoxicillin, frequently and erroneously reported 727
Hepatitis C
as drug-induced erythema multiforme.

Kang_CH043_p0723-0732.indd 727 07/12/18 2:05 pm

 7 similarities. Literature reports of drug-associated EM
also include typical cases of SJS or TEN, particularly
under the moniker EMPACT syndrome (EM, phenyt-
oin and cranial radiation therapy).7 Such terms create
more confusion on EM and minimize the potential
severity of drug reactions.
Idiopathic cases are those in which neither HSV
infection nor any other cause can be identified. These
cases are fairly common in routine clinical circum-
stances. However, HSV has been found in situ by PCR
in up to 40% of such presentations.3 Some idiopathic
cases respond to prophylactic antiviral treatment and
are thus likely to have been triggered by asymptomatic
HSV infection. Others are resistant and probably have
Part 7
another cause.
Another suspected variant of recurrent EMM was
reported to be associated with desmoplakin I and II
autoantibodies.16 However, the presence of acantholy-
::
sis in skin biopsies of such cases suggests a variant of
Reactive Erythemas
pemphigus that clinically resembles EM. The recently
reported efficacy of rituximab in such cases also sup-
ports this hypothesis.17 Conversely, in a series of 54
cases of typical EMM, antiepidermal antibodies were
not found.18
The underlying mechanisms of HSV-associated
EM have been extensively investigated.11,13,19,20 It is
unknown whether similar mechanisms apply to EM
from other causes.
Complete, infective HSV has never been isolated
from lesions of HSV-associated EM, but the presence of
HSV DNA in skin lesions has been reported in numer-
ous studies using PCR assays. These studies demon-
strated that keratinocytes contain viral DNA fragments
that always include the viral polymerase (Pol) gene.
HSV Pol DNA is located in basal keratinocytes and in
the lower spinous cell layers, and viral Pol protein is
synthesized. HSV-specific T cells, including cytotoxic
cells, are recruited, and the virus-specific response is
followed by a nonspecific inflammatory amplifica-
tion by autoreactive T cells. The cytokines produced
in these cells induce the delayed hypersensitivity–like
appearance in histopathologic evaluation of biopsy
sections of EM lesions.
HSV is present in the blood for a few days during
an overt recurrence of herpes. If keratinocytes were
infected from viremia, one would expect signs and
symptoms of disseminated herpes rather than EM.
Instead, HSV DNA is transported to the epidermis
by monocytes, macrophages, and CD34+ Langerhans
cell precursors harboring the skin-homing receptor
cutaneous lymphocyte antigen that engulf the virus
and fragment its DNA. Upregulation of adhesion mol-
ecules greatly increases binding of HSV-containing
mononuclear cells to endothelial cells and contributes
to the dermal inflammatory response. Upon reaching
the epidermis, the cells transmit the viral polymerase
gene Pol to keratinocytes. Viral genes may persist for
a few months, but the synthesis and expression of
the Pol protein will last for only a few days. This may
explain the transient character of clinical lesions that
728 are likely induced by a specific immune response
to Pol protein and amplified by autoreactive cells.
Kang_CH043_p0723-0732.indd 728
Effector cells are CD4 T lymphocytes with a restricted
Vβ repertoire. Incomplete fragmentation of viral
DNA, increased number of circulating CD34+ cells, or
increased immune response to Pol protein character-
ize the small proportion of individuals with recurrent
herpes infections who develop EM.
DIAGNOSIS
An approach to the diagnosis and management of EM
is shown in Fig. 43-10. EM is usually diagnosed clini-
cally. A skin biopsy and laboratory investigations are
useful when the diagnosis is not certain. After making
the diagnosis, the need for hospitalization is consid-
ered. Admission is suggested for patients with EMM
with oral lesions severe enough to impair drinking and
feeding, when a diagnosis of SJS is suspected, or when
severe constitutional symptoms are present. Estab-
lishing the underlying cause of EM is also part of the
evaluation.
SUPPORTIVE STUDIES
LABORATORY
There are no specific laboratory tests for EM. In more
severe cases, an elevated erythrocyte sedimentation
rate, moderate leukocytosis, increased levels of acute-
phase proteins, and mildly elevated liver aminotrans-
ferase levels may occur. Antidesmoplakin antibodies
are not found.18
HISTOPATHOLOGY
Early lesions of EM exhibit lymphocyte accumulation
at the dermal–epidermal interface with exocytosis
into the epidermis, lymphocytes attached to scattered
necrotic keratinocytes (satellite cell necrosis), spon-
giosis, vacuolar degeneration of the basal cell layer,
and focal junctional and subepidermal cleft forma-
tion. Acantholysis is not a feature of EM. The papillary
dermis may be edematous but principally contains a
moderate to dense mononuclear cell infiltrate, which
is more abundant in older lesions. The vessels are
ectatic with swollen endothelial cells, and there may
be extravasated erythrocytes and eosinophils. In
advanced lesions, subepidermal blister formation may
occur, but necrosis rarely involves the entire epider-
mis (Fig. 43-11). In late lesions, melanophages may be
prominent. Immunofluorescence findings are negative
or nonspecific.
The histopathologic appearance of EM lesions dif-
fers from that of EN, in which dermal inflammation
is moderate to absent and epidermal necrosis is much
more pronounced (see Chap. 44). Still, the histopath-
ologic appearances are somewhat overlapping and
often do not allow the distinction of EM from EN,
especially if the sample is obtained from the bullous
center of the lesion. The main reason for performing
07/12/18 2:05 pm
 Approach to a patient with erythema multiforme
7
Pros: Cons:
Typical papules with target features Transient lesions
Acral distribution Widespread erythema
Mucous membrane erosions
Is it EM? Macules and blisters, flat targets
Previous episodes Subacute evolution
Maybe

Biopsy
Yes Direct IF No
Serum antibodies

Chapter 43 :: Erythema Multiforme

Is hospitalization needed? Urticaria
Drug rash with some
EM-like features
Autoimmune blisters
SJS…
What is the probable cause?

History of RECENT Cough, URT Other patient

No clue
recurrent herpes infection infection (eg, Orf virus)

No clinical herpes: HA-related EM MP-related EM EM related to infection

HSV serology, excludes other than HSV or MP
HA-EM if negative

Possible HA-EM Idiopathic EM

Frequent recurrences
of EM
Anti-HSV prophylaxis Azathioprine
even in absence Thalidomide
of patent of HSV Mycophenolate
causality mofetil

Figure 43-10 Approach to a patient with erythema multiforme (EM). ADR, adverse drug reaction; HA-EM, herpes-
associated erythema multiforme; IF, immunofluorescence; MP, Mycoplasma pneumoniae; SJS, Stevens-Johnson syndrome;
URT, upper respiratory tract.

a biopsy in EM is to rule out other diagnoses, such as

autoimmune blistering diseases, Sweet syndrome, and
vasculitis.

Figure 43-11 Histopathology of erythema multiforme.
UNDERLYING ETIOLOGY
In the presence of respiratory symptoms, a chest
radiograph is indicated to evaluate for pneumonia,
and PCR assay or serologic testing may help detect
M. pneumoniae infection. In the case of recurrent EM,
a link to HSV can be confirmed by evaluating preced-
ing lesions of herpes labialis using HSV PCR, direct
fluorescent antibodies, or viral culture. However,
these studies are not useful when applied to the tar- 729
get lesions. Amplification of HSV Pol gene from biopsy

Kang_CH043_p0723-0732.indd 729 07/12/18 2:05 pm

 7 samples of EM lesions is not done routinely. A nega-
tive result on serologic testing for HSV may be helpful
only to exclude the possibility of herpes-association.
The positive predictive value of the presence of HLA-
DQB1∗0301 is too low to have clinical value.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of EM is reviewed in
Table 43-3.
The most important differential diagnosis, SJS, should
be recognized promptly for three reasons: (1) the pos-
sibility of life-threatening complications, (2) the risk of
Part 7
progression to TEN, and (3) the need for urgent with-
drawal of suspected causative drug(s) (see Chap. 44).
Pain, constitutional symptoms, severe erosions of muco-
sae, rapid progression, and dusky or violaceous often
::
confluent macules and blisters are alerting features.
Reactive Erythemas
In rare cases of EM affecting only mucous mem-
branes, the diagnosis is especially difficult and often
made when further bouts include a few skin lesions.
The history is extremely important, especially related
to infections and recurrence. Pemphigus, cicatricial
pemphigoid, allergic or toxic contact stomatitis, toxic
erosive stomatitis, aphthae, and lichen planus should
be considered.
COURSE AND PROGNOSIS
EMm runs a mild course in most cases, and each indi-
vidual attack subsides within 1 to 4 weeks. Recovery
is complete, and there are usually no sequelae, except
for transient skin discoloration. The ocular erosions of
EMM may cause severe residual scarring of the eyes,
especially in adults and in non–herpes-related cases.21
M. pneumoniae–related EMM may be associated with
severe erosive bronchitis that may rarely lead to
sequelae.22
Whatever the cause of EM, recurrences are com-
mon and may characterize the majority of cases. In
reports of large series of patients with recurrent EM,
the mean number of attacks was 6 per year (range,
2 to 36), and the mean total duration of disease was
6 to 9 years. In 33%, the condition persisted for more
than 10 years.23 Up to 50 recurrences have been
described in a single patient. The severity of epi-
sodes in patients with recurrent EM is highly vari-
able and unpredictable. The frequency of episodes
and cumulative duration of disease are not correlated
with the severity of attacks. The frequency and sever-
ity of recurrent EM tends to decrease spontaneously
over time (after 2 years or longer), parallel with the
improvement of recurring HSV infection when asso-
ciated. In a substantial proportion of recurrent cases,
a cause cannot be determined.24 A small fraction of
patients experience prolonged series of overlapping
attacks of EM; this has been labeled continuous EM or
persistent EM.25 Persistent EM may be related to HSV
730 but also to other viral infections, inflammatory bowel
diseases, or malignancy.
Kang_CH043_p0723-0732.indd 730
MANAGEMENT
Based on retrospective series or small controlled trials,
the use of systemic corticosteroids seems to shorten
the duration of fever and eruption, especially swelling
and pain of the mucosae but may increase the length
of hospitalization because of complications. However,
the methodology of most studies was poor, with small
series often mixing the various forms of idiopathic and
virus-associated EM and drug-induced SJS. The use of
systemic corticosteroids can neither be recommended
nor blamed.20,26
Administering anti-HSV drugs for the treatment
of an established episode of postherpetic EM is
useless.27
When symptomatic, patients with M. pneumoniae
infection should be treated with antibiotics (macro-
lides in children; macrolides or quinolones in adults).
There is no evidence indicating whether it improves
the evolution of the associated EM. Therefore, when
asymptomatic infection is diagnosed by PCR or sero-
logic testing, treatment is not mandatory.
Liquid antacids, topical glucocorticoids, and local
anesthetics relieve symptoms of painful mouth or
genital erosions. In case of eye involvement, an ocular
lubricant should be administered at least three times
a day, and topical steroids may be recommended by
the ophthalmologist. There are no specific studies on
the use of amniotic membrane in EMM cases with eye
involvement. However, a number of patients consid-
ered to have SJS who were treated successfully with
amniotic grafts may have actually had EMM. Because
the mucosal involvement is the same in EMM and SJS,
grafting of amniotic membrane in EMM cases with
severe eye involvement should be helpful.
PREVENTION
Continuous therapy with oral anti-HSV drugs is effec-
tive at preventing recurrences of herpes-associated
EM, including some cases without clinical evidence
of precipitating HSV.13 Topical acyclovir therapy used
in a prophylactic manner does not prevent recurrent
herpes-associated EM.28
In a series of 65 patients with recurrent EM, 11
were treated with azathioprine when all other treat-
ments had failed. Azathioprine was beneficial in
all 11 patients.23 Mycophenolate mofetil can be also
useful.
Retrospective uncontrolled analyses of thalido-
mide therapy have indicated that it is moderately
effective for the treatment of established EM.29 Tha-
lidomide is probably the most effective treatment of
recurrent or persistent cases when anti-HSV drugs
have failed.30,31
In one randomized controlled trial, levamisole
appeared useful. Because agranulocytosis is a severe
and not exceptional adverse effect, levamisole use is
permitted in only a few countries. The benefit–risk
ratio is probably too low to support its use in the treat-
ment of EM.
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Kang_CH043_p0723-0732.indd 731

TABLE 43-3
Differential Diagnoses of Erythema Multiforme (EM)
MUCOUS
MEMBRANE LESIONS SKIN LESIONS PATTERN HISTOPATHOLOGIC FINDINGS LABORATORY TESTING COURSE

Urticaria No Annular, circinate, blanching erythema Edema   More acute than EM

Transient lesions (individual lesions last ≤24 hr)
Maculopapular drug eruption Rare (lips) Widespread polymorphous, targetlike lesions, Most often nonspecific    
macules, papules, plaques
Lupus erythematosus (“Rowell syndrome”) Possible (mouth) Face and thorax Interface dermatitis Antinuclear antibodies present Subacute
    Large targetlike lesions, annular plaques Positive result of DIF (“lupus band”)    
Paraneoplastic pemphigus Always; tends to be EM-like lesion plus lichenoid papules Acantholysis, positive DIF Antibodies present (not always) Chronic
severe
    Positive Nikolsky sign      
Cicatricial pemphigoid Constant Circinate erythematous patches Subepidermal blister, positive DIF Antibodies present Chronic
Bullous pemphigoid (BP)/IgA-linear Possible in BP; rare in Bullae and crusts in different stages Subepidermal blister, positive DIF Antibodies present Chronic (or relapsing)
dermatosis IgA-linear dermatosis
Antidesmoplakin “EM majus” Constant EM-like lesions Basal acantholysis, positive DIF Antibodies present Acute relapsing
Stevens-Johnson syndrome Constant Widespread small blisters Interface dermatitis, epidermal necrosis   Acute
    Atypical targets, typically confluent      
    Constitutional symptoms      
Sweet syndrome (acute febrile neutrophilic Rare Erythematous papules and succulent plaques Spongiosis with subcorneal vesicles and Neutrophilia Acute
dermatosis) pustules

DIF, direct immunofluorescence testing; IgA, immunoglobulin A.

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Chapter 43 :: Erythema Multiforme
 7 REFERENCES
1. Bastuji-Garin S, Rzany B, Stern RS, S et al. A clinical clas-
sification of cases of toxic epidermal necrolysis, Ste-
vens-Johnson syndrome and erythema multiforme.
Arch Dermatol. 1993;129:92.
2. Auquier-Dunant A, Mockenhaupt M, Naldi L, et al.
Correlations between clinical patterns and causes of
erythema multiforme majus, Stevens-Johnson syn-
drome and toxic epidermal necrolysis. Arch Dermatol.
2002;138:1019.
3. Wetter DA, Camilleri RJ. Clinical, etiologic and
histopathologic features of Stevens-Johnson syndrome
during an 8-year period at Mayo Clinic. Mayo Clin Proc.
2010;85:131.
Part 7
4. Canavan TN, Mathes EF, Frieden I, et al. Mycoplasma
pneumoniae-induced rash and mucositis as a syn-
drome distinct from Stevens-Johnson syndrome and
::
erythema multiforme: a systematic review. J Am Acad
Dermatol. 2015;72:23.
Reactive Erythemas
5. Schröder W, Mockenhaupt M, Schlingmann J, et al.
Clinical re-classification of severe skin reactions and
evaluation of their etiology in a population-based
registry. In: Victor N, et al, eds. Medical Informatics,
Biostatistics and Epidemiology for Efficient Health Care
and Medical Research: Contributions from the 44th
Annual Conference of the GMDS. Heidelberg: Urban &
Vogel; 1999:107-110.
6. Rzany B, Mockenhaupt M, Baur S, et al. Epidemiology
of erythema exsudativum multiforme majus, Stevens-
Johnson syndrome, and toxic epidermal necrolysis in
Germany (1990-1992): structure and results of a popu-
lation-based registry. J Clin Epidemiol. 1996;49:769.
7. Roujeau JC. Re-evaluation of “drug-induced” erythema
multiforme in the medical literature. Br J Dermatol.
2016;175(3):650-651.
8. Bonciolini V, Antiga E, Caproni M, et al. Rowell
syndrome. Does it exist? Clin Exp Dermatol. 2014;39:58.
9. Khalil I, Lepage V, Douay C, et al. HLA DQB1∗0301 allele
is involved in the susceptibility to erythema multi-
forme. J Invest Dermatol. 1991;97:697.
10. Moreau JF, Watson RS, Hartman ME, et al. Epidemiology
of ophthalmologic disease associated with erythema
multiforme, Stevens-Johnson syndrome, and toxic
epidermal necrolysis in hospitalized children in the
United States. Pediatr Dermatol. 2014;31:163.
11. Brice SL, Krzemien D, Weston WL, et al. Detection of
simplex virus DNA in cutaneous lesions of erythema
multiforme. J Invest Dermatol. 1989;93:183.
12. Ng PPL, Sun YJ, Tan HH, et al. Detection of Herpes
simplex virus genomic DNA in various subsets of
erythema multiforme by polymerase chain reaction.
Dermatology. 2003;207:349.
13. Tatnall FM, Schofield JK, Leigh IM. A double-blind, pla-
cebo-controlled trial of continuous acyclovir therapy
in recurrent erythema multiforme. Br J Dermatol.
1995;132:267.
14. Prindaville B, Newell BD, Nopper AJ, et al. Mycoplasma
pneumoniae–associated mucocutaneous disease in
children: dilemmas in classification. Pediatr Dermatol.
2014;6:670.
15. Starnes L, Patel T, Skinner RB. Urticaria multiforme—a
case report. Pediatr Dermatol. 2011;28:436.
732
Kang_CH043_p0723-0732.indd 732
16. Foedinger D, Elbe-Bürger A, Sterniczky B, et al. Erythema
multiforme associated human autoantibodies against
desmoplakin I and II: biochemical characterization
and passive transfer studies into newborn mice.
J Invest Dermatol. 1998;111:503.
17. Hirsch G, Ingen-Housz-Oro S, Fite C, et al. Rituximab, a
new treatment for difficult-to-treat chronic erythema
multiforme major? Five cases. J Eur Acad Dermatol
Venereol. 2016;30:1140.
18. Komorowski L, Mockenhaupt M, Sekula P, et al. Lack of
a specific humoral autoreactivity in sera from patients
with early erythema exsudativum multiforme majus.
J Invest Dermatol. 2013;133:2799.
19. Kokuba H, Imafuku S, Burnett JW, et al. Longitudinal
study of a patient with herpes-simplex-virus-
associated erythema multiforme: viral gene expression
and T cell repertoire usage. Dermatology. 1999;198:
233-242.
20. Ono F, Bhuvnesh K. Sharma BK, et al. CD34+ cells
in the peripheral blood transport Herpes simplex
virus DNA fragments to the skin of patients with
erythema multiforme (HAEM). J Invest Dermatol.
2005;124:1215-1224.
21. Kunimi Y, Hirata Y, Aihara M, et al. Statistical
analysis of Stevens-Johnson Syndrome caused by
Mycoplasma pneumonia infection in Japan. Allergol
Int. 2011;60;525-532.
22. Edwards C, Penny M, Newman J. Mycoplasma pneu-
moniae, Stevens-Johnson syndrome, and chronic
obliterative bronchitis. Thorax. 1983;38:867.
23. Schofield JK, Tatnall FM, Leigh IM. Recurrent erythema
multiforme: clinical features and treatment in a large
series of patients Br J Dermatol. 1993;128:542.
24. Wetter DA, Davis MD. Recurrent erythema multiforme:
Clinical characteristics, etiologic associations, and
treatment in a series of 48 patients at Mayo Clinic,
2000 to 2007. J Am Acad Dermatol. 2010;62:45.
25. Chen CW, Tsai TF, Chen YF, et al. Persistent erythema
multiforme treated with thalidomide. Am J Clin Derma-
tol. 2008;9:123.
26. Riley M, Jenner R. Towards evidence based emer-
gency medicine: best BETs from the Manchester Royal
Infirmary. Bet 2. Steroids in children with erythema
multiforme. Emerg Med J. 2008;25:594.
27. Weston WL, Morelli JG. Herpes simplex virus-
associated erythema multiforme in prepubertal chil-
dren. Arch Pediatr Adolesc Med. 1997;151:1014.
28. Fawcett HA, Wansbrough-Jones MH, Clark AE, et al.
Prophylactic topical acyclovir for frequent recurrent
herpes simplex infection with and without erythema
mutliforme. BMJ. 1983;287:798.
29. Cherouati K, Claudy A, Souteyrand P, et al. Treatment
by thalidomide of chronic multiforme erythema: its
recurrent and continuous variants. A retrospective
study of 26 patients [in French] Ann Dermatol Venereol.
1996;123:375.
30. Wu JJ, Huang DB, Pang KR, et al. Thalidomide: derma-
tological indications, mechanisms of action and side-
effects. Br J Dermatol. 2005;153:254.
31. Lozada F. Levamisole ion the treatment of erythema
multiforme; a double-blind trial in 14 patients. Oral
Surg Med Oral Pathol. 1982;53:28.
07/12/18 2:06 pm