43 - ERYTHEMA MULTIFORME Flashcards
Define Erythema multiforme (EM)
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 histopathology 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.
Historically, a variety of factors have contributed to a confusing nosology, especially with the concept of a socalled “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 process termed epithelial necrolysis (EN; see Chap. 44) and to separate them from EM. The validity of that classification has been established by several studies, especially the prospective international Severe Cutaneous Adverse Reactions study 2 and by recent series 3,4 showing 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 clownlike 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. pneumoniaeassociated SJS, especially in the pediatric realm. However, we consider these cases EMM caused by M. pneumoniae. Other authors have proposed that mucocutaneous 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
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 sometimes 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 versus SJS-TEN.
Erythema Multiforme (EM) Subtypes
Epidemiology
EM is considered relatively common, but the true incidence is unknown. There is selection bias for severe cases requiring hospitalization in the medical literature; 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 urticaria, serum sickness–like eruption, polymorphous maculopapular eruptions, 7 subacute cutaneous lupus erythematosus, 8and even SJS or TEN.
EM occurs in patients of all ages but is most prevalent in adolescents and young adults. There is a male preponderance (male:female ratio of 2 to 3:1). Recurrence happens in about 10% of patients with EMM and up to 30% in EMm, more frequently, but not exclusively, in HSV-associated cases.
There are no established associations of underlying disease with risk for EM. HIV infection and collagen vascular disorders increase the risk of SJS and TEN but not EM. Cases may occur in clusters, which supports a role for infectious agents. The incidence does not vary with ethnicity or geographic location.
Predisposing genes have been reported. A total of 66% of EM patients have HLA-DQB1 ∗ 0301 allele compared with 31% of control participants. 9 However, this association has not translated into a meaningful clinical test or intervention.
Clinical history
Prodromal symptoms are absent in most cases. If present, they are usually mild, suggesting an upper respiratory 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 symptoms 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 predominates 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 duration of the lag period appears to be specific for individual 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.
Cutenous 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 extremities (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 a centripetal manner. Mechanical factors (Koebner phenomenon) and actinic factors (predilection for sunexposed 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 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 approximately 3 cm and may expand slightly over 24 to 48 hours. Although the periphery remains erythematous and edematous, the center becomes violaceous and dark; inflammatory activity may regress or relapse in the center, which gives rise to concentric rings of color (see Figs. 43-1 to 43-4). Often, the center turns purpuric or necrotic or transforms into a tense vesicle or bulla. The result is the classic target or iris lesion.
According to the current classification, typical target lesions consist of at least three concentric components:
(1) a dusky central disk or blister;
(2) more peripherally, an infiltrated pale ring; and
(3) an erythematous halo.
Not all lesions of EM are typical; some display two rings only (raised atypical targets). 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.
NONCUTANEOUS FEATURES
Mucosal lesions are present in up to 70% of patients, most often limited to the oral cavity.
Predilection sites are the lips, on both the cutaneous 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 cutaneous 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 conjunctivitis in which vesicles and erosions can occur (Fig. 43-8). In children, ocular lesions appear to be more frequent and more severe in M. pneumoniae–associated cases. 10 The nasal, urethral, and anal mucosae also may be inflamed and eroded.
RELATED PHYSICAL FINDINGS
Fever and other constitutional symptoms are usually absent in EMm, and the noncutaneous physical 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 alimentation. 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 urinary retention. Cough and hypoxia may occur in M. pneumoniae–related cases.
COMPLICATIONS
In contrast to SJS, in which cutaneous lesions may progress to extensive detachment of the epidermis, there is no risk of “skin failure” or visceral involvement in EMM. Mouth erosions may impair oral alimentation. Reflex anuria from periurethral erosions rarely needs bladder catheterization. Severe ocular lesions leading to sequelae are rare but can occur, and ocular symptoms must be checked by an ophthalmologist in the acute phase of the disease and followed appropriately.
Conditions Commonly Associated with Erythema Multiforme
Most cases of EM are related to infections (Table 43-2). HSV is the most common cause, principally in recurrent 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 recurrences. Not all symptomatic HSV recurrences are followed 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
to establish. Clinical and radiologic signs of atypical pneumonia can be mild, and M. pneumoniae is usually 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 evidence for causality of these other agents is only circumstantial. Published reports have implicated infection with EBV, Orf virus, varicella zoster virus, parvovirus B19, hepatitis B and C viruses, and a variety of other bacterial or viral infections. Immunization has been also implicated as a cause in children, but a spurious association can be suspected.
Drugs are also a reported cause of EM, although a true association is unlikely. Most reports of drugassociated EM actually deal with imitators, 7 for example, annular urticaria (also called urticaria multiforme) 15 or disseminated maculopapular eruptions with some lesions resembling targets (Fig. 43-9). EM-like dermatitis may also result from contact sensitization. These eruptions should be viewed as imitators of EM despite some clinical and histopathologic
similarities. Literature reports of drug-associated EM also include typical cases of SJS or TEN, particularly under the moniker EMPACT syndrome (EM, phenytoin 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 circumstances. 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 another cause.
Another suspected variant of recurrent EMM was reported to be associated with desmoplakin I and II autoantibodies. 16 However, the presence of acantholysis in skin biopsies of such cases suggests a variant of pemphigus that clinically resembles EM. The recently reported efficacy of rituximab in such cases also supports 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 numerous studies using PCR assays. These studies demonstrated 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 amplification 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 molecules 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 are likely induced by a specific immune response to Pol protein and amplified by autoreactive cells.
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 characterize the small proportion of individuals with recurrent herpes infections who develop EM.
Approach to a patient with erythema multiforme (EM).
An approach to the diagnosis and management of EM is shown in Fig. 43-10. EM is usually diagnosed clinically. A skin biopsy and laboratory investigations are useful when the diagnosis is not certain. After making the diagnosis, the need for hospitalization is considered. 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. Establishing the underlying cause of EM is also part of the evaluation.
Histopathology of erythema multiforme.
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), spongiosis, vacuolar degeneration of the basal cell layer, and focal junctional and subepidermal cleft formation. 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 epidermis (Fig. 43-11). In late lesions, melanophages may be prominent. Immunofluorescence findings are negative or nonspecific.
The histopathologic appearance of EM lesions differs from that of EN, in which dermal inflammation is moderate to absent and epidermal necrosis is much more pronounced (see Chap. 44). Still, the histopathologic 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 a biopsy in EM is to rule out other diagnoses, such as autoimmune blistering diseases, Sweet syndrome, and vasculitis.
Differential Diagnoses of Erythema Multiforme (EM)
The most important differential diagnosis, SJS, should be recognized promptly for three reasons: (1) the possibility of life-threatening complications, (2) the risk of progression to TEN, and (3) the need for urgent withdrawal of suspected causative drug(s) (see Chap. 44). Pain, constitutional symptoms, severe erosions of mucosae, rapid progression, and dusky or violaceous often confluent macules and blisters are alerting features.
In rare cases of EM affecting only mucous membranes, 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.
