INTRODUCTION — Erythema multiforme (EM) is an acute, immune-mediated condition characterized by the appearance of distinctive target-like lesions on the skin (picture 1A-H). These lesions are often accompanied by erosions or bullae involving the oral, genital, and/or ocular mucosae (picture 2A-C). "Erythema multiforme major" is the term used to describe EM with severe mucosal involvement (and may have associated systemic symptoms, such as fever and arthralgias). Erythema multiforme minor refers to EM without (or with only mild) mucosal disease (and without associated systemic symptoms).
A variety of factors have been implicated in the pathogenesis of EM. The disorder is most commonly induced by infection, with herpes simplex virus being the most frequent precipitator. The clinical course of EM is usually self-limited, resolving within weeks without significant sequelae. However, in a minority of cases, the disease recurs frequently over the course of years.
Similarities in clinical and histopathologic findings have led to controversy over the distinction between EM and Stevens-Johnson syndrome (SJS), an often drug-induced disorder that may present with cutaneous, targetoid lesions and mucosal erosions. However, there is suggestive evidence that EM with mucous membrane involvement and SJS are different diseases with distinct causes [1,2]. The term "erythema multiforme major" should not be used to refer to SJS. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)
The epidemiology, pathogenesis, clinical features, evaluation, and diagnosis of EM will be reviewed here. The treatment of EM is discussed separately. (See "Erythema multiforme: Management".)
EPIDEMIOLOGY — The annual incidence of EM is unknown, although it is estimated to be far less than 1 percent . EM most frequently occurs in young adults between the ages of 20 and 40 and exhibits a slight male predominance. Children and older adults can also be affected [3-5].
ETIOLOGY — Many factors, including infections, medications, malignancy, autoimmune disease, immunizations, radiation, sarcoidosis, and menstruation, have been linked to the development of EM . Infections (viral, bacterial, or fungal) account for approximately 90 percent of cases, with herpes simplex virus (HSV) as the most commonly identified precipitant (table 1) [3,6-8]. Mycoplasma pneumoniae infection is another important cause of EM, particularly in children [3,9]. EM-like lesions have also been observed in association with coronavirus disease 2019 (COVID-19) and after COVID-19 vaccination [10,11].
It has been estimated that drugs induce EM in less than 10 percent of cases , although higher rates of drug-induced EM (particularly penicillin-related EM) have been reported in children . A wide variety of medications have been associated with the eruption . The most common precipitators appear to be nonsteroidal anti-inflammatory drugs, sulfonamides, antiepileptics, and antibiotics (table 1) . Of note, interpretation of the literature on drug-induced EM is complicated by confusion regarding the nosology of EM as compared with Stevens-Johnson syndrome and other conditions with target lesions. In an analysis of 37 published cases of drug-induced EM, 24 (65 percent) did not meet clinical criteria for EM [13,14].
PATHOGENESIS — Much of the available data on the pathogenesis of this disorder have been derived from studies investigating herpes simplex virus (HSV)-associated EM. The development of EM secondary to HSV infection is thought to involve a cell-mediated immune process directed against viral antigens deposited in lesional skin . The detection of HSV DNA in skin biopsy specimens from patients with EM supports this theory [15-20].
The following mechanism has been proposed for the development of mucocutaneous lesions in the setting of HSV infection [21,22]:
●Virus released into the blood during reactivation of HSV infection is phagocytosed by circulating peripheral blood mononuclear cells, particularly CD34+ Langerhans cell precursors.
●CD34+ cells containing HSV travel to the epidermis, where they transfer viral DNA fragments to epidermal keratinocytes. The migration to the epidermis is facilitated by virus-induced upregulation of E-cadherin expression on these cells and the presence of adhesion molecules on microvascular endothelial cells.
●Expression of HSV genes in the skin leads to the recruitment of HSV-specific CD4+ Th1 cells that produce interferon (IFN)-gamma in response to viral antigens.
●The release of IFN-gamma initiates an inflammatory cascade that promotes the lysis of HSV-infected keratinocytes and the recruitment of autoreactive T cells. These events lead to the epidermal damage and the inflammatory infiltrate that characterize cutaneous lesions of EM.
It is unclear whether a similar pathway is responsible for the development of EM related to other inciting agents. In drug-induced EM, the presence of tumor necrosis factor (TNF)-alpha rather than IFN-gamma correlates with the development of skin lesions . However, EM has occurred in the setting of TNF-alpha inhibitor therapy .
EM does not occur in most people infected with HSV and does not appear with every recurrence of HSV infection among individuals with a history of HSV-associated EM . The reason for this is unknown. It is postulated that a variety of factors may influence the development of EM, such as the presence of a key peripheral blood mononuclear cell subset, differences in the processing of viral DNA by phagocytic cells, variation in the specific viral proteins expressed in the skin, or the presence of other factors that affect the development of the autoreactive immune response [21,22].
Genetic susceptibility may play a role in the preferential development of EM. In a study of 35 patients with EM and 80 controls, the HLA-DQB1*0301 allele was detected more frequently in patients with EM than in the control population (66 versus 31 percent, respectively) . The strongest association with the allele was found among patients with herpes-associated EM . Associations with HLA types Aw33, DRw53, B15(62), B35, and DQ3 have also been reported; however, the relationship of Aw33 and DQ3 to EM has been questioned .
CLINICAL MANIFESTATIONS — EM most often manifests with both cutaneous and mucosal lesions but may also exhibit cutaneous lesions alone. Infrequently, EM presents only with mucous membrane involvement . (See 'Mucosal' below.)
Cutaneous — The term "multiforme" describes the myriad clinical manifestations. Though most lesions appear similar in a particular patient at a given time, the morphology of EM lesions may vary between patients and may also evolve over the course of the disease in a single patient [3,28]:
●Appearance – Target lesions are the hallmark of the disorder, although they may not always be present. Initial lesions may begin as round, erythematous papules that evolve into classic target lesions . Typical target lesions consist of three components: a dusky, central area or blister, a dark red inflammatory zone surrounded by a pale ring of edema, and an erythematous halo on the extreme periphery of the lesion (picture 1A, 1E, 1I) [4,28]. Target lesions in EM are generally less than 3 cm in diameter.
Atypical target lesions may also occur in patients with EM. These manifest as raised, edematous, palpable lesions with only two zones of color change and/or a poorly defined border (picture 1C, 1H, 1J) .
●Distribution – Cutaneous lesions most commonly appear in a symmetrical distribution on the extensor surfaces of the acral extremities and subsequently spread in a centripetal manner (picture 1B-G) . The face, neck, palms, soles, flexural surfaces of the extremities, and/or trunk may also be involved [3,4].
EM may also occur at sites of physical trauma and sunburn, thus displaying the isomorphic (Koebner) phenomenon [3,4]. Other features that may be observed in EM include erythema and swelling of the nail folds and clusters of lesions on and around the elbows and knees (picture 3) .
●Symptoms – Although cutaneous lesions are usually asymptomatic, some patients experience itching and burning .
Mucosal — Mucous membrane involvement usually occurs in association with cutaneous lesions. Lesions can involve the oral, ocular, and/or genital mucosa and commonly manifest as diffuse areas of mucosal erythema, painful erosions, and/or bullae.
Oral involvement occurs most commonly and can affect up to 70 percent of patients with EM (picture 2A-B) [24,29,30]. Lesions tend to affect the vermilion lip and mucosal surfaces, including the buccal mucosa, labial mucosa, nonattached gingiva, and tongue [31-33]. Rarely, involvement can extend to the pharynx and upper respiratory tract .
Systemic — Prodromal symptoms (eg, fever, malaise, myalgias) are uncommon in mild cases of EM but can be seen in cases with significant mucosal involvement . Cough and respiratory symptoms may be present in patients with EM related to M. pneumoniae infection.
Etiologic impact — The cause of EM may influence the clinical presentation. A retrospective study found prominent mucositis, atypical target lesions, and a nonacral distribution more common among 33 patients with M. pneumoniae-induced EM than among 100 patients with non-M. pneumoniae-induced EM .
Laboratory findings — Laboratory findings are not specific for EM. In severe cases, elevations of the erythrocyte sedimentation rate, white blood cell count, and liver enzymes may be detected [3,4,28].
COURSE — In most patients, EM is a transient condition that spontaneously resolves without long-term morbidity. Occasional patients experience frequent recurrences, persistence, or serious complications. (See 'Recurrent erythema multiforme' below and 'Persistent erythema multiforme' below and 'Complications' below.)
Typical course — EM lesions usually appear over the course of three to five days and resolve within approximately two weeks. . Although the skin lesions do not scar, postinflammatory hyperpigmentation may remain for months after resolution, particularly in patients with dark skin.
In herpes simplex virus (HSV)-associated EM, the eruption usually occurs 2 to 17 days after an episode of herpes simplex (mean interval is eight days) . EM can also be induced by asymptomatic subclinical recurrences of HSV infection [24,28]. (See 'Recurrent erythema multiforme' below.)
Recurrent erythema multiforme — A subset of patients with EM experience frequent episodes over many years leading to substantial morbidity, a condition termed "recurrent erythema multiforme." Studies of patients with this disorder found average rates of recurrence of six episodes per year, with mean durations of disease ranging from 6 to 10 years [24,29].
Similar to isolated episodes of EM, recurrent EM has been linked to a variety of inciting factors. Recurrent EM can occur in association with HSV infection, and some studies have estimated that 61 to 100 percent of cases are due to HSV [5,24,27,29,30,35-37]. However, in one series of 48 patients with recurrent disease, a clear relationship to HSV was detected in only 23 percent of subjects . Other conditions reported to occur in association with recurrent EM have included repeated M. pneumoniae infections [29,38], hepatitis C [29,39,40], vulvovaginal candidiasis , menses , complex aphthosis , polymorphic light eruption , and ingestion of benzoic acid, a preservative in food .
The cause of recurrent EM may be unclear in up to 60 percent of patients , and there is evidence that some cases classified as idiopathic EM may be related to subclinical HSV infection [15,18]. One study utilizing polymerase chain reaction (PCR) on lesional skin biopsy specimens from patients with recurrent EM found that HSV DNA was detected in 6 out of 12 specimens from patients with idiopathic recurrent disease . Another study found similar results; HSV DNA was detected in three out of five patients with idiopathic recurrent EM .
Persistent erythema multiforme — Persistent EM is a rare variant of EM characterized by the uninterrupted occurrence of typical and atypical EM lesions [42-45]. Cutaneous lesions are often widespread and papulonecrotic or bullous; mucosal lesions may or may not be present. Laboratory abnormalities including hypocomplementemia and circulating immune complexes also can occur but are not found in all affected patients .
Persistent EM has been reported in association with viral infections, such as HSV, Epstein-Barr virus, hepatitis C, and influenza, as well as inflammatory bowel disease and malignancy . The disorder may continue for longer than one year without therapy.
COMPLICATIONS — Patients with severe EM in whom oral intake may be compromised may develop fluid and electrolyte abnormalities. Infrequently, ocular involvement can lead to keratitis, conjunctival scarring, and visual impairment [3,4]. Esophagitis and upper airway involvement leading to pneumonia have rarely been described [3,4]. Infrequently, significant mucosal involvement in sites other than the eye can exhibit scarring .
HISTOPATHOLOGY — Pathologic findings in EM typically include basal cell vacuolar degeneration, scattered necrotic keratinocytes, and lymphocyte exocytosis (picture 4). A dense superficial dermal lymphohistiocytic infiltrate surrounding blood vessels and the dermoepidermal junction is also present [47-49]. Papillary dermal edema and red blood cell extravasation may be evident, particularly in early lesions [48,49]. Subepidermal clefting and vesiculation, the results of extensive basal cell vacuolar degeneration, are present in some specimens . A histopathologic pattern characterized by confluent keratinocyte apoptosis with minimal dermal change may be more common in M. pneumoniae-induced EM compared with EM from other causes .
The site of the biopsy within an EM lesion can influence the histopathologic findings. While specimens from the dusky, central portions of lesions may reveal subepidermal separation with necrotic keratinocytes, biopsies from the peripheral portions often show predominantly dermal changes, such as papillary dermal edema, vascular dilation, and a perivascular mononuclear cell infiltrate .
Mucous membrane lesions in EM demonstrate similar histologic features to those observed in cutaneous lesions. Additionally, more prominent spongiosis and intracellular edema and vesiculation may be present .
Findings on direct immunofluorescence microscopy are usually nonspecific. One study found granular deposits of C3 and immunoglobulin M (IgM) at the dermoepidermal junction and around superficial dermal blood vessels . In addition, fibrin was detected around dermal blood vessels and in a band-like distribution at the dermoepidermal junction in regions of necrosis or blister formation.
DIAGNOSIS — The history and clinical findings provide the most important information for the diagnosis of EM. Skin biopsies may help to confirm the diagnosis when necessary. (See 'Biopsy' below and 'Additional evaluation' below.)
History and physical examination — Patients should be asked about the course of the disease prior to presentation and associated cutaneous, oral, ocular, and genital symptoms. A complete examination of skin and mucous membranes (conjunctiva, oral cavity, genitalia) should be performed to assess lesion morphology and the distribution of involvement.
The key clinical finding that should raise strong suspicion for EM is the acute development of multiple typical or atypical target lesions on the skin (see 'Cutaneous' above). The presence of multiple typical target lesions that are acrally distributed and are less than 3 cm in diameter essentially confirms the diagnosis.
Additional common findings that support the diagnosis but are not always present include:
●Concomitant mucosal erythema, erosions, or bullae
●Recent history of active herpes simplex virus (HSV) infection
Findings that may suggest other disorders include a predominance of macular rather than papular skin lesions, skin lesions that migrate or persist for less than 24 hours, prominent pruritus, and an absence of skin lesions with at least two zones of color change. (See 'Differential diagnosis' below.)
Biopsy — When the diagnosis is in question, a skin biopsy should be performed. The findings may support a diagnosis of EM or assist with the exclusion of other disorders. (See 'Histopathology' above and 'Differential diagnosis' below.)
If the differential diagnosis includes autoimmune bullous diseases, such as paraneoplastic pemphigus (eg, persistent, targetoid lesions and severe oral involvement) or bullous pemphigoid (eg, tense bullae and urticarial plaques), direct immunofluorescence studies should be performed on a second biopsy specimen taken from unaffected skin adjacent to a lesion. Blood tests for indirect immunofluorescence may also be useful for the diagnosis of autoimmune blistering disease. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid" and "Paraneoplastic pemphigus".)
ADDITIONAL EVALUATION — Further evaluation should be performed to investigate potential triggering factors for EM and to identify complications that require intervention.
Identification of trigger — Patients with EM should be examined for recent signs or symptoms of common causes, including skin lesions suggestive of herpes simplex virus (HSV) infection, respiratory symptoms suggestive of M. pneumoniae infection, and other findings suggestive of infection. Laboratory testing can be used to support infectious associations. New medications and systemic symptoms should also be reviewed (table 1). (See 'Etiology' above.)
Herpes simplex virus infection — A careful history and clinical examination should always be performed to identify signs or symptoms of a recent HSV eruption. If lesions concerning for active HSV infection are found, sampling of lesions can be performed to confirm the presence of the virus. Recommended tests for HSV infection are reviewed in detail separately. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection" and "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection".)
Additional testing for HSV infection is often performed for patients with recurrent EM for whom history and clinical examination do not support a clear relationship to HSV or another cause. Serologic testing for HSV antibodies will help to exclude HSV-associated EM when negative. Positive results indicate a possible association but cannot confirm this in the absence of correlation between clinical recurrences of HSV infection and EM. HSV antibody titers are not useful for detecting episodes of recurrent infection. (See 'Recurrent erythema multiforme' above and "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Serologic testing'.)
Limited data suggest that molecular testing (polymerase chain reaction [PCR] or in-situ hybridization) for HSV on skin biopsy specimens may be useful for identifying patients in whom subclinical HSV reactivation is responsible for recurrent EM. Such testing is an option for patients with both recurrent EM of unclear cause and positive serology for HSV antibodies. (See 'Recurrent erythema multiforme' above.)
M. pneumoniae infection — In patients who present with respiratory symptoms, molecular or serologic testing for M. pneumoniae infection can help to support a diagnosis of M. pneumoniae-related EM. (See "Mycoplasma pneumoniae infection in adults", section on 'Diagnosis' and "Mycoplasma pneumoniae infection in children", section on 'Diagnosis'.)
Assessment for complications — Patients with severe EM in whom oral intake may be compromised should be assessed for fluid and electrolyte abnormalities. Cutaneous lesions with signs concerning for secondary infection should be cultured and treated as appropriate.
DIFFERENTIAL DIAGNOSIS — The identification of typical target lesions with three color zones is a hallmark for the diagnosis of EM. However, classic target lesions may be few in number, and a variety of disorders may present with cutaneous or mucosal lesions that resemble the other manifestations of EM [6,50].
●Urticaria – Urticaria presents as erythematous, edematous plaques that lack the central dusky, bullous, or crusted zones that are typical for lesions of EM (picture 5A-B). Individual lesions are transient, lasting less than 24 hours. Histopathologic findings can help differentiate urticaria from EM when necessary. (See "New-onset urticaria".)
Urticaria multiforme is a morphologic subtype of urticaria in children that presents with annular and polycyclic lesions that may exhibit a dusky, ecchymotic, central portion, thus simulating EM (picture 6) [51,52]. In contrast to EM (and similar to other subtypes of urticaria), individual lesions of urticaria multiforme last less than 24 hours.
●Stevens-Johnson syndrome – Both Stevens-Johnson syndrome (SJS) and EM may present with mucosal erosions and atypical target lesions on the skin (picture 7). A helpful clinical finding is that the atypical target lesions of SJS tend to be macular, rather than the papular lesions associated with EM (table 2). Unlike EM, medication is the most frequent cause of SJS. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)
●Fixed drug eruption – Fixed drug eruptions are characterized by single or multiple dusky, erythematous plaques with or without central bullae or necrosis (picture 8). In some cases, the clinical and histologic features of a generalized fixed drug eruption are difficult to differentiate from EM. Fixed drug eruption typically has fewer lesions present at the time of first outbreak . A thorough medication history also may assist with the diagnosis. (See "Fixed drug eruption".)
●Bullous pemphigoid – Bullous pemphigoid is a chronic autoimmune blistering disorder that can present with urticarial, erythematous plaques and tense bullae, with or without mucosal involvement (picture 9). Typical target lesions and the dusky erythema associated with epidermal necrosis in EM are extremely rare. A biopsy taken directly from a lesion for routine processing and a second biopsy taken from adjacent skin for direct immunofluorescence studies can distinguish this disorder from EM. Indirect immunofluorescence studies can also aid in the distinction between bullous pemphigoid and EM. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)
●Paraneoplastic pemphigus – Paraneoplastic pemphigus can present with polymorphous skin lesions (including lesions reminiscent of EM) and mucosal erosions. Skin biopsy, direct immunofluorescence microscopy, and indirect immunofluorescence studies aid in the differentiation of paraneoplastic pemphigus from EM. (See "Paraneoplastic pemphigus".)
●Sweet syndrome – Sweet syndrome (also known as acute febrile neutrophilic dermatosis) may present with edematous, erythematous plaques reminiscent of EM (picture 10A-B). Routine histopathology demonstrating a predominantly neutrophilic infiltrate easily distinguishes Sweet syndrome from EM. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis".)
●Rowell syndrome – Rowell syndrome describes the occurrence of EM-like lesions in patients with cutaneous lesions of lupus erythematosus. These patients frequently have a positive antinuclear antibody (speckled pattern) [53,54]. Histopathologic and serologic findings can help differentiate this process from EM.
●Polymorphous light eruption – Pediatric cases of herpes simplex virus (HSV)-induced EM that clinically and histopathologically resemble the photodistributed erythematous papules, plaques, and bullae of polymorphous light eruption and juvenile spring eruption have been reported [55,56]. A history of herpetic lesions preceding the eruption are clues to the diagnosis of EM. (See "Polymorphous light eruption".)
●Cutaneous small vessel vasculitis – Cutaneous small vessel vasculitis can present with urticarial lesions (eg, urticarial vasculitis) or targetoid lesions (eg, IgA vasculitis) that may appear similar to EM (picture 11) [57,58]. Routine histopathology demonstrating leukocytoclastic vasculitis, as well as direct immunofluorescence studies, can readily differentiate this condition from EM. (See "Urticarial vasculitis" and "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis".)
●Mycoplasma-induced rash and mucositis – "Mycoplasma-induced rash and mucositis" (MIRM) has been proposed as a term to encompass M. pneumoniae-induced mucocutaneous disease . "Reactive infectious mucocutaneous eruption" (RIME) has been proposed as an umbrella term to encompass MIRM and other clinically similar, mucosal-predominant eruptions triggered by non-M. pneumoniae infections .
A clear consensus does not exist on whether M. pneumoniae-induced EM would be better classified as MIRM or RIME. We feel it is appropriate to refer to presentations with typical targets or raised atypical targets as M. pneumoniae-induced EM, in keeping with a previously proposed morphologic classification of EM .
Oral erythema multiforme — The differential diagnosis of patients with oral EM includes paraneoplastic pemphigus, pemphigus vulgaris, mucous membrane pemphigoid, oral lichen planus, and complex aphthosis, all of which can present with oral erosions [31,32]. In contrast to these chronic conditions, the course of EM is typically self-limited. However, the possibility of these other disorders should be considered in patients with frequently recurring disease. Biopsies with direct immunofluorescence studies are useful for establishing the diagnosis. Indirect immunofluorescence studies on serum can also be performed to evaluate for specific autoimmune blistering diseases. (See 'Histopathology' above and 'Differential diagnosis' above and "Pathogenesis, clinical manifestations, and diagnosis of pemphigus" and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)
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●Basics topic (see "Patient education: Erythema multiforme (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Erythema multiforme (EM) is an uncommon, immune-mediated disorder that presents with cutaneous and/or mucosal lesions. EM most frequently affects young adults but may occur at any age. (See 'Epidemiology' above.)
●EM can be induced by a variety of factors. Infections are the most common causes of EM; herpes simplex virus (HSV) is the most frequent etiologic agent. Less than 10 percent of cases of EM are associated with medications. (See 'Etiology' above.)
●The pathogenesis of HSV-induced EM is thought to involve a cell-mediated immune process directed against viral antigens deposited in lesional skin. Genetic susceptibility may also play a role in the development of the disorder. (See 'Pathogenesis' above.)
●The target lesion is a characteristic finding in EM, although not present in all patients. Target lesions consist of three concentric zones of color change: a central, dusky or blistered area, a dark red inflammatory zone surrounded by a pale ring of edema, and a peripheral, erythematous halo (picture 1A). (See 'Cutaneous' above.)
●Cutaneous lesions frequently begin on the extensor acral extremities and may spread centripetally to other areas (picture 1A-H). Lesions are usually asymptomatic, although some patients may note pruritus or a burning sensation. EM may also involve mucosal surfaces, presenting as painful erythematous patches, erosions, or bullae. EM typically resolves in approximately two weeks. Some patients with EM may experience frequently recurring disease. (See 'Clinical manifestations' above and 'Recurrent erythema multiforme' above.)
●The diagnosis of acute EM typically is based upon the patient's history and clinical findings. When the diagnosis is uncertain, skin biopsies are useful for establishing the diagnosis. Direct immunofluorescence studies are sometimes indicated to exclude the possibility of autoimmune blistering disease. (See 'Diagnosis' above.)
●HSV infection is the most common cause of EM, and the possibility of HSV-induced disease should be considered in all patients. Serologic testing is useful for excluding HSV-associated EM when negative (See 'Diagnosis' above.)