Version May 2024
INTRODUCTION — Erythema multiforme (EM) is an acute, immune-mediated condition characterized by the appearance of distinctive, target-like lesions on the skin. These lesions are often accompanied by erosions or bullae involving the oral, genital, and/or ocular mucosae (picture 1A-F). "Erythema multiforme major" is the term used to describe EM with 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. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis", section on 'Clinical manifestations'.)
EM is most commonly induced by infection, with herpes simplex virus (HSV) being the most frequent precipitator. The clinical course of EM is usually self-limited, resolving within a few weeks without significant sequelae. In a minority of cases, the disease recurs frequently over the course of years.
The management of acute and recurrent EM will be reviewed here. The pathogenesis, clinical features, and diagnosis of this disorder are discussed separately. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".)
Of note, EM and Stevens-Johnson syndrome, an often drug-induced disorder that may present with cutaneous targetoid lesions and mucosal erosions, are distinct conditions. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis", section on 'Introduction' and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)
OVERVIEW — The management of EM is divided into interventions for acute episodes and interventions for suppression of recurrent disease. Treatments for acute episodes primarily aim to improve symptoms (eg, pain) and support resolution because acute episodes typically spontaneously resolve within two weeks. Involvement of the ocular mucosa is an exception; prompt intervention and close monitoring is advised to minimize risk for long-term complications. (See 'Acute episodes' below and 'Ocular mucosa involvement' below.)
Recurrent EM affects a subset of patients and may present with multiple recurrences each year for several or more years. In addition to management of symptoms during acute flares, interventions for these patients aim to reduce or eliminate recurrent episodes of disease. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis", section on 'Recurrent erythema multiforme' and 'Suppression of recurrences' below.)
ACUTE EPISODES — Management of an acute episode of EM includes assessment for the need for hospitalization, removal of the underlying trigger (when feasible), treatment of associated symptoms, and specialist referral for patients with involvement of the ocular mucosa. (See 'Decision to hospitalize' below and 'Removal of cause' below and 'Treatment of specific sites' below.)
Decision to hospitalize — Most patients with EM can be managed in the outpatient setting. However, severe mucous membrane involvement that prevents sufficient oral intake may require hospitalization for nutrition and pain control.
Removal of cause — Data are insufficient to determine whether removal or treatment of an identified trigger for EM reduces the severity or shortens the course of acute episodes. In general, removal or appropriate treatment of an identified underlying cause is advised, when feasible.
The suggested approach to an acute episode of EM associated with infection consists of appropriate treatment of the infection. For herpes simplex virus (HSV)-associated EM, this typically does not involve antiviral treatment because EM typically develops several days or more after the onset of clinical signs of HSV infection [1], when treatment for HSV infection is no longer indicated. In two case series, treatment with oral antiviral drugs after the appearance of HSV-associated EM did not appear to affect the clinical course of EM [1,2]. (See "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults" and "Treatment of genital herpes simplex virus infection".)
If the onset of EM is associated with drug exposure, it is generally accepted that the causative suspect drugs should be promptly discontinued, if feasible. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis", section on 'Etiology'.)
Treatment of specific sites — Interventions to improve symptoms of EM are based upon the clinical presentation.
Cutaneous involvement — Clinical experience suggests that topical corticosteroids can be helpful for alleviating pruritus and skin discomfort. We typically prescribe twice-daily application of a medium-potency (eg, groups 4 or 5) topical corticosteroid to affected skin on the trunk or extremities (table 1). A low-potency topical corticosteroid (eg, groups 6 or 7) is preferred for the treatment of affected facial or intertriginous skin (table 1). Oral sedating antihistamines (eg, hydroxyzine) may also be helpful for pruritus.
Nondisabling oral involvement — For patients with limited oral mucosal involvement that is not disabling, management is focused on symptomatic relief. Painful oral erosions can be treated with a high-potency (eg, groups 1 or 2) topical corticosteroid gel (table 1) and mouthwashes that contain a mixture of lidocaine, diphenhydramine, and antacids. We typically use fluocinonide 0.05% gel applied two to three times per day and a mouthwash containing equal parts of viscous lidocaine 2%, diphenhydramine (12.5 mg/5 mL), and an aluminum hydroxide and magnesium hydroxide mixture (eg, Maalox) as a swish-and-spit, as needed, up to four times per day.
Disabling oral involvement — Extensive oral mucosal involvement may result in severe pain, leading to an inability to ingest foods or liquids. In addition to the comfort measures used for nondisabling oral involvement, systemic glucocorticoids are often prescribed in an attempt to decrease the severity of symptoms and to shorten the course of the disease. However, no high-quality studies to validate efficacy of this approach have been performed, and the available data from a small, uncontrolled study and case series conflict on whether glucocorticoid treatment is beneficial [3-5].
We typically prescribe oral glucocorticoid therapy for patients with disabling oral involvement. Our preferred regimen for adults consists of 40 to 60 mg per day of prednisone or its equivalent tapered over two to four weeks. Preferred dosing for children is less established. We consider 0.5 to 1 mg/kg of prednisone per day tapered over two to four weeks reasonable for most children; higher doses are sometimes used for children with severe disease. We do not use systemic glucocorticoids for patients with milder oral involvement or skin-limited disease.
Some authors have expressed concern that systemic glucocorticoids only partially suppress disease activity and may increase the risk for disease chronicity and prolonged duration of attacks [6,7]. However, a French multicenter, retrospective study of patients with EM who required inpatient hospitalization did not find a statistically significant difference in length of stay between 40 patients who were treated with systemic glucocorticoids and 218 patients who did not receive systemic glucocorticoids [8].
Ocular mucosa involvement — Patients with ocular involvement should be immediately referred to an ophthalmologist for assessment and treatment to minimize risk for long-term sequelae, such as conjunctival scarring and visual impairment. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis", section on 'Complications'.)
Therapy usually involves the use of topical ophthalmic preparations. Topical corticosteroid drops (eg, nonpreserved dexamethasone 0.1%) are recommended for treatment of ocular Stevens-Johnson syndrome (SJS) and may be used, under the guidance of an ophthalmologist, for the treatment of ocular EM [9]. Similar to ocular SJS, frequent use of a lubricant (eg, nonpreserved hyaluronate or carmellose eye drops) is also considered an important intervention [9].
Follow-up — The plan for clinical follow-up is influenced by the severity of disease and the needs of specific patients. Patients with significant mucosal involvement may benefit from reevaluation after one to two weeks to ensure that improvement is occurring and to provide an opportunity to address patient concerns. Follow-up on an as-needed basis may be sufficient for patients with milder disease.
SUPPRESSION OF RECURRENCES — Elimination of the inciting factor for recurrence is the preferred mode of treatment for patients with recurrent EM. However, this is not possible in most patients, given that many cases of recurrent EM are idiopathic or induced by reactivation of herpes simplex virus (HSV) infection, which is an incurable infection.
Limited data preclude definitive treatment recommendations for the suppression of recurrent EM [4,5]. A variety of therapies have been utilized in attempts to suppress recurrence of disease. Recurrent EM often persists for several years or longer [1,10]; thus, prolonged suppressive therapy may be necessary.
Who to treat — Suppressive therapy is not mandatory; limiting treatment to acute episodes of EM is also an option. The decision to attempt suppressive therapy is influenced by the frequency and severity of acute episodes as well as the impact of recurrences on the patient's quality of life. Typical candidates for suppressive therapy include patients who experience at least a few recurrences per year. Our threshold for suppressive therapy tends to be lower for patients in whom episodes are associated with significant disability and distress than for patients with episodes that are less debilitating.
The threshold for suppressive therapy is also influenced by the risks of the selected treatment. The threshold for prescribing antiviral therapy, which is generally well tolerated, is lower than the threshold for immunosuppressive therapies.
Herpes simplex virus-induced or idiopathic erythema multiforme — Antiviral therapy is the preferred initial treatment for HSV-induced recurrent EM and recurrent EM without an identifiable cause. Other therapies are generally reserved for patients who do not improve with antiviral therapy. (See 'Failure of antiviral therapy' below.)
Continuous oral antiviral therapy — Continuous oral antiviral therapy is considered the preferred mode of antiviral treatment of HSV-associated EM.
Administration — Typical regimens for the initial treatment of recurrent EM in adults include:
●Acyclovir – 400 mg twice daily
●Valacyclovir – 500 mg twice daily
●Famciclovir – 500 mg twice daily
These agents have also been utilized for pediatric EM, but dosing for children is less established [11]. In one series, all three children with recurrent EM who were given acyclovir 20 mg/kg per day for six months had successful suppression of EM during treatment, suggesting benefit of this regimen [2].
There are insufficient data to support a recommendation for use of a specific antiviral drug. The low cost of acyclovir makes it the preferred drug in some instances.
We typically treat with an antiviral drug for at least six months prior to assessing efficacy. For patients who do not respond to initial treatment with an antiviral agent, we double the dose of the antiviral agent (eg, 1000 mg twice daily for valacyclovir). In our experience, the higher doses are necessary for the treatment of some patients. If the higher dose is not effective in patients with suspected HSV-induced recurrent EM, we often try an alternative antiviral drug (eg, famciclovir or acyclovir for patients who respond poorly to valacyclovir). If the response remains inadequate, we proceed to alternative therapies. (See 'Failure of antiviral therapy' below.)
Data are insufficient to support definitive recommendations for the duration of treatment in patients who respond well to continuous antiviral therapy. We typically treat for one to two years prior to attempting to discontinue therapy. If EM recurs after treatment is stopped, we restart the antiviral drug at the lowest effective dose and reattempt cessation of therapy every 6 to 12 months thereafter. Many patients may require long-term therapy; in one series, remission of EM was maintained in only 4 of 15 patients following discontinuation of a six-month course of acyclovir [1].
Efficacy — Only acyclovir has been evaluated in a randomized trial [5]. The efficacy of acyclovir was investigated in a six-month trial in which 20 patients with recurrent EM (most with HSV-induced disease) were randomly assigned to either acyclovir (400 mg twice daily) or placebo [7]. Patients treated with acyclovir were less likely to have recurrent attacks than patients given placebo (36 versus 100 percent), and the median number of attacks per patient was lower (zero versus three).
A systematic review that summarized treatment response rates reported in case series with at least 10 patients found complete responses in 17 of 48 patients (35 percent) treated with acyclovir, 7 of 22 patients (32 percent) treated with valacyclovir, and 1 of 7 patients (14 percent) treated with famciclovir. These findings do not confirm lesser efficacy of famciclovir. In a case series of three patients with recurrent HSV-associated EM who had failed other therapies, including valacyclovir, all three patients had complete responses to famciclovir (500 mg one to three times daily) [12].
Antiviral therapy appears to be less effective in EM that is not clearly associated with HSV based upon case series [1,10]. The presence of subclinical HSV infection may account for patients with idiopathic EM who respond to antiviral therapy [7].
Alternative antiviral regimen — Intermittent antiviral therapy (ie, a short course of antiviral treatment given at the first sign of HSV reactivation) is an alternative approach to suppressive antiviral therapy that is generally considered less effective than continuous therapy. In a series of 35 patients with recurrent EM, a short course of acyclovir (200 mg five times daily for five days) given at the initial sign of recurrent HSV infection or rash was associated with no response in 19 patients, partial suppression in 12 patients, and complete suppression in 4 patients [1].
We typically treat recurrent EM with continuous antiviral therapy. If used, intermittent therapy may be best reserved for patients with infrequent, mild EM episodes with a clear HSV prodrome before onset of EM. Optimal dosing for intermittent therapy is unclear; use of the regimen recommended for the underlying HSV infection (eg, orolabial or genital HSV infection) is reasonable.
Data are limited on the efficacy of topical acyclovir. In a randomized, crossover trial of 18 patients, daily application of topical 5% acyclovir cream to areas of recurrent HSV infection was not effective for the prevention of HSV-associated, recurrent EM [13]. We do not use topical acyclovir for the treatment of EM.
Failure of antiviral therapy — Patients who have recurrent EM that does not improve with continuous antiviral therapy may be treated with an immunomodulatory drug, usually mycophenolate mofetil, dapsone, or azathioprine. Efficacy data for these drugs are limited, particularly for children, and the relative efficacy of these therapies is unclear. Selection among these agents is based upon consideration of comorbidities, potential side effects, and patient preference. For adult patients, mycophenolate mofetil is our most common immunomodulatory treatment. Prior to initiating immunomodulatory treatment, other diseases should be adequately ruled out. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis", section on 'Differential diagnosis'.)
Suggested treatment course — Based upon clinical experience, we continue treatment with mycophenolate mofetil, dapsone, or azathioprine for at least six months before concluding that the drug is ineffective. If there is no response to a treatment within this time period, we change the therapy (eg, switch from dapsone to azathioprine).
If remission is achieved, we continue therapy for 6 to 12 months followed by a taper of the medication (over two to four months) to the lowest effective dose or to cessation. If EM recurs, we restart the drug at the lowest effective dose for four to six months prior to another attempt at tapering.
Mycophenolate mofetil — Our typical dose of mycophenolate mofetil for adult patients is 1000 to 1500 mg twice daily.
Data from a case series and case report suggest efficacy of mycophenolate mofetil [10,14]. In a series of 48 patients with recurrent EM, 6 out of 8 patients treated with mycophenolate mofetil achieved complete or partial suppression of disease [10].
Gastrointestinal distress is a common side effect of mycophenolate mofetil. Examples of potentially serious adverse effects include infections and hematologic abnormalities. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Adverse effects'.)
Dapsone — Our typical dose for dapsone therapy for adults is 100 to 200 mg per day.
Dapsone has appeared effective for recurrent EM in small series [1,5,10,15]. In a study of nine patients with recurrent EM treated with dapsone, eight had either partial or complete suppression of disease at a dose of 100 to 150 mg/day [1]. In another report of 10 patients, dapsone (≤200 mg/day) led to complete suppression of disease in 3 patients and partial suppression in 2 patients [10]. In a study of 13 patients treated with dapsone (≤200 mg/day) for recurrent EM unresponsive to at least one oral antiviral therapy, 11 had either partial (5 patients) or complete (6 patients) suppression of disease [15].
Hematologic side effects, including hemolytic anemia (especially in glucose-6-phosphate-deficient individuals), methemoglobinemia, and agranulocytosis, may occur with dapsone therapy. Other important side effects include hypersensitivity syndrome and peripheral neuropathy (table 2).
Azathioprine — We typically prescribe azathioprine at a dose of 100 to 150 mg per day or 2 mg/kg per day for adult patients with normal thiopurine methyltransferase (TPMT) activity.
Successful treatment with azathioprine has been reported in case reports and small series [1,6,16,17]. In one report, azathioprine (100 to 150 mg daily) was associated with complete disease suppression in 11 patients with severe recurrent EM who failed all other therapies, although the condition recurred upon discontinuing therapy [1]. The total number of patients who received azathioprine was not reported. In another series, two out of five patients treated with azathioprine achieved a complete or partial response [10]. A systematic review of case series with at least 10 patients that documented responses to treatments for recurrent EM found documentation of complete responses to azathioprine in 12 of 15 patients [5].
Myelosuppression is a serious adverse effect of azathioprine that may occur more frequently in patients with low activity of TPMT, an enzyme involved in the metabolism of this drug. Examples of other important adverse effects include gastrointestinal distress, infection, and malignancy. (See "Overview of pharmacogenomics", section on 'Thiopurines and polymorphisms in TPMT and NUDT15' and "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Adverse effects'.)
Other therapies — Other treatments that have been utilized for the treatment of recurrent EM in a limited number of patients include intramuscular immune globulin G [1,18], hydroxychloroquine [1], cyclosporine [19], thalidomide [20,21], lenalidomide [22], interferon alfa (in patients with associated hepatitis C virus infection [23,24] and in one patient without hepatitis C infection [25]), apremilast [26], adalimumab [27], tofacitinib [28,29], levamisole [30], and cimetidine [31].
Rituximab was effective for severe and chronic EM in a case series of five patients unresponsive to other typical therapies; four patients achieved complete remission and one achieved partial remission, although disease relapsed within 3 to 11 months in all patients [32]. Three patients received a second cycle of rituximab after relapse, resulting in partial or complete remissions lasting five months to one year.
Erythema multiforme due to other causes — Recurrent EM that has a clear association with a cause other than HSV infection that cannot be managed with treatment or removal of the cause may be treated similarly to HSV-associated, recurrent EM that does not respond to antiviral therapy. The cause of EM should be considered in treatment selection; for example, immunosuppressive therapies may be less appropriate for patients with malignancy-associated EM. (See 'Failure of antiviral therapy' above and "Erythema multiforme: Pathogenesis, clinical features, and diagnosis", section on 'Etiology'.)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Erythema multiforme (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Erythema multiforme (EM) is an acute, immune-mediated disorder that involves the skin and/or mucosal surfaces. The treatment of acute EM varies according to the manifestations of the acute eruption and the presence of recurrent disease. (See 'Introduction' above and 'Overview' above.)
●Infection is a common inciting factor for EM, particularly herpes simplex virus (HSV) infection. Underlying infections should be treated as appropriate for the infection. In patients with HSV-induced EM, treatment with oral antiviral drugs after the onset of EM does not appear to alter the course of EM. (See 'Removal of cause' above.)
●Patients with skin-limited EM and nondisabling oral EM can be managed with symptomatic therapy alone. Topical corticosteroids and oral antihistamines may be helpful for pruritus or discomfort from skin involvement. Patients with oral EM may achieve some relief with an anesthetic mouthwash. (See 'Cutaneous involvement' above and 'Nondisabling oral involvement' above.)
●Severe oral mucosal involvement may be accompanied by intense pain and an inability to eat or drink. For patients with severe oral mucosal involvement, we suggest treatment with oral prednisone (Grade 2C). Patients with disabling symptoms may require hospitalization for nutrition and pain control. (See 'Disabling oral involvement' above and 'Decision to hospitalize' above.)
●Ocular mucosa involvement rarely may lead to keratitis, conjunctival scarring, or visual impairment. Patients with ocular symptoms should be referred to an ophthalmologist. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis", section on 'Complications' and 'Ocular mucosa involvement' above.)
●Some patients with EM develop recurrent disease. When feasible, the inciting agent should be identified and eliminated. For patients with HSV-induced or idiopathic EM that recurs multiple times per year and is disabling or psychologically distressing, we recommend treatment with continuous antiviral therapy (Grade 1B). (See 'Continuous oral antiviral therapy' above.)
●For patients with severe, recurrent, HSV-associated or idiopathic EM who fail to respond to continuous systemic antiviral therapy and for whom other diseases have been ruled out, we suggest treatment with mycophenolate mofetil, dapsone, or azathioprine (Grade 2C). (See 'Failure of antiviral therapy' above and "Erythema multiforme: Pathogenesis, clinical features, and diagnosis", section on 'Differential diagnosis'.)
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