Erythema Multiforme: Recognition and Management Kathryn P. Trayes, MD; Gillian Love, MD; and James S. Studdiford, MD Thomas Jefferson University Hospital, Philadelphia, Pennsylvania Erythema multiforme is an immune-mediated reaction that involves the skin and sometimes the mucosa. Classically described as target-like, the erythema multiforme lesions can be isolated, recur- rent, or persistent. Most commonly, the lesions of erythema multiforme present symmetrically on the extremities (especially on extensor surfaces) and spread centripetally. Infections, especially herpes simplex virus and Mycoplasma pneumoniae, and medications constitute most of the causes of erythema multiforme; immunizations and autoimmune diseases have also been linked to erythema multiforme. Erythema multiforme can be differentiated from urticaria by the duration of individual lesions. Ery- thema multiforme lesions are typically fixed for a minimum of seven days, whereas individual urticarial lesions often resolve within one day. Erythema multiforme can be confused with the more serious con- dition, Stevens-Johnson syndrome; however, Stevens-Johnson syndrome usually contains widespread erythematous or purpuric macules with blisters. The management of erythema multiforme involves symptomatic treatment with topical steroids or antihistamines and treating the underlying etiology, if known. Recurrent erythema multiforme associated with the herpes simplex virus should be treated with prophylactic antiviral therapy. Severe mucosal erythema multiforme can require hospitalization for intravenous fluids and repletion of electrolytes. (Am Fam Physician. 2019; 100(2):82-88. Copyright © 2019 American Academy of Family Physicians.) Erythema multiforme is an acute, typically self-limited to cause erythema multiforme8 (Figure 1). Mycoplasma skin condition with lesions that can be isolated, recur- pneumoniae is the second most common etiology, espe- rent, or persistent.1 Erythema minor affects only the skin cially in children.6,9 Although medications cause less than and erythema major includes mucocutaneous involve- 10% of erythema multiforme cases, many drugs have been ment.1,2 Although it was previously thought that ery- associated with erythema multiforme, most commonly thema multiforme was on the same pathologic spectrum nonsteroidal anti-inflammatory drugs, antiepileptics, and as Stevens-Johnson syndrome (SJS) and toxic epidermal antibiotics.1,4,6 Drug-associated lesions have tested positive necrolysis, it is now accepted that erythema multiforme is for tumor necrosis factor-α (TNF-α), and HSV-associated a distinct disease.3,4 lesions have tested positive for interferon-γ.10 Types of anti- The annual incidence of erythema multiforme is estimated biotics associated with erythema multiforme include sul- at less than 1%.5,6 It is more common in adults younger than fonamides, penicillins, erythromycin, nitrofurantoin, and 40.6 There is no apparent association with race.7 tetracyclines. Other medications include barbiturates, phe- nothiazines, statins, and TNF-α inhibitors11 (Table 1). Etiology Vaccines such as measles, mumps, and rubella; smallpox; Erythema multiforme is caused by a cell-mediated immune hepatitis B; meningococcal (Figure 2); pneumococcal; vari- response, and infections are associated with 90% of cases.6 cella; influenza; and Haemophilus influenzae have also been Although herpes simplex virus (HSV) type 1 is the most associated with erythema multiforme, although incidence commonly identified etiology, HSV-2 also has been shown is low.12-16 Less commonly, erythema multiforme has been associated with autoimmune diseases, such as inflammatory bowel disease17 and malignancies, specifically leukemia and CME This clinical content conforms to AAFP criteria for 18 continuing medical education (CME). See CME Quiz on lymphoma. Persistent erythema multiforme and refrac- page 79. tory erythema multiforme have been found in patients with Author disclosure: No relevant financial affiliations. solid organ cancers, such as renal cell carcinoma and gastric adenocarcinoma.19,20 Downloaded82 from the American Family Physician website at www.aafp.org/afp. Copyright © 2019 American Academy of Family Physicians. For the private,◆ noncom- mercialAmerican use of Familyone individual Physician user of the website. All other rightswww.aafp.org/afp reserved. Contact [email protected] for copyrightVolume questions 100, and/or Number permission 2 July requests. 15, 2019 TABLE 1 Most Commonly Reported Causes and Associations with Erythema Multiforme Clinical Presentation Infections Cytomegalovirus TYPICAL APPEARANCE Epstein-Barr virus Erythema multiforme lesions typically begin as pink or Hepatitis C virus red papules, which can then become plaques.21,22 These Herpes simplex virus type 1, herpes simplex lesions can cause burning or itching.23 Over the next three virus type 2 to five days, the lesions transform into a variety of appear- Influenza virus ances.1,3,6,24 The classic lesion of erythema multiforme is Mycoplasma pneumoniae called the target or iris lesion. It is a round lesion of three Vulvovaginal candidiasis concentric segments: a dark center, surrounded by a lighter Drugs Antibiotics pink ring, both of which are surrounded by a red ring1,8 (Figure 3). Atypical lesions may only have two zones of Erythromycin color and may have poorly defined borders1,25 (Figure 4). Nitrofurantoin Lesions are initially found symmetrically on the extrem- Penicillins ities, especially on extensor surfaces. The lesions usu- Sulfonamides ally spread centripetally but tend to be fewer on patients’ Tetracyclines trunks. Palms and soles also may be involved. Erythema Antiepileptics multiforme has a predilection for areas of current sunburn Barbiturates 6 or physical trauma. Cutaneous lesions usually heal with- Nonsteroidal anti-inflammatory drugs 1 out complication, but skin hyperpigmentation may occur. Phenothiazines Isolated episodes of erythema multiforme most commonly Statins follow HSV infections by an interval of 10 days and usually Sulfonamides resolve within two weeks.22 However, some episodes of ery- Tumor necrosis factor- inhibitors thema multiforme have been documented to persist for up α to five weeks.26 Vaccines Mucosal lesions are present in 25% to 60% of patients Other Inflammatory bowel disease 6 with erythema multiforme. Prodromal weakness, fever, conditions Malignancy and malaise are common symptoms in patients with Menstruation mucosal involvement.1,6 When these associated symptoms FIGURE 1 FIGURE 2 Erythema multiforme lesions on the extensor surface of the hand following a herpes simplex virus type 1 Erythema multiforme polycyclic lesions, targetoid in infection. appearance, following meningococcal vaccination. Copyright © Thomas Jefferson University Copyright © Thomas Jefferson University Downloaded from the American Family Physician website at www.aafp.org/afp. Copyright © 2019 American Academy of Family Physicians. For the private, noncom- ◆ 83 mercial use of one individual user of the website. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests. July 15, 2019 Volume 100, Number 2 www.aafp.org/afp American Family Physician ERYTHEMA MULTIFORME are present, they usually occur at least one week before skin lesions occur.4 Although the oral mucosa is the most FIGURE 4 commonly involved, genital and ocular mucosa also may develop lesions.2 Mucosal lesions usually begin as edema- tous, erythematous lesions that may develop into shallow erosions with pseudomembranes6 (Figure 5). Mucosal ero- sions may be extremely painful; therefore, clinicians should assess the patient’s ability to maintain oral intake. RECURRENT AND PERSISTENT ERYTHEMA MULTIFORME Patients may experience recurrent erythema multiforme with multiple episodes. A study of 48 patients with recurrent erythema multiforme reported an average of six episodes per year.27 The mean disease duration was from six to 10 years.27,28 Recurrent erythema multiforme may occur because of the reactivation of HSV (Figure 6), even if there are no symptoms FIGURE 3 Atypical erythema multiforme lesions consisting of two zones of color. Copyright © Thomas Jefferson University FIGURE 5 Erythema multiforme typical target or iris lesions in a Mucosal shallow erosions of erythema multiforme in patient with inflammatory bowel disease. a patient with rheumatoid arthritis. Copyright © Thomas Jefferson University Copyright © Thomas Jefferson University 84 American Family Physician www.aafp.org/afp Volume 100, Number 2 ◆ July 15, 2019 FIGURE 6 TABLE 2 Differential Diagnosis of Erythema Multiforme Differential diagnosis Clinical manifestation Bullous Pruritic, erythematous plaques with tense pemphigoid bullae; with or without mucosal involvement Fixed drug Few, well-circumscribed erythematous eruption plaques with medication history Hyper- Morbilliform eruption most commonly sensitivity found on the upper extremities, trunk, face reaction Paraneo- Polymorphous, erythematous mucocuta- plastic neous lesions, including papules, bullae, pemphigus and erosive lesions; presence of underlying malignancy Pityriasis Scaly, erythematous plaques following rosea herald patch formation on trunk Polymor- Erythematous papules and plaques in areas phous light exposed to sunlight eruption Stevens- Atypical macular target lesions with central Johnson dusky erythema, bullae; several mucosal syndrome involvements at one or more sites Urticaria Pruritic, sharply demarcated papules/ plaques; transient, usually