OVERVIEW: What every practitioner needs to know. Are you sure your patient has erythema multiforme? What are the typical findings for this disease?

Erythema multiforme (EM) is an acute eruption characterized by fixed, targetoid skin lesions with or without mild mucosal lesions. EM historically was considered to be on a spectrum with Stevens-Johnson syndrome (SJS) because they both can have necrotic skin lesions and both can have mucous membrane disease. Most authors believe that EM is a separate entity from SJS because EM is self-limited, not life threatening and generally has a more acral distribution, with more limited mucous membrane involvement. This chapter will discuss EM as an entity separate and distinct from SJS.

EM is very commonly confused with annular urticaria (hives). Urticaria is far more common than EM. Because urticaria can mimic EM so closely, the term “urticaria multiforme” has been proposed, but this is just a different name for severe annular urticaria. Clinical lesions resembling EM can also be the cutaneous manifestation of Kawasaki disease.

If there are two or more mucous membranes involved (typically lips and conjunctivae), the diagnosis is much more likely SJS, which is much more severe and can be life threatening.

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The following describes the cutaneous features differentiating EM from urticaria:

Clinical Characteristics of EM

The individual lesions appear as targets typically with 3 rings (Figure 1).

Figure 1.

Targetoid lesions on the legs with central purple and crust and acral location typical of erythema multiforme.

an outer ring of red or purple (this may be difficult to see in dark-skinned patients)

an inner ring of pallor

central duskiness, blister, crust or erosion (depending on the duration and severity of the lesion)

The lesions of EM are fixed; if circled one day they will still be present the next day (perhaps larger but still present).

The lesions are most typically acral, (i.e., predominantly on the hands, feet, and face).

The lesions may be somewhat itchy or painful.

There may be some mucosal targets but there should not be two mucous membranes involved (as seen in SJS).

Clinical Characteristics of Urticaria

The individual lesions appear as red/pink patches or plaques that can be annular but have or pale centers typically. There are often arcuate, half-moon lesions that do not form complete circles.

The lesions are evanescent; if circled one day they will be in different areas or gone the next day.

The lesions can be anywhere, but there can be hand/foot and face edema if severe.

The lesions are usually itchy.

The patients are often dermatographic (gentle stroking of the skin will induce a linear hive) and have a rapid response to combination antihistamines such as cetirizine in combination with ranitidine.

Proposed subtypes of erythema multiforme

EM minor is defined as classic targets of EM with very little if any mucosal involvement. If a mucous membrane is involved with vesicles or erosions, these may actually be the herpetic infection that is inducing the EM and not EM itself.

EM major is a problematic term because it implies more severe mucous membrane involvement, but if there are two mucous membranes involved, the eruption should be classified as SJS. SJS is life threatening, EM is not. If the disease is severe with severe mucous membrane involvement, the patient likely has SJS. Mycoplasma Pneumonia can cause a very severe mucositis with limited target lesions on the cutaneous surface. Some term this mucosal sloughing with targetoid lesions EM, but it can also be labeled mycoplasma induced mucositis or Mucosal predominant SJS.

Rowell syndrome is a combination of EM and lupus erythematosus. There is associated laboratory findings of a positive antinuclear antibody (ANA) typically in a speckled pattern, rheumatoid factor positivity, anti-La antibody assays. This is a disease of mostly adult women and should be considered a manifestation of lupus erythematosus.

What other disease/condition shares some of these symptoms?

The main clinical differential diagnosis for EM, as described above, is urticaria (especially when it is in an annular configuration), SJS, and Kawasaki disease. The lesions of secondary syphilis may also resemble EM. Fixed drug reactions are also in the differential diagnosis because they often present with targetoid or bullous lesions, but there are typically many fewer than in EM. The lesions of fixed drug eruptions will recur in the identical location with each exposure to the offending medication.

What caused this disease to develop at this time?

The list of causes presented here is long, but it must be noted that many reports of EM may have actually represented urticaria or SJS, and therefore it is very difficult to go back in the literature and determine what are true causes of EM. The most common inciting agent by far is herpes simplex virus (HSV), especially in recurrent EM.

Subclinical HSV infection or HSV that occurred 1-3 weeks before the EM may be the culprit, so always make sure the initial history and physical examination fully evaluates for HSV (oral or genital) before looking for another less common cause of EM.

If there are two mucous membranes involved, the diagnosis is much more likely actually SJS, which is almost exclusively caused by newly initiated medications or by mycoplasma infection.

Causes of EM


Other viruses reported: Epstein-Barr virus (EBV), H1N1 influenza, Orf virus

Vaccinations: including diphtheria, tetanus, smallpox, hepatitis B, Bacille Calmette-Guerin, smallpox

Bacterial infections including: Mycoplasma, Gardnerella vaginalis, Yersinia, Mycobacteria

Medications, including:

Nonsteroidal anti-inflammatory medications

Antibiotics such as sulfa-based medications, aminopenicillins, cephalosporins, griseofulvin

Other medications: progesterone, gemfibrozil, methotrexate, barium contrast medium

Other: there are many other reports, but the majority are either solitary reports or “EM-like” reactions or actually SJS so are not included here.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

A skin biopsy helps rule out urticaria and differentiate EM from SJS. Histopathologic features show an interface dermatitis with necrotic keratinocytes, either in the basal layer only or full thickness (this full-thickness necrosis leads clinically to a blister or crust).

HSV testing may be helpful if this is thought to be the cause. Ideally a mucosal lesion would be tested directly, as serologic testing may simply show a past infection/exposure.

A high sedimentation rate or C-reactive protein levels can help to screen for Kawasaki disease if there is persistently high fever and any clinical concern.

Serologic findings of Mycoplasma or polymerase chain reaction (PCR; if available) can help confirm if mycoplasma infection is suspected as the inciting factor.

Would imaging studies be helpful? If so, which ones?

Imaging is not typically helpful, unless Mycoplasma is suspected, and then chest radiography may be helpful.

Confirming the diagnosis

EM is a clinical diagnosis and is heavily supported by its classically acral (hands, feet, face) predominance, history of recent herpetic infection, and patients with some discomfort or itching but who do not appear extremely ill.

Infectious, vaccination, and medication history are key.

If you are able to confirm that the patient has erythema multiforme, what treatment should be initiated?

Antihistamines may help with itching.

Topical steroids (midpotency ointment twice a day for 1-2 weeks as needed for the hands and feet) may help symptomatically; if more long-term use is needed, topical tacrolimus can be considered.

If there is a clear active herpes infection, treating with acyclovir may be helpful, but often the infection is resolved by the time the EM occurs.

Systemic steroids have been associated with longer courses of EM, but in severe cases they may play a role.

Pediatric patients with widespread EM, especially involving the mouth, may need parenteral nutrition, but this is rarely necessary.

Longer term therapy with prophylactic acyclovir may help if there is an HSV infection inducing EM. Oral dapsone has also been shown to be effective.

Thalidomide is an option in severe recalcitrant recurrent disease, but the benefits must outweigh the risks (this will rarely be the case)

What are the adverse effects associated with each treatment option?

EM is self-limited but has some morbidity due to pain and discomfort.

Acyclovir is generally very well tolerated and can be used for prophylaxis if the EM is severe and recurs frequently.

Topical steroids (typically midpotency ointment for the hands and feet and low-potency ointment for the face for 1-2 weeks) may lead to systemic absorption or striate if used for long periods.

Systemic steroids can lead to hypertension, gastrointestinal upset, diabetes, mood alteration, weight gain, aseptic necrosis of bones, and other problems, but for 5-10 days are generally well tolerated.

Thalidomide is teratogenic, can lead to neuropathy and a hypercoagulable state, and is rarely justified.

What are the possible outcomes of erythema multiforme?

EM is self-limited; therefore, therapy is symptomatic. The usual course of EM is 1-4 weeks. There can be scarring with bullous and necrotic lesions. Oral lesions can cause enough discomfort to affect nutrition and hydration. Recurrence is possible, especially if HSV is the cause.

What causes this disease and how frequent is it?

EM can be seen at any age and has no sex or racial predilection.

There is likely a genetic predisposition to EM. HLA B-15, HLA Aw33, HLA DRw53, and HLA DQB-1 and HLA DQ3 have been associated.

How do these pathogens/genes/exposures cause the disease?

It is unclear how HSV induces EM, but the virus can be found by PCR in the acral lesions of EM.

What complications might you expect from the disease or treatment of the disease?

EM is typically self-limited. Patients may have a response to systemic steroids, and given the recurrence it can be difficult to discontinue their administration.

Are additional laboratory studies available; even some that are not widely available?

PCR of skin lesions may help prove HSV causation.

How can erythema multiforme be prevented?

EM minor is most commonly caused by HSV, so prevention of flares of HSV may prevent flares of EM.

Prevention of herpes simplex

Acyclovir can be used for suppression, but this is not a US Food and Drug Administration (FDA)-approved use in pediatrics.

Age 2-10 years old: acyclovir prophylaxis is not well established and is not FDA-approved, but off-label 10-20 mg/kg/dose given twice daily may be effective.

Age 12 years and older: acyclovir 400 mg twice a day or 200 mg three to five times per day (not an FDA-approved use).

Many flares of HSV will be on the lips, and sun protection may prevent these flares.

The amino acid supplement lysine may help prevent flares of herpes.

If there is a known medication or supplement causing a certain patient’s EM, it should be avoided.

What is the evidence?

Shah, KN, Honig, PJ, Yan, AC. “"Urticaria multiforme": a case series and review of acute annular urticarial hypersensitivity syndromes in children”. Pediatrics. vol. 119. 2007. pp. e1177-83. (Excellent article helping differentiate urticaria from EM.)

Griffith, RS, Norins, AL, Kagan, C. “A multicentered study of lysine therapy in Herpes simplex infection”. Dermatologica. vol. 156. 1978. pp. 257-67. (This is an article discussing a trial using lysine for prevention of herpes.)

Samad, I, Chong, VH, Lim, SS. “Erythema multiforme secondary to H1N1 vaccine”. South Med J. vol. 104. 2011. pp. 73-4. (EM related to H1N1.)

Chen, CL, Chow, KC, Wong, CK. “A study on Epstein-Barr virus in erythema multiforme”. Arch Dermatol Res. vol. 290. 1998. pp. 446-9. (EM related to EBV.)

Chen, CW, Tsai, TF, Chen, YF. “Persistent erythema multiforme treated with thalidomide”. Am J Clin Dermatol. vol. 9. 2008. pp. 123-7. (Thalidomide for EM.)

Zeitouni, NC, Funaro, D, Cloutier, RA. “Redefining Rowell's syndrome”. Br J Dermatol. vol. 142. 2000. pp. 343-6. (Rowell syndrome.)

Duvic, M, Reisner, EG, Dawson, DV, Ciftan, E. “HLA-B15 association with erythema multiforme”. J Am Acad Dermatol. vol. 8. 1983. pp. 493-6. (HLA associations with EM.)

Malo, A, Kämpgen, E, Wank, R. “Recurrent herpes simplex virus-induced erythema multiforme: different HLA-DQB1 alleles associate with severe mucous membrane versus skin attacks”. Scand J Immunol. vol. 47. 1998. pp. 408-11. (HLA association with herpes infection.)

Rasmussen, JE. “Erythema multiforme in children. Response to treatment with systemic corticosteroids”. Br J Dermatol. vol. 95. 1976. pp. 1810-6. (Shows possible link to complications with steroids in SJS.)

Ongoing controversies regarding etiology, diagnosis, treatment

Stevens-Johnson syndrome (SJS) is likely a separate disease from EM. SJS is more severe, typically caused by a medication or Mycoplasma, involves two mucous membranes, and can be life-threatening.