Derm Dx: Blisters, blotches and burning in a 42-year-old woman

This patient was diagnosed with recurrent erythema multiforme (EM), a self-limited, recurrent disease that typically affects young adults and is rare in those younger than three and those older than 50 years of age. Patients with EM minor do not...

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This patient was diagnosed with recurrent erythema multiforme (EM), a self-limited, recurrent disease that typically affects young adults and is rare in those younger than three and those older than 50 years of age. Patients with EM minor do not experience prodromal symptoms, and cases usually occur in the spring and fall.

Virtually all cases of EM have been linked to infection with HSV,¹ including herpes labialis and herpes genitalis as well as subclinical disease. In most prospective studies, EM skin lesions contain HSV proteins that elicit a delayed-type hypersensitivity reaction. This is true whether or not classic HSV lesions are present elsewhere in the body.²

Clinical Presentation

Herpes-associated EM lesions appear on average 10 days after HSV lesions (range: one-to-three weeks). They evolve abruptly as monomorphous, sharply marginated, annular, dull erythematous macules that progress over a 24- to 48-hour period to edematous papules or urticarial plaques 1 to 3 cm in diameter. Unlike urticaria, EM lesions remain fixed for days, typically requiring one to four weeks to resolve.

The classic iris lesion of EM comprises central, dusky purpura; an elevated, edematous, pale ring; and an outer ring of macular erythema. Some lesions form central bullae with peripheral erythema and no central purpura, as with this patient.

Lesions typically appear on the palms and soles. EM favors the acral areas, especially the dorsal hands. Lesions may then spread centripetally. The dorsal feet, extensor surfaces of the extremities, elbows, knees, palms and soles are frequently involved. By definition, EM lesions cover less than 10% of total body surface area.

Not all cases of EM are associated with clinical HSV infection. Herpes DNA has been found in many EM skin lesions when no clinical HSV infection is present.^2,3 It has even been found in healed skin at the site of prior EM lesions three months after it’s resolution.³

Furthermore, continuous acyclovir therapy reduces recurrent EM outbreaks in patients with no history of clinical HSV infection.⁴ Not all patients with recurrent HSV develop EM. Those with certain HLA types, such as HLA-DQ3, are more likely to develop EM in response to HSV infection.⁵

Predisposing factors for herpes-associated EM include sun exposure, as UVB radiation can reactivate latent oral HSV infection. Medications have been associated with EM, but in most cases, the medications were given for symptoms of infection that in many cases turned out to be HSV. Several drugs do cause EM-like lesions that can develop into Stevens-Johnson syndrome (SJS).

Nosology

EM’s nosology has been debated. It was once thought that EM and SJS represented a spectrum of one disease process, but researchers have since classified them as two distinct clinical disorders that produce similar mucosal reactions, with different patterns of cutaneous lesions and precipitating factors.

EM has since been classified into two variants: EM minor, which consists of cases confined to the skin with minor mucous membrane involvement, and EM major, which features significant mucous membrane involvement of at least two sites.

EM major cases are usually drug induced (sulfonamides, antiepileptics, nonsteroidal anti-inflammatory drugs and others) or involve bacterial infections with pathogens including Mycoplasma pneumoniae, Yersinia, salmonella and others.

Some cases overlap these definitions. For example some cases of EM minor are due to drugs, although the pathophysiology of these clinically similar lesions is quite different from herpes-associated EM.⁶ Herpes-associated EM lesions demonstrate a cytokine profile associated with delayed-type hypersensitivity, whereas drug-induced cases have high levels of tumor necrosis factor.

Regardless of the nosologic difficulties, the majority of EM cases with mild to no mucous membrane involvement can be recognized clinically.^1,5 The differential diagnosis includes urticaria, but urticarial lesions are very pruritic and evanescent, do not blister and do not favor acral sites. On occasion, they may form incomplete target lesions.

Urticarial vasculitis features fixed urticaria with palpable purpura. Histologic analysis reveals vasculitis, not the interface dermatitis seen in EM.

Other differential diagnoses include Sweet’s syndrome (acute febrile neutrophilic dermatosis), granuloma annulare, bullous pemphigoid and fixed drug eruption. Lesions of Sweet’s syndrome demonstrate asymmetric, oozing, erythematous papules and nodules in a patient who is systemically ill. Granuloma annulare lesions can resemble incomplete targets, but they develop very slowly.

Bullous pemphigoid in the urticarial phase can resemble EM, but lesions favor flexural sites and elderly individuals and have no predilection for acral or mucosal surfaces. Individual lesions of fixed drug eruption are often indistinguishable from EM, but EM presents with multiple lesions.

Patients with HIV infection, corticosteroid exposure, bone marrow transplant, systemic lupus erythematosus (SLE), graft versus host disease (GVHD), and inflammatory bowel disease (IBD) are at higher risk for EM, as well as those undergoing radiation, chemotherapy or neurosurgery for brain tumors.

Treatment

Treatment of herpes-associated EM is based on the cause and extent of lesions.^1,5 Sunscreen should be used on the face and lips to prevent UVB-sensitive HSV recurrences. Symptomatic treatment with topical steroids sometimes helps.

Systemic antihistamines, salicylates and other NSAIDs offer no benefit. Systemic corticosteroids are used in severe cases, but they often have no effect and sometimes reactivate HSV infection, leading to increased frequency of EM recurrences. Treatment with antiviral medication does not influence those EM lesions already present.

The best treatment is prevention with acyclovir (400 mg twice daily), which is typically instituted when patients have four or five outbreaks per year. After six to 12 months, treatment should be stopped to check for necessity. Some patients experience long-lasting remissions after such a course.⁴

If EM recurs, another six- to 12-month course is warranted. The patient in this case was given a seven-day course of acyclovir 400 mg five times per day. She did not follow up.¹

Thomas W. McGovern, MD, is a Mohs surgeon and general dermatologist with Fort Wayne Dermatology in Fort Wayne, Ind.

References

1. Odom RB, James WD, Berger TG. Andrews’ Diseases of the Skin: Clinical Dermatology. 9th ed. Philadelphia, Pa.: WB Saunders; 2000:147.

2. Kokuba H, Imafuku S, Burnett JW et al. Longitudinal study of a patient with herpes-simplex-virus-associated erythema multiforme: viral gene expression and T cell repertoire usage. Dermatology. 1999;198:233.

3. Brice SL, Leahy MA, Ong L et al. Examination of non-involved skin, previously involved skin, and peripheral blood for herpes simplex virus DNA in patients with recurrent herpes-associated erythema multiforme. J Cutan Pathol. 1994;21:408.

4. Tatnall FM, Schofield JK, Leigh IM. A double-blind, placebo-controlled trial of continuous acyclovir therapy in recurrent erythema multiforme. Br J Dermatol 1995;132:267.

5. Fritsch PO, Elias PM. Erythema multiforme and toxic epidermal necrolysis. Fitzpatrick’s Dermatology in General Medicine. 4th ed. New York, N.Y.: McGraw-Hill.

6. Kokuba H, Aurelian L, Burnett J. Herpes simplex virus associated erythema multiforme (HAEM) is mechanistically distinct from drug-induced erythema multiforme: interferon-gamma is expressed in HAEM lesions and tumor necrosis factor-alpha in drug-induced erythema multiforme lesions. J Invest Dermatol. 1999;113:808.

7. Mockenhaupt M, Viboud C, Dunant A et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol. Jan 2008;128(1):35-44.