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Erythema Multiforme
Tyler S. Rogers, MD
John Scott Earwood, MD
image BASICS
  • Erythema multiforme (EM) is relatively common, acute, reccurent, self-limiting inflammatory disease.
    • Mostly (˜90% of cases) triggered by infectious agents (up to 50% by herpes simplex virus [HSV]-1 or -2), or less commonly, by drugs and vaccinations (1,2)
    • Skin lesions include acrally distributed, distinct targetoid lesions with concentric color variation, sometimes accompanied by oral, genital, or ocular mucosal lesions (1,3).
    • Flat, atypical lesions and macules with or without blisters are more suggestive of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) (4,5,6).
  • There is no universal diagnostic criteria, but clinical history, clinical examination, skin biopsy, laboratory studies, and special consideration of persistent EM are all included in making a diagnosis.
DESCRIPTION
  • Two subtypes, erythema multiforme minor (EMm) and erythema multiforme major (EMM), with the former involving none or one mucous membrane, and the latter involving at least two mucous membrane sites. EMM is now separate from SJS and TEN (4).
  • Recurrent EM is defined as >3 attacks but has a mean number of 6 attacks (range 2 to 24) per year and a mean duration of 6 to 9.5 years (range 2 to 36) (1).
EPIDEMIOLOGY
Incidence
Annual U.S. incidence is estimated at 0.01-1% (1).
Prevalence
  • Peak incidence in 20s and 40s; rare <3 years and >50 years of age (4)
  • Male > female (3:2 to 2:1)
ETIOLOGY AND PATHOPHYSIOLOGY
  • The exact pathophysiology of EM is incompletely understood but appears to be the result of a TH1-mediated immune reponse to an inciting event such as infection or drug exposure.
  • Genetic susceptibility can be a predisposing factor in some patients with EM. Different HLA alleles have been found to be consistent in patients with EM.
  • HSV containing a certain HSV pol, a polymerase associated with the HSV-triggered EM seems to involve autoimmune activation (1)
  • With electron microscopy, there is evidence of lichenoid inflammatory infiltrate and epidermal necrosis including circulating immune complexes, deposition of C3, IgM, and fibrin around the upper dermal blood vessels.
  • SJS and TEN have an increased granulysin and perforin expression within T cells than in EM (5,6).
  • Previous viral infections, particularly; also Epstein-Barr, coxsackie, echovirus, varicella, mumps, polio-virus, hepatitis C, cytomegalovirus, HIV, molluscum contagiosum virus (1)
  • Bacterial infections, particularly M. pneumoniae; other reported bacterial infections include Treponema pallidum and Gardnerella vaginalis (1)
  • Medications, including NSAIDs, antibiotics, sulfonamides, and antiepileptics (1,3)
  • Vaccines: stronger association with HPV, MMR, and small pox vaccines, but also associated with hepatitis B, meningococcal, pneumococcal, varicella, influenza, diphtheria-pertussis-tetanus, and H. influenzae (2,7)
  • Occupational exposures: herbicides (alachlor and butachlor), iodoacetonitrile
  • Radiation therapy
  • Premenstrual hormone changes (3)
  • Malignancy (3)
Genetics
Strong association with HLA-DQB10301, particularly in herpes-related cases (1); possible association in recurrent cases with HLA-B35, -B62, -DR53
RISK FACTORS
Previous history of EM
GENERAL PREVENTION
  • Known or suspected etiologic agents should be avoided.
  • Acyclovir or valacyclovir may help prevent herpes-related recurrent EM.
COMMONLY ASSOCIATED CONDITIONS
See “Etiology and Pathophysiology” earlier.
image DIAGNOSIS
Clinical
PHYSICAL EXAM
  • Acral extremities
  • Symmetric cutaneous eruptions composed of targetoid lesions with concentric color variation.
  • Mucosal involvement
    • Oral involvement manifest as erythema, erosions, bullae, and ulcerations on both nonkeratinized and keratinized mucosal surfaces and on the vermilion of the lips. Minimal involvement in EMm, if present, most commonly involves the mouth.
    • Can include any mucosal tissue including genital, ocular, oral, and so forth
    • At least two mucosal sites involved in EMM, including eyes (conjunctivitis, keratitis); mouth (stomatitis, cheilitis, characteristic blood-stained crusted erosions on lips); and probable trachea, bronchi, GI tract, or genital tract (balanitis and vulvitis) (6)
DIFFERENTIAL DIAGNOSIS
  • SJS
    • Generalized distribution of lesions; concentrated on the trunk
    • Macular atypical targetoid lesions
    • Flat target lesions or macules with coalescence of lesions
    • Blisters and skin detachment <10% of the total body surface area (6)
    • 1-5% mortality (4)
    • Presence of constitutional symptoms with presence of high fever (>38.5°C) more likely with SJS than EM
    • More likely to have mucosal involvement at ≥2 sites, lymphadenopathy, high C-reactive protein levels (>10 mg/dL), and hepatic dysfunction, and >90% have severe mucosal involvement at least at one site (1)
  • TEN
    • Similar to SJS but has full-thickness skin necrosis and skin detachment >30% of the total body surface area (6,8)
    • 34-40% mortality rate (4)
  • Urticaria
  • Fixed drug eruption
  • Bullous pemphigoid
  • Paraneoplastic pemphigoid
  • Sweet syndrome
  • Rowell syndrome
  • Polymorphus light eruption
  • Cutaneous small-vessel vasculitis
  • Mucocutaneous lymph node syndrome
  • Erythema annulare centrifugum
  • Acute hemorrhagic edema of infancy
  • Subacute cutaneous lupus erythematosus
  • Contact dermatitis
  • Pityriasis rosea
  • HSV
  • Secondary syphilis
  • Tinea corporis
  • Dermatitis herpetiformis
  • Herpes gestationis
  • Septicemia
  • Serum sickness
  • Viral exanthem
  • Rocky Mountain spotted fever
  • Meningococcemia
  • Lichen planus
  • Behçet syndrome
  • Recurrent aphthous ulcers
  • Herpetic gingivostomatitis
  • Granuloma annulare
P.361

DIAGNOSTIC TESTS & INTERPRETATION
  • No lab test is indicated to make the diagnosis of EM (1,4,9).
  • Skin biopsy of lesional and perilesional tissue in equivocal conditions
  • Direct and indirect immunofluorescence (DIF and IIF) to differentiate EM from other vesiculobullous diseases. DIF is detected on a biopsy of perilesional skin, and IIF is detected from a blood sample (1).
  • HSV tests in recurrent EM (serologic tests, swab culture, or tests using skin biopsy sample to check HSV antigens or DNA in keratinocytes by DIF or direct fluorescent antibody [DFA] or polymerase chain reaction [PCR])
  • Antibody staining to IFN-&ggr; and TNF-&agr; to differentiate HSV from drug-associated EM
  • As the second most common cause of EM, M. pneumoniae should be worked up with CXR, swabs, and serologic test.
  • In persistent EM, check complement levels (1).
Initial Tests (lab, imaging)
No imaging studies are indicated in most cases unless there is suspicion for M. pneumoniae.
Follow-Up Tests & Special Considerations
Chest x-ray may be necessary if an underlying pulmonary infection (M. pneumoniae) is suspected.
Test Interpretation
  • Vacuolar interface dermatitis with CD4+ T lymphocytes and histiocytes in papillary dermis and the dermal-epidermal junction
  • Superficial perivascular lymphocytic inflammation
  • Satellite cell necrosis
  • Necrotic keratinocytes mainly in the basal layer
  • Papillary dermal edema
image TREATMENT
GENERAL MEASURES
  • Step 1 DISCONTINUE OR TREAT INCITING FACTOR (1,4,9)
  • Wound care for severe cases with epidermal detachment.
  • Oral lesions should be addressed to insure maintenance of PO intake. This can include oral anesthetic solutions and antiseptic rinses.
MEDICATION
  • Acute EM
    • Discontinuation of inciting factors and treatment of underlying disease (1,4,9)[B]
    • Symptomatic treatment with oral antihistamines and topical (1)[B]
    • HSV-induced EM: Most recent sources report no proven effect on the course of EM using antivirals with acute mild EM (1,9)[B]
    • M. pneumoniae-associated EM may require antibiotics.
  • Mucosal membrane EM
    • Consider high-potency topical corticosteroid gel, oral antiseptic, and oral anesthetic solutions if mild.
    • If more severe, consider prednisone 40 to 60 mg/day with dosage tapered over 2 to 4 weeks (1)[B].
    • Ophthalmology consultation is imperative for ocular involvement (4)[A].
  • Recurrent EM
    • First-line treatment for HSV-associated and idiopathic recurrent EM is antiviral prophylaxis; 12 to 24 months of prophylaxis is most effective (1,10)[B].
    • Therapy includes acyclovir 400 mg BID, valacyclovir 500 mg BID, famciclovir 250 mg BID (1)[B]
    • Second-line therapy includes dapsone (100 to 150 mg/day), azathioprine (Imuran, 100 to 150 mg/day), thalidomide (100 to 200 mg/day), tacrolimus (0.1% ointment daily), mycophenolate mofetil (CellCept 1,000 to 1,500 mg BID), hydroxychloroquine (400 mg/day) (1)[B]
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
  • Care at home
  • Hospitalization needed for fluid and electrolyte management in patient with severe mucous membrane involvement, impaired oral intake, and dehydration
  • IV antibiotics if secondary infection develops
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • The disease is self-limiting.
  • Complications are rare, with no mortality.
DIET
As tolerated, with increased fluid intake
PATIENT EDUCATION
  • The disease is self-limiting. However, the recurrence risk may be 30%.
  • Avoid any identified etiologic agents.
PROGNOSIS
  • Rash evolves over 1 to 2 weeks and subsequently resolves within 2 to 6 weeks, generally without scarring or sequelae.
  • Following resolution, there may be some postinflammatory hyper- or hypopigmentation.
REFERENCES
1. Sokumbi O, Wetter DA. Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. Int J Dermatol. 2012;51(8):889-902.
2. Rosenblatt AE, Stein SL. Cutaneous reactions to vaccinations. Clinical Dermatology. 2015;33(3): 327-332.
3. Levin J, Hofstra T. Recurrent erythema multiforme. JAMA. 2014;312(4):426-427.
4. Habif TP. Erythema multiforme. Clinical Dermatology. 5th ed. St. Louis, MO: Mosby-Elsevier; 2010:710-714.
5. Iwai S, Sueki H, Watanabe H, et al. Distinguishing between erythema multiforme major and Stevens-Johnson syndrome/toxic epidermal necrolysis immunopathologically. J Dermatol. 2012;39(9):781-786.
6. Scwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis: part I. Introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis. J Am Acad Dermatol. 2013;69(2):173.e1-173.e13.
7. Storie EB, Perry A. Erythema multiforme following smallpox vaccination. Mil Med. 2014;179(1): e113-e115.
8. Scwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis: part II. Prognosis, sequelae, diagnosis, differential diagnosis, prevention, and treatment. J Am Acad Dermatol. 2013;69(2): 187.e1-187.e16.
9. Sola CA, Beute TC. Erythema multiforme. J Spec Oper Med. 2014;14(3):90-92.
10. Wetter DA, Davis MD. Recurrent erythema multiforme: clinical characteristics, etiologic associations, and treatment in a series of 48 patients at Mayo Clinic, 2000 to 2007. J Am Acad Dermatol. 2010;62(1):45-53.
See Also
&NA;
Cutaneous Drug Reactions; Dermatitis Herpetiformis; Pemphigoid Gestationis; Stevens-Johnson Syndrome; Toxic Epidermal Necrolysis; Urticaria
Codes
&NA;
ICD10
  • L51.9 Erythema multiforme, unspecified
  • L51.8 Other erythema multiforme
  • L51.0 Nonbullous erythema multiforme
Clinical Pearls
&NA;
  • EM is diagnosed clinically by careful review of the history, thorough detailed physical exam, and by excluding other similar disorders. No lab tests are required for the diagnosis.
  • Typical lesions are characteristic targetoid or “iris” lesions but can include raised targetoids.
  • Lesions are symmetrically distributed on palms, soles, dorsum of the hands, and extensor surfaces of extremities and face. The oral mucosa is the most affected mucosal region in EM.
  • Management of EM involves determining the etiology when possible. The first step is to treat the suspected infection or discontinue the causative drug.
  • Complications are rare. Most cases are self-limited. However, the recurrence risk may be as high as 30%.
  • Recurrent cases often are secondary to HSV infection. Antiviral therapy may be beneficial.