Erythema Multiforme

Erythema Multiforme

Symposium on Pediatric Dermatology Erythema Multiforme Betty I. Edmond, M.D.,* I. Clark Huff, M.D., t and William L. Weston, M.D.:j: The term "eryth...

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Symposium on Pediatric Dermatology

Erythema Multiforme Betty I. Edmond, M.D.,* I. Clark Huff, M.D., t and William L. Weston, M.D.:j:

The term "erythema multiforme" was introduced by Ferdinand von He bra in the mid 1800's to describe an acute, self-limited cutaneous eruption characterized by symmetrically distributed skin lesions evolving through multiple morphologic stages.l8• 42 The disease was mild in course, with occasional recurrences. In 1922, Stevens and Johnson described a severe form of erythema multiforme characterized by an acute febrile course, skin lesions similar to those of Hebra's erythema multiforme, and severe stomatitis and purulent conjunctivitis. 44 Unfortunately, since these early descriptions physicians have had a tendency to use the term "erythema multiforme" in describing any polymorphous skin rash with or without a mucous membrane eruption, thereby labeling such entities as papular drug eruptions or urticaria with annular skin lesions as erythema multiforme. Much confusion has arisen from application of the term "multiforme" to the presence of different types of skin lesions at one time, rather than to the original derivation of the term which denoted an evolution of each skin lesion through distinct morphologic stages. In an attempt to aid in the appropriate diagnosis of erythema multiforme, Thomas classified the disorder into two categories. 47 Erythema multiforme minor refers to the mild cutaneous form originally described by Hebra, and erythema multiforme major applies to the severe mucocutaneous form of disease described by Stevens and Johnson. Until the pathogenesis of erythema multiforme is more clearly defined, its classification into a minor and a major type provides a more consistent approach to diagnosis. Currently, it appears that erythema multiforme is not a single disease but represents a syndrome with common clinical and histopathol-

*Assistant Professor of Dermatology and Microbiology, University of Colorado School of Medicine, Denver, Colorado t Associate Professor of Dermatology and Internal Medicine, University of Colorado School of Medicine, Denver, Colorado :j:Professor and Chairman, Department of Dermatology, University of Colorado School of Medicine, Denver, Colorado Supported by Grant AI 16637 from the National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland

Pediatric Clinics of North America-Yo!. 30, No. 4, August 1983

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ogic features. In this review, emphasis will be placed on the clinical and histopathologic features essential to the diagnosis. In addition, we will consider current knowledge of the pathogenesis of this syndrome.

Clinical Features Erythema multiforme occurs primarily in healthy adolescents and young adults and may be classified into two types.

Erythema Multiforme

Minor (Classical Erythema Multiforme).

Prodromal symptoms characteristic of a mild upper respiratory illness occur within one week of the onset of erythema multiforme in approximately one third of patients. 23 The appearance of the exanthem marks the onset of erythema multiforme, the skin lesion being the most characteristic feature of the disease.!· 18· 42 A round erythematous macule rapidly evolves into a papule that frequently displays a circumferential pallor (Fig. lA). Over a period of days, papules may enlarge or coalesce to form small plaques. The central portion of the papule then changes color because of epidermal necrosis. Most typically, central necrosis results in a depressed white, yellow, or gray area surrounded by the red edges of the papule and a pale edematous ring around the entire skin lesion. Beyond the edematous ring may be a bright red margin. The contrast between the color of the central region and concentric zones of color in these lesions has resulted in application of the descriptive term "target lesion," also known as iris lesion (Figs. lB and C). Target lesions further evolve by coalescing, developing central crusting or clearing centrally. If fluid accumulates, central vesicles

Figure l. Evolution of erythema multiforme minor. Earliest lesions begin as grouped dome-shaped red papules (A), then develop over several days into target (iris) lesions with rings of concentric color changes (B), then finally develop central blisters and crusts (C).

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or bulla may form. Resolution of lesions occurs with crusting or scaling (Fig. 1C), but is not characterized by scar formation. Post-inflammatory hyperpigmentation, particularly in dark-skinned individuals, is usual. The course of erythema multiforme minor is characterized by an acute onset, with evolution of skin lesions over 3 to 5 days and complete healing within 2 to 4 weeks. 8· 23 Typically, skin lesions are symmetrically distributed and occur over the dorsum of the hands, nailfolds, and extensor surfaces of the extremities. There is a particular tendency for lesions to be grouped over the elbows and knees. Although less frequent, lesions can occur on the palms and soles. The scalp is usually not involved. Erythema multiforme appears to spread from the extensor surface of the extremities to the flexural surfaces and then to the trunk. Two additional features regarding the distribution of skin lesions are worthy of note. First careful examination of the skin frequently reveals a photodistribution of skin lesions.20 Secondly, the skin lesions appear to have a propensity to occur at sites of physical trauma, referred to as the isomorphic (Koebner' s) phenomenon (Fig. 2). 21 In addition to the skin lesions that characterize erythema multiforme minor, a mild form of mucous membrane involvement is observed in up to 60 per cent of cases. 28· 48 Early mucosal lesions display erythema and edema, and progress within hours to shallow ulcers, with or without preceding vesicle formation. Mucosal lesions usually appear simultaneously with the onset of the cutaneous eruption, although mucous membrane involvement may precede or follow skin lesions by days. 26 Erythema multiforme minor typically is not associated with symptoms other than those related to skin and mucosal involvement. 18· 48 Skin lesions may cause itching and burning and mucosal ulcers may be associated with pain. Erythema Multiforme Major (Stevens-Johnson Syndrome). The clinical features of erythema multiforme major are more variable than those described for erythema multiforme minor, and involvement is universally more severe. 5 Prodromal symptoms commonly occur 1 to 14 days prior to the onset of mucocutaneous disease and include malaise, fever, headache, sore throat, cough, chest pain, vomiting, diarrhea, myalgias, and arthral-

Figure 2. Erythema multiforme minor with isomorphic (Koebner) phenomena. Early papular lesions of erythema multiforme minor with the appearance of linear lesions in skin sites of previous trauma (scratches).

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gias. In contrast to erythema multiforme minor, mucosal lesions are a more prominent and consistent feature than cutaneous lesions.5. 12 EM major is characterized by the sudden onset of inflammatory bullous lesions on the mucous membranes, predominantly the oral mucosa, lips, and bulbar conjunctiva (Fig. 3A). Rupture of bullae results in pseudomembrane formation on lips. Ocular involvement presents as a bilateral purulent conjunctivitis with associated papules or vesicles (Fig. 3B). The development of corneal ulceration, anterior uveitis or panophthalmitis is common. 6 The skin lesions of EM major are more variable in presentation than those described for EM minor. They may evolve from maculopapular lesions to the target lesions of classical erythema multiforme, or develop confluent areas of erythema, large bullae, or extensive areas of desquamation known as toxic epidermal necrolysis (Fig. 4). 4 • 5· 30 • 44 New lesions may continue to erupt over 10 days to 4 weeks, with healing of cutaneous and mucosal lesions requiring up to 6 weeks. 5, 13, 47 Beyond the more common areas of involvement noted above, severe erythema multiforme major may extend to the mucosal surfaces of the nasopharynx, esophagus, respiratory mucosa, and urogenital tract. Mucosal lesions are associated with severe pain which may lead to difficulties in breathing, eating, and urinary retention. Systemic symptoms are common in erythema multiforme major and consist of high fever, weakness and prostration lasting up to 3 weeks. Because of the extent of mucocutaneous disease that characterizes erythema multiforme major, complications are common, the more severe being secondary to ocular disease. 3• 14 Corneal opacities, synechiae, and blindness have been described. Although infrequently reported, pneumonia and renal disease with hematuria or tubular necrosis have been observed. Histopathology of Erythema Multiforme Lesions There are two major histopathologic findings observed in EM.l9 First, early lesions are characterized by an accumulation of primarily mononuclear cells around upper dermal blood cells.!· 7, 36 , 38 It is important to note

Figure 3. Erythema multiforme major. A, Severe crusting of lips and epidermal necrosis of skin of lower face. B, Edema, redness, and purulence of conjunctival mucosa.

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Figure 4. Toxic epidermal necrolysis. Separation of full-thickness necrotic epidermis from dermis with extensive involvement of trunk.

that the presence of large numbers of neutrophils, or neutrophils occurring in blood vessel walls (leukocytoclastic vasculitis), is inconsistent with the histologic diagnosis of erythema multiforme. Secondly, erythema multiforme is associated with damage to the epidermal layer of skin, with necrosis occurring either in individual keratinocytes or throughout the entire epidermis. I, 7, 19, 36, 38 Differential Diagnosis When considering the diagnosis of erythema multiforme, the following distinguishing features are of particular importance: l. The term "multiforme" refers to the evolution of fixed skin lesions through multiple morphologic stages, and not the presence of many different types of skin lesions at any given time. 2. Skin lesions evolve over a period of days, rather than hours. 3. Target lesions are characteristically round and well demarcated, with a central area of tissue necrosis. 4. Skin lesions are symmetrically distributed primarily over the extensor surfaces of the extremities, 5. The course of erythema multiforme is self-limited and frequently recurrent, with individual episodes lasting days to weeks rather than months. 6. Histopathologically, skin lesions are characterized by a lymphocytic infiltrate and evidence of epidermal damage.

A number of disorders common to the pediatric age group may be confused with erythema multiforme. Urticaria may develop polycyclic forms that display concentric color changes superficially resembling the target or iris lesions of erythema multiforme minor. 49 Distinguishing features of urticaria are the evolution of lesions over hours rather than days, and the lack of epidermal necrosis seen in erythema multiforme. Urticaria also may occur anywhere on the skin and is not symmetric in distribution. A second entity often misdiagnosed as erythema multiforme minor is erythema annulare centrifugum. 49 In erythema annulare centrifugum, skin lesions may have concentric color changes with a dusky center and ery-

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thematous border. As the name implies, lesions are annular, and annular lesions have also frequently been observed in erythema multiforme. The distinguishing features of erythema annulare centrifugum compared with erythema multiforme are the lack of a central area of necrosis in skin lesions and the chronic nature of disease, lasting months rather than days to weeks as in erythema multiforme. In addition, the distribution of erythema annulare centrifugum is centrifugal, with lesions typically occurring first on the trunk and buttocks, in contrast to the symmetric involvement of extremities seen in erythema multiforme. Mucous membrane lesions do not occur in erythema annulare centrifugum. A disease which has been frequently confused with severe forms of erythema multiforme major is staphylococcal scalded skin syndrome (SSSS). 49 This syndrome is caused by the exfoliative toxin elaborated by Staphylococcus aureus, resulting in intraepidermal separation of cells within the granular layer of the epidermis, intraepidermal blister formation, and subsequent exfoliation of the entire granular layer and stratum corneum. Inflammatory cells are not typically present. Patients with the scalded skin syndrome appear acutely ill with high fever, generalized erythema, and tender skin, areas of skin shedding, and crusting around the mouth and eyes. The clinical appearance SSSS is very similar to toxic epidermal necrolysis (TEN). 49 Toxic epidermal necrolysis is an exfoliative skin disease that is most commonly drug-induced and may be a stage of progression of severe forms of erythema multiforme major related to drug reactions. Its characteristic clinical features are similar to those in SSSS; however, TEN results from cleavage of skin between the epidermis and dermal layers, with full thickness necrosis of epidermis, rather than the intraepidermal cleavage seen in SSSS. In addition, TEN is frequently associated with a history of either drug-related urticaria or the target lesions of erythema multiforme preceding the desquamation by 2 to 3 days. Pathogenesis Although erythema multiforme has been associated with a wide variety of precipitating factors, only three etiologic associations have been well-documented when strict diagnostic criteria for erythema multiforme are employed: the association of erythema multiforme minor with recurrent herpes simplex virus infections and the association of erythema multiforme major with either Mycoplasma pneumoniae infections or drugs. 23 Herpes-associated erythema multiforme accounts for 15 to 63 per cent of cases of erythema multiforme minor seen by clinical dermatologists.24· 32· 41 Typically, an episode of recurrent Herpes simplex virus infection with Herpes labialis2 • 16· 35· 41 or Herpes genitalis2 precedes the onset of erythema multiforme by approximately 10 days. Erythema multiforme is not associated with primary Herpes simplex virus infections. It is of additional interest that individuals with herpes-associated erythema multiforme tend to have recurrent episodes of erythema multiforme following recurrent attacks of herpes. Furthermore, the distribution of skin lesions is frequently similar for each recurrent episode. The association of Mycoplasma pneumoniae with erythema multiforme has been documented both by the presence of high titers of serum anti-

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body to M. pneumonia and by cultures of the organism from the respiratory tract.n. 29, 31 · 40· 43 Typically, erythema multiforme major follows a respiratory infection in a child or young adult by days to weeks. As anticipated, pneumonia is frequently associated with the M. pneumonia infection and may be responsible for many of the cases of pneumonia reported with erythema multiforme major. Recurrences of mycoplasmaassociated erythema multiforme are uncommon.3I Erythema multiforme major is the most common severe mucocutaneous reaction precipitated by drugs. The drugs most frequently associated with well-documented cases of erythema multiforme are sulfonamides and sulfonamide derivatives (e.g., thiazides), penicillins, diphenylhydantoin, and phenylbutazone. 8• 9· 11 • 39· 46 Erythema multiforme major typically follows drug therapy by 1 to 3 weeks of exposure to the offending drug, and may follow drug administration by hours or days when the patient has been previously exposed to the drug. Although the pathogenesis or erythema multiforme has not been determined, clinical and histopathologic features suggest that it results from a host immune response to foreign antigen. Most of the current hypotheses on the pathogenesis of erythema multiforme have been derived from data accumulated on herpes-associated erythema multiforme. Recently, Kazmierowski and co-workers, as well as other groups, have proposed a mechanism of immune complex vasculitis resulting from circulating immune complexes responsible for the development of herpes-associated erythema multiforme.IO, 22 · 25 · 27· 33 · 50 In the immune complex theory, the antigen (e.g., Herpes simplex virus) and specific antibody combine and circulate in the blood, localizing in small blood vessels with subsequent damage to the vessels. However, acute vascular injury with an inflammatory infiltrate is not consistent with the histopathology observed in erythema multiforme and does not explain localization of disease to the skin or mucosal surfaces. An alternative hypothesis addressing the pathogenetic mechanism of herpes-associated erythema multiforme is based on the premise that herpes antigen may be localized in the skin of erythema multiforme patients and may precipitate a generalized hypersensitivity response under appropriate conditions. There have been occasional reports of recovery of Herpes simplex virus from erythema multiforme lesions; 15, 34 • 45 however, appropriate documentation of the lesion as erythema multiforme was not provided. If the virus is present in the skin, it may be in small quantity or in a latent stage that has been difficult to detect by current methods. Recently, Huff and co-workers demonstrated herpes antigens in erythema multiforme lesions by indirect immunofluorescent staining techniques. 37 It is of additional interest, when considering this hypothesis, that M. pneumoniae has been cultured from bullous skin lesions of mycoplasma-associated erythema multiforme. 31 Further studies on the pathogenesis of erythema multiforme are required to define the mechanisms involved. Therapy As a mild, self-limited disorder, erythema multiforme minor should be managed conservatively. 49 When the patient is experiencing pruritus or pain with skin or mucosal lesions, implementation of a few general thera-

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peutic measures may enhance the patient's comfort. For pruritus, warm water tub soaks along with use of an oral antihistamine preparation prior to bedtime is usually helpful. For painful oral lesions, gentle debridement with half-strength hydrogen peroxide is advocated. When oral ulcers are associated with foul breath and lymphadenopathy, lesions may be secondarily infected and, thereby, require additional oral antibiotic therapy. Local or systemic glucocorticosteroids are not indicated in erythema multiforme minor. Because of the extensive tissue necrosis which can accompany erythema multiforme major, hospitalization is recommended. Skin lesions are managed with wet dressings or whirlpool baths, and application of an ointment to healing lesions aids re-epithelialization. Careful monitoring for eye involvement is essential in an attempt to prevent subsequent ocular complications. Consultation with an opthalmologist is advisable and topical steroid preparations for the eyes may be indicated. Indications for the use of systemic glucocorticosteroids in erythema multiforme major remain a controversial issue. Since erythema multiforme major can progress to widespread epidermal necrosis with a mortality approaching 50 per cent, 30 early use of systemic steroids to decrease tissue damage seems appropriate. High-dose therapy (prednisone 1 to 2 mg/kg) should be initiated during the stage of extension of lesions, with tapering of the medication during a 1-to-3-week healing phase. If advanced tissue damage is already evident, secondary bacterial infections are a more prominent concern and steroid therapy is not advisable.

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12. Chanda, J. J., and Callen, J. P.: Erythema multiforme and the Stevens-Johnson syndrome. South. Med. J., 71:566-570, 1978. 13. Claxton, R. C.: A review of 31 cases of Stevens-Johnson syndrome. Med. J. Austral., 50:963-966, 1963. 14. Finland, M., et a!.: Pneumonia and erythema multiforme exudativum. Am. J. Med., 4:473-492, 1958. 15. Foerster, D. W., and Scott, L. V.: Isolation of herpes simplex virus from a patient with erythema multiforme exudativum (Stevens-Johnson syndrome). New Engl. J. Med., 259:473-475, 1958. 16. Forman, L., and Whitwell, G. P. B.: The association of herpes catarrhalis with erythema multiforme (Hebra). Brit. J. Dermatol., 46:307-311, 1934. 17. Foy, H. M., Kenny, G. H., and Koler, J.: Mycoplasma pneumoniae in Stevens-Johnson syndrome. Lancet, 2:550-551, 1966. 18. He bra, F., von: On diseases of the skin including the exanthemata. Translated by C. H. Fagge, London, 1866, New Sydenham Society, Vol. 1,pages 285-289. 19. Howland, W. W., eta!.: Erythema multiforme: Clinical histopathologic and immunologic study. J. Amer. Acad. Dermatol. (in press) 1983. 20. Huff, J. C., and Weston, W. L.: The photo-distribution of erythema multiforme. Arch. Dermatol., 116:477, 1980. 21. Huff, J. C., and Weston, W. L.: Isomorphic phenomenon in erythema multiforme. Clin. Exper. Dermatol. (in press), 1983. 22. Huff, J. C., Weston, W. L., and Carr, R. I.: Mixed cryoglobulinemia, 125 I Clq binding, and skin immunofluorescence in erythema multiforme. J. Invest. Dermatol., 74:375377, 1980. 23. Huff, J. C., Weston, W. L., and Tonnesen, M. G.: Erythema multiforme: A critical review of characteristics, diagnostic criteria, and causes. J. Am. Acad. Dermato!. (in press) 1983. 24. Hutchinson, T. H., Kelly, A. M. T., and Mawhinney, H.: A review of aetiological factors in erythema multiforme. Ulster. Med. J., 47:95-99, 1978. 25. Imamura, S. et a!.: Erythema multiforme: Demonstration of immune complexes in the sera and skin lesions. Brit. J. Dermatol., 102:161-166, 1980. 26. Jensen, J. L., eta!.: Acute episodic inflammatory lesions of the mucous membrane and skin. J. Am. Dent. Assoc., 100:896-898, 1980. 27. Kazmierowski, J. A., and Wuepper, K. D.: Erythema multiforme: Immune complex vasculitis of the superficial cutaneous microvasculature. J. Invest. Dermatol., 71:366-369, 1978. 28. Keil, H.: Erythema multiforme exudativum (Hebra): A clinical entity associated with systemic features. Ann. Intern. Med., 14:449-494, 1940. 29. Ludlam, G. B., Bridges, J. B., and Benn, E. C.: Association of Stevens-Johnson syndrome with antibody for Mycoplasma pneumoniae. Lancet, 1:958-959, 1964. 30. Lyell, A.: A review of toxic epidermal necrolysis in Britain. Brit. J. Dermatol., 79:662671, 1967. 31. Lyell, A., eta!.: Mycoplasma and erythema multiforme. Lancet, 2:1116-1118, 1967. 32. Lynch, F. W.: Erythema multiforme. A review. South. Med. J., 48:279-286, 1955. 33. Mackel, S. E., et a!.: Circulating immune complexes in cutaneous vasculitis: Detection with Clq and monoclonal rheumatoid factor. J. Clin. Invest., 64:1652-1660, 1979. 34. Maja, P. P., Morisset, R., Kurstak, C., eta!.: Isolation of herpes simplex virus type 1 from lesions of erythema multiforme. Canad. Med. Assoc. J., 118:821-822, 1978. 35. Nasemann, T.: Uber das post herpetische erythema exudativum multiforme. Der Hautarzt, 15:346-352, 1964. 36. Orfanos, C. E., Schamburg-Lever, G., and Lever, W. F.: Dermal and epidermal types of erythema multiforme. Arch. Dermatol., 109:682-688, 1976. 37. Orton, P. W., Huff, J. C., and Weston, W. L.: Immunofluorescence examination of erythema multiforme skin for herpes antigens. Clin. Res., 30:601A, 1982. 38. Pierard, J., and Whemster, I.: The histopathological diagnosis of dermatitis herpetiformis, bullous pemphigoid and erythema multiforme. Brit. J. Dermatol., 73:253-266, 1961. 39. Pollack, M. A., Bark, P. G., and Nathanson, G.: Mucocutaneous eruptions due to antiepileptic drug therapy in children. Ann. Neural., 5:262-267, 1979.

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40. Sanders, D. Y., and Johnson, H. W.: Stevens-Johnson syndrome associated with Mycoplasma pneumoniae infection. Am. J. Dis. Child., 121:243-245, 1971. 41. Shelley, W. B.: Herpes simplex virus as a cause of erythema multiforme. J.A.M.A., 201:153-156, 1967. 42. Shelly, W. B., and Crissey, J. T.: Classics in Dermatology. Springfield, Illinois, Charles C Thomas, 1953, pages 103-109. 43. Sontheimer, R. D., Baribaldi, R. A., and Krueger, G. G.: Stevens-Johnson syndrome associated with Mycoplasma pneumoniae infections. Arch. Dermatol., 114:241-244, 1978. 44. Stevens, A. M., and Johnson, F. C.: A new eruptive fever associated with stomatitis and ophthalmia. Am. J. Dis. Child., 24:526--533, 1922. 45. Stran, J.: Herpes simplex virus as a cause of allergic mucocutaneous reactions (Ectodermosis Erosiva Pluriorificialis, Stevens-Johnson's syndrome, etc.) and generalized infection. Scandinav. J. Infect. Dis., 1:3-10, 1969. 46. Stran, J.: Aetiology of febrile mucocutaneous syndromes with special reference to the provocative role of infections and drugs. Acta Med. Scand., 201:131-136, 1977. 47. Thomas, B. A.: The so-called Stevens-Johnson syndrome. Brit. Med. J., 1:1393-1397, 1950. 48. Ustvedt, H. J.: Erythema exudativum multiforme: I. The clinical picture. Acta Med. Scand., 131:23-50, 1948. 49. Weston, W. L.: Practical Pediatric Dermatology. Boston, Massachusetts, Little, Brown and Company, 1979, pages 73, 207, 246, and 256. 50. Wuepper, K .. D., Watson, P. A., and Kazmierowski, J. A.: Immune complexes in erythema multiforme and the Stevens-Johnson syndrome. J. Invest. Dermatol., 74:368371, 1980. University of Colorado Health Sciences Center 4200 East Ninth Avenue Box B-153 Denver, Colorado 80262