Bajaj P et al. Multiforme.

Review Article

Erythema Multiforme: Classification and Immunopathogenesis

Puneet Bajaj, Robin Sabharwal, Rajesh Mohammed PK, Deepti Garg, Charu Kapoor Department of Oral Pathology and Microbiology, Bhojia Dental College and Hospital, Solan

Corresponding Author: Abstract: is a skin condition considered to be a hypersensitivity reaction to Dr. Puneet Bajaj infections or drugs. It consists of a polymorphous eruption of macules, papules, and characteristic Professor & HOD, “target” lesions that are symmetrically distributed Department of Oral Pathology with a propensity for the distal extremities. There is minimal mucosal involvement. Erythema multiforme Bhojia Dental College and Hospital, can be triggered by a range of factors, but more Solan, Himachal Pardesh, India. commonly it is associated with herpes simplex virus (HSV). Most other cases are initiated by drugs. The Contact Number: +91 9814278407 clinical classification of these disorders has often been variable, thus making definitive diagnosis sometimes Email: [email protected] difficult. The present article reviews the classification and highlights the associated potential etiologic Received: 01-09-2013 agents, pathogenic mechanisms and treatment of Erythema multiforme. Revised: 01-10-2013 Keywords: Erythema multiforme, Target lesions, Accepted: 12-10-2013 TEN

This article may be cited as: Bajaj P, Sabharwal R, PK Mohammed R, Garg D, Kapoor C. Erythema Multiforme: Classification and Immunopathogenesis. J Adv Med Dent Scie 2013;1(2):40-47.

Introduction: Erythema multiforme (EM) is a typically exanthematous, cutaneous variant with mild, self-limiting, and recurring minimal oral involvement (EM minor) to a mucocutaneous reaction characterized by progressive, fulminating, severe variant with target or iris lesions of the skin and mucous extensive mucocutaneous epithelial necrosis membranes. 1 (Stevens-Johnson syndrome: SJS; and toxic EM usually affects apparently healthy young epidermal necrolysis: TEN). All variants adults and the peak age at presentation is share two common features: typical or less 20–40 years although as many as 20% of typical cutaneous target lesions and satellite cases are children. 2 cell or more widespread necrosis of the Erythema multiforme is a reactive epithelium. These features are considered to mucocutaneous disorder that comprises be sequelae of a cytotoxic immunologic variants ranging from a self-limited, mild,

40

Bajaj P et al. Erythema Multiforme. attack on keratinocytes expressing non-self- cell mediated immune reaction to the antigens. 3 precipitating agent. The pathogenesis of

herpes-associated Erythema multiforme is Immunopathogenesis: Erythema multiforme is probably an consistent with a delayed-type immunologically mediated process. It is hypersensitivity reaction. The disease begins considered to be a hypersensitivity reaction with the transport of viral DNA fragments to associated with certain infections and distant skin sites by peripheral blood medications. mononuclear cells. HSV genes within DNA fragments are expressed on keratinocytes, • Infections leading to the recruitment of HSV-specific V Herpes simplex virus 1 and 2 CD4+ TH1 cells (helper T cells involved in Herpes simplex virus (HSV) is the cell-mediated immunity). The CD4+ cells most commonly identified etiology respond to viral antigens with production of of this hypersensitivity reaction. interferon-γ, initiating an inflammatory V Mycoplasma pneumoniae cascade. This cytokine then amplifies the V Fungal infections immune response and stimulates the • Medications production of additional cytokines and V Barbiturates chemokines, which aids the recruitment of V Hydantoins further reactive T cells to the area. These V Non-steroidal anti-inflammatory cytotoxic T cells, NK cells or chemokines drugs can all induce epithelial damage (Figure I). V Penicillins Drug-associated erythema multiforme V Phenothiazines lesions test positive for tumor necrosis factor V Sulfonamides α and not interferon-γ as in herpes Erythema multiforme is also associated with associated erythema multiforme lesions, Vaccines (diphtheria-tetanus, hepatitis B,14 suggesting a varying mechanism. 1 smallpox) and appears to be the result of a

Figure I: Pathogenesis of Erythema Multiforme

Much of the tissue damage in drug-induced SJS, there is some evidence for a Fas–FasL lesions appears to be due to apoptosis and, interaction. FasL mediates apoptotic cell because of the paucity of the inflammatory death by binding to Fas on cells and reaction. However, particularly in TEN and inducing the formation of caspases. Fas is

41

Bajaj P et al. Erythema Multiforme. present on keratinocytes and FasL is found • Bullous erythema multiforme, on activated T cells and NK cells and thus detachment below 10% of the body binding of keratinocytes to T cells or NK surface area plus localized "typical cells can induce apoptosis. 4,5 targets" or "raised atypical targets"; • Stevens-Johnson syndrome, Clinical features The presentation of EM ranges from a self- detachment below 10% of the body surface area plus widespread limited, mild, exanthematous variant with minimal oral involvement (EM minor) to a erythematous or purpuric macules or flat progressive, fulminating, severe variant with atypical targets; • extensive mucocutaneous epithelial necrosis Overlap Stevens-Johnson syndrome - toxic epidermal necrolysis, detachment (Stevens–Johnson syndrome), with EM major intermediate in severity. between 10% and 30% of the body surface area plus widespread The current classification of EM and related disorders is based upon the presence, purpuric macules or flat atypical targets; morphology, and extent of cutaneous and • Toxic epidermal necrolysis with spots, mucosal disease. The cutaneous lesions of detachment above 30% of the body erythema multiforme comprise typical surface area plus widespread purpuric targets, raised atypical targets, flat atypical macules or flat atypical targets; targets, and macules with or without blisters. • Toxicepidermal necrolysis without spots,

A summary of types and clinical features is detachment above 10% of the body presented in (Table I and II).6 surface area with large epidermal sheets

The following consensus classification in and without any purpuric macule or five categories was proposed: target.

Extent of Clinical type Patterns of lesions Distribution blisters/ detachment,% Erythema multiforme Typical targets raised Localized (acral) <10 major (EMM) atypical targets.

Widespread <10 Stevens-johnson Blisters on macules, flat syndrome (SJS) atypical targets.

Widespread Overlap SJS-TEN Blisters on macules, flat 10-29 atypical targets. Widespread Toxic epidermal Blisters on macules, flat ≥30 necrolysis (with spots) atypical targets.

Widespread TEN without spots No discrete lesions, ≥10 large erythematous areas.

Table 1: Showing five type of EM and their clinical features

42

Bajaj P et al. Erythema Multiforme.

Table II: Showing clinical features that distinguish SJS, SJS-TEN overlap, and TEN

Clinical entity SJS SJS-TEN overlap TEN

Primary lesions Dusky red Dusky red lesions, flat Poorly delineated lesions, flat atypical targets erythematous atypical targets plaques, epidermal detachment, dusky red lesions, flat atypical targets

Distribution Isolated lesions, Isolated lesions, Isolated lesions, confluence (+) confluence (++) on confluence(+++) on on face and face and trunk. face and trunk and trunk. elsewhere.

Mucosal Yes Yes Yes involvement

Systemic Usually Always Always symptoms

Detachment <10 10 -30 >30 (%body surface area) Erythema Multiforme is a self-limited the lesions. The characteristic “target” or eruption that usually has mild or no “iris” lesion has a regular round shape and prodromal symptoms. All lesions typically three concentric zones: a central dusky or present within approximately 3 days of darker red area, a paler pink or edematous onset. There may be hundreds of lesions, but zone and a peripheral red ring. Some target less than 10% of the body surface area is lesions have only two zones, the dusky or usually involved. The lesions are in a fixed darker red center and a pink or lighter red position with a symmetric distribution. 7 border. 8 They present as circular erythematous Target lesions may not be apparent until plaques in a concentric array with lesion size several days after the onset, when lesions of ranging from 2 to 20 mm. The individual various clinical morphology usually are lesions begin acutely as numerous sharply present, hence the name erythema demarcated red or pink macules that then “multiforme.” become popular. The papules may enlarge Initially the lesions are seen acrally (dorsal gradually into plaques several centimeters in surfaces of hands, feet, elbows, and knees). diameter. The central portion of the papules The face may also be involved. Less or plaques gradually becomes darker red, commonly, lesions may also be seen on the brown, dusky, or purpuric. Crusting or palms, soles, thighs, and buttocks. Lesions blistering sometimes occurs in the center of

43

Bajaj P et al. Erythema Multiforme. may appear at sites of trauma or physical painful (Figure II) . The oral lesions may be irritation and at sites of sun exposure. mistaken for acute necrotizing ulcerative ginigvostomatitis. The mucosal involvement Oral manifestations is more severe in Steven Johnson Syndrome Oral involvement is seen in some 70% of than in erythema multiforme major. patients with EM. Mucosal vesicles or Sometimes extensive hemorrhagic sloughing bullae occur which rupture and leave tissue extends to whole oral cavity, larynx, surfaces covered with a thick white or esophagus and respiratory tract. Erosions of yellow exudates. The lips may exhibit the pharynx are also common. 3 ulceration with bloody crusting and are

Figure II: Showing lip lesions in a patient with Erythema Multiforme

Histopathological features: of keratinocytes predominate. A second Cutaneous or mucosal lesions exhibit histologic pattern of blister formation is intercellular edema of the spinous layer of characterized by a predominant infiltrate of epithelium and edema of the superficial mononuclear cells around superficial dermal connective tissue which may actually vessels and marked edema of the papillary produce a subepidermal vesicle (Figure III). dermis. A subepidermal blister and less There is a zone of severe liquefaction necrosis of epidermal cells is seen. 10, 11, 12 degeneration in the upper layers of epithelium, intraepithelial vesicle formation Diagnosis: and thinning with frequent absence of the Erythema multiforme is diagnosed basement membrane. Blister formation in clinically. In SJS/TEN there is an elevation erythema multiforme involves hydropic in the blood sedimentation rate. Moderate degeneration and mononuclear cell leukocytosis, fluid and electrolyte infiltration in the epidermis, associated with imbalances, microalbuminuria, degenerative changes within the basal cell hyponatremia, elevated liver transaminase, layer and in keratinocytes. 9 When basal cell hypoproteinuria and anemia also may be degeneration is marked, a subepidermal present. A transient decline in CD4+ T- blister is produced, while a spongiotic lymphocyte counts may also be seen during multilocular intradermal blister may result the acute phase of TEN. when intercellular edema and degeneration

44

Bajaj P et al. Erythema Multiforme.

Figure III : Showing inflammation and intraepithelial vesicle formation in the basilar portion of the epithelium. Numerous necrotic eosinophilic keratlnoc ytes are present in the blister area.

Histological examination and • Stevens-Johnson syndrome immunostaining often show intraepithelial • Toxic epidermal necrolysis oedema and spongiosis early on, with • Urticaria satellite cell necrosis (individual • Urticarial vasculitis eosinophilic necrotic keratinocytes • Vasculitis surrounded by lymphocytes), vacuolar • Viral exanthems degeneratio n of the basement membrane • Other hypersensitivity reactions zone and severe papillary oedema with sub - epithelial or intra-epithelial vesiculation. Treatment: There is intense lymphocytic infiltration at Management of erythema multiforme the basement m embrane zone and involves determining the etiology when perivascularly and non-spec ific immune possible. The first step is to treat the deposits of IgM, C3 and fibrin at these sites. suspected infectious disease or to However, signs can be variable and discontinue the casual drug. Mild cases of immunostaining is not specific for erythema multiforme do not require 13,14,15 treatment. Some of the drugs which ca n be EM. In patients who have target 17, 18 lesions with a preceding or coexisting HSV used in its treatment are infection, the diagnosis can be made easily • Oral antihistamines - used to provide Laboratory tests (e .g., HSV -1 & 2, symptom relief. immunoglobulin M and G) may confirm a • Topical steroids - used to provide suspected history of HSV infection .16 symptom relief. • Antiviral drugs -oral acyclovir Differential Diagnosis • (Zovirax), topical acyclovir, Autoimmune bullous diseases Valacyclovir, famciclovir • • Prednisone • Figurate erythema • Oral antacid may be helpful for discrete • oral ulcers. • Pityriasis rosea • Liquid antiseptics, such as 0.05% • Polymorphic light eruption chlorhexidine.

45

Bajaj P et al. Erythema Multiforme.

Prognosis: Depending on the severity, the clinical system has been developed to correlate course of SJS and TEN may last up to a few mortality with selected parameters (Table weeks. A SCORTEN prognostic scoring III). 19

Table III: Showing SCORTEN prognostic scoring system

Prognostic factors Points SCORTEN Mortality Rate Age > 40 1 0-1 3.2%

Heart rate >120/min 1 2 12.1%

Cancer or haematologic 1 3 35.8% malignancy

>10% body surface area 1 4 58.3%

Serum urea >10mm/L 1 >5 90%

Serum bicarbonate<20mm/L 1

Serum glucose >14mm/L 1

References:

1.Farthing P, Bagan JV, Scully C. Mucosal 6.keratinocytes in vivo and induction of disease series. Number IV. Erythema apoptosis in cultured keratinocytes. J multiforme. Oral Dis 2005; 11: 261–7. Invest Dermatol 1994; 103: 330–4. 2.Williams PM, Conklin RJ. Erythema 7.Al-Johani et al. Erythema multiforme and multiforme: a review and contrast from related disorders. OOOE 2007;103: 642- Stevens–Johnson syndrome/toxic 54. epidermal necrolysis. Dent Clin North 8.John A. Kazmierowski and Kirk D. Am 2005; 49: 67–76. Wuepper. Erythema Multiforme: Clinical 3.Ayangco L and Rogers RS III. Oral Spectrum and Immunopathogenesis. manifestations of erythema multiforme. Springer Semin. Immunopathol. 1981; Dermatol Clin 2003; 21: 195–205. 4:45~-53. 4.Iwai K, Miyawaki T, Takizawa T et al. 9.Michele R. Lamoreux, Marna R. Differential expression of bcl-2 and Sternbach, and W. Teresa Hsu. Erythema susceptibility to anti-Fas-mediated cell Multiforme. American Family Physician death in peripheral blood lymphocytes, 2006; 74: 65-8. monocytes, and neutrophils. Blood 1994; 10. Ackerman AB, Penneys NS, Clark WH, 84: 1201–8. Jr. Erythema multiforme exudativum: 5.Sayama K, Yonehara S, Watanabe Y, Distinctive pathological process. Br J Miki Y. Expression of Fas antigen on Dermatio 1971; 84:554. 11. MacVicar DN, Graham JH, Burgoon CF. Dermatitis herpetiformis, erythema

46

Bajaj P et al. Erythema Multiforme.

multiforme and butlous pemphigoid: A characteristics, diagnostic criteria, and comparative histological and causes. J Am Acad Dermatol 1983; histochemical study. J Invest Dermatol 8:763–75. 1963; 41:289. 17. Aslanzadeh J, Helm KF, Espy MJ, 12. Pierard J, Whimster t. The Muller SA, Smith TF. Detection of HSV- histopathological diagnosis of dermatitis specific DNA in biopsy tissue of patients herpetiformis, bullous pemphigoid and with erythema multiforme by polymerase erythema multiforme. Br J Dermatol chain reaction. Br J Dermatol 1992; 1961: 73:253. 126:19–23. 13. Orfanos CE, Schamburg-Lever G, 18. Goldberg LH, Sperber J. Erythema Lever WF. Dermal and epidermal types multiforme due to herpes simplex: of erythema multiforme. Arch Dermatol treatment with oral acyclovir. South Med 1974; 109:682. J 1986; 79:757-9. 14. Bagot M, Charue D, Heslan M, 19. Engelhardt SL, Schurr MJ, Helgerson Wechsler J, Roujeau JC, Revuz J, et al. RB. Toxic epidermal necrolysis: an Impaired antigen presentation in toxic analysis of referral patterns and steroid epidermal necrolysis. Arch Dermatol usage. J Burn Care Rehabil 1997; 1993; 129:721–7. 18:520–4. 15. Crispian Scully, Jose Baganb. Oral 20. Bastuji-Garin S, Fouchard N et al: mucosal diseases: Erythema multiforme. SCORTEN: a severity-of-illness score for British Journal of Oral and Maxillofacial toxic epidermal necrolysis. J Invest Surgery2008;46: 90–5. Dermatol 2000; 115:149-153. 16. Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a critical review of

Source of support: Nil Conflict of interest: None declared

47