Hospital Medicine

Erythema multiforme

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Erythema Multiforme

I. What every physician needs to know.

Erythema Multiforme (EM) is an acute usually self-limiting but occasionally recurrent dermatologic condition that is considered to be the result of a hypersensitivity reaction. The hallmark of the condition is target like lesions of the skin (including the palms and soles) with or without associated bullae or erosions. Traditionally, it is broken down into two categories based on severity. Erythema Multiforme minor describes patients with EM and little to no mucosal involvement while Erythema Multiforme major describes those patients with EM and mucosal involvement of the oral, genital and ocular mucosa.

II. Diagnostic Confirmation: Are you sure your patient has Erythema Multiforme?

The hallmark of the diagnosis of EM rests on the presence of the typical target lesions however atypical lesions can occur. Mucosal involvement in EM major most commonly will occur in the presence of cutaneous EM.

Diagnostic Criteria for Erythema Multiforme minor

  • Clinical Course

    • Acute, self-limited or episodic outbreak

  • Duration

    • Attack between days to weeks in evolution

  • Primary skin lesions

    • Symmetrically appearing discrete, round erythematous skin lesions lasting usually > 7 days in duration

    • Skin lesions have the presence of concentric color changes in at least some:

      • dusky central/necrotic area which is surrounded by pale edematous ring and a peripheral erythematous halo

  • Mucous membrane involvement

    • Absent or only limited to involvement of the oral mucosa

  • Skin biopsy/histopathology

    • Compatible results with primary mononuclear cell infiltrate with edema in the dermis and if bullae formed eosinophilic necrosis of the keratinocytes with subepidermal bullae

Diagnostic Criteria for Erythema Multiforme major

  • Clinical Course

    • Acute, self-limited or episodic outbreak

  • Duration

    • Attacks between days to weeks in evolution

  • Primary skin lesions

    • Symmetrically appearing discrete, round erythematous skin lesions lasting usually > 7 days in duration

    • Skin lesions have the presence of concentric color changes in at least some:

      • dusky central/necrotic area which is surrounded by pale edematous ring and a peripheral erythematous halo

  • Mucous membrane involvement

    • Absent or only limited to involvement of the oral mucosa

  • Skin biopsy/histopathology

    • Compatible results with a primary mononuclear cell infiltrate with edema in the dermis and if bullae formed eosinophilic necrosis of the keratinocytes with subepidermal bullae

A. History Part I: Pattern Recognition:

The most characteristic symptoms that occur in this disorder would include the following:

  • Acute development over days of erythematous papules on the skin, extremities, oral/genital or ocular mucosa

  • Skin lesions are often pruritic and painful

  • Lesions may become bullous or eroded

  • Associated symptoms might include fever, malaise or myalgias with pulmonary symptoms (cough, shortness of breath, sputum production) noted in patients with underlying Mycoplasma pneumoniae infection

  • Rarely ocular involvement may lead to painful red eye suggesting a secondary keratitis or conjunctivitis; the mucosa of the pharynx/larynx/esophagus or trachea can be involved with associated pain and risk for secondary pneumonia

B. History Part 2: Prevalence:

The majority of causes of EM are induced by acute or chronic infections (viral, bacterial, fungal) with acute herpes simplex virus (HSV) infections being the most common. Additionally, underlying malignancy, autoimmune disorders (Systemic Lupus Erythematosus, Behcet’s etc.), sarcoidosis, radiation treatment, menstrual abnormalities and importantly a large number of drugs and vaccines have all been linked to cases of EM.

Common drugs implicated in causing EM include the following classes of drugs: antibiotics, antiepileptics, sulfonamides and nonsteroidal anti-inflammatory drugs. Recurrent EM is most commonly associated with the presence of recurrent outbreaks of oral/genital HSV, however, it has been reported in association with other recurrent infection with Mycoplasma pneumoniae, vulvovaginal candidiasis, chronic hepatitis C and even autoimmune disorders like Systemic Lupus Erythematosus, Behcet’s.

C. History Part 3: Competing diagnoses that can mimic Erythema Multiforme.

Conditions that might mimic EM and how they can be differentiated from EM:

EM major

  • Stevens Johnson Syndrome (may present with mucosal involvement and atypical lesions on the skin, however, they are usually macular in nature with the most common cause being drugs)

  • Bullous Pemphigus (autoimmune blistering disorder that involves the skin and can involve the mucus membranes which can be differentiated from EM by autoimmune antibodies to hemidesmosomes and/or skin biospy)

  • Paraneoplastic Pemphigus (autoimmune blistering disorder associated with lymphoproliferative disorders like lymphoma, leukemia, Castleman's and others) that can resemble EM clinically but can be differentiated by the presence of autoimmune antibodies to plakin proteins and skin biopsy)

EM minor

  • Urticaria (acute erythematous pruritic plaques can resemble EM but characteristically last up to 24 hrs with new lesions appearing continuously over the outbreak time period)

  • Fixed drug eruptions (development of usually single or multiple erythematous plaques with or without necrosis or bullae in association with drug therapy which may be difficult to differentiate from EM but whose lesions characteristically develop post inflammatory hyperpigmentation and will redevelop in the same location/s on re-exposure to the culprit drug)

  • Sweet's syndrome (acute febrile neutrophilic dermatosis may present with erythematous and edematous plaques that might resemble lesions of EM but can be differentiated by skin biopsy histopathology revealing a dense neutrophilic infiltrate)

  • Systemic lupus erythematosus (development of EM like lesions in a patient with cutaneous lupus most characteristically differentiated by the clinical picture and presence of positive antinuclear antibody [ANA] antibodies)

D. Physical Examination Findings.

The most characteristic physical findings in EM include the following:

  • Typical target like lesions with associated concentric color zones, bullae and/or necrosis symmetrically on the skin (trunk, back, extremities or face), palms and/or soles with or without oral, genital and ocular mucosa involvement

  • Associated conjunctivitis and/or ciliary flush (indicating probably associated keratitis, uveitis or scleritis)

  • Associated oral and genital ulcerations (from EM itself or primary HSV if that is the trigger)

E. What diagnostic tests should be performed?

The diagnosis of EM rests primarily on the history and characteristic physical findings of the rash with or without its associated mucous membrane involvement. There is infrequently the need to do additional diagnostic tests unless there is diagnostic uncertainty and evaluation with additional serological and/or skin biopsy is necessary.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

There are no routine laboratory tests that are helpful to establish the diagnosis of Erythema Multiforme. Occasionally a case might require you to evaluate for precipitating acute or chronic infections or it might require specific serological testing for conditions like autoimmune blistering disorders with autoantibodies to hemidesmosomes or plakin proteins or to evaluate for possible Systemic Lupus Erythematosus with ANA testing.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

There are no helpful routine imaging tests that are that are helpful to establish the diagnosis of Erythema Multiforme.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

A number of tests are often over-utilized in the evaluation of a patient with Erythema Multiforme and they include the following:

  • Erythrocyte Sedimentation Rate (ESR)

  • C-Reactive Protein

  • Complement (C3, C4)

  • Liver enzyme tests (aspartate transaminase [AST], alanine transferase [ALT], Alkaline phosphatase, bilirubin)

III. Default Management.

The management of Erythema Multiforme requires the following four steps:

  1. Establish the severity of the presentation (Erythema Multiforme minor or major)

  2. Investigate for the possible underlying etiology

  3. Treat any potential life threatening etiology (i.e. Mycoplasma pneumoniae pneumonia or stop offending drug therapy)

  4. Treat any suspected secondary skin infections

  5. Refractory cases of recurrent Erythema Multiforme may require immunosuppressant treatment in consultation with Dermatology.

A. Immediate management.

After establishing the diagnosis, the most immediate management issue surrounds the need to treat life threatening underlying acute or chronic infection that might be manifesting with Erythema Multiforme or to stop any offending drug therapy that might have caused it. Patients with Erythema Multiforme major might have difficulty with taking in oral fluids and food and special attention should be paid to evaluate and manage their volume and nutrition status. All patients with suspected secondary bacterial infections superimposed on their Erythema Multiforme should receive appropriate skin antimicrobial therapy.

B. Physical Examination Tips to Guide Management.

The most important part of the physical examination to follow is the skin exam with a focus on associated pathology in the mucosa of the oral, genital or ocular areas.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

There is no particular set of laboratory tests that will need to be followed during the course of a patient's bout of Erythema Multiforme.

D. Long-term management.

Recurrent Erythema Multiforme associated with recurrent herpes simplex virus (HSV):

Patients with recurrent HSV associated Erythema Multiforme can be treated with secondary prevention with suppressive doses of acyclovir, famciclovir or valacyclovir to reduce both recurrent HSV and Erythema Multiforme development.

E. Common Pitfalls and Side-Effects of Management.

N/A

IV. Management with Co-Morbidities.

N/A

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure.

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management.

E. Diabetes or other Endocrine issues.

No change in standard management.

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

No change in standard management.

J. Hematologic or Coagulation Issues.

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment.

No change in standard management.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

No specific sign-out considerations.

B. Anticipated Length of Stay.

Anticipated length of stay is variable depending on the severity of presentation and underlying etiology.

C. When is the Patient Ready for Discharge.

If hospitalized patients with Erythema Multiforme are appropriately ready for discharge when:

  • Treatment of the underlying cause has been successful (i.e. Mycoplasma pneumoniae pneumonia better, offending drug removed)

  • Erythema Multiforme improving

D. Arranging for Clinic Follow-up.

No special instructions.

1. When should clinic follow up be arranged and with whom.

Patients with Erythema Multiforme should have follow-up arranged after hospital discharge based on the etiology and severity of their presentation:

  • General Internal Medicine/Family Medicine within 1-2 weeks of discharge

  • Dermatology if undiagnosed recurrent Erythema Multiforme in 1 month of discharge

  • Ophthalmology if developed EM associated conjunctivitis, scleritis, uveitis or keratitis in 1- 2 weeks

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

None

E. Placement Considerations.

None

F. Prognosis and Patient Counseling.

None

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Appropriate skin hygiene to prevent secondary infection.

VI. What's the Evidence?

Schofield, JK, Tatnall, FM, Leigh, IM. "Recurrent erythema multiforme: clinical features and treatment in a large series of patients". British Journal of Dermatology. vol. 128. 1993. pp. 542-5.

Lamoreux, Michele, R, Sternbach, Marna, R, Hsu, Teresa, W. "Erythema Multiforme". American Family Physician. vol. 74. 2006. pp. 1883-8.

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