Erythema Multiforme


Article Author:
Wissem Hafsi


Article Editor:
Talel Badri


Editors In Chief:
William Gossman


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
5/2/2019 9:41:58 PM

Introduction

Erythema multiforme (EM) is a cutaneous and mucosal hypersensitivity reaction with characteristic lesions in target triggered by certain antigenic stimuli. It represents an acute condition, sometimes recurrent, of the skin and mucosal membranes manifested by papular, bullous, and necrotic lesions. Its causes are variable and numerous, and its evolution is generally favorable.[1][2][3][4]

Etiology

The etiology of EM is dominated by Herpes simplex virus (HSV) type 1 and 2 infections and Mycoplasma pneumoniae, but many other viral and bacterial infections have been implicated. More rarely, and in a more questionable way, vaccines have been incriminated.[5][6][7]

Epidemiology

EM is reported worldwide without any ethnic predilection. It occurs at any age, more frequently in young adults. The average age is between 20 and 30 years, and 20% of cases occur in children. It is more common in men with a sex ratio of 1 in 5. Prevalence is not known but appears to be well below 1%. As the classification is not always clear, cases of Stevens-Johnson syndrome (SJS) have frequently been included in studies on EM.

Pathophysiology

EM is often associated with viral or bacterial infections, especially HSV. Studies have demonstrated the presence of HSV-DNA by polymerase chain reaction in acute or sequellar EM lesions. The predisposing factors are unknown. HLA-DQ3 is reported to be associated with postherpetic EM and has been suggested as an additional diagnostic marker. Other human leukocyte antigen groups have also been reported as markers of the recurrent EM.

History and Physical

A fever and a feeling of general unease may precede and/or accompany the eruption the first days. Sometimes there is arthralgia or even joint swelling. 

Clinically, the typical lesion of the EM is the target, described as a rounded lesion that is regular with three concentric circles and a well-defined border. The peripheral ring is erythematous, sometimes microvesicular; the middle zone is often clearer, oedematous, and palpable, and the center is erythematous, covered by a blister. These different aspects evoke different stages of the evolving lesion.

The lesions measure less than 3 centimeters, and their location is mainly acral. They are symmetrical in the palms and backs of the hands, the feet, and the extended faces of the limbs. The trunk is often spared, but the face and ears can be reached. There is no pruritus, but rather sensations of burning in some patients.

Mucosal lesions are common, mostly in the mouth, but also in the genital and ocular mucous membranes. They are initially bullous, then quickly turn into painful erosions. Thick hemorrhagic crusts may cover the labial lesions, and a fibrin-whitish coating may line the mucosal erosions of the cheeks, palate, and genitalia. These mucosal lesions occur most often at the same time as the skin lesions but can be shifted a few days before or after the eruption of targets. While skin lesions are nonpainful, mucosal lesions are frequently painful.

Pulmonary signs may also be present, such as a cough and dyspnea. They testify to a respiratory attack most often related to the inducing infection of the EM (mainly due to Mycoplasma pneumoniae).

Evaluation

The diagnosis of EM is clinical. In case of doubt, a skin biopsy of the lesion center can be performed for histological study with immunofluorescence. It then shows an epithelial intercellular edema with keratinocyte necrosis responsible for an intra- or sub-epidermal blister covered with a necrotic epidermis. A peri-vascular lymphohistiocytic infiltrate is present in the superficial dermis without necrotic vascular lesion. Direct immunofluorescence is negative. The biological assessment provides no argument for the diagnosis of EM. However, it is useful to appreciate the severity of the disease. The chest x-ray may show interstitial radiological infiltrate (mainly in EM due to Mycoplasma pneumoniae). Renal, hepatic or hematologic lesions have also been described and are not systematically sought after in the mild forms.[8]

The etiological assessment must be adapted to the symptoms. In no case is an exhaustive report justified:

  • Herpes infection, mainly with HSV-1, is most frequently in the cause. This is most often a minor EM. Herpes lesions precede EM for a few days (7 to 10 days). In contrast, all herpes outbreaks are not accompanied by EM and some outbreaks of EM can be caused by asymptomatic herpes recurrences. Viral research is often negative at the moment of the diagnosis. In the case of a recurrence of EM, a herpes origin must be suspected. It is observed in 70% of cases of recurrent EM. In clinical practice, the diagnosis of the herpes origin is mainly based on the anamnesis.
  • Mycoplasma pneumoniae should be systematically sought for treatment in children. EM complicates 2% to 10% of infections with Mycoplasma pneumoniae in children and most often has a mucosal involvement. It is responsible for about two-thirds of EM with mucosal involvement. It is advisable to systematically perform a chest x-ray in addition to bacteriological research, if possible by gene amplification (PCR). 
  • Other viral (adenovirus, influenza, Epstein Barr, hepatitis virus, Coxsackie, parvovirus B19, human immunodeficiency virus) and bacterial (tuberculosis, streptococci) infections were incriminated.

EM cases have been attributed to some pediatric vaccines. The link is frequently controversial with regard to a large number of vaccines and the rarity of this association.

Treatment / Management

Treatment of the Acute Phase

  • Topical treatment is based on antiseptics for bullous lesions, antiseptic mouthwashes, and anesthetic. Ocular involvement is managed by ophthalmologists. Healing is promoted by the application of vaseline on the lips and vitamin A ointment on the eyes.
  • General treatment is used in cases of general statehood and dietary difficulty, requiring hospitalization to treat the pain, hydrate, or even re-enter the patient. The place of systemic corticosteroids and intravenous immunoglobulins has been discussed without demonstrating its effectiveness. Daily monitoring is necessary in cases of extensive lesions.
  • Etiological treatment must be instituted when a cause is identified (or sometimes probable). Mycoplasma pneumoniae infection justifies treatment with azithromycin for three days without even waiting for the results of the bacteriological examinations, especially if there is a cough or pulmonary radiological abnormalities. Some suggest treating herpes with aciclovir or valaciclovir if herpes is suspected although this has not shown its interest.

Prevention of Recurrent EM Form

  • It is in the majority of the cases of herpes origin. Even if the evidence has not been established by specimens, long-term treatment with aciclovir or valaciclovir should be proposed. 
  • It is indicated, in theory, above 5 EM outbreaks per year or fewer in the case of EP severe forms. Valaciclovir treatment prevents HSV-induced EM outbreaks but appears to have no impact on an EM outbreak if it was started after the beginning of the eruption. 
  • If no germ is identified, other therapeutics may be proposed in the long term, such as hydroxychloroquine (Plaquenil), dapsone (Disulone) or early treatment of sprouts by systemic corticosteroids.[9][10][11]

Differential Diagnosis

Stevens-Johnson Syndrome (SJS): It affects up to 10% of the body surface area, a larger area than in EM. The mucosal involvement is similar. The cutaneous involvement differs from EM by the absence of typical targets and the predominantly axial disposition. The target-like lesions are asymmetrical and made of two concentric zones and purpuric evolution. A drug origin is most often involved, and the outcome is more severe since it can progress into a Lyell syndrome, unlike EM.

Staging

Erythema multiforme minor (EMm): It essentially touches the skin with typical lesions symmetrical acral disposition. The mucosal involvement is rare, and when it is present, it is light and affects a single mucosa, often the mouth.

Erythema multiforme major (EMM): The skin lesions are more extensive, but they do not exceed 10% of the body surface area. Typical target lesions are present. The mucosal involvement is severe, and affects at least two different mucosal sites; the oral mucosa typically affected.

Prognosis

The prognosis is mainly related to the body surface area detached. The healing is obtained spontaneously in 2 to 3 weeks for the EMm and in 4 to 6 weeks in the EMM. The mucosal lesions always take longer to heal. The healing of the mucocutaneous lesions is without scarring, but with frequent dyschromia. Recurrences are seen in less than 5% of cases, mainly in forms due to herpes infection.

The main long-term risk is the development of synechias in case of mucosal involvement. Ocular sequelae can be serious, leading to blindness. At the genital level, synechiae can produce functional sequels.

Particular vigilance during the acute episode must be put in place to prevent these sequels. The vital prognosis is only exceptionally brought into play when the care is adapted. Two situations deserve particular vigilance are (1) severe mucosal involvement and (2) bacterial superinfections.

Enhancing Healthcare Team Outcomes

The management of EM is multiforme. While the diagnosis is often made by the dermatologist, the follow up of these patients is with the primary care provider and nurse practitioner. In general, supportive care will suffice in most patients. Patients need to be educated about general skin care. Once the primary condition is managed, EM resolves. However, time to healing may take weeks or even months. Particular vigilance during the acute episode must be put in place to prevent these sequels. The vital prognosis is only exceptionally brought into play when the care is adapted. Two situations deserve particular vigilance are (1) severe mucosal involvement and (2) bacterial superinfections. [12](Level V)


  • Image 5931 Not availableImage 5931 Not available
    Contributed by Talel Badri
Attributed To: Contributed by Talel Badri

Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Erythema Multiforme - Questions

Take a quiz of the questions on this article.

Take Quiz
What organism most commonly induces erythema multiforme?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which if the following is not associated with erythema multiforme?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following exanthems can be associated with mycoplasmal pneumonia?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What type of reaction is erythema multiforme?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is the least likely cause of erythema multiforme?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A patient with pharyngitis is started on penicillin for streptococcal pharyngitis. A few days later he develops multiple skin lesions on his forearms and hands. There is no mucosal involvement. The lesions are symmetrical, red, and have pale vesicular centers. A biopsy shows dermal inflammation, edema, epidermal necrosis, and spongiosis. What is the most probable diagnosis?

(Move Mouse on Image to Enlarge)
  • Image 234 Not availableImage 234 Not available
    Contributed by DermNetNZ
Attributed To: Contributed by DermNetNZ



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Target lesion with nonblanching center is a classic manifestation of which condition?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which is the most common cause of erythema multiforme?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A patient has "target" or "iris" lesions. What is the most likely diagnosis?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Erythema Multiforme - References

References

Fitzpatrick SG,Cohen DM,Clark AN, Ulcerated Lesions of the Oral Mucosa: Clinical and Histologic Review. Head and neck pathology. 2019 Jan 31;     [PubMed]
Magri F,Chello C,Pranteda G,Pranteda G, ERYTHEMA MULTIFORME: DIFFERENCES BETWEEN HSV-1 AND HSV-2 AND MANAGEMENT OF THE DISEASE - A CASE REPORT AND MINI REVIEW. Dermatologic therapy. 2019 Jan 28;     [PubMed]
de Risi-Pugliese T,Sbidian E,Ingen-Housz-Oro S,Le Cleach L, Interventions for erythema multiforme: a systematic review. Journal of the European Academy of Dermatology and Venereology : JEADV. 2019 Jan 25;     [PubMed]
Paulino L,Hamblin DJ,Osondu N,Amini R, Variants of Erythema Multiforme: A Case Report and Literature Review. Cureus. 2018 Oct 16;     [PubMed]
Hashemi DA,Carlos C,Rosenbach M, Herpes-Associated Erythema Multiforme. JAMA dermatology. 2018 Nov 21;     [PubMed]
Case of Erythema Multiforme Drug Eruption Induced by Ledipasvir/Sofosbuvir: Erratum. American journal of therapeutics. 2018 Nov/Dec;     [PubMed]
Trayes KP,Savage K,Studdiford JS, Annular Lesions: Diagnosis and Treatment. American family physician. 2018 Sep 1;     [PubMed]
La Placa M,Chessa MA, Erythema multiforme major with swollen lips and crusted erosions. Lancet (London, England). 2018 Aug 18;     [PubMed]
Lerch M,Mainetti C,Terziroli Beretta-Piccoli B,Harr T, Current Perspectives on Erythema Multiforme. Clinical reviews in allergy     [PubMed]
Dinulos JG, What's new with common, uncommon and rare rashes in childhood. Current opinion in pediatrics. 2015 Apr;     [PubMed]
Femiano F,Lanza A,Buonaiuto C,Gombos F,Rullo R,Festa V,Cirillo N, Oral manifestations of adverse drug reactions: guidelines. Journal of the European Academy of Dermatology and Venereology : JEADV. 2008 Jun;     [PubMed]
Dore J,Salisbury RE, Morbidity and mortality of mucocutaneous diseases in the pediatric population at a tertiary care center. Journal of burn care     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Adult Ambulatory-Medical Student. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Adult Ambulatory-Medical Student, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Adult Ambulatory-Medical Student, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Adult Ambulatory-Medical Student. When it is time for the Adult Ambulatory-Medical Student board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Adult Ambulatory-Medical Student.