What is the cause of erythema multiforme ?

 ERYTHEMA MULTIFORME :

Erythema multiforme (EM) is a skin condition that appears with red patches evolving into target lesions typically on both hands.

It is a type of erythema possibly mediated by deposition of immune complexes (mostly IgM-bound complexes) in the superficial microvasculature of the skin and oral mucous membrane that usually follows an infection or drug exposure. It is an uncommon disorder, with peak incidence in the second and third decades of life. The disorder has various forms or presentations, which its name reflects (multiforme, "multiform", from multi- + formis). Target lesions  are a typical manifestation. Two types, one mild to moderate and one severe, are recognized (erythema multiforme minor and erythema multiforme major). Erythema multiforme was first described by von Hebra in 1860.

Erythema multiforme is an immune-mediated, typically self-limiting, mucocutaneous condition characterised by ‘target’ lesions. Significant mucosal involvement distinguishes erythema multiforme major from multiforme minor. Episodes can be isolated, recurrent, or persistent.

In most cases, erythema multiforme is precipitated by herpes simplex virus (HSV) infection; alternative triggers include other infections, medications, and vaccinations. Classic ‘target’ lesions present as concentric rings of colour variation which develop symmetrically in an acral distribution, with or without involvement of mucous membranes.

WHAT ARE THE SIGN AND SYMPTOMS OF ERYHTEMA  MULTIFORME ?

The condition varies from a mild, self-limited rash (E. multiforme minor) to a severe, life-threatening form known as erythema multiforme major (or erythema multiforme majus) that also involves mucous membranes. Consensus classification: Erythema multiforme minor—typical targets or raised, edematous papules distributed acrally

• Erythema multiforme major—typical targets or raised, edematous papules distributed acrally with involvement of one or more mucous membranes; epidermal detachment involves less than 10% of total body surface area

Stevens–Johnson syndrome and toxic epidermal necrolysis used to be considered part of the erythema multiforme spectrum, but that is no longer the case.

The mild form usually presents with mildly itchy (but itching can be very severe), pink-red blotches, symmetrically arranged and starting on the extremities. It often takes on the classical "target lesion" appearance, with a pink-red ring around a pale center. Resolution within 7–10 days is the norm.

Individuals with persistent (chronic) erythema multiforme will often have a lesion form at an injury site, e.g. a minor scratch or abrasion, within a week. Irritation or even pressure from clothing will cause the erythema sore to continue to expand along its margins for weeks or months, long after the original sore at the center heals.

WHAT ARE THE CAUSES OF ERYTHEMA MULTIFORME  ?

EM minor is regarded as being triggered by HSV in almost all cases. A herpetic etiology also accounts for 55% of cases of EM major. Among the other infections, Mycoplasma infection appears to be a common cause.

Herpes simplex virus suppression and even prophylaxis  has been shown to prevent recurrent erythema multiforme eruption.

Many suspected etiologic factors have been reported to cause EM.

• Infections: bacterial (including Bacillus Calmette–Guérin (BCG) vaccination, haemolytic Streptococci, legionellosis, leprosy, Neisseria meningitidis, Mycobacterium, Pneumococcus, Salmonella species, Staphylococcus species, Mycoplasma pneumoniae), chlamydial.
• Fungal (Coccidioides immitis)
• Parasitic (Trichomonas species, Toxoplasma gondii),
• Viral (especially Herpes simplex)
• Drug reactions, most commonly to: antibiotics (including, sulphonamides, penicillin), anticonvulsants (phenytoin, barbiturates), aspirin, modafinil, antituberculoids, and allopurinol and many others.
• Physical factors: radiotherapy, cold, sunlight
• Others: collagen diseases, vasculitides, non-Hodgkin lymphoma, leukaemia, multiple myeloma, myeloid metaplasia, polycythemia

HOW IS A ERYTHEMA MULTIFORME DIAGNOSIS ?

Diagnosis is often made based on history and clinical examination.

Where there is doubt about the diagnosis, consider:

• Complete blood examination
• Liver functions tests
• ESR
• Serological testing for infectious causes
• Chest x-ray.

Skin biopsy with histopathology and direct immunofluorescence can be non-specific but helps to distinguish erythema multiforme from other more serious differentials, such as autoimmune blistering diseases. Upper dermal oedema and individual epidermal keratinocyte necrosis are suggestive pathological features. 

All patients with recurrent erythema multiforme should be tested for herpes simplex virus, including sampling of skin or mucosal lesions. In recurrent or persistent erythema multiforme without a clear precipitant, consider work up for solid organ or haematological malignancies. 

HOW TO TREAT  ERYTHEMA MULTIFORME ?

Erythema multiforme is frequently self-limiting and requires no treatment. The appropriateness of glucocorticoid therapy can be uncertain, because it is difficult to determine if the course will be a resolving one . Treatment is often not needed as episodes are typically self-limiting with no ongoing complications. However, ocular involvement should always prompt ophthalmology referral given the risk for more serious sequelae.

Treatment of symptomatic mild cases:

• Itch — oral antihistamines and/or topical steroids for itch or discomfort associated with cutaneous lesions
• Pain —  for mild mucosal involvement, oral washes containing antiseptic or local anaesthetic.

Other treatments are dependent on cause:

• Precipitating infections — treat appropriately (note treatment of HSV does not significantly alter the course of single episode erythema multiforme)
• Offending medications — cease and avoid in future.

Severe mucosal disease:

• May require hospital admission for support of oral intake
• Although evidence is limited, prednisone has been suggested to reduce the severity and duration of symptoms in these cases.

Recurrent disease:

• At least 6 months of continuous oral antiviral therapy (typically acyclovir/aciclovir), even if a clear cause has not been identified
• Remission can be difficult to achieve; may require trial of more prolonged therapy or alternative antiviral.
• Other systemic agents used (with variable evidence) for antiviral-resistant cases include azathioprine, dapsone, mycophenolate mofetil, and antimalarials.