NEWSLETTER 20: ERYTHEMA MULTIFORME AND STEVENS-JOHNSON SYNDROME

Most cases of SJS are caused by an ADR (Adverse Drug Reaction). While doctors strive to prevent and/or minimize any ADR, they do happen with great frequency. This can lead the provider into complacency. To avoid a medical malpractice action doctors must vehemently pursue all ADRs as quickly as possible with special attention to rashes that may be the beginning of SJS.

What are erythema multiforme and Stevens-Johnson syndrome?
Erythema multiforme (E. multiforme) is a rash that can range from spots to sores. When severe, the condition is called Stevens-Johnson syndrome. In this severe form you have sores over much of your body and you feel sick.

How does erythema multiforme occur?
E. multiforme usually occurs as a reaction to:

• infections, such as infections caused by the herpes simplex virus
• some medicines, such as sulfa drugs and the seizure medicine phenytoin (Dilantin).

What are the symptoms?
The first symptom is red spots on the skin, especially on the backs of the arms and the fronts of the legs. The hands and feet also usually have spots. Sometimes the spots are flat, red patches, and sometimes they are raised bumps. They may look like targets with a red center, a lighter area around the red center, and then a red outer ring. The rash can also be on the inside of the mouth and in genital areas. Usually the rash does not itch.

In Stevens-Johnson syndrome the rash worsens and spreads. Sometimes the rash becomes blisters. It can cause large areas of skin to peel and be like a burn. You also have symptoms of serious illness, such as fever, chills, headache, and fatigue. Stevens-Johnson syndrome can be severe, even fatal.

How is it diagnosed?
Your health care provider will ask about your recent medical history, including what infections you have had and what medicines you have been taking. Your provider will ask about your symptoms and examine you.

Usually your health care provider can diagnose E. multiforme by looking at the rash. The only way to confirm the diagnosis is with a skin biopsy. If you have a biopsy, you will be given a numbing medicine and then your provider will remove a small piece of skin (skin biopsy). The skin sample will be sent to a lab for tests.

Your health care provider will try to determine the cause so it can be treated, if possible. It is helpful to know the cause because E. multiforme can be recurrent. Preventing the cause may prevent E. multiforme from occurring again. For example, you may need to avoid certain medicines or treat some infections, such as herpes outbreaks, as soon as the first symptoms appear. However, sometimes it is difficult to find the cause.

How is it treated?
Mild cases are treated with anti-inflammatory, or steroid, creams. Sometimes health care providers prescribe steroid tablets, such as prednisone, to take by mouth. If the rash has become infected by bacteria on the skin, you will need to take an antibiotic.

In more severe cases, especially Stevens-Johnson syndrome, you may need to stay in the hospital. There you will be given fluids and anti-inflammatory medicine intravenously (IV). You will also be given pain medicine. You may need antibiotics.

When the underlying cause of E. multiforme is known, treating the cause is part of treating the E. multiforme. For example, if a herpes infection is the cause, the infection must be treated. If a medicine may be the cause, you will need to stop taking the medicine.

How long will the effects last?
The rash or bumps may last up to a few weeks. Sometimes it comes and goes, even several times a year. It can come and go over several years.

You may have complications, such as scarring and infection. If the rash has caused sores in your eyes, your vision could be permanently damaged.

How can I help prevent erythema multiforme?
E. multiforme is an uncommon reaction that cannot be predicted. This makes it difficult to prevent. However, recurrences can sometimes be prevented if the cause is known and can be avoided or treated early. For example, you may need to avoid certain medications or treat infections such as herpes as soon as symptoms appear.

Erythema multiforme
Erythema multiforme is a hypersensitivity reaction associated with infectious agents and medications. Fifty percent of all cases of erythema multiforme are thought to be drug-induced. The mechanism is not completely defined, but is thought to be a lymphocyte cell-mediated mechanism. The development of cutaneous lesions in erythema multiforme usually begins symmetrically from the distal extremities, progressing proximally. Initial involvement is typically seen on the palms, soles, and dorsal aspects of the hands and feet. The distinctive iris or target lesions have dusky centers and pink-to-red peripheries. The size and morphology can be variable; however, a single morphology is usually present in an individual patient. The skin manifestations typically occur 1 to 2 weeks after exposure to the drug. Multiple drugs have been associated with erythema multiforme. The most common ones include sulfonamides, penicillins, NSAIDs, hydantoins, phenothiazines, and barbiturates. Re-challenge with the medication usually results in a return of the erythema multiforme. The time course for erythema multiforme is typically 4 weeks if there is no progression to erythema major/Stevens-Johnson syndrome/TEN.

Management of erythema multiforme includes stopping the offending medication and ruling out infectious causes such as herpes simplex virus infections or Mycoplasma pneumoniae. It is difficult to predict when and if erythema multiforme will progress to erythema major/Stevens-Johnson syndrome. The patient should be watched closely for progression of the lesions. The use of systemic corticosteroids is controversial. There is no clear evidence that such use will prevent the progression of lesions, and the drugs may immunosuppress the patient.

Erythema multiforme major/Stevens-Johnson syndrome/toxic epidermal necrolysis
Erythema multiforme major, Stevens-Johnson syndrome, and TEN are thought to be similar disorders of varying severity of erythema multiforme. Erythema multiforme major is characterized by target and bullous lesions involving the extremities and mucous membranes. Stevens-Johnson syndrome features confluent purpuric macules on the face and trunk and severe mucosal erosions, usually at more than one mucosal site. This appearance is accompanied by severe constitutional symptoms and high fever. TEN is also associated with bullous lesions, mucosal involvement, and skin detachment. TEN and Stevens-Johnson syndrome are distinguished by the amount of skin detachment, which is less than 10% in Stevens-Johnson syndrome and more than 30% in TEN. Epidermal detachment between 10% and 30% is considered an overlap of Stevens-Johnson syndrome and TEN.

Approximately 50% of cases of Stevens-Johnson syndrome and 80% of cases of TEN are drug induced. More than 100 drugs have been associated with Stevens-Johnson syndrome and TEN. The medications with the highest relative risk are sulfonamides, Beta-lactam antibiotics, imidazole agents, and NSAIDs. Drugs in the moderate risk category include quinolones, aromatic anticonvulsants, and allopurinol. The treatment of Stevens-Johnson syndrome remains controversial. In some cases, the use of corticosteroids has been associated with delayed recovery, whereas in other studies, they have been found to be of benefit. Otherwise, management is geared toward symptom relief. Antihistamines can be used for pruritus, and cutaneous blisters can be treated with cool wet Burow's solution compresses. Papules and plaques can be treated with topical steroids, but topical steroids should not be applied to eroded areas. Ocular involvement should be monitored by an ophthalmologist.

In contrast, most authorities recommend that corticosteroids not be used in the management of TEN . Because of the similar pathophysiology to burn injury, treatment is best conducted in a multidisciplinary burn center. Intensive treatment includes temporary skin substitutes, fluid and electrolyte monitoring, internal alimentation, infection control, and pain management. In small studies, cyclophosphamide, cyclosporine, plasma exchange, and plasmapheresis have produced an improvement in symptoms. More recently, intravenous immunoglobulin has been shown to lead to marked clinical improvement in TEN by inhibiting Fas-mediated keratinocyte cell death by blocking the Fas receptor.

Sincerely:

Joseph Saponaro, MD, DABIM, FACP, CPI, CCI, CCTI, CCRC, CCRP
Member, ACFEI (American College of Forensic Examiners Institute of Forensic Science)
Expert Medical Witness, ExpertMD
PI (Principal Investigator), DSI (Drug Study Institute)
Board Certified Internist, JPMC (Jupiter Preventive Medicine Center)
DABIM (Diplomat American Board of Internal Medicine)
FACP (Fellow American College of Physicians)
CPI (Certified Physician Investigator) by the APPI (American Academy of Pharmaceutical Physicians)
CCTI (Certified Clinical Trial Investigator) by the ACRP (Association of Clinical Research Professionals)
CCI (Certified Clinical Investigator) by the DIA (Drug Information Association)
CCRC (Certified Clinical Research Coordinator) by the ACRP (Association of Clinical Research Professionals)
CCRP (Certified Clinical Research Professional) by SoCRA (Society of Clinical Research Associates)
Member, SIMPD (Society for Innovative Medical Practice Design)
Member, ACPM (American College Preventive Medicine)
Ethics Committee Member, Jupiter Medical Center
IRB Member, Jupiter Medical Center
Founder, CertifiedResearchers.com