Mucocutaneous exfoliative disease
Staphylococcal scalded skin syndrome
Generalized exfoliative disease
Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a severe skin reaction most often triggered by particular medications. Although Stevens-Johnson syndrome and toxic epidermal necrolysis were once thought to be separate conditions, they are now considered part of a continuum. Stevens-Johnson syndrome represents the less severe end of the disease spectrum, and toxic epidermal necrolysis represents the more severe end.
These disorders are differentiated by the degree of skin detachment. The consensus definition published in 1993 states that SJS affects less than 10% of the body surface area; TEN affects more than 30% of the body surface area. The intermediate form, with 10 to 30 percent body surface area involvement, is called "SJS/TEN." Although there was initially debate about whether TEN and SJS fall on a spectrum of disease that includes erythema multiforme (EM), they are now considered separate conditions.
The reaction may start with a persistent fever and nonspecific, flu-like symptoms followed by appearance of erythematous macules (red spots) that may cover a large part of the body, and painful blistering of the skin and mucous membranes. The eyes are often involved. Numerous drugs have been reported to cause SJS and TEN and the following have shown an increased risk in larger studies: antibacterial sulfonamides, non-steroidal anti-inflammatory drugs of the oxicam type, certain anti-seizure drugs (antiepileptics), allopurinol and nevirapine. However, approximately one quarter (25%) of cases are not caused by drugs, but potentially by infections or have to be considered as idiopathic (of unknown cause).
Individuals suspected of SJS or TEN should immediately stop taking the offending drug if it is known and all nonessential medications if it is not. Prompt recognition and early treatment are essential. It is also important to note that these disorders represent a spectrum of disease ranging from mild cases to those with severe, life-threatening complications. Consequently, every case is unique and the description of symptoms below will not apply to all individuals.
Subdivisions of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis:
- Stevens-Johnson Syndrome (SJS)
- Toxic Epidermal Necrolysis (TEN)
SJS/TEN often begins with a fever and flu-like symptoms. Within a few days, the skin begins to blister and peel, forming very painful raw areas called erosions that resemble a severe hot-water burn. The skin erosions usually start on the face and chest before spreading to other parts of the body. In most affected individuals, the condition also damages the mucous membranes, including the lining of the mouth and the airways, which can cause trouble with swallowing and breathing. The painful blistering can also affect the urinary tract and genitals. SJS/TEN often affects the eyes as well, causing irritation and redness of the conjunctiva, which are the mucous membranes that protect the white part of the eye and line the eyelids, and damage to the clear front covering of the eye (the cornea).
Severe damage to the skin and mucous membranes makes SJS/TEN a life-threatening disease. Because the skin normally acts as a protective barrier, extensive skin damage can lead to a dangerous loss of fluids and allow infections to develop. Serious complications can include pneumonia, overwhelming bacterial infections (sepsis), shock, multiple organ failure, and death. About 10 percent of people with Stevens-Johnson syndrome die from the disease, while the condition is fatal in up to 50 percent of those with toxic epidermal necrolysis.
Among people who survive, long-term effects of SJS/TEN can include changes in skin coloring (pigmentation), dryness of the skin and mucous membranes (xerosis), excess sweating (hyperhidrosis), hair loss (alopecia), and abnormal growth or loss of the fingernails and toenails. Other long-term problems can include impaired taste, difficulty urinating, and genital abnormalities. A small percentage of affected individuals develop chronic dryness or inflammation of the eyes, which can lead to increased sensitivity to light (photophobia) and vision impairment.
An abnormal reaction to various medications are the cause of most cases of SJS and TEN. Approximately 75% of SJS and TEN cases are caused by medications, but this percentage varies according to age, with a higher percentage in adults and a lower percentage in children. The drugs most commonly associated with these disorders include antibacterial sulfa drugs, anti-epileptics including phenytoin, carbamazepine, lamotrigine, and phenobarbital; allopurinol, a drug commonly used to treat gout or kidney stones; nonsteroidal anti-inflammatory drugs (NSAIDs) of the oxicam such as piroxicam, and nevirapine. Drug groups with a much lower, but still substantial risk are antibiotics and NSAIDs of the acetic acid type such as diclofenac.
Less often, infections, especially bacterial or viral infection can cause SJS or TEN. A bacterial infection known as Mycoplasma pneumoniae has been linked to these disorders. However, more frequently unspecific viral infections affecting the airways have been observed with SJS and TEN. Individuals with human immunodeficiency virus, vaccination or who have graft-versus-host disease can also develop the disorders. In other cases, no underlying cause can be identified (idiopathic cases).
Most likely, SJS and TEN develop due to multiple factors (multifactorial) including various genetic, environmental, and immunologic factors. Individuals may have a genetic predisposition to developing these disorders. A genetic predisposition means an individual carries a gene (or genes) for a disorder, but it may not be expressed unless it is triggered or "activated" under certain circumstances, such as due to particular environmental factors. Researchers have determined that certain Asian populations have a particular genetically-determined human leukocyte antigen or HLA types. HLAs are proteins that play an important role in the body's immune system. HLA B*1502 appears to convey a risk of developing these disorders in persons of Chinese or Southeast Asian ancestry when taking the drug carbamazepine.
In recent years, additional HLA associations have been identified, including HLA B*3101 and HLA B*1511 with carbamazepine, although not restricted to SJS and TEN and more likely relevant for milder types of cutaneous adverse reactions; HLA B*5801 with allopurinol (mainly in Chinese but also in 55% of Europeans with SJS/TEN); HLA B*38 with sulfamethoxazole or lamotrigine; and HLA B*73 with oxicam-NSAIDs. The exact role these HLAs play in the development of SJS and TEN is not fully understood.
The exact, underlying mechanisms that lead to the symptoms of SJS and TEN are not fully understood. It is unknown how individual drugs specifically cause the symptoms of the disorder. Researchers believe that the immune system intervenes in the process of breaking down (metabolizing) the drug to which the body is reacting. The improper immune response against the drug results in damage to healthy cells of the body. Keratinocytes, which are the precursor cells that develop into skin cells, are affected in these disorders and are destroyed during the disease process. Keratinocytes are the major cell of the outer layer of the skin (epidermis) and they stick (adhere) together to form the barrier that is the epidermis and they serve as an anchor to the underlying skin layer (dermis). One theory suggests that improper activation of certain white blood cells (T-cells) ultimately leads to keratinocyte death (apoptosis) although the exact method how is unknown. Keratinocyte death, in turn, causes the epidermis to become damaged and pull away (detach) from the underlying layers of the skin. Certain substances that are known to regulate (mediate) cell death such as FasL, granulysin, and annexin A1 have also been proposed as possible playing a role in the development of SJS and TEN. Studies have shown that granulysis is the most important molecule in widespread keratinocyte death.
Recent studies have also indicated other factors that may contribute to keratinocyte death such as perforin/granzyme B, nitric oxide, tumor necrosis factor-alfa, and highly reactive molecules known as reactive oxygen stress. Research is ongoing to determine the underlying mechanisms that occur in the development of these disorders.
Individuals who have a history of SJS or TEN due to a specific medication must avoid the causative drug and any potential cross-reacting medications.
A diagnosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a skin biopsy. The appearance of the lesions and their rapid progression may enable a physician to make a diagnosis of SJS or TEN. In all cases, a skin biopsy, in which a tiny piece of affected skin is removed and studied under a microscope, should be performed. A biopsy can reveal the layer of skin blistering (subepidermal in SJS/TEN) and dead (necrotic), thickened epithelial tissue, which is indicative of SJS and TEN.
A skin biopsy is crucial and should always be performed. Whether a skin biopsy for immunofluorescence test is done may be decided in each case individually, although it is highly recommended. An immunofluorescence test uses antibodies chemically linked to fluorescent dyes to identify or quantify antigens in a tissue sample and is used to rule out other conditions.
A disease severity scoring system called SCORTEN (Score of TEN) has been established to help physicians assess the severity of illness in people with SJS and TEN. This scoring system includes seven distinct factors: age; malignancy; percentage of body surface area detached; heart rate, serum urea; serum glucose; and serum bicarbonate levels. For each prognostic factor that is present in an affected individual, one point is scored. The more points a patient has, the higher is the risk of fatality.
The mortality for toxic epidermal necrolysis is 25-30%. Loss of the skin leaves patients vulnerable to infections from fungi and bacteria, and can result in sepsis, the leading cause of death in the disease. Death is caused either by infection or by respiratory distress which is either due to pneumonia or damage to the linings of the airway. Microscopic analysis of tissue (especially the degree of dermal mononuclear inflammation and the degree of inflammation in general) can play a role in determining the prognosis of individual cases.
Treatment is primarily symptomatic and supportive and may require the coordinated efforts of a team of specialists. Pediatricians, dermatologists, ophthalmologists, urologists, and other healthcare professionals may need to systematically and comprehensively plan an affect individual's treatment. Psychosocial support for the entire family is essential as well. Prompt recognition and treatment of these disorders is critical. Treatment may require a highly specialized skin (dermatological) center. Severe cases with large areas of skin detachment and high SCORTEN values may require treatment in an ICU or burn-care center.
In cases caused by drug hypersensitivity, immediately stopping and avoiding the offending medication(s) is required. In some cases, determining which medication is causing the reaction may be difficult. If the offending medication is unknown, all suspected and unnecessary medications should be stopped. Generally, the earlier the offending drug is removed, the better the overall prognosis. In case of infection being identified as the most likely cause, this has to be treated appropriately.
Fluid replacement with electrolytes is critical and should be administered immediately. Blood products and supplemental nutrition are given as needed. Topical care can include antiseptic solutions or ointments that act as disinfectants, including chlorhexidine, octenisept, polyhexanide, or silver nitrate. Silver sulfadiazine is not recommended. Affected individuals must be monitored for infection and antibiotics may be given to control infection. Protective (prophylactic) systemic antibiotic treatment is not recommended. Pain medications (analgesics) may be used.
Wound treatment should be conservative; aggressive surgical removal of affected skin (debridement), which is often performed at burn centers is not recommended. Intact blisters may serve as a protective "biologic" dressing. The use of non-adhesive dressings is helpful, especially in cases with large areas of skin detachment, e.g. Suprathel®.
The lips and mouth may require special care. Oral hygiene is necessary and a disinfectant mouthwash is beneficial Lips may be treated with appropriate ointments. In severe cases, affected individuals may not be able to eat, requiring the use of a gastric tube, which is a small thin tube inserted directly into the stomach through a small surgical opening, or a nasogastric tube.
Individuals with eye involvement should receive a consultation with an ophthalmologist as soon as possible. Treatment may require continued lubrication of the eyes, topical antibiotics, and surgically separating adhesions. Regular ophthalmologic care is needed by many patients on a daily or every-other-day basis. In recent years, the application of a cryopreserved amniotic membrane to the eyes and eyelids during the acute phase of these disorders has been effective in preventing some of the eye complications.