Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent opposite ends of a spectrum of disease that results from an adverse reaction, most often to certain medications. SJS is the less severe end, but still represents a serious condition and potential medical emergency. TEN is a severe, life-threatening disorder. 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 term SJS/TEN-overlap syndrome is used to describe cases in which 10%-30% of the body surface area is detached. 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.Introduction
SJS and TEN are classified as severe cutaneous adverse reactions (SCAR), a subcategory of adverse drug reactions (ADR). Unlike individuals with SJS and TEN, most individuals with a reactive skin disease have a mild and self-limiting condition. For years, confusing and contradictory terminology has been used to describe these disorders and controversy still exists as to the best way to classify them. In the past, erythema multiforme (EM) was considered part of this disease spectrum, but is now considered a distinct disorder. NORD has a separate report on erythema multiforme. These disorders are generally broken down into SJS, SJS/TEN overlap, and TEN. SJS was first described in the medical literature in 1922 by doctors A.M. Stevens and F.C. Johnson. The term toxic epidermal necrolysis was introduced in the medical literature in 1956 by Dr. A. Lyell and is also known as Lyell syndrome.
Most cases involve the development of general, nonspecific symptoms including a persistent fever, burning or stinging eyes, body aches, and discomfort or difficulty swallowing. Additional nonspecific symptoms include headaches, chills, joint paint, and a general feeling of poor health (malaise). A pus-producing (purulent) cough that also brings up mucous, phlegm and saliva (sputum) may also occur. Such symptoms may precede the development of skin involvement by a few days.
The initial skin symptom is often the development of a superficial reddening of the skin (erythema) or reddish spots on the skins (macules) that rapidly spread and come together (coalesce) to form a rash. In some cases, these lesions may resemble a target or bull’s eye, so-called “target” lesions. A rash often first develops on the upper chest, face, and the palms and soles. The rash may remain limited to these areas or it may spread, within a few hours or days, to cover a significant portion of the body. The rash may be itchy (pruritic) or painful. Blisters appear on the confluent eruption leading to detachment of the skin and leaving erosions.
Blisters may form on various external and internal mucous membranes of the body including the lining inside of the mouth (stomatitis), nose and genitals. Blisters can cause pain and lead to erosions and bleeding. The lips and the inside of the mouth may develop mucosal lesions that are extremely painful and may make eating difficult. Lesions in the genitourinary tract can cause diminished urine flow (dysuria) or an inability to pass urine due to pain. Mucous membrane involvement can precede or follow skin symptoms and often begins with soreness, then little blisters or “bumps” that rupture and leave erosions.
The eyes may also be affected. Affected individuals may experience pain and reddish discoloration in the whites of the eyes. Conjunctivitis, which is inflammation of the thin, clear membrane that lines the inner surface of the eyelids and the outer surface of the eye (conjunctiva), is common. Swelling due to fluid accumulation (eyelid edema) may also occur. Eye crusts may form and there may be a sensation of sand or grit in the eyes. Affected individuals may be abnormally sensitive to light (photophobia) and experience inflammation of the eyelids (blepharitis).
Skin and mucous membrane involvement initially can be mild or it can rapidly progress. Some individuals may have severe skin symptoms and mild mucosal involvement while others have mild skin involvement and severe mucosal symptoms. Eventually, the upper layer of the skin (epidermis) may pull away (detach) from the underlying layers. In SJS, this affects less than 10% of the body surface area. Patients with TEN have more widespread skin detachment (more than 30% of body surface area) and large areas of skin may shed off (slough) exposing the underlying layers of skin. Scarring and secondary infection may occur in the affected areas if not treated appropriately. Affected individuals can potentially develop sepsis, a widespread, life-threatening infection of the blood and body tissues. Individuals with TEN may resemble patients with severe burns.
If untreated, these disorders can cause significant, disabling symptoms and even death. Some individuals who survive the initial, acute episode of SJS or TEN may experience severe, chronic symptoms.
Long-term skin issues can include itching (pruritus), excessive sweating (hyperhidrosis), and abnormal dryness of the skin. Abnormal lightening or darkness of affected areas of skin (hypopigmentation and hyperpigmentation) may occur and take years to get better. Permanent loss of nail beds may occur, or the fingernails and toenails may grow back abnormally (onychodystrophy).
Chronic eye abnormalities can include chronic inflammation, abnormal dryness of the cornea (corneal xerosis), dry eye syndrome, folding inward of one or both of the eyelids (entropion), eyelashes that are inverted so that they grow back toward the eyeball (trichiasis), and one or both eyelids may become stuck to the eyeballs (symblepharon). Eye tissue can be significantly damaged resulting in scarring, vision loss and, in rare cases, blindness.
Involvement of the mucous membranes lining the respiratory tract can lead to lung damage, bronchitis, chronic obstructive pulmonary disease, and scarring of the esophagus. Dental complications including dry mouth (xerostomia), inflammation of the gums, and gum disease have been observed due to changes in the quantity and quality of saliva.
Genitourinary abnormalities can include urethral erosions and inflammation of the head of the penis (balanitis) in males and narrowing of the opening of the vagina and abnormal sticking together (adhesion) of the vaginal lips (labia) so that the vagina appears closed (vaginal synechia) in females.
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.
SJS and TEN can affect individuals of any age including children, but the incidence is much higher in the elderly population. Individuals of every race and ethnicity can develop these disorders. Some reports suggests that females are affected slightly more often than males. The incidence is western societies is 1-2 per 1,000,000 million people in the general population. These adverse reactions usually do not occur again, unless the culprit drug is taken again, but even then often not.
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.
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.
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.
The U.S. Food and Drug Administration (FDA) recommends screening for HLA B*1502 in individuals of Chinese and Southeast Asian ethnicity before beginning treatment with the drug carbamazepine.
To date supportive care as described above is the gold standard for treatment of SJS and TEN. Various immuno-modulating treatments for SJS/TEN have been proposed, such as glucocorticosteroids, intravenous immunoglobulins (IVIG) and cyclosporine, but their usefulness is still discussed controversially. Cyclosporine 3 mg per kg body weight for 10 days seems to be the therapy with the highest chance to halt the progression of skin detachment (Valeyrie-Allanore et al. 2010), however, the exact mechanism is not understood. Antibodies in pooled human IVIG are thought to block the Fas-mediated necrosis of keratinocytes in vitro. Interestingly, granulysin levels could not be reduced by IVIG, which might explain the lack of effect of IVIG on disease progression, and treatment with IVIG is therefore questioned (Bachot et al. 2003, Chung et al. 2008). A large retrospective observational study revealed that treatment with corticosteroids in doses between 60 mg and 500 mg suggests a benefit for SJS/TEN-patients with a reduced mortality, whereas treatment with IVIG did not (Schneck et al. 2008). Plasmapheresis, hyperbaric oxygen, and cyclophosphamide have been reported as a successful treatment of TEN in case reports and small case series. Thalidomide, an effective TNF-alpha-inhibitor in vitro and successfully used in GvHD, caused a higher death rate in the only randomized controlled trial in TEN, therefore treatment with TNF-alpha-inhibitors have to be used with caution (Mockenhaupt 2011).
Treatment trials including a large number of patients would be very helpful to determine the efficacy and safety of immunomodulating therapies in SJS/TEN, but they are difficult to undertake due to the rareness and unpredictable sudden occurrence of the condition.
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