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stevens johnson syndrome pathophysiology

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Stevens Johnson Syndrome Understanding Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

USPharmacist.com > Cutaneous Adverse Reactions: Stevens . Pathophysiology. While certain categories of drug reactions involve immunologic mechanisms, . Stevens-Johnson syndrome, an immune complex?mediated hypersensitivity .

5-Minute Clinical Consult: Results 5-Minute Clinical Consult for Mobile + Web provides information and evidence on 700+ medical conditions, 4000 drugs, 1000+ AAFP patient handouts, 200+ pediatric .

Arch Dermatol - Abstract: Stevens-Johnson Syndrome . The Stevens-Johnson syndrome is a multisystem inflammatory disorder associated with a widespread erythematous eruption that can result in death.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Pathophysiology. Stevens-Johnson syndrome and toxic epidermal

necrolysis are often drug . Stevens-Johnson syndrome may prove fatal in roughly 5% of patients; toxic .

DISEASES - Steven-Johnson Syndorme - Pusat Informasi Penyakit . Stevens-Johnson syndrome (SJS) is an immune-complex?mediated hypersensitivity . Sane SP, Bhatt AD: Stevens-Johnson syndrome and toxic epidermal necrolysis-challenges of .

StevensJohnson syndrome without skin lesions The denomination incomplete StevensJohnson syndrome' has been suggested. However, severe forms of Stevens. Johnson syndrome (SJS) with conjunctivitis, ulcerative .

Review of Intravenous Immunoglobulin in the Treatment of . by Saira B. Momin, DO James Q. Del Rosso, DO, FAOCD Abstract Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and

StevensJohnson syndrome
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StevensJohnson syndrome
Classification and external resources

Man with StevensJohnson syndrome

ICD-10 ICD-9 OMIM DiseasesDB MedlinePlus eMedicine MeSH

L51.1 695.13 608579 4450 000851 emerg/555 derm/405 D013262

StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN)[1] are two forms of a life-threatening skin condition, in which cell death causes the epidermis to separate from the dermis. The syndrome is thought to be a hypersensitivity complex that affects the skin and the mucous membranes. Although the majority of cases are idiopathic (without a known cause), the main class of known causes is medication, followed by infections and, rarely, cancers.

Contents
[hide]

1 Classification 2 Signs and symptoms 3 Causes o 3.1 Infections o 3.2 Medication/drugs o 3.3 Genetics 4 Treatment 5 Prognosis 6 Epidemiology 7 History 8 Notable cases 9 References 10 External links

[edit] Classification

There is agreement in the medical literature that StevensJohnson syndrome (SJS) can be considered a milder form of toxic epidermal necrolysis (TEN). These conditions were first recognised in 1922.[2] Both diseases can be mistaken for erythema multiforme. Erythema multiforme is sometimes caused by a reaction to a medication but is more often a type III hypersensitivity reaction to an infection (caused most often by Herpes simplex) and is relatively benign. Although both SJS and TEN can also be caused by infections, they are most often adverse effects of medications. Their consequences are potentially more dangerous than those of erythema multiforme.

[edit] Signs and symptoms

Mucosal desquamation in a person with Steven Johnson's syndrome

Conjunctivitis (inflammation of eye and eyelid) in SJS

SJS usually begins with fever, sore throat, and fatigue, which is misdiagnosed and usually treated with antibiotics. Ulcers and other lesions begin to appear in the mucous membranes, almost always in the mouth and lips but also in the genital and anal regions. Those in the mouth are usually extremely painful and reduce the patient's ability to eat or drink. Conjunctivitis of the

eyes occurs in about 30% of children who develop SJS. A rash of round lesions about an inch across arises on the face, trunk, arms and legs, and soles of the feet, but usually not the scalp.[3]

[edit] Causes
SJS is thought to arise from a disorder of the immune system.[3]

[edit] Infections
It can be caused by infections (usually following infections such as herpes simplex virus, influenza, mumps, cat-scratch fever, histoplasmosis, Epstein-Barr virus, mycoplasma pneumoniae or similar).

[edit] Medication/drugs
See also: List of SJS inducing substances

It can be caused by adverse effects of drugs (allopurinol a.k.a. Aloprim, Zyloprim, Dilantin, Depakote, Levaquin, diclofenac, etravirine, isotretinoin a.k.a. Accutane, fluconazole,[4] valdecoxib, sitagliptin, oseltamivir, penicillins, barbiturates, sulfonamides, phenytoin, azithromycin, oxcarbazepine, zonisamide, modafinil,[5] lamotrigine, nevirapine, pyrimethamine, ibuprofen,[6] ethosuximide, carbamazepine, nystatin, and gout medications).[7][8] Although StevensJohnson Syndrome can be caused by viral infections, malignancies or severe allergic reactions to medication, the leading cause appears to be the use of antibiotics and sulfa drugs. Medications that have traditionally been known to lead to SJS, erythema multiforme and toxic epidermal necrolysis include sulfonamides (antibiotics), penicillins (antibiotics), barbiturates (sedatives), lamotrigine and phenytoin (e.g. Dilantin) (anticonvulsants). Combining lamotrigine with sodium valproate increases the risk of SJS. Non-steroidal anti-inflammatory drugs are a rare cause of SJS in adults; the risk is higher for older patients, women and those initiating treatment.[2] Typically, the symptoms of drug-induced SJS arise within a week of starting the medication. People with systemic lupus erythematosus or HIV infections are more susceptible to drug-induced SJS.[3] SJS may also be caused by cocaine usage.[9]

[edit] Genetics
In some East Asian populations studied (Han Chinese and Thai), carbamazepine- and phenytoininduced SJS is strongly associated with HLA-B*1502 (HLA-B75), an HLA-B serotype of the broader serotype HLA-B15.[10][11][12] A study in Europe suggested that the gene marker is only relevant for East Asians.[13][14] Based on the Asian findings, similar studies in Europe showed

61% of allopurinol-induced SJS/TEN patients carried the HLA-B58 (B*5801 allele - phenotype frequency in Europeans is typically 3%). One study concludedm, "Even when HLA-B alleles behave as strong risk factors, as for allopurinol, they are neither sufficient nor necessary to explain the disease."[15]

[edit] Treatment
SJS constitutes a dermatological emergency. All medications should be discontinued, particularly those known to cause SJS reactions. Patients with documented mycoplasma infections can be treated with oral macrolide or oral doxycycline.[3] Initially, treatment is similar to that for patients with thermal burns, and continued care can only be supportive (e.g. intravenous fluids and nasogastric or parenteral feeding) and symptomatic (e.g., analgesic mouth rinse for mouth ulcer). Dermatologists and surgeons tend to disagree about whether the skin should be debrided.[3] Beyond this kind of supportive care, there is no accepted treatment for SJS. Treatment with corticosteroids is controversial. Early retrospective studies suggested that corticosteroids increased hospital stays and complication rates. There are no randomized trials of corticosteroids for SJS, and it can be managed successfully without them.[3] Other agents have been used, including cyclophosphamide and cyclosporine, but none has exhibited much therapeutic success. Intravenous immunoglobulin (IVIG) treatment has shown some promise in reducing the length of the reaction and improving symptoms. Other common supportive measures include the use of topical pain anesthetics and antiseptics, maintaining a warm environment, and intravenous analgesics. An ophthalmologist should be consulted immediately, as SJS frequently causes the formation of scar tissue inside the eyelids, leading to corneal vascularization, impaired vision and a host of other ocular problems.

[edit] Prognosis
SJS proper (with less than 10% of body surface area involved) has a mortality rate of around 5%. The risk for death can be estimated using the SCORTEN scale, which takes a number of prognostic indicators into account.[9] Other outcomes include organ damage/failure, cornea scratching and blindness.

[edit] Epidemiology
StevensJohnson syndrome is a rare condition, with a reported incidence of around 2.6[3] to 6.1[2] cases per million people per year. In the United States, there are about 300 new diagnoses per year. The condition is more common in adults than in children. Women are affected more often than men, with cases occurring at a two to one (2:1) ratio.[2]

[edit] History

Stevens-Johnson Syndrome is named for Albert Mason Stevens and Frank Chambliss Johnson, American pediatricians who in 1922 jointly published a description of the disorder in the American Journal of Diseases of Children.[16][17][18][19]

[edit] Notable cases

[20]

Padma Lakshmi, actress, model, television personality, and cookbook writer;

Tessa Keller of MTV show Laguna Beach;[21] Sabrina Brierton Johnson, whose family unsuccessfully sued the manufacturer of Children's Motrin, Johnson & Johnson, after a case of SJS blinded her.[22] Manute Bol, former professional basketball player and member of NBA's Washington Bullets, Golden State Warriors, Philadelphia 76ers, and Miami Heat, who died from complications.[23]

Stevens-Johnson syndrome
Alternative eponyms

Baader's dermatostomatitis Baader's syndrome Fiessinger-Rendu syndrome Baader-Fiessinger-Stevens-Johnson syndrome Fuchs' syndrome Klauder's syndrome Neumann's syndrome (Isidor Neumann) Stevens-Baader-Fiessinger-Johnson syndrome

Related people

Ernst Baader Nol Fiessinger Ernst Fuchs Frank Chambliss Johnson Joseph Victor Klauder Isidor Neumann, Edler von Heilwart Henri Jules Louis Marie Rendu Albert Mason Stevens

A syndrome characterized by severe erythema multiforme-like eruption of the skin and lesions of the oral, genital and anal mucosa, and haemorrhagic crusting on the lips, associated with fever, headache and arthralgia.

Description
A syndrome characterized by severe erythema multiforme-like eruption of the skin and lesions of the oral, genital and anal mucosa, and haemorrhagic crusting on the lips, associated with fever,

headache and arthralgia. The macular eruptions are usually on extremities, appearing in successive eruptions of short duration. No itching, burning, or rheumatic pains. May appear in separate rings, concentric rings, disk-shaped patches, distributed elevations, and figured arrangements. A very long list of symptoms and signs affecting the eyes, the gastrointestinal tract, etc. It affects all ages, with highest incidence in first or third decades, rarely in infants, or adults over 50 years of age. Prevalent in men. The more severe forms of the disorder occur in boys and young adults. It can be associated with malignant disease and systemic lupus erythematosus. Attacks usually come during the spring and fall. The syndrome has been classified into two forms. Erythema multiforme exudativum minor is a mild form characterized primarily by cutaneous and oromucosal lesions, while erythema multiforme exudativum major is a severe form characterized by fever, and ocular, genital, cutaneous, and oral mucosal lesions. Some authors believe this syndrome to be merely a severe form of Hebras erythema multiforme exudativum. Stevens and Johnson reported two patients, boys aged 7 and 8 years.

What is Stevens Johnson Syndrome?

Stevens-Johnson Syndrome is a potentially deadly skin disease that usually results from a drug reaction. Another form of the disease is called Toxic Epidermal Necrolysis, and again this usually results from a drug-related reaction. Both forms of the disease can be deadly as well as very painful and distressing. In most cases, these disorders are caused by a reaction to a drug, and one drug that has come under fire lately is the cox-2 inhibitor Bextra, which is already linked to these disorders. There are other drugs that have been linked to Stevens-Johnson Syndrome, and these include some other NSAIDS (non-steroid anti-inflammatory drugs), Allopurinol, Phenytoin, Carbamazepine, barbiturates, anticonvulsants, and sulfa antibiotics. The condition can sometimes although not very often be attributed to a bacterial infection, and in some cases there is no known cause for the onset of Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis. However, the most common cause is through drug related reaction. Stevens-Johnson Syndrome can affect any age group. However, it occurs most commonly in older people, and this could be because older people tend to use more of the drugs associated with the disease and are therefore collectively more at risk from the disease. People that have AIDS are also at an increased risk of contracting Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis. Those in the higher risk groups are urged to remain vigilant for any signs of these skin diseases, and are also advised to remain well informed about the symptoms that could indicate the presence or onset of Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis.

The symptoms :
Both Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis can start with non-specific symptoms such as cough, aching, headaches, and feverishness. This may be followed by a red rash across the face and the trunk of the body, which can continue to spread to other parts of the body. The rash can form into blisters, and these blisters can form in areas such as the eyes, mouth and vaginal area. The mucous membranes can become inflamed, and with Toxic Epidermal Necrolysis layers of the skin can also come away with ease and often the skin peels away in sheets. The hair and nails can also come away in some cases, and sufferers can become cold and feverish. With Toxic Epidermal Necrolysis the most common cause of death is infection, which can enter through the exposed areas. This disease can leave the skin looking as though it has been burned, and areas where skin has flayed away can seep copiously and quickly become infected.

Treating these diseases:

Those suffering from SJS or TEN are treated in hospital, and if the cause of the problem is drug related then the drugs are stopped with immediate effect. Surviving patients are treated intravenously to replace any lost fluids, and the skin is left to re-grow on its own. However, the

chances of survival can be hit and miss depending on the level of damage and the degree of infection incurred by the patient. It is vital that those taking drugs that could result in these skin diseases are vigilant and can identify the danger signs associated with these problems. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis can be deadly, and the earlier the symptoms are recognised the faster treatment can be initiated. Of course, those affected by drugs in this way or the families of those that have passed away from these skin problems have every right to file for compensation against the manufacturer of the drug in question. Lawyers now specialize in this type of litigation, and those that feel as though they have grounds for compensation are advised to go through an experienced drugs litigation lawyer.

Common Causes: Steven Johnson syndrome

Some of the possible common medical causes of Steven Johnson syndrome may include:

Penicillin Sulphonamides Barbiturates Azithromycin Lamotrigine Ethosuximide Carbamezepine Valdecoxib Phenytoin Herpes simplex Cat-scratch fever

Other Causes: Steven Johnson syndrome

Some of the less common causes of Steven Johnson syndrome may include:

Viral infections Malignancies Sodium valproate Histoplasmosis Fluconazole Influenza Mumps Epstein Barr virus Phenytoin

Steven Johnson syndrome: Treatments

Some of the possible treatments for Steven Johnson syndrome from various sources may include:

Call emergency services Maintain airway, breathing and circulation Intravenous access Analgesic mouth rinses Nasogastric or parenteral feeding Cyclophosphamide Cyclosporine Antiseptics Topical pain anaesthetics Intravenous analgesics

Treatments for Causes of Steven Johnson syndrome

Review the treatment information pages for various causes of Steven Johnson syndrome:

Barbiturates Cat-scratch fever Viral infections

More causes: not all possible causes for Steven Johnson syndrome are listed above; for a full list refer to causes of Steven Johnson syndrome.

Treatment Notes

Only your doctor can advise whether any of these treatments are appropriate for your specific medical situation. Always discuss all treatment options with your doctor before making a decision, including whether to start or discontinue any treatment plan.

Conditions listing medical symptoms: Steven Johnson syndrome:

The following list of conditions have 'Steven Johnson syndrome' or similar listed as a symptom in our database. This computer-generated list may be inaccurate or incomplete. Always seek prompt professional medical advice about the cause of any symptom

Conditions listing symptom: Steven Johnson syndrome:

The following list of conditions have 'Steven Johnson syndrome' or similar listed as a symptom in our database. This computer-generated list may be inaccurate or incomplete. Always seek prompt professional medical advice about the cause of any symptom.

Azithromycin Barbiturates Carbamezepine Cat-scratch fever Epstein Barr virus Ethosuximide Fluconazole Herpes simplex Histoplasmosis Influenza Lamotrigine Malignancies

Mumps Penicillin Phenytoin Sodium valproate Sulphonamides Valdecoxib Viral infections

Stevens-Johnson syndrome
RightHealth and Natural Standard

Full Article Background Causes Adverse Effect Vs. Allergic Reaction Symptoms Treatment Prevention Support For Patients Author Information Bibliography

Copyright 2011 Natural Standard (www.naturalstandard.com) Background

Stevens-Johnson syndrome (SJS) is a type of allergic reaction that usually occurs in response to medications. It is a severe type of erythema multiforme, which is a skin disease characterized by skin eruptions and blisters. SJS is a less severe form of another disease called toxic epidermal necrolysis (TENS). Pediatricians, A.M. Stevens and S.C. Johnson, discovered the disease in 1922 when they treated two young male patients with skin lesions, fever, inflamed mucosa and conjunctivitis (pinkeye). SJS is a systemic disorder that is potentially life threatening, especially if left untreated. About 315% of patients with severe SJS die. In severe cases, the lesions can cause significant scarring of the involved organs, which often leads to loss of function of the organ systems. For instance, restriction of the esophagus and of the respiratory tract can occur due to lesions and scaring. SJS typically involves many areas of the body and extensive lesion formation. The lesions can extend to the mucous membranes and affect any organ, including the lungs, eyes, mouth, stomach and intestines. The disease can cause severe damage to the mouth, nose, eye, vagina, urethra, gastrointestinal tract and/or lower respiratory tract. It is estimated that about one million Americans are diagnosed with SJS each year.

SJS is an immune-complex-mediated hypersensitivity disorder that may be caused by medications, viral infections and malignancies (cancers). In up to half of cases, no specific etiology has been identified. The ratio of male to female occurrence is two to one. Since the causes of SJS are not well understood, it is unclear why it is more common among males. Currently, there is no treatment for the specific disease. Instead, treatment focuses on alleviating the symptoms. In general, the condition lasts about two to six weeks.
Causes

Drug-induced: Almost any medication, including over-the-counter medications, like ibuprofen (Motrin or Advil) may lead to SJS. Medications most often associated with SJS include penicillins and sulfa antibiotics. Anticonvulsants (like phenytoin, carbamazepine, valproic acid and lamotrigine) and nonsteroidal ant-inflammatory drugs (NSAIDs) have also caused SJS. In late 2002, the U.S. Food and Drug Administration (FDA) and the manufacturer Pharmacia noted that SJS had been reported in patients taking the cyclooxygenase-2 (COX-2) inhibitor valdecoxib. There have also been recent reports of cocaine-induced SJS. Herbs/supplements: Since many herbs or supplements have pharmaceutical properties, they may also cause SJS in some patients. SJS has been reported with the use of ginseng-containing products, as well as belladonna and Ginkgo biloba. Infection: More than half of the patients with SJS report having had a recent upper respiratory tract infection before the onset of SJS. Viral diseases that are commonly associated with SJS include herpes simplex virus (HSV), AIDS, coxsackie viral infections, influenza, hepatitis, mumps, mycoplasmal infection, lymphogranuloma venereum (LGV), rickettsial infections and variola (smallpox). Tumor-related: Various cancers and lymphomas have been associated with SJS. Tumor-related SJS is more common among adults than children. Idiopathic: When the cause of SJS is unknown, it is considered idiopathic. About 25-50% of SJS cases are idiopathic.
Adverse Effect Vs. Allergic Reaction

Not all adverse reactions to drugs are allergies. In fact, less than 10 percent of adverse drug reactions are allergic because most drug side effects are not related to the immune system. Instead, the drug directly affects various organs throughout the body.

For instance, a nasal decongestant constricts the capillaries in the nose in order to reduce nasal swelling and open the airway passages. However, a side effect is that it also constricts the capillaries in other regions of the body, which may lead to an increased heart rate, headache, dizziness or increased blood pressure. Since a decongestant is not specific to a single part of the body or one single action, many people could experience side effects. Therefore, it is a nonallergic reaction because the body's immune system is not involved. Other causes of adverse reactions include interactions between two or more drugs, overdose or the body's inability to break the drug down completely as a result of liver or kidney damage. Allergic reactions can be classified into four immunopathologic categories using various classification systems. These classifications are based on the immune system's response to the allergen, not on the severity of the reaction. SJS is technically an immune-complex-mediated hypersensitivity (allergic) condition. Therefore, SJS is a type III allergic reaction. This category involves the formation of an antigen-antibody immune complex, which deposits on blood vessel walls and activates cell components known as complements. This causes a serum-sickness like syndrome, involving fever, swelling, skin rash and enlargement of the lymph nodes in about three to eight hours. It may be caused by a variety of allergens, including penicillins, sulfonamides, intravenous (IV) contrast media and hydantoins.
Symptoms

About 3-15% of patients with severe SJS die. SJS is potentially life threatening because in severe cases, the lesions can cause significant scarring of the involved organs, which often leads to loss of function of the organ systems. The disease typically starts with a nonspecific upper respiratory tract infection. The patient may experience flu-like symptoms, including, fever, sore throat, chill, headache and malaise (generally feeling of discomfort) for anywhere from one to 14 days. Some individuals will also experience diarrhea and vomiting. As the disease progresses, mucocutaneous (mucus membrane and the skin) lesions quickly develop. Patients may experience extensive sloughing (shedding of the skin). Skin lesions may occur anywhere, but they are most common on the palms, soles of the feet, back of the hands and extremities. Mucosal involvement may include erythema (reddening of the skin), edema (fluid in body tissues), blistering, ulceration (open sore on the skin) and necrosis (dead skin). Clusters of outbreaks generally last about two to four weeks. Lesions may become bullous and rupture, making the skin vulnerable to secondary infection. The lesions usually do not itch. Lesions in the mouth and/or mucous membranes may make it difficult for the patient to eat or drink. Patients who experience symptoms in the genitourinary tract may also experience painful urination.

Other common symptoms of SJS include, persistent fever, swelling of eyelids or red eyes, conjunctivitis (pinkeye), flu-like symptoms, tachycardia, low blood pressure, epistaxis (nosebleeds), seizures or coma. SJS is a life-threatening reaction, if left untreated. Complications may include permanent blindness, dry-eye syndrome, photophobia (sensitivity to light), lung damage, chronic obstructive pulmonary disease (COPD), asthma, permanent loss of nail beds, scarring of the esophagus and other mucous membranes, arthritis and chronic fatigue syndrome. Extensive skin involvement may cause the loss of large quantities of body fluids, causing shock in addition to the risk of infection.
Treatment

If the condition is drug-induced, the affected individual should stop taking the offending medication immediately. No specific drug treatment exists for SJS. Recovery may take two to six weeks. Severe cases may require hospitalization in an intensive care unit or burn unit, where the patient will receive intravenous fluids and nutritional supplements. Acetaminophen: Acetaminophen (Tylenol) has been used to reduce fever and discomfort associated with SJS. Antibiotics: Antibiotics are prescribed to treat secondary infections that are often associated with SJS. Commonly prescribed antibiotics include penicillin, amoxicillin, erythromycin and cefadroxil. Corticosteroids: The use of systemic corticosteroids is controversial. High doses taken early in the reaction have been effective. However, they might increase risk of secondary infections because of their immunosuppressive properties. Immunosupressants: Immunosuppressants like cyclophosphamide and cyclosporine have been used to treat allergic symptoms. IVIG: Human intravenous immunoglobulin (IVIG) has been used to treat severe cases of SJS. IVIG may help prevent secondary infections in patients suffering from SJS by increasing immunoglobulin levels in the bloodstream. Moist compress: For mild symptoms, a moist compress has been applied to skin lesions. Areas of denuded skin should be covered with compresses of saline or burow solution. Oral rinse: Analgesic mouth rinse has been used to treat mouth ulcers associated with SJS. Topical anesthetics: Topical anesthetics like lidocaine (Lidoderm) have been applied to the skin to relieve pain associated with lesions.

Prevention

Avoid exposure to known antigens that have caused SJS in the past. Consider wearing a medical alert ID bracelet or necklace.

Read more: http://www.righthealth.com/topic/StevenJohnson_Disease/overview/NaturalStandard20_s#ixzz1V5o5Monu

Background

Erythema multiforme (also known as Stevens-Johnson syndrome [SJS]) and toxic epidermal necrolysis (TEN) are often confused in the medical literature. In 1860, Ferdinand von Hebra initially described erythema multiforme as an acute, self-limited condition with characteristic red papular skin lesions.[1] The papules evolve into pathognomonic target lesions or iris lesions that appear within a 72-hour period and begin on the extremities. Lesions remain in a fixed location for at least 7 days and then begin to heal. Precipitating factors include herpes simplex virus (HSV), Epstein-Barr virus, and histoplasmosis. Because this condition may be related to a persistent antigenic stimulus, recurrence is the rule rather than the exception, with most affected individuals experiencing 1-2 recurrences per year. Erythema multiforme is typically a benign, self-limited disorder. SJS is a mucocutaneous disorder. It was first described by Stevens and Johnson in 1922 as febrile erosive stomatitis, severe conjunctivitis, and disseminated cutaneous eruption.[2] Lesions typically begin on the face and trunk. They are flat, atypical lesions, described as irregular purpuric macules with occasional blistering. Most patients also have extensive mucosal involvement. More than 50% of all cases are attributed to medications. This is a more serious illness and is potentially life threatening. The confusion between these two separate clinical entities began in 1950, when Thomas coined the terms erythema multiforme minor and erythema multiforme major to describe conditions he encountered.

Erythema multiforme minor was applied to patients with the illness originally described by von Hebra as erythema multiforme. Erythema multiforme major was applied to patients who also displayed oral mucosal involvement, similar to that described by Stevens and Johnson.

Up to 50% of patients with HSV-associated erythema multiforme have been found to have oral ulcers. However, this is now recognized as a variant of erythema multiforme, rather than SJS. Because SJS and erythema multiforme have different precipitating factors and different clinical patterns, the terms erythema multiforme major and erythema multiforme minor should no longer be used.

Erythema multiforme with mucosal involvement is now termed bullous erythema multiforme. SJS is recognized as a separate clinical entity.

Lyell first described TEN in 1956.[3] His original description made no reference to the work of Stevens and Johnson. The distinction between SJS and TEN is not clear. In fact, these conditions probably represent differing severities of the same disease process. SJS and TEN have similar precipitating factors, identical histopathologic lesions, and similar clinical patterns. By current convention, the following terminology is used:

The term SJS is used when the disease involves less than 10% of the total body surface area.

TEN is used when the disease involves more than 30% of the body surface area. Patients whose disease involves 10-30% of their body surface area are said to have SJS/TEN overlap. Mortality increases as the percentage of involved body surface increases, making TEN the more severe of the skin reactions.

This article explores SJS in greater detail.

Pathophysiology
The pathophysiology of SJS is not completely understood. The disease process is probably immunologically mediated and often involves an abnormal metabolism of the responsible drug. The keratinocyte is the ultimate target of this disease process with keratinocyte necrosis being the earliest pathological finding. Patients frequently display an altered metabolism of the responsible drug, and are considered to be slow acetylators, both genotypically and phenotypically. This means that an increased proportion of drug metabolism is directed toward the alternative pathway of oxidation by the cytochrome P-450 system, resulting in increased production of reactive and potentially toxic metabolites. Affected individuals have a defect in the ability to detoxify these reactive metabolites, which may then behave as haptens by binding covalently to proteins on the surface of epithelial cells. This may then induce the immune response, leading to the severe skin reaction. Cell-mediated immunity appears to be responsible for the destruction of epithelial cells observed in SJS. Early in the disease process, the epidermis becomes infiltrated with CD8 T lymphocytes and macrophages, while the dermis displays a slight influx of CD4 lymphocytes. These immunologically active cells are not present in sufficient numbers to be directly responsible for epithelial cell death. Instead, they release diffusable cytokines, which mediate the inflammatory reaction and resultant apoptosis of epithelial cells. In some patients, circulating T cells transiently demonstrate (for < 30 d) a TH1 cytokine response (interferon gamma, tumor necrosis factor [TNF] alpha, interleukin 2). Results of immunohistochemical analysis have also shown lesion blister fluid to contain TNF, an important proinflammatory cytokine. Other evidence supports the hypothesis that SJS is the result of cell-mediated immune reactions. Individuals possessing HLA-B12 are 3 times more likely to develop this disorder. The classic timing for a primary cell-mediated immune reaction is 9-14 days after the initiation of the offending drug. In recurrent exposure, the reaction occurs within several hours to 1-2 days, which is consistent with the timing of a secondary cell-mediated immune response.

Epidemiology
Frequency

International

Frequency is estimated at approximately 1.2-6 cases per million individuals per year. The following medical conditions seem to predispose individuals to a higher risk of developing the disorder: HIV infection, corticosteroid exposure, bone marrow transplant, systemic lupus erythematosus, graft versus host disease, and inflammatory bowel disease. Individuals undergoing radiation, chemotherapy, or neurosurgery for brain tumors are also at higher risk. For more information on inflammatory bowl disease, see Medscape's Inflammatory Bowel Disease Resource Center.

Mortality/Morbidity

The mortality rate is approximately 5% and is directly proportional to the total body surface area of sloughed epithelium. Sepsis secondary to loss of the cutaneous barrier is the principle cause of death.

Note extensive sloughing of epidermis in a patient with Stevens-Johnson syndrome. Courtesy of David F. Butler, MD. Advanced age, visceral involvement, increased serum urea nitrogen level, and prior bone marrow transplant are poor prognostic factors. Surprisingly, although the incidence is increased among individuals with HIV (approaching 1 case per 1000 individuals per year), they do not appear to have a higher mortality rate.

Race

SJS occurs throughout the world in all racial or ethnic groups exposed to medications.

Sex

Before the HIV epidemic among young males, there was a slight female predominance of this disease. Incidence is now approximately equal between the sexes.

Age

All age groups are susceptible. The median age is approximately 48 years. Elderly individuals have an increased incidence and severity of disease.

History
Patient history may include the presence of an influenzalike prodrome consisting of fever, cough, and malaise.

Ten to 30% of patients relate this history. Patients may also present with mucocutaneous eruptions with the following characteristics: o The classic time course of development o Lesions that are usually symmetrical and that extend from the face and torso to the trunk and proximal extremities o Difficulty eating or drinking secondary to oral ulceration o Painful micturition secondary to genitourinary tract ulceration o Photophobia, burning eyes, or visual impairment secondary to ocular ulceration o Profuse diarrhea secondary to gastrointestinal tract ulceration o Shortness of breath or difficulty in breathing secondary to tracheobronchial epithelial involvement Obtain a history of all medications, with particular attention to those started in the previous 2 months. Obtain a history of recent or current HSV or Mycoplasma pneumoniae infection, which may cause erythema multiforme. Patients may have a history of anxiety. Discrete, irregular, flat, dark red, purpuric macules o Macules begin as symmetrically distributed lesions over the face and trunk. o Over the course of a few hours or days, the lesions rapidly progress to involve the abdomen, back, and proximal extremities. o By definition, lesions cover less than 10% of total body surface area. o The center of each lesion may reveal a blister or a denuded, red, oozing dermis. Mucous membrane involvement is noted in 90% of patients. The most common sites in order of frequency are the oropharynx, conjunctivae, genitalia, anus, tracheobronchial tree, esophagus, and bowel. Hyperventilation and mild hypoxia may result from anxiety or tracheobronchial involvement. Mild temperature elevation is usually noted. Dehydration may range from mild to massive as a result of the following factors: o Evaporation through open skin lesions o Poor oral intake secondary to oropharyngeal mucous membrane involvement o Profuse diarrhea from involvement of bowel mucosa o Increased insensible losses secondary to elevated core body temperature More than 50% of cases are related to medication use, but no test reliably proves the link between a single case and a specific drug. Over 100 different drugs have been implicated in numerous case reports. o Sulfonamides are generally considered the most common cause, accounting for 30% of all cases. These include the following agents: Sulfadoxine and pyrimethamine (Fansidar-R)

Sulfadiazine Sulfadoxine Sulfasalazine Trimethoprim-sulfamethoxazole o The second most commonly involved agents are the anticonvulsants. Carbamazepine Phenobarbital Phenytoin o The following medications are also implicated in the evolution of StevensJohnson syndrome (SJS): Acetaminophen Allopurinol Aminopenicillins Amithiozone Amoxapine Barbiturates Cephalosporins Chlormezanone Clobazam Diclofenac Fluvoxamine Hydantoins Imidazole antifungals Indapamide Lamotrigine Macrolides Mianserin Oxicam nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, piroxicam, tenoxicam) Propionic NSAIDs Propranolol Pyrazolone derivatives (eg, dipyrone) Quinolones Salicylates Sertraline Tetracycline Tiapride Trazodone Valproic acid Following the institution of a new drug regimen, the mean time of onset of clinical disease is 9-14 days. The highest risk occurs during the first 2 months following the initiation of a new medication. The second most common cause of SJS is infectious agents, with numerous agents being implicated. The following infectious diseases have also been reported to cause this disorder: o Adenoviruses

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Calmette-Gurin virus Deep fungal infections Enterobacter Enteroviruses HSV Influenza Measles Mumps Mycobacterium tuberculosis M pneumoniae Streptococcus pneumoniae Syphilis Typhoid fever

Laboratory Studies

No laboratory tests are specific to Stevens-Johnson syndrome (SJS). The following laboratory abnormalities are frequently encountered: o Lymphopenia, possibly secondary to the depletion of CD4 lymphocytes (90% of patients) o Neutropenia (30% of patients), which indicates a poor prognosis o Thrombocytopenia (15% of patients) o Anemia o Prerenal azotemia and elevated serum urea nitrogen levels (indicate a poor prognosis) o Elevated erythrocyte sedimentation rate o Elevated serum aminotransferase levels

Other Tests

Direct immunofluorescence staining and examination may identify an alternative diagnosis (eg, pemphigoid, IgA linear dermatosis).

Procedures

Perform a skin biopsy of the cutaneous lesions to confirm or exclude the presence of other blistering disorders.

Histologic Findings

Initially, vacuolar change occurs at the dermoepidermal junction and shows sparse lymphocytic and macrophage infiltration. This vacuolar change represents individual or small groups of necrotic (apoptotic) keratinocytes.

Vacuolization then becomes confluent, which is clinically observed as blistering. The overlying epidermis shows full-thickness necrosis and sloughs off at the dermoepidermal junction, exposing a relatively normal-appearing dermis. The upper dermis displays mild inflammation with perivascular lymphohistiocytic infiltrates. Immunohistopathological analysis shows a predominance of CD8 T cells and macrophages in the epidermis, whereas CD4 T cells form the perivascular infiltrates in the papillary dermis. Histological examination of skin biopsies in staphylococcal scalded skin syndrome reveals cleavage of cell layers within the epidermis.

Medical Care
In severely affected patients, care in a surgical specialty burn unit may provide the greatest likelihood of survival.

The most important components of the treatment of Stevens-Johnson syndrome (SJS) are rapid recognition and aggressive treatment. o Death is frequently a consequence of inappropriate, incorrect, or delayed therapy. o Maintain a high index of clinical awareness for this rare but potentially lifethreatening disorder. No specific treatment exists for this disease, and survival and recovery ultimately depend on aggressive supportive care and removal of the offending agent. o Symptomatic supportive care is administered to keep the patient alive through the initial phase of the disease and the subsequent healing process. o Transfer the patient to an intensive care burn unit under isolation precautions to decrease the risk of nosocomial infection. o The altered immunologic function of patients with SJS makes the likelihood of developing sepsis much greater. Sepsis is the leading cause of death in SJS. Immediately withdraw all potentially causative drugs. o This includes all medications begun during the preceding 2 months. o Discontinue all unnecessary medications. The healing process usually takes about 2 weeks, during which time proper skin care is essential. o Practice aseptic handling and avoid adhesive materials. o Use topical agents such as 0.5% silver nitrate solution or 0.05% chlorhexidine solution to cleanse the skin. Warm these solutions before application. o Avoid silver sulfadiazine because of its causative association. Fluid and electrolytes may be lost through the disrupted skin barrier, from profuse diarrhea, or from increased core body temperature. The patient's ability to increase fluid intake may be compromised secondary to oral eruptions. o Fluid and electrolyte resuscitation are approximately 66-75% of that required for a similarly sized burn wound. o Administer warmed fluids through a peripheral intravenous angiocatheter at a site removed from the skin eruptions.

Avoid central venous access if at all possible in order to decrease the risk of line infection. o Change all catheters, peripheral or central, at regular intervals. o Monitor the adequacy of fluid resuscitation with the use of a urinary bladder catheter. o Minimum urine output for adults is 0.5 mL/kg/h; for children, it is 1 mL/kg/h. Maintain thermoregulation by keeping the environmental temperature at 30-32C, administering only warmed fluids, and using heating lamps or warming blankets. Patients with tracheobronchial involvement may present with hyperventilation and mild hypoxemia. Careful monitoring and aggressive pulmonary support may lead to early detection and treatment of diffuse interstitial pneumonitis and thus prevent the development of acute respiratory distress syndrome (ARDS). The use of a pressure support surface, an air or gel mattress, or a specialty bed is recommended to prevent pressure sores. Treat patients for HSV or M pneumoniae -related erythema multiforme. Provide adequate pain control. Administer subcutaneous heparin to prevent the development of deep venous thrombosis. Use antacids, proton pump inhibitors, or histamine 2 blockers to prevent stress ulceration.
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Surgical Care
After the acute period of illness has passed and the patient has survived, mucous membrane sequelae may require surgical intervention.

Consultations

Consult a burn or trauma surgeon familiar with caring for critically ill patients with burn wounds who have open wounds. An ophthalmologist should examine the patient daily for signs of ocular involvement. If necessary, disruption of synechiae can be accomplished by administration of wetting or antibiotic eyedrops. Physical or occupational therapists may be consulted. Infectious disease specialists evaluate for intercurrent infections and advise regarding treatment. If tracheobronchial involvement is likely, a respiratory therapist may be helpful. Psychologists, psychiatrists, or social workers may be helpful.

Diet

Several issues make nutritional support critical in patients with SJS. o Widespread, painful oral erosions may make feeding difficult. In such cases, pass a soft, flexible feeding tube into the stomach or small bowel, and institute appropriate feedings. o Profuse diarrhea may result from gastrointestinal involvement, making oral or enteral feeding difficult. Parenteral nutrition may be appropriate. o Increased energy expenditure must be recognized and treated appropriately. Nitrogen balance and other nutritional parameters are useful to estimate nutritional needs and to evaluate the efficacy of nutritional therapy. o SJS often results in decreased insulin release and increased tissue resistance to insulin. Supplemental insulin may be necessary.

Activity

Protect affected skin from any pressure or shear forces. Otherwise, early institution of physical and occupational therapies is appropriate.

Medication Summary
No specific medicinal therapy is available for treatment of Stevens-Johnson syndrome (SJS). However, several controversial topics deserve mention.

Corticosteroid use is of no benefit in these patients. In fact, a correlation of prior corticosteroid exposure and SJS has identified corticosteroid use as an independent risk factor for development of this disease. Furthermore, corticosteroid use impairs the immune system, and sepsis is the usual cause of death. Prophylactic antibiotics are not recommended because of the increased likelihood of selecting out resistant strains. However, evidence of infection should lead to prompt culturing and the selection of appropriate antimicrobial therapy based on culture and sensitivity results. Some authors recommend routine alternate-day skin biopsy for culture to distinguish simple skin colonization from true infectious invasion and to guide antimicrobial therapy.

Further Inpatient Care

Once the patient has stabilized in the intensive care burn unit, the peak of disease progression has passed, and reepithelialization has begun, it may be appropriate to transfer the patient to a regular surgical ward.

Reepithelialization usually takes 10-14 days, which is also the approximate length of hospitalization for patients without acute complications.

Further Outpatient Care

The medical professional treating the patient during hospitalization should see the patient regularly. Such practitioners may include burn or trauma surgeons, ophthalmologists, nephrologists, infectious disease specialists, and gastroenterologists.

Inpatient & Outpatient Medications

For ocular involvement, the ophthalmologist caring for the patient may prescribe artificial wetting solutions, antibiotic solutions, or ointments. To reduce the likelihood of developing hyperpigmentation, recommend the use of sunscreens for 1 year after the incident has resolved.

Transfer

If the initial treating facility does not have facilities or experienced individuals to care for critically ill burn patients, the patient should be transferred to a regional tertiary care medical center by the most rapid means available.

Deterrence/Prevention

No specific screening methods identify persons who may be susceptible to StevensJohnson syndrome (SJS). o However, once the disorder has been diagnosed, the patient should never be rechallenged with the same drug or any other drug of the same class or similar chemical structure. o Chemically related compounds often share a common metabolic pathway that may be abnormal in the affected individual. First-degree relatives of an affected patient have an increased risk of reactions to similar drugs.

Complications

Approximately 20% of patients suffer from ocular sequelae. o Conjunctival synechiae o Epiphora secondary to obstruction of the lacrimal ducts

Sjgren-like sicca syndrome of dry eyes, punctate keratitis, corneal pannus, and mucin deficiency in tears o In-turned eyelashes, corneal scarring, corneal and conjunctival neovascularization, epithelial proliferation with squamous metaplasia, photophobia, burning eyes, visual impairment, and blindness Patchwork appearance of the skin, with hypopigmented regions and potential hypertrophic scarring Pneumonia/ARDS Esophageal strictures[4] Vaginal synechiae Nephritis
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Prognosis

If diagnosed promptly and treated aggressively, patients usually do well. The mortality rate is approximately 5%.

Patient Education

For excellent patient education resources, visit eMedicine's Skin, Hair, and Nails Center. Also, see eMedicine's patient education article Life-Threatening Skin Rashes.