Stevens-Johnson Syndrome

Each year, allergic reactions to drugs are a major cause of death in the United States.  One disease that contributes to the annual death rate caused by allergic reactions to drugs is Erythema multiforme major, also known as Stevens-Johnson syndrome (SJS).  SJS is a serious and life-threatening allergic reaction to medication.  It is a complex immunological skin disease that can be fatal.  Also known as erythema multiforme major, SJS is part of an overlapping spectrum of three related diseases that manifest symptoms on the skin and in the eyes.  SJS occurs most often in children and young adults.The entire spectrum of related diseases includes Steven-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN) and erythema multiforme (EM).  These encompass an overlapping spectrum of acute, self-limited exanthems.  EM is a relatively common but mild form frequently related to herpes simplex virus (HSV) infection.  SJS and TEN are less common and can be life-threatening forms with mucocutaneous involvement usually due to a reaction to drug medications.  Generally, the term SJS is used to refer to disease limited to less than 10% of the body surface area and TEN to disease involving more than 30% of the skin.  Both are characterized by acute skin blistering and blistering on at least two mucous membranes.  Although EM, SJS, and TEN are widely believed to represent various expressions of a disease continuum (Chan H.L. 1984; Revus et al. 1984) referred to as the “EM/SJS/TEN disease spectrum” (Power et al., 1995; Wilkins et al., 1992), this view is not universally held. (Roujeau, 1997; Auquier-Dunant et al 2002)  TEN is the most severe form of erythema.  Many researchers consider SJS and TEN as different manifestations of the same disease.  Individuals with TEN can experience skin loss because the skin sloughs off is sheets as the name implies (epidermal necrolysis).Ferdinand von Hebra first reported erythema multiforme (EM) in 1860.  He described it as a self-limited cutaneous disease that was characterized by multiform skin lesions.  Just over sixty years later, in 1922, Stevens and Johnson (Mondino, 1990; Power et al., 1995) for whom SJS was subsequently named described two boys with Stevens-Johnson syndrome (SJS), a more severe mucocutaneous disease (eruptive fever and stomatitis) with ophthalmologic manifestations.  A similar and apparently related disease was later uncovered and described by Lyell (5, 6) who characterized the condition by extensive epidermal “scalding,” and named it “toxic epidermal necrolysis” (TEN).  Today EM, SJS and TEN are generally viewed as related conditions or different extremes of a set of related diseases.The cause of the EM/SJS/TEN complex remains unknown, but it is generally assumed to be an autoimmune response to an environmental factor such as a drug or virus. (Revus et al. 1984; Wilkins et al., 1992)  Certain drugs and classes of drugs are now known to trigger some cases of the EM/SJS/TEN complex as will be discussed later.  Abe et al. showed that the epidermal necrolysis, that is, the breaking off of dead skin, of SJS/TEN is caused by massive keratinocyte cell death through apoptosis, and the activation of a specific binding factor secreted by peripheral mononuclear blood cells.  This appears to be an important initial step in the disease and in understanding the disease.Although the EM/SJS/TEN disease spectrum involves epidermal skin layers, it also affects the eyes.  There is little available information as to the natural history of the chronic ocular disease in SJS.  Severe corneal damage can result when SJS reaches acute stages, but corneal damage usually develops as a result of the chronic complications from the disease.  Corneal damage is the most severe long-term complication for survivors of TEN and SJS (Holland and  Hardten, 1996; Robin and Hoang-Xuan, 2001; Mondino, B. J. 1990; Power et al., 1995; Pleyer et al., 1997).  Ocular damage can range from mild to severe.  In patients with severe ocular complications, the complications generally arise early after the acute stage.  These complications are thought to be caused by conjunctival scarring. (Holland and  Hardten, 1996; Robin and Hoang-Xuan, 2001; Mondino, B. J. 1990; Power et al., 1995; Pleyer et al., 1997)  The chronic complications have different causes and may coexist or occur in sequence in a patient.  The cause of the chronic disease is stem cell failure or recurrent conjunctival inflammation.  Some cases of late SJS involve the ocular mucous membrane in a pemphigoid manner.  Pemphigoid refers to dermatological syndromes that are similar to the pemphigus group, a group of chronic, relapsing and sometimes fatal skin diseases characterized by crops of vesicles and blisters and histological signs.  However, despite the similarity, pemphigoid situations are clearly distinguishable from those of the pemphigus group.  The mortality rate for SJS proper is between 5% and 15%.  SJS can result in organ damage and blindness.II.             SymptomsThe signs and symptoms of SJS often appear suddenly.  Stevens Johnson Syndrome can begin with a fever, sore throat that lasts two weeks or more and headaches.  After a few days, these symptoms can turn into skin lesions and blisters.  SJS is characterized by inflammation of the mucous membranes of the mouth, throat, eyes, genital tract and intestinal tract.  Ulcers inside the mouth are the most common, irritation to the throat, tongue, gums, and lips. Affected individuals may also have skin lesions, blisters and bleeding in the lips, eyes, mouth, nasal passage and genital areas.  Hepatitis, nephritis, gastrointestinal bleeding, pneumonia, arthritis, arthralgia, fever and myalgia may also be associated with SJS.Symptoms and complications from SJS can include permanent blindness, dry-eye syndrome, photophobia, 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.  The clinical manifestations and histological features of EM, SJS, and TEN show considerable overlap.  For example, some patients with severe SJS eventually developed extensive epidermal necrolysis and shedding (characteristic of TEN) (7) and many patients with TEN have target-like lesions (characteristic of SJS) adjacent to areas of full-thickness skin loss.  In addition, some of the same classes of medications have been implicated as causes of both SJS and TEN.  Accordingly, it is widely believed, although not universally accepted (Roujeau 1997; Auquier-Dunant et al 2002)) that EM, SJS, and TEN may represent various forms of expression of a disease continuum (Chan H.L. 1984; Revus et al. 1984) referred to as the “EM/SJS/TEN disease spectrum.” (Power et al., 1995; Wilkins et al., 1992)Stevens Johnson Syndrome is characterized by inflammation of the mucous membranes of the mouth, throat, eyes, genital tract and intestinal tract.  Erythema multiforme major (SJS) is a complex immunologic syndrome characterized by acute skin blisters that affect at least two mucous membranes in the skin.  Toxic epidermal necrolysis (TEN) is the most severe form of erythema multiforme and involves over 30% of the skin.  Large sheets of skin slough off in this situation.  Ulcers inside the mouth are the most common symptoms but irritation to the throat, tongue, gums, and lips are also common.  Affected individuals may have skin lesions, blisters and bleeding in the lips, eyes, mouth, nasal passage and genital areas.  Stevens Johnson Syndrome evolves into a situation where the skin literally sloughs off in sheets.  Such patients are typically treated in a hospital’s burn unit.  Skin infections in the presence of these lesions can cause death. Lesions that develop in the lungs can also be life threatening.Large blood filled vesicles and erosions in the mouth are universal features in the EM/SJS/TEN complex.  The lips show hemorrhagic crusting.  The genitals may commonly be discolored and bear other symptoms of the disease.  Lesions consist of a red center that is encircled by a peripheral red ring frequently on the palms of the hands and feet.  Skin blisters are usually transient and temporary but widespread and may be associated with hemorrhaging and death of skin cells.  The initial signs of the complex may include transient membranous conjunctivitis that may later develop into conjunctival cicatrization.  Conjunctivitis, also called pinkeye and red eye, is the inflammation of the conjunctiva, the membrane covering the white of the eyes.SJS and TEN are often preceded by a nonspecific viral-like prodrome, a premonitory precursor symptom.  An erythematous macular (red spots on the skin) or maculopapular rash begins on the face, neck and central trunk and then may spread to the extremities.    These individual lesions are round to irregularly shaped macules or patches with a dusky center.  The lesions may increase in size and number and may eventually coalesce.  Large, flaccid blisters form and rupture, leading to denudation and erosions.  Symptoms generally occur over two or more mucosal surfaces including the oral cavity, the anus, the conjunctivum or the genitals.  Lesions of the mucous membranes may also occur throughout the pulmonary and gastrointestinal tract.Ocular involvement and symptom manifestations commonly occur in a high proportion of patients with EM/SJS/TEN and may cause significant morbidity.     Ocular sequelae occurred during the 3-month follow-up period after 24 of the 128 attacks with ocular manifestation (18.8%, 24 patients).  The most frequent sequelae were dry eye, conjunctival or corneal scar, and symblepharon.  None of the ocular sequelae required immediate surgery.Most studies reporting on the ocular manifestations of EM/SJS/TEN were conducted among Western populations. (Revus et al. 1984; Power et al., 1995)  However, in two studies of Asian populations, only the more severe disorders (SJS-TEN, 16 and SJS, 17) were reported.  In what the authors thought to be the largest study of the ocular manifestations of EM/SJS/TEN complex in the literature, Chang et al (2007) compared the ocular/mucocutaneous features, causes and management of  the EM/SJS/TEN complex in Western and Asian populations.  They found that carbamazepine and allopurinol were the most frequent causes of the EM/SJS/TEN complex and advised that ophthalmic evaluation and consultation are mandatory.  In Chang et al’s study, more than half the patients with the EM/SJS/TEN complex developed acute ocular problems.  They suggest early ophthalmic consultation and frequent follow-ups for all patients with the complex.  This is suggested to minimize the possibility and severity of late ocular damage.  They also recommend extreme caution when prescribing medications to such patients because of the connection between the onset of diseases in the complex and the use of certain medications.At least one study has suggested several different causes of SJS related delayed ocular disease that follows the acute episode.  Most ophthalmologists do not recognize the symptoms because the related events are infrequently reported and are not generally described in reviews or text books.  However, de Rojas, Dart and Saw (2007) point out that the recognitions of these symptoms is important for the prognosis for vision and in order to use the appropriate anti-inflammatory therapy.  Chang et al. found ocular manifestations of the disease in almost two-thirds of the individuals in their study (Chang et al., 2007).III.           CausesThe cause of the EM/SJS/TEN complex is obscure.  Drugs are known to be an important cause of SJS, but infections or a combination of infections and drugs has also been implicated.  More than 100 drugs have been implicated as causing SJS.  (Roujeau et al, 1995)  SJS and TEN are probably mediated immunologically. (Lyell, 1979; Roujeau and Stern 1994)  The ocular aspect of the disease may progress due to acute inflammatory conditions and may occur at variable periods of time after the disease becomes acute.  Drugs used for medication are the most frequent cause of the EM/SJS/TEN complex.  This is more likely in the case of SJS and TEN than for EM.  Viral infections have also been noticed to preceed EM and mycoplasmal infections have been noticed prior to EM and SJS.  At least 56 drugs and herbal remedies have been associated with triggering EM/SJS/TEN.  The most common triggers are anticonvulsants, non-steroidal anti-inflammatory drugs, anti-gout agents and antibiotics.  Carbamazepin, suflonamides and penicillin are among the leading drugs seen to cause the complex.  (Chang et al, 2007)  The allergic reaction to drugs appears to be one cause of SJS.  Drugs used to treat arthritis are among those known to trigger SJS.  The most frequently observed and most commonly identified cause of the EM/SJS/TEN complex is an allergic reaction to medication.  One study found that the drugs known to most frequently cause the EM/SJS/TEN complex were carbamazepine and allupurinol.This is an uncommon, acute, serious but generally self-limiting mucocutaneous disease.  The most common precipitating factors are hypersensitivity reaction to drugs and infections caused by Mycoplasm pneumoniae and herpes simplex virus.  In over 50% of cases no cause can be found.  Ocular manifestation are frequent.  There is not much information regarding the natural history of the chronic ocular disease in SJS.  Little is known about the cause and method of introduction of the chronic ocular disease in SJS.  Studies suggest may different causes and methods of introduction for the disease even in the same patient. (Chang et al., 2007).  Stem cell failure (ocular surface failure) is a major cause of the chronic disease in some patients.  Recurring conjunctival inflammatoin is another cause.Drugs are the most frequent cause of the EM/SJS/TEN spectrum accounting for an estimated two thirds of the attacks in one study (Chang et al., 2007).  However, this is not true of the entire EM/SJS/TEN complex.  While account for about 85% of the attacks of SJS and TEN in one study, they contributed to less than 30% of the attacks of EM.  Viral infections and mycoplasmal infections are also associated with attacks of EM and SJS. (Chang et al, 2007)  The drugs most commonly associated with triggering the EM/SJS/TEN system are anticonvulsants, non-steroidal anti-inflammatory drugs and antibiotics. (Chang et al., 2007)  Drugs such as carbamazepine, allopurinol, phenytoin, ketoprofen, penicillin and sulfonamides.  Carbamazepine is the most common cause of SJS while allopurinol is the most common cause of EM and TEN.  Multiple drugs can trigger some attacks.Common over-the-counter (OTC) drugs such as prescription pain relievers and antibiotics like Advil, Ibuprofen, Bextra, Arava, Bactrim, Cotrim, Septra, Remicade, Daypro, Topamax, Children’s Motrin and Bactrim Pediatric have been known to contribute to SJS.  These have caused suffering and death from SJS.  SJS has also been linked to the painkillers Bextra and Arava, both used to treat rheumatoid arthritis.Studies on Western populations (Power et al., 1995) and an Indian population, have shown that antibiotics, particularly the class of antibiotics known as sulfonamides, commonly trigger the disease complex.  However, one study of an Asian population showed that anticonvulsants, particularly carbamazepine (35 to 87 cases of SJS, 40.0%) and allopurinol (20 of 144 drug-related cases of EM/SJS/Ten) were the class of drugs that most frequently triggered an attack.  Severe adverse skin reactions including SJS and TEN have long been associated with the use of anticonvulsant drugs.  Roujeau et al have demonstrated that valproic acid also has a significant risk similar to that of aromatic anticonvulsants.  For anticonvulsants, the risk is greatest during the first two months of treatment.  The risk persists for some long-term users of phenobarbital and valproic acid.  Carbamazepine was also the most frequent cause of SJS in a study conducted in Singapore (5 of 23 cases, 27.7%) (16).  Chang et al (2007) proposed that SJS or TEN can be caused by a specific type of medication, but that the cause differs geographically because of region-dependent differences in the types of medications prescribed.  Other environmental factors may be involved.  Region specific differences may arise because of inherited differences in the risk of SJS or TEN with exposure to various drugs.  A recent study revealed that in Han Chinese there is a strong relationship between a genetic marker, the human leukocyte antigen histocompatibility B*1 502, and SJS induced by carbamazepine (20).  Another study revealed a strong relationship between allopurinol and the onset of SJS or TEN. (21). Thus, it is very important to consider the pharmacological factors that are related to the genetic mechanism involved with the occurrence of SJS and TEN.Minoxidil, often used in cases of advanced renal disease who have been unresponsive to other antihypertensive agents, is one drug that has led to severe oral lesions and multiple pustular blisters on many sites of his body indicative of minoxidil-induced Stevens-Johnson syndrome.  In one study of the minoxidil induced occurence of SJS, the patient improved when minoxidil use was discontinued. (Callen et al., 2007)Some commonly used drugs are not associated with SJS or the EM/SJS/TEN continuum.  Analgesics, salicylates (aspirin and aspirin related) and pyrazolone derivatives are not linked to the continuum.  (Roujeau et al., 1995)  The link between acetaminophen and the continuum is not as clear.  There was no association between acetaminophen and SJS in France, but there was a significant association in other countries.  Cocaine use has recently been added to the list of drugs associated with SJS.IV.           TreatmentTreatment of SJS involves eliminating the underlying cause and managing the signs and symptoms of the disease.  Recovery may take several weeks but prompt diagnosis of the condition within 24 to 48 hours of the onset can shorten the duration of the illness.  SJS can usually be diagnosed when the characteristic rash that cannot be explained by another diagnosis appears about 1 to 3 weeks after exposure to a known stimulus.  Treatment must include a careful evaluation of the patient’s history use of medication.  Cyclophosphamide and cyclosporine have been used to treat SJS but without great success.  Topical pain anesthetics and antiseptics are also used.  The treatment depends, in part, on the suspected precipitating cause.  Corticosteroids are the most commonly prescribed medication for SJS.  Since drugs are one known cause of the SJS continuum of diseases, one obvious means of managing and treating the disease continuum is to discontinue the use of drugs known to contribute to or cause the disease.  The general approach is to discontinue use of the suspected drug agents immediately combined with adding supportive treatments such as treatment for acute ocular inflammation using antibiotic eye drops and corticosteroid eye drops.  Using corticosteroids is controversial because high doses of steroids may increase the risk of infection and mortality even though they may inhibit inflammation during the initial stages of the SJS complex. (Chave et al., 2005).  There have been a few recent cases where small beneficial affects have been achieved with anti-inflammatory and/or immunosuppressive drugs such as cyclosporine, cyclophosphamid, N-acetylcysteine, plasmapheresis and intravenous immunoglobulins. (Chave et al., 2005)  These studies need further confirmation.In SJS and TEN, with more extensive skin and mucous membrane involvement, morbidity andmortality are increased.  The mortality rate in TEN is between 5% and 50% with septicemia.  Particular attention should be paid to early detection of infection, with a low threshold for initiating antibiotic therapy.  Management includes careful mucous membrane hygiene and would care.  Depending on the severity of erosions or ulcerations, consider a petrolatum gauze dressing or an absorptive dressing.  Corticosteroids have been show to increase the mortality of SJS-TEN when given after extensive skin involvement and blistering have developed.  Some authors have found administration of a short course of high-dose steroids (80-120 mg methylprednisolone PO q.d. and tapering over 1 week or sooner if tolerated) useful early on in drug-induced SJS-TEN to prevent progression of skin involvement and blistering.  Some studies suggest a benefit of treatment with intravenous immune globulin.  When there is a widespread mucocutaneous involvement, the patient should be managed in a burn unit, with particular attention to fluid loss and thermoregulation.  With gastrointestinal involvement, aggressive nutritional support is required.  The patient should be followed closely for conjunctival involvement and, if present, ophthalmology should be considered.When medications were suspected to have provoked EM/SJS/TEN, the suspected agent(s) were discontinued immediately, and supportive treatments were administered.  The most common treatments for acute ocular inflammation were antibiotic eye drops, corticosteroid eye drops, and topical ophthalmic lubricant.  None of the patients required punctal occlusion or an invasive procedure.Since ocular signs of SJS are common, an ophthalmic consultation and evaluation are required and ophthalmic management is also mandatory.  An ophthalmologist should be contacted if ocular problems arise.VI.           Summary and ConclusionSJS is a serious and life-threatening allergic reaction to medication.  It involves inflammation of the mucous membranes of the mouth, throat, eyes, genital tract and intestinal tract and acute skin blisters that affect at least two mucous membranes in the skin.  It may also affect the eyes.  The disease is generally considered to be part of a continuum of diseases that include EM, TEN and SJS each of which is considered to be a different manifestation of the same disease.  Although More than 100 drugs have been implicated as causing the continuum, the drugs most commonly associated with triggering the disease continuum include anticonvulsants, non-steroidal anti-inflammatory drugs, anti-gout agents and antibiotics.  Carbamazepin, suflonamides and penicillin.  Cocaine has also been associated with triggering the continuum.  Mortality from the disease is between 5% and 15%, and it can be managed and treated quickly and successfully if the initial symptoms are recognized within 24 to 48 hours or the onset.  Treatment involves taking the patient off the drugs that might be triggering the disease and managing the symptoms.


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