Done by : Ghadeer Hassan suwaimil

1-Stevens-Johnson Syndrome

Stevens-Johnson syndrome is an immune-complex–mediated hypersensitivity complex that typically involves the skin and the mucous membranes. Although several classification schemes have been reported, the simplest classification breaks the disease down as follows[1] :

Stevens-Johnson syndrome: A minor form of toxic epidermal necrolysis, with less than 10% body surface area (BSA) detachment

Overlapping Stevens-Johnson syndrome/toxic epidermal necrolysis: Detachment of 10-30% of the BSA

Toxic epidermal necrolysis: Detachment of more than 30% of the BSA

Essential update: Acetaminophen raises risk of Stevens-Johnson syndrome

In August 2013, the FDA issued a safety announcement advising that anyone who develops a rash, blister, or some other skin reaction while taking acetaminophen should stop using the drug and seek medical care immediately.[2, 3] The drug poses a risk for the following 3 rare but potentially fatal skin disorders:

Stevens-Johnson syndrome Toxic epidermal necrolysis Acute generalized exanthematous pustulosis

The FDA warning was based on a review of medical literature and cases of adverse reactions reported to the FDA Adverse Event Reporting System (FAERS) database.[3]

Signs and symptoms

Typical prodromal symptoms of Stevens-Johnson syndrome are as follows:

Cough productive of a thick, purulent sputum Headache Malaise Arthralgia

Patients may complain of a burning rash that begins symmetrically on the face and the upper part of the torso. The cutaneous lesions are characterized as follows:

The rash can begin as macules that develop into papules, vesicles, bullae, urticarial plaques, or confluent erythema

The typical lesion has the appearance of a target; this is considered pathognomonic

In contrast to the typical lesions of erythema multiforme, these lesions have only 2 zones of color

The lesion’s core may be vesicular, purpuric, or necrotic; that zone is surrounded by macular erythema

Lesions may become bullous and later rupture, leaving denuded skin; the skin becomes susceptible to secondary infection

Urticarial lesions typically are not pruritic Infection may be responsible for the scarring associated with morbidity Although lesions may occur anywhere, the palms, soles, dorsum of the hands, and

extensor surfaces are most commonly affected The rash may be confined to any one area of the body, most often the trunk

Signs of mucosal involvement can include the following:

Erythema Edema Sloughing Blistering Ulceration Necrosis

The following ocular signs may be noted on slit-lamp examination:

Eyelids: Trichiasis, distichiasis, meibomian gland dysfunction, blepharitis Conjunctiva: Papillae, follicles, keratinization, subepithelial fibrosis, conjunctival

shrinkage, foreshortening of fornices, symblepharon, ankyloblepharon Cornea: Superficial punctate keratitis, epithelial defect, stromal ulcer,

neovascularization, keratinization, limbitis, conjunctivalization, stromal opacity, perforation

Diagnosis

Minimal dermal inflammatory cell infiltrate and full-thickness necrosis of the epidermis are typical histopathologic findings in patients with Stevens-Johnson syndrome. Histopathologic examination of the skin can also reveal the following:

Changes in the epidermal-dermal junction ranging from vacuolar alteration to subepidermal blisters

Dermal infiltrate: Superficial and mostly perivascular Apoptosis of keratinocytes CD4+ T lymphocytes predominating in the dermis; CD8+ T lymphocytes

predominating in the epidermis; the dermoepidermal junction and epidermis is infiltrated mostly by CD8+ T lymphocytes

Ocular examination can demonstrate the following:

Conjunctival biopsies from patients with active ocular disease show subepithelial plasma cells and lymphocyte infiltration; lymphocytes also are present around vessel walls; the predominant infiltrating lymphocyte is the helper T cell

Immunohistology of the conjunctiva reveals numerous HLA-DR–positive cells in the substantia propria, vessel walls, and epithelium

Management

Most patients with Stevens-Johnson syndrome are treated symptomatically. In principle, the symptomatic treatment of patients with this disorder does not differ from the therapy applied to patients with extensive burns.

Patients should be treated with special attention to airway and hemodynamic stability, fluid status, wound/burn care, and pain control. Therapy for Stevens-Johnson syndrome proceeds as follows:

Withdrawal of any agent suspected of causing the condition is critically important Oral lesions are managed with mouthwashes; topical anesthetics are useful in

reducing pain and allowing the patient to take in fluids Areas of denuded skin must be covered with compresses of saline or Burow

solution Tetanus prophylaxis must be addressed

Extensive debridement of nonviable epidermis followed by immediate cover with biologic dressings is among the recommended treatments.

Ocular therapy

The treatment of acute ocular manifestations usually begins with aggressive lubrication of the ocular surface. As inflammation and cicatricial changes ensue, most ophthalmologists use topical steroids, antibiotics, and symblepharon lysis.

In the case of mild chronic superficial keratopathy, long-term lubrication may be sufficient. In cases of severe ocular involvement, treatment includes the following:

Removal of keratinized plaques from the posterior lid margins Mucous membrane grafting and/or amniotic membrane grafting Limbal stem cell transplantation and amniotic membrane grafting Superficial keratectomy removing conjunctivalized or keratinized ocular surface

A patient with severe eye involvement associated with Stevens-Johnson syndrome. Note corneal neovascularization and conjunctivalization of the ocular surface.

BackgroundStevens-Johnson syndrome (SJS) is an immune-complex–mediated hypersensitivity complex that typically involves the skin and the mucous membranes. While minor presentations may occur, significant involvement of oral, nasal, eye, vaginal, urethral, gastrointestinal, and lower respiratory tract mucous membranes may develop in the course of the illness. GI and respiratory involvement may progress to necrosis. Stevens-Johnson syndrome is a serious systemic disorder with the potential for severe morbidity and even death.

The syndrome was first described in 1922, when the American pediatricians Albert Mason Stevens and Frank Chambliss Johnson reported the cases of 2 boys aged 7 and 8 years with "an extraordinary, generalized eruption with continued fever, inflamed buccal mucosa, and severe purulent conjunctivitis." Both cases had been misdiagnosed by primary care physicians as hemorrhagic measles.

Erythema multiforme (EM), originally described by von Hebra in 1866, was part of the differential diagnosis in both cases but was excluded because of the "character of skin lesions, the lack of subjective symptoms, the prolonged high fever, and the terminal heavy crusting." Despite the presence of leukopenia in both cases, Stevens and Johnson in their initial report suspected an infectious disease of unknown etiology as the cause.

In 1950, Thomas divided EM into 2 categories: erythema multiforme minor (von Hebra) and erythema multiforme major (EMM). Since 1983, erythema multiforme major and Stevens-Johnson syndrome had been considered synonymous.

In the 1990s, however, Bastuji and Roujeau each proposed that erythema multiforme major and Stevens-Johnson syndrome are 2 distinct disorders.[4] They suggested that the denomination of erythema multiforme should be restricted to patients with typical targets or raised edematous papules, with or without mucosal involvement. This clinical picture is in accordance with the original description by von Hebra.

Bastuji and Roujeau further proposed that the denomination of Stevens-Johnson syndrome should be used for a syndrome characterized by mucous membrane erosions and widespread small blisters that arise on erythematous or purpuric maculae that are different from classic targets.

According to this clinical classification, erythema multiforme major and Stevens-Johnson syndrome could be 2 distinct disorders with similar mucosal erosions, but different patterns of cutaneous lesions. This hypothesis is supported further by a strong correlation between clinical classification and the probable cause.

Conversely, several investigators propose that Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) represent the same disease at different levels of severity. A unifying classification of "acute disseminated epidermal necrosis" or "exanthematic necrolysis" has been suggested.

Although several classification schemes have been reported, the simplest breaks the disease down as follows[1] :

Stevens-Johnson syndrome - A "minor form of TEN," with less than 10% body surface area (BSA) detachment

Overlapping Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) - Detachment of 10-30% BSA

Toxic epidermal necrolysis - Detachment of more than 30% BSA

An argument against this unifying concept was that HSV infection had been described as a frequent cause of Stevens-Johnson syndrome/erythema multiforme major but not of toxic epidermal necrolysis. However, reports showed that HSV infection has not been related to Stevens-Johnson syndrome, and suggested that clinical manifestations and pathology results support the linking of Stevens-Johnson syndrome and toxic epidermal necrolysis, and their differentiation from erythema multiforme.

Various etiologic factors (eg, infection, drugs, malignancies) have been implicated as causes of Stevens-Johnson syndrome. However, as many as half of cases are idiopathic. There is strong evidence for a genetic predisposition to Stevens-Johnson syndrome provoked by certain drugs.

There are no specific laboratory studies (other than biopsy) that can definitively establish the diagnosis of Stevens-Johnson syndrome .No specific treatment of Stevens-Johnson syndrome is noted; most patients are treated symptomatically. In principle, the symptomatic treatment of patients with Stevens-Johnson syndrome does not differ from the treatment of patients with extensive burns. Withdrawal of the suspected offending agent is critically important. Immunomodulatory treatment is controversial.

PathophysiologyAn idiosyncratic, delayed hypersensitivity reaction has been implicated in the pathophysiology of Stevens-Johnson syndrome. Certain population groups appear more susceptible to develop Stevens-Johnson syndrome than the general population. Slow acetylators, patients who are immunocompromised (especially those infected with HIV[5, 6]

), and patients with brain tumors undergoing radiotherapy with concomitant antiepileptics are among those at most risk.

Slow acetylators are people whose liver cannot completely detoxify reactive drug metabolites. For example, patients with sulfonamide-induced toxic epidermal necrolysis

have been shown to have a slow acetylator genotype that results in increased production of sulfonamide hydroxylamine via the P-450 pathway. These drug metabolites may have direct toxic effects or may act as haptens that interact with host tissues, rendering them antigenic.[7, 8]

Antigen presentation and production of tumor necrosis factor (TNF)–alpha by the local tissue dendrocytes results in the recruitment and augmentation of T-lymphocyte proliferation and enhances the cytotoxicity of the other immune effector cells.[9] A "killer effector molecule" has been identified that may play a role in the activation of cytotoxic lymphocytes.[10] The activated CD8+ lymphocytes, in turn, can induce epidermal cell apoptosis via several mechanisms, which include the release of granzyme B and perforin.

In 1997, Inachi et al demonstrated perforin-mediated apoptosis in patients with Stevens-Johnson syndrome.[11] Perforin, a pore-making monomeric granule released from natural killer cells and cytotoxic T lymphocytes, kills target cells by forming polymers and tubular structures not unlike the membrane attack complex of the complement system.

Apoptosis of keratinocytes can also take place as a result of ligation of their surface death receptors with the appropriate molecules. Those can trigger the activation of the caspase system, leading to DNA disorganization and cell death.[12]

Apoptosis of keratinocytes can be mediated via direct interaction between the cell-death receptor Fas and its ligand. Both can be present on the surfaces of the keratinocytes. Alternatively, activated T-cells can release soluble Fas ligand and interferon-gamma, which induces Fas expression by keratinocytes.[1] Researchers have found increased levels of soluble Fas ligand in the sera of patients with SJS/TEN before skin detachment or onset of mucosal lesions.[13]

The death of keratinocytes causes separation of the epidermis from the dermis. Once apoptosis ensues, the dying cells provoke recruitment of more chemokines. This can perpetuate the inflammatory process, which leads to extensive epidermal necrolysis.[14]

Higher doses and rapid introduction of allopurinol[15] and lamotrigine[16] may also increase the risk of developing SJS/TEN. Risk is lessened by starting these at the low doses and titrating gradually.[17]

There is evidence that systemic lupus is a risk factor as well.[18]

EtiologyVarious etiologic factors have been implicated as causes of Stevens-Johnson syndrome. Drugs most commonly are blamed. The 4 etiologic categories are as follows:

Infectious Drug-induced Malignancy-related Idiopathic

Stevens-Johnson syndrome is idiopathic in 25-50% of cases. Drugs and malignancies are most often implicated as the etiology in adults and elderly persons. Pediatric cases are related more often to infections.

1. Infectious causes

Viral diseases that have been reported to cause Stevens-Johnson syndrome include the following:

Herpes simplex virus (possibly; remains a debated issue) AIDS Coxsackie viral infections Influenza Hepatitis Mumps

In children, Epstein-Barr virus and enteroviruses have been identified. More than half of the patients with Stevens-Johnson syndrome report a recent upper respiratory tract infection.

Bacterial etiologies include the following:

Group A beta-hemolytic streptococci Diphtheria Brucellosis Lymphogranuloma venereum Mycobacteria Mycoplasma pneumoniae[19, 20]

Rickettsial infections Tularemia Typhoid

Possible fungal causes include coccidioidomycosis, dermatophytosis, and histoplasmosis. Malaria and trichomoniasis have been reported as protozoal causes.

2. Drug-induced

Antibiotics are the most common cause of Stevens-Johnson syndrome, followed by analgesics, cough and cold medication, NSAIDs, psychoepileptics, and antigout drugs. Of antibiotics, penicillins and sulfa drugs are prominent; ciprofloxacin has also been reported[21]

The following anticonvulsants have been implicated:

Phenytoin Carbamazepine oxcarbazepine (Trileptal)

Valproic acid Lamotrigine Barbiturates

Mockenhapupt et al stressed that most anticonvulsant-induced SJS occurs in the first 60 days of use.[22]

Antiretroviral drugs implicated in Stevens-Johnson syndrome include nevirapine and possibly other non-nucleoside reverse transcriptase inhibitors.[23] Indinavir has been mentioned.

Stevens-Johnson syndrome has also been reported in patients taking the following drugs:

Modafinil (Provigil) Allopurinol[24]

Mirtazapine[25]

TNF-alpha antagonists (eg, infliximab, etanercept, adalimumab)[26]

Cocaine Sertraline Pantoprazole Tramadol

3. Genetic factors

There is strong evidence for a genetic predisposition to severe cutaneous adverse drug reactions such as Stevens-Johnson syndrome. Carriage of the following human leukocyte antigens has been associated with increased risk:

HLA-B*1502 HLA-B*5801 HLA-B*44 HLA-A29 HLA-B12 HLA-DR7 HLA-A2 HLA-B*5801 HLA-A*0206 HLA-DQB1*0601

Certain of these HLA alleles are associated with an increased probability of developing Stevens-Johnson syndrome upon exposure to specific drugs. The US Food and Drug Administration (FDA) and Health Canada advise screening for HLA-B*1502 in patients of southeastern Asian ethnicity before starting treatment with carbamazepine. (The risk is much lower in other ethnic populations, making screening impractical in them). HLA-B*5801 confers a risk of allopurinol-related reactions.[27] Pretreatment screening is not readily available.[28]

Whites with HLA-B*44 appear to be more susceptible to develop Stevens-Johnson syndrome. HLA-A29, HLA-B12, and HLA-DR7 are frequently associated with sulfonamide-induced Stevens-Johnson syndrome, while HLA-A2 and HLA-B12 are often encountered in Stevens-Johnson syndrome induced by nonsteroidal anti-inflammatory drugs (NSAIDs).

HLA-A*0206 and HLA-DQB1*0601 allele have been shown to be was strongly associated with Stevens-Johnson syndrome with ocular disease.[29, 30]

Nevertheless, whether the presence of those genes constitutes a predisposition to Stevens-Johnson syndrome or whether those genes are in linkage disequilibrium with more relevant adjacent genes is unknown.[31]

EpidemiologyStrom et al reviewed Medicaid billing data from 1980-1984 in Michigan, Minnesota, and Florida to determine the incidence of Stevens-Johnson syndrome; the incidence rates were 7.1, 2.6, and 6.8 cases per million population per year, respectively.[32]

Cases tend to have a propensity for the early spring and winter.

For overlapping SJS and TEN, oxicam NSAIDs (piroxicam, meloxicam, tenoxicam) and sulfonamides are most commonly implicated in the United States and other western nations.

SJS occurs with a worldwide distribution similar in etiology and occurrence to that in the United States. However, a study from Germany reported only 1.1 cases per 1 million person-years.

In contrast to the drugs most often implicated in western nations, allopurinol is the most common offending agent in Southeast Asian nations, including Malaysia, Singapore, Taiwan, and Hong Kong.

Race-, sex-, and age-related demographics

Stevens-Johnson syndrome has been described worldwide in all races, although it may be more common in whites. Interestingly, disease is not limited to humans; cases have been reported in dogs, cats, and monkeys.

The proportion of females has been estimated to be 33-62%. The largest series reports 39.9% of females in a group of 315 patients with Stevens-Johnson syndrome.

In a large cohort, the mean age of patients with Stevens-Johnson syndrome was 25 years. In a smaller series, the mean age of patients with Stevens-Johnson syndrome was reported as 47 years. However, cases have been reported in children as young as 3 months.

PrognosisIndividual lesions typically should heal within 1-2 weeks, unless secondary infection occurs. Most patients recover without sequelae.

Mortality is determined primarily by the extent of skin sloughing. When body surface area (BSA) sloughing is less than 10%, the mortality rate is approximately 1-5%. However, when more than 30% BSA sloughing is present, the mortality rate is between 25% and 35%, and may be as high as 50% Bacteremia and sepsis appear to play a major role in increased mortality.

The SCORTEN score (a severity-of-illness score for toxic epidermal necrolysis) calculates the risk for death in both SJS and TEN on the basis of the following variables:

Age >40 years Malignancy Heart rate >120 Initial percentage of epidermal detachment >10% Blood urea nitrogen (BUN) level >10 mmol/L Serum glucose level >14 mmol/L Bicarbonate level < 20 mmol/L

Each variable is assigned a value of 1 point. Mortality rates are as follows:

0-1 points, ≥3.2% 2 points, ≥12.1% 3 points, ≥35.3% 4 points, ≥58.3% 5 or more points, ≥90%

Other negative prognostic factors include persistent neutropenia (defined as neutropenia lasting more than 5 days), hypoalbuminemia (usually < 2 g/dL), and persistent azotemia.

In a survival analysis of a cohort of patients with either Stevens-Johnson syndrome or toxic epidermal necrolysis, Sekula et al found that the severity of the cutaneous reaction causing either of these disorders was a risk factor for mortality, but only during the first 90 days following reaction onset.[35] The investigators also found that serious comorbidities and age were risk factors for mortality after 90 days, but not beyond 1 year, past reaction onset. Mortality among patients was 23% at 6 weeks and 34% at 1 year.

Although some patients rapidly progress to lose very large areas of the epidermis in a matter of days, the process suddenly ceases in others and reepithelialization begins a few days later. Predicting the course of disease in a given patient at the initial presentation is not possible. Reepithelialization is usually complete within 3 weeks, but pressure and mucosal areas may remain eroded and crusted for 2 weeks or longer.

Survivors of Stevens-Johnson syndrome may experience numerous long-term sequelae; the most disabling are those of the eye. Cicatrization of conjunctival erosions may lead to the following:

Inverted eyelashes Photophobia A burning sensation in the eyes

Watery eyes A siccalike syndrome Corneal and conjunctival neovascularization

As many as 40% of survivors of toxic epidermal necrolysis have residual potentially disabling lesions that may cause blindness.

TreatmentManagement of patients with Stevens-Johnson syndrome is usually provided in intensive care units or burn centers. No specific treatment of Stevens-Johnson syndrome is noted; therefore, most patients are treated symptomatically. In principle, the symptomatic treatment of patients with Stevens-Johnson syndrome does not differ from the treatment of patients with extensive burns.

Prehospital and emergency department care

Paramedics should recognize the presence of severe fluid loss and should treat patients with Stevens-Johnson syndrome as they would patients with thermal burns.

Most patients present early and prior to obvious signs of hemodynamic compromise. The single most important role for the ED physician is to detect Stevens-Johnson syndrome/toxic epidermal necrolysis early and initiate the appropriate ED and inpatient management.

Withdrawal of the suspected offending agent is critically important. Timing of withdrawal has been linked to outcome. Underlying diseases and secondary infections must be identified and treated.

Patients should be treated with special attention to airway and hemodynamic stability, fluid status, wound/burn care, and pain control. Care in the ED must be directed to fluid replacement and electrolyte correction. Treatment is primarily supportive and symptomatic. Some have advocated corticosteroids, cyclophosphamide, plasmapheresis, hemodialysis, and immunoglobulin.

Manage oral lesions with mouthwashes. Topical anesthetics are useful in reducing pain and allowing the patient to take in fluids.

Skin lesions are treated as burns. Areas of denuded skin must be covered with compresses of saline or Burow solution.

Address tetanus prophylaxis.

Supportive Systemic TherapyFluid management is provided by macromolecules and saline solutions during the first 24 hours. Phosphate salts are necessary in the presence of hypophosphatemia. The amount of

fluids required in patients with Stevens-Johnson syndrome is usually less than in those patients with burns covering the same body surface area.

After the second day of hospitalization, oral intake of fluids provided by nasogastric tube is often begun, so that intravenous fluids can be tapered progressively and discontinued, usually in 2 weeks.

Massive parenteral nutrition is necessary as soon as possible to replace the protein loss and to promote healing of cutaneous lesions. Intravenous insulin therapy may be required because of impaired glycoregulation.

Environmental temperature raised to 30-32°C reduces caloric loss through the skin. Fluidized air beds are recommended if a large portion of the skin on the patient's backside is involved. Heat shields and infrared lamps are used to help reduce heat loss.

Anticoagulation with heparin for the duration of hospitalization is recommended. Antacids reduce the incidence of gastric bleeding.

Pulmonary care includes aerosols, bronchial aspiration, and physical therapy. Tranquilizers are used to the extent limited by respiratory status.

Infection ControlPatients with Stevens-Johnson syndrome are at a high risk of infection. Sterile handling and/or reverse-isolation nursing techniques are essential to decrease the risk of nosocomial infection. Cultures of blood, catheters, gastric tubes, and urinary tubes must be performed regularly.

Because of the association between Stevens-Johnson syndrome and sulfonamides, avoid the use of silver sulfadiazine, which is commonly used in burn units. Instead, use another antiseptic, such as 0.5% silver nitrate or 0.05% chlorhexidine, to paint and bathe the affected skin areas.

Prophylactic systemic antibiotics are not recommended. Antimicrobials are indicated in cases of urinary tract or cutaneous infections, either of which may lead to bacteremia.

The diagnosis of sepsis is difficult. Carefully consider the decision to administer systemic antibiotics. The first signs of infection are an increase in the number of bacteria cultured from the skin, a sudden drop in fever, and deterioration of the patient's condition, indicating the need for antibiotic therapy.

The choice of antibiotic is usually based on the bacteria present on the skin. Because of impaired pharmacokinetics, similar to that present in burn patients, the administration of high doses may be required to reach therapeutic levels. Monitoring the serum levels is necessary to adjust the dosage.

Skin CareSeveral skin care approaches have been described. Extensive debridement of nonviable epidermis, followed by immediate cover with biologic dressings, are among the recommended treatments. Biologic dressings may include the following:

Porcine cutaneous xenografts Cryopreserved cutaneous allografts Amnion-based skin substitutes Collagen-based skin substitutes

The ophthalmology literature supports concurrent coverage of the involved eye(s) with amniotic membrane.[37]

Leaving the involved epidermis that has not yet peeled off in place and using biologic dressings only on raw dermis also has been recommended. Skin allotransplantation reduces pain, minimizes fluid loss, improves heat control, and prevents bacterial infection. Hyperbaric oxygen can also improve healing.

Immunomodulatory TherapyStevens-Johnson syndrome is a rare disorder with relatively high mortality and morbidity rates. To date, because of a lack of consensus on the proposed therapeutic modalities, intensive supportive management and withdrawal of the offending drug remain the criterion standard.

For any intervention, a prospective randomized controlled trial would be the most appropriate step to validate its use. However, a large number of patients are required to reach statistical significance. Furthermore, for ethical reasons, withdrawal of a potentially life-saving therapy for the sake of randomization with a placebo control is not possible.

Several therapeutic modalities have been advocated for the treatment of Stevens-Johnson syndrome based on the current, yet incomplete, understanding of its pathogenetic mechanisms. Plasmapheresis, immunosuppressive therapy, and intravenous immunoglobulin (IVIG) have been used with variably successful results.

The use of systemic steroids remains controversial. Some authors believe that they are contraindicated, especially because there may be some question about the diagnosis. Patients with infection-induced erythema multiforme do worse when steroids are given. (Note that the differentiation between Stevens-Johnson syndrome and erythema multiforme should be possible even in the acute stage.)[38] Prolonged treatment with systemic steroids has been associated with an increased prevalence of complications.

However, concerns about the safety of systemic corticosteroids in the treatment of Stevens-Johnson syndrome are based on a few case series; in those reports, systemic corticosteroids were administered too late in the course of the disease, in inappropriately low doses, and for a very long duration that actually impaired the healing process and increased the risk of sepsis. The currently advocated approach for corticosteroid use suggests the early use of short-term (4-7 days), high-dose intravenous corticosteroids.[39, 40]

The ophthalmology literature contains several papers that advocate systemic and topical steroids to minimize ocular morbidity.[41, 42] Authors have cited salvage of vision when pulse steroid therapy has been given.[38, 42] Others have concluded that IV steroids and immunoglobulins do not improve outcome.[43]

The role of other immunosuppressive therapy, that is, cyclosporine, azathioprine, or cyclophosphamide, in the acute phase is less popular, particularly since such medication typically takes weeks to begin to influence immunological reactions. Cyclophosphamide has been reported to be the culprit drug that induced Stevens-Johnson syndrome in one instance.[44]

Nevertheless, the role of cyclosporine in the treatment of the acute phase of Stevens-Johnson syndrome has been revisited, and, indeed, it showed encouraging results.[12] Also, immunosuppressive therapy may play a pivotal role in the management of the chronic ocular surface inflammation that can occur later on in selected cases.

The rationale for the use of IVIG is the most appealing. Based on in vitro and clinical data, IVIG can block the Fas receptors on the surface of the keratinocytes, thus interfering with the Fas-Fas ligand mediated apoptosis.[45] Encouraging results were reported when IVIG was used in high doses very early in the course of the disease and for a short period. Unfortunately, there is no consensus with regard to either the dose or the duration of treatment with IVIG.[8]

Prophylactic use of IVIG has also been reported. One group used IVIG in a patient who underwent cardiac catheterization but who had 4 previous Stevens-Johnson syndrome episodes after intravenous contrast injection.[46]

However, a large European study designed to evaluate the efficacy of various treatments, the EuroSCAR Study, "found no sufficient evidence of a benefit for any specific treatment."[47] The group looked at mortality in patients treated with IVIG and corticosteroids. However, in a letter to the editor, Pehr disagreed with the findings in the EuroSCAR study citing inadequate doses of IVIG and corticosteroids in that study.[48]

Interestingly, few studies have addressed the effect of systemic steroids or IVIG on either the development or the outcome of ocular manifestations in Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN). Neither treatment appeared to have an effect on the ocular outcome in patients in two reports.[49, 4]

Treatment of Acute Ocular ManifestationsTreatment of acute ocular manifestations usually begins with aggressive lubrication of the ocular surface. As inflammation and cicatricial changes ensue, most ophthalmologists use topical steroids, antibiotics, and symblepharon lysis.

In case of exposure keratopathy, tarsorrhaphy may be required.

Maintenance of ocular integrity can be achieved through the use of amniotic membrane grafting, adhesive glues, lamellar grafts, and penetrating keratoplasty, either in the acute phase or in subsequent follow-up care.

Visual rehabilitation in patients with visual impairment can be considered once the eye has been quiet for at least 3 months.

Treatment of Chronic Ocular Manifestations

In the case of mild chronic superficial keratopathy, long-term lubrication may be sufficient. In addition to lubrication, some patients may require a cosmetically acceptable long-term lateral tarsorrhaphy.

The visual rehabilitation in patients with severe ocular involvement, resulting in profound dry eye syndrome with posterior lid margin keratinization, limbal stem cell deficiency, persistent epithelial defects with subsequent corneal neovascularization, and frank corneal opacity with surface conjunctivalization and keratinization, is difficult and often frustrating for both the patient and the physician. A close, usually long-term, relationship between the patient and the ophthalmologist needs to be established to achieve the best possible result.

The removal of keratinized plaques from the posterior lid margins, along with mucous membrane grafting and/or amniotic membrane grafting, is usually the first step and one of the most important determining factors in the future success of corneal surgeries. Preferably, a skilled oculoplastic surgeon with specific experience on patients with Stevens-Johnson syndrome should perform this procedure.

Subsequently, limbal stem cell transplantation and amniotic membrane grafting with superficial keratectomy removing conjunctivalized or keratinized ocular surface can follow. Patients with persistent corneal opacity require lamellar or penetrating keratoplasty in the next step, but each exposure to alloantigenic material increases the odds of tissue rejection. Therefore, the author’s advice is to strive for major, if not perfect, resurrection of the useful vision, rather than perform allografts of both eyes and keratoplasties.

To preserve corneal clarity after the visual reconstruction, the long-term use of gas-permeable scleral contact lenses may be necessary to protect the ocular surface. Long-term management frequently involves the treatment of trichitic lashes and/or eyelid margin repair for distichiasis or entropion. If the ocular surface repeatedly fails to heal after multiple surgical interventions, keratoprosthesis may be considered as a last resort.

Consultations and Long-Term MonitoringConsultants may help establish the diagnosis and direct inpatient care. A dermatologist is the most likely clinician to establish the diagnosis, with or without biopsy. Severe cases may require the involvement of a burn specialist or plastic surgery specialist. Internal medicine, critical care, or pediatrics consultants direct inpatient care. Ophthalmology consultation is mandatory for those with ocular involvement. Depending on organ system involvement, consultations with a gastroenterologist, pulmonologist, and nephrologist may be helpful.

Patients with SJS require regular monitoring of their medications and status. Although patients with erythema multiforme minor may be treated as outpatients with topical steroids, those with erythema multiforme major (ie, Stevens-Johnson syndrome) must be hospitalized. Cases of erythema multiforme minor must be followed closely. Some authors recommend daily follow-up.

2- Toxic Epidermal Necrolysis

Toxic epidermal necrolysis (TEN) is a potentially life-threatening dermatologic disorder characterized by widespread erythema, necrosis, and bullous detachment of the epidermis and mucous membranes, resulting in exfoliation and possible sepsis and/or death (see the image below). Mucous membrane involvement can result in gastrointestinal hemorrhage, respiratory failure, ocular abnormalities, and genitourinary complications.

Diffuse maculopapular rash in toxic epidermal necrolysis (TEN).

TEN is most commonly drug induced. However, the disorder has other potential etiologies, including infection, malignancy, and vaccinations (see Etiology). TEN is idiosyncratic, and its occurrence is not easily predicted.

Some authors believe that Stevens-Johnson syndrome (SJS; also known as erythema multiforme major) is a manifestation of the same process involved in TEN, with the latter involving more extensive necrotic epidermal detachment. TEN involves more than 30% of the body surface, whereas SJS involves less than 10% (see Differentials).

A classification system, based largely on the extent of epidermal detachment and morphology of the skin lesions, aids in differentiating opposite spectrums of the same disease entity.[1] This system comprises the following:

TEN with spots TEN without spots Overlap Stevens-Johnson syndrome and TEN (SJS-TEN)

TEN with spots is defined as widespread, irregularly shaped erythematous or purpuric macules with blistering that occurs on all or part of the macule. Blisters become more confluent and result in detachment of the epidermis and erosions on greater than 30% of the body surface area. Mucosal surfaces are usually involved.

TEN without spots is defined as widespread, large areas of erythema with no discrete lesions. Epidermal detachment is greater than 10% of the body surface area. Mucosal surfaces are usually involved.

Overlap Stevens-Johnson syndrome and TEN (SJS-TEN) is characterized by widespread, irregularly shaped erythematous or purpuric macules with blistering that occurs on all or part of the macule. Blisters become confluent and result in detachment of the epidermis and erosions on 10-29% of the body surface area.

TEN is a clinical diagnosis, confirmed by histopathologic analysis of lesional skin (see Clinical and Workup). The mainstay of treatment is supportive care until the epithelium regenerates. Early transfer of patients to a burn or intensive care unit has been shown to reduce the risk of infection, mortality rate, and length of hospitalization (see Treatment).

Historical background

Alan Lyell provided an early description of TEN in 1956, describing the condition as "an eruption resembling scalding of the skin."[2] This dermatologic condition is characterized by extensive epidermal loss suggestive of severe scalding. In that same year, Lang and Walker reported a case of TEN.[3] The disorder was originally described by Debre et al in 1939 in French as l'erythrodermie bulleuses avec epidermolyse.[4]

Lyell later reclassified the conditions of 2 of his patients as having staphylococcal scalded skin syndrome,[5] which is due to Staphylococcus aureus infection rather than to a probable drug hypersensitivity-type reaction. Histopathologic analysis of the skin remains the main tool for discrimination between the two conditions.

Patient education

Patients who have had TEN must be counseled regarding the likely causative medication or agent, and they must be advised to avoid these medications and those of the same or similar classes in the future. Cross-reactivity may occur with agents that chemically resemble the causative agent. Patients must call a pharmacist whenever they start a new prescription.

Genetic factors are suspected in drug-induced blistering disorders, and blood relatives of the patient also should not use the suspected drug.

PathophysiologyThe pathophysiology of TEN has not been fully elucidated; however, various theories have received wide acceptance. TEN is believed to be an immune-related cytotoxic reaction aimed at destroying keratinocytes that express a foreign antigen.

TEN mimics a hypersensitivity reaction, with its characteristic delayed reaction to an initial exposure and an increasingly rapid reaction with repeated exposure.

The widespread epidermolysis and blistering of TEN results from keratinocyte apoptosis—an organized series of biochemical reactions leading to cell changes and cell death.[6]

However, the number of inflammatory T cells in the skin of patients with TEN is variable and perhaps too low to explain the widespread destruction.[7]

There is evidence supporting several immunopathologic pathways leading to keratinocyte apoptosis in TEN, including the following:

Fas ligand activation on keratinocyte membranes leading to death receptor–mediated apoptosis[8]

Release of destructive proteins (perforin and granzyme B) from cytotoxic T lymphocytes (CTLs) generated from an interaction with cells expressing major histocompatability complex (MHC) class I[9]

Overproduction of T cell– and/or macrophage-derived cytokines (interferon-γ [INF-γ], tumor necrosis factor-α [TNF-α], and various interleukins)[10, 11]

Drug-induced secretion of granulysin from CTLs, natural killer cells, and natural killer T cells[12]

Precisely how the inciting agent triggers the proposed pathways is yet to be elucidated.

EtiologyTEN can be induced by drugs or infection or can be idiopathic. Medications are the major precipitating cause. Numerous medications have been implicated,[13] including antibiotics, antiepileptic drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), ampicillin, allopurinol, corticosteroids (topical and systemic), and the antiretroviral drugs nevirapine and abacavir.[14, 15]

Antibacterial drugs associated with TEN include the following:

Sulfonamides (4.5 cases per million users per week) Chloramphenicol Macrolides (eg, erythromycin) Penicillins Quinolones (eg, ciprofloxacin,[16] trovafloxacin[17] )

Anticonvulsants associated with TEN include the following:

Phenobarbital Phenytoin[18]

Carbamazepine Valproic acid Lamotrigine

TEN in patients taking anticonvulsants has most often been reported within 2 months of starting the drug. However, some cases associated with long-term use have been reported.

NSAIDs associated with TEN include the following:

Phenylbutazone and oxybutazone - Implicated most commonly, although they are no longer available in the United States

Oxicams (eg, piroxicam, tenoxicam) - Implicated more often than other NSAIDs Ibuprofen Indomethacin Sulindac Tolmetin

With allopurinol, risk is not constant over time. Patients have a 5.5 relative risk. However, during the first 2 months of therapy, the relative risk is 52, and the long-term therapy risk is 0.5.

No laboratory test is able to confirm a specific drug etiology. A causal link is suggested when TEN occurs during the first 4 weeks of medication therapy, usually between 1 and 3 weeks. Drugs with longer half-lives and those with circulating active metabolites may result in more fulminant disease.

Infectious agents (ie, Mycoplasma pneumoniae, herpes virus, hepatitis A), immunizations, and bone marrow or solid organ transplantation have also been associated with TEN.

EpidemiologyIn the United States, the annual frequency of TEN is reported to be 0.22-1.23 cases per 100,000 population. In the HIV-positive population, the incidence of TEN increases to 1 case per thousand per year.[19]

Worldwide, the average annual incidence of TEN is 0.4-1.3 cases per million population.[20] In 1992, the cumulative incidence of TEN and SJS in Germany was 1.9 cases per million population. A French survey of dermatologists and health care facilities reported an annual incidence of 1 case per million population.

Race-, sex-, and age-related demographics

A genetic predilection toward carbamazepine-induced TEN has been observed in HLA-B*1502–positive Han Chinese patients.[21] The US Food and Drug Administration recommends screening for the HLA-B*1502 allele before initiating carbamazepine in patients of Asian ancestry.[22]

For unclear reasons, TEN appears to have a predilection for females. The female-to-male ratio is 1.5:1.[23]

TEN may occur in all age groups; however, the mean age of patients with TEN is reported to be between 46 and 63 years. Infection is more commonly implicated as an etiology in children, whereas medication exposure is more common in adults. Elderly persons may be at greater risk because of their tendency to use multiple medications.

PrognosisThe estimated mortality associated with TEN varies widely in different reports, from 10-70%. Outcome depends in part on the quality of care and the rapidity with which treatment is initiated.

Septicemia and multisystem organ failure are the primary causes of death. Epithelial loss results in vulnerability to bacterial and fungal infections. Sloughing of stratified epithelium of mucosal membranes can result in GI hemorrhage, respiratory failure, ocular abnormalities, and genitourinary lesions. Significant fluid loss from extensive skin

exfoliation and an inability to tolerate oral intake can lead to hypovolemia, acute tubular necrosis, and shock.

Age, extent of epidermal involvement, and serum urea level are said to be the most important prognostic factors in TEN.[24] Mortality rates in children are much lower than in adults.[25] Elderly patients have a poor prognosis.

Other negative prognostic factors include the following:

Elevated blood urea nitrogen (BUN) and serum creatinine levels Respiratory failure Multiple drugs Thrombocytopenia Lymphopenia Neutropenia Leukopenia Sepsis

Severity-of-illness score

A severity-of-illness score that estimates the risk of death in TEN (SCORTEN) has been developed and validated.[26] Each of the following independent prognostic factors is given a score of 1:

Age >40 years Heart rate >120 beats per minute Cancer or hematologic malignancy Involved body surface area >10% Blood urea nitrogen level >10 mmol/L (28 mg/dL) Serum bicarbonate level < 20 mmol/L (20 mEq/L) Blood glucose level >14 mmol/L (252 mg/dL)

The number of positive criteria and the corresponding mortality rates are as follows:

0: 1 to 3% 2: 12% 3: 35% 4: 58% 5 or more: 90%

Treatment

Prehospital care for patients with TEN is similar to that for patients with burns. Supplement with oxygen by face-mask as needed; do not perform prophylactic tracheal intubation. Prevent hypothermia with rewarming devices and blankets.

In severe TEN, the barrier function of the skin is compromised. Thus, contamination and evaporation must be minimized. The patient should be treated similarly to one with extensive burns, that is, with the application of sterile coverings. Fluid and pulmonary status must be carefully monitored.

Emergency Department CareFor the emergency physician, the two most important elements in the treatment of TEN are discontinuation of the offending drug and admission to a burn unit.[33] Evidence suggests that rapid institution of these two measures is associated with a more favorable prognosis.[34, 35]

Emergency department care should be directed toward the following:

Maintaining fluid and electrolyte homeostasis Mitigating temperature loss Providing adequate analgesia Preventing secondary infection

Aggressive fluid and electrolyte management, pain control, and meticulous skin care are important. Fluid resuscitation with crystalloids should follow standard guidelines used for burn patients. However, patients with TEN typically require less aggressive fluid replacement than that of burn patients because of less severe microvascular injury.

A goal of resuscitation should be to maintain sufficient mean arterial blood pressure (ABP >65 mm Hg), central venous pressure (CVP 8-12 mm Hg), and central oxygenation (Svco2 >70%) for adequate tissue perfusion and renal perfusion.[23] Fluid management should be based on the physiologic endpoint of urine output of 0.5-1 mL/kg/h.[33]

Patients with extensive skin involvement require reverse isolation and a sterile environment. Areas of skin erosion should be covered with nonadherent protective dressings such as petrolatum gauze. Respiratory distress may result from mucosal sloughing and edema and may necessitate endotracheal intubation and ventilation.

Approach ConsiderationsManagement of toxic epidermal necrolysis (TEN) requires prompt recognition of the disorder and withdrawal of all potential causative agents. The mainstay of treatment is supportive care until the epithelium regenerates. Supportive measures include isolation, fluid and electrolyte balance, nutritional support, pain management, and protective dressings. Early transfer of patients to a burn or intensive care unit has been shown to reduce the risk of infection, mortality rate, and length of hospitalization.

Withdraw the offending agent, if one is identified, as soon as possible. One observational study showed a reduction in mortality from 26% to 5% when the implicated drugs with short elimination half-lives were withdrawn no later than the day the blisters or erosions first developed.

No controlled prospective treatment studies or generally accepted guidelines exist. In 1991, Avakian and colleagues published the University of Florida treatment protocol for

toxic epidermal necrolysis.[31] In 2007, these guidelines were revised by Fromowitz and colleagues.[32] The guidelines are as follows:

Monitor fluids and electrolytes. Administer fluids and titrate based on central venous pressure and urine output; on average, 3-4 L are needed in patients with 50% of the body surface area affected.

Parenteral nutrition or nutrition provided enterally via a soft-fine bore nasogastric tube is usually needed. Start total parenteral nutrition in patients unable to take nourishment. Early and continuous enteral nutrition reduces the risk of stress ulcers, reduces bacterial translocation and enterogenic infection, and allows earlier discontinuation of venous lines.

Supportive Systemic TherapyThe patient should be placed in a heated environment to enhance reepithelialization. However, this may enhance water losses, and appropriate hydration must be maintained. Institute a bed warmer.

Saline applied to skin hourly is important, and then emollients are smeared. Chlorhexidine solution is used to bathe the patient's skin. Chlorhexidine mouthwash is administered 4 times a day, and white petrolatum is administered to the lips. Rinse the patient’s mouth frequently and apply a topical anesthetic or spray for buccal pain.

Provide daily physical therapy for range-of-motion exercises.

Place a Foley catheter and nasogastric tube only when needed.

Energy requirements for patients with TEN must be carefully calculated and nutritional support provided. Protein loss can be significant.[25]

Patients with mucosal vulnerability may have severe bleeding complications. Coagulation factors and blood counts should be held within the normal ranges, and transfusion of red cells, platelets, and plasma products should be considered when necessary.[23]

Ocular complications are common and can be debilitating. Early consultation with an ophthalmologist is recommended to assess and minimize the risk of ocular damage. Treatments with topical lubricants/antibiotics and steroid drops are often needed.

Wound care

Meticulous wound care is necessary to prevent secondary infection. Debate continues in the literature regarding whether or not to debride the wounds associated with toxic epidermal necrolysis. To date, no conclusive evidence supports early, late, or no debridement of the wounds. Cutaneous lesions heal in approximately 2 weeks; mucosal membrane lesions take longer.

If debridement of necrotic and desquamation areas is chosen, it is performed with the patient under general anesthesia. Apply porcine xenografts to involved areas.

Provide hydrotherapy (whirlpool) twice a day. Repair and replace porcine xenografts. Apply Kerlix dressings soaked in silver nitrate 0.5% to involved areas after each whirlpool session.

Pharmacologic therapies

Emergence of resistance precludes the use of prophylactic antibiotics. Bacterial sampling of skin lesions should be performed the first day and every 48 hours. Indicators for antibiotic treatment include increased number of bacteria cultured from the skin with selection of a single strain, sudden decrease in temperature, or deterioration of the patient's condition.

Empiric antimicrobial therapy should include broad-spectrum antimicrobials that cover gram-negative, gram-positive, and anaerobic organisms. phylococcus aureus is the main bacteria present during the first days, with gram-negative strains appearing later. If staphylococcal infection is involved, administer an appropriate antistaphylococcal agent (ie, nafcillin/oxacillin for methicillin-sensitive organisms or vancomycin for methicillin-resistant organisms).

Provide pain relief with patient-controlled analgesia (PCA). Opiate analgesics for skin pain and anxiety are essential for comforting patients. Hydroxyzine may be used to relieve the intense pruritus that may occur when reepithelialization begins.

Patients remain nonambulatory until skin begins to heal. Until that time, anticoagulant therapy is imperative. Heparin is indicated for prophylaxis of thromboembolic events.

Apply chloramphenicol ointment to prevent infection. Silver sulfadiazine should be avoided because it is a sulfonamide derivative and may precipitate TEN. Silver compounds not utilizing sulfadiazine or other sulfa medications should be used because they assist in wound healing and prevent infection and bacterial growth.

No specific treatment modality has been proven effective, including the following:

Plasmapheresis Corticosteroids Cyclophosphamide Cyclosporine Tumor necrosis factor–alpha (TNF-alpha) inhibitors Intravenous immune globulin (IVIg)[6, 36]

Multiple studies of these modalities have been completed, and multiple studies are ongoing. Completed studies have shown that either the risk of the medication outweighs the benefit or the data are inconclusive to support its utilization. Therefore, there is a significant need for randomized control studies to further evaluate potential treatment modalities in TEN.

Corticosteroids are commonly used to control progression of TEN, but this is highly controversial. In some studies, corticosteroids have increased the incidence of mortality.

Consider the use of plasmapheresis, if available, daily for 3 days. Although prospective randomized studies have not been performed, limited data suggest that plasmapheresis may enhance elimination of the drug or offending agent or inflammatory mediators such as cytokines and should be considered.[37]

Anti–TNF-α treatment has been reported to rapidly resolve skin lesions due to TEN. TNF-α is strongly expressed in keratinocytes and macrophages of lesional skin, and high concentrations are found in cutaneous blister fluid.

Sucrose-depleted IVIg 1 g/kg/d (infused over 4 h) for 3 days may be beneficial if started within 48-72 hours of bulla onset. If more than 72 hours have elapsed since the onset of bulla but TEN is still actively progressing, with new lesions, IVIg may still be useful.

ConsultationsMost patients with TEN require specialized care under the direction of a team of physicians with experience in handling this disorder. Burn-unit care represents an option worthy of serious consideration.

Required consultations may include the following:

A dermatologist is consulted to identify and to confirm the diagnosis of TEN A plastic surgeon is consulted to debride areas of skin necrosis, as indicated An ophthalmologist is consulted for assisting in the treatment of ocular

manifestations and preventing long-term sequelae An internal medicine specialist is consulted to assist in patient treatment Consultation with a respiratory medicine specialist may be important, since

respiratory mucosa may slough; establishment of pulmonary toilet may be advisable

Otolaryngologic or urologic consultation may be helpful in patients with significant mucous membrane involvement of those areas.

Sequelae

Major sequelae are generally limited to the affected organ systems (ie, the skin and mucosal membranes).

Cutaneous sequelae of TEN include the following:

Changes in skin pigment (hypopigmentation or hyperpigmentation; sun exposure must be avoided for several months because ultraviolet light can worsen hyperpigmentation; sunblock is recommended)

Nail loss and nail dystrophy Hypohidrosis (inability to sweat) Scarring, alopecia, and hypertrophic scarring Dermal desiccation, causing deep dermal wounds

Chronic xerostomia Esophageal strictures Vulvovaginal synechiae Phimosis Chronic erosion of the mouth and genitalia

Ocular complications generally result from abnormal keratinization of the tarsal conjunctiva. A Sjogrenlike syndrome with decreased lacrimal secretion causes dry eye and predisposes to corneal abrasions and corneal scarring with neovascularization. In addition, patients have been reported to have palpebral synechiae, entropion, or symblepharon (adhesion of the eyelids).[27]

A study by Power and colleagues found that 50% of patients with TEN developed ocular complications.[28] Patients treated with steroids fared no better than those treated without steroids. Therefore, TEN remains a common cause of visual loss in a significant number of patients. Ultimately, 5-9% of patients can become blind as a result of some of these complications.

3-Erythema Multiforme

Erythema multiforme (EM) is an acute, self-limited, and sometimes recurring skin condition that is considered to be a type IV hypersensitivity reaction associated with certain infections, medications, and other various triggers.[1]

Erythema multiforme may be present within a wide spectrum of severity. Erythema multiforme minor represents a localized eruption of the skin with minimal or no mucosal involvement. The papules evolve into pathognomonic target lesions or iris lesions that appear within a 72-hour period and begin on the extremities (see the following image). Lesions remain in a fixed location for at least 7 days and then begin to heal. Lesions may also appear as arcuate lesions (see the second image below). Precipitating factors include herpes simplex virus (HSV), Epstein-Barr virus (EBV), 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.

Target lesion of erythema multiforme

. Raised atypical targets and arcuate lesions.

Erythema multiforme major and Stevens-Johnson syndrome (SJS), however, are more severe, potentially life-threatening disorders (see the image below). Lesions of Steven-Johnson syndrome 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.

Note extensive sloughing of epidermis.

Erythema multiforme vs SJS and TENS

Controversy exists in the literature with regard to the clinical definitions of erythema multiforme and Steven-Johnson syndrome and whether they are distinct entities or whether they represent a spectrum of one disease process.[2, 3, 4, 5, 6, 7] International collaborators have suggested that erythema multiforme and Steven-Johnson syndrome could be separated as 2 distinct clinical disorders with similar mucosal reactions but different patterns of cutaneous lesions.

The confusion between these 2 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 Ferdinand von Hebra as erythema multiforme (acute, self-limited condition with characteristic red papular skin lesions) (1860).[2] Erythema multiforme major was applied to patients who also displayed oral mucosal involvement, similar to that described by Stevens and Johnson (mucocutaneous disorder; febrile erosive stomatitis, severe conjunctivitis, and disseminated cutaneous eruption) (1922).[3]

Up to 50% of patients with herpes simple virus (HSV)–associated erythema multiforme have been found to have oral ulcers. However, this is now recognized as a variant of erythema multiforme, rather than Steven-Johnson syndrome. Erythema multiforme and Steven-Johnson syndrome have different precipitating factors and different clinical patterns and are generally recognized to be separate clinical entities. Erythema multiforme with mucosal involvement is now termed bullous erythema multiforme.

Consensus classification

According to a consensus definition, Steven-Johnson syndrome was separated from the erythema multiforme spectrum and added to toxic epidermal necrolysis.[3] Essentially Steven-Johnson syndrome and toxic epidermal necrolysis (TEN) are considered severity variants of a single entity. The 2 spectra are now divided into the following: (1) erythema multiforme consisting of erythema minor and major and (2) Steven-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN).

The clinical descriptions are as follows:

Erythema multiforme minor - Typical targets or raised, edematous papules distributed acrally

Erythema multiforme major - Typical targets or raised, edematous papules distributed acrally with involvement of one or more mucous membranes; epidermal detachment involves less than 10% of total body surface area (TBSA).

SJS/TEN - Widespread blisters predominant on the trunk and face, presenting with erythematous or pruritic macules and one or more mucous membrane erosions; epidermal detachment is less than 10% TBSA for Steven-Johnson syndrome / toxic epidermal necrolysis and 30% or more for toxic epidermal necrolysis.

Historical information

Stevens-Johnson syndrome was considered an extreme variant of erythema multiforme for many years, whereas toxic epidermal necrolysis (TEN) was considered a different entity. However, in 1993, a group of medical experts proposed a consensus definition and classification of erythema multiforme, Steven-Johnson syndrome, and toxic epidermal necrolysis based on a photographic atlas and extent of body surface area involvement.[3]

PathophysiologyThe pathophysiology of erythema multiforme (EM) is still not completely understood, but it is probably immunologically mediated and appears to involve a hypersensitivity reaction that can be triggered by a variety of stimuli, particularly bacterial, viral, or chemical products.

Cell-mediated immunity appears to be responsible for the destruction of epithelial cells. Early in the disease process, the epidermis becomes infiltrated with CD8 T lymphocytes and macrophages, whereas 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 T-helper cell type 1 (TH1) cytokine response (interferon [IFN] gamma, tumor necrosis factor [TNF] alpha, interleukin [IL] 2). Results of immunohistochemical analysis have also shown lesion blister fluid to contain TNF, an important proinflammatory cytokine.

Other evidence supports the hypothesis that the disease is the result of cell-mediated immune reactions. Individuals possessing human leukocyte antigen (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.

Herpes simplex virus

A major cause of erythema multiforme is the herpes virus (HSV). In fact, recent or recurrent herpes has been reported as the principle risk factor for erythema multiforme.

Herpes-associated erythema multiforme (HAEM) appears to represent the result of a cell-mediated immune reaction associated with HSV antigen.[8, 9] The immunologic reaction affects HSV-expressing keratinocytes. Cytotoxic effector cells, CD8+ T lymphocytes in the epidermis, induce apoptosis of scattered keratinocytes and lead to satellite cell necrosis. Neighboring epidermal cells are HLA-DR positive.

A relationship exists between HLA types A33, B35, B62 (B15), DR4, DQB1*0301, DQ3, and DR53 and recurrent erythema multiforme.[10] In particular, HLA-DQ3 is especially related to recurrent erythema multiforme and may be a helpful marker for distinguishing HAEM from other cutaneous diseases.[11]

Drug hypersensitivity

The disease process also often involves an abnormal metabolism of a responsible drug. As noted above, the keratinocyte is the ultimate target of this disease process, with keratinocyte necrosis being the earliest pathologic 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.

EtiologyMany suspected etiologic factors have been reported to cause erythema multiforme (EM). Both erythema multiforme and Steven-Johnson syndrome may be induced by medications, but infectious agents are also considered to be a major cause of erythema

multiforme. However, approximately 50% of cases are idiopathic, with no precipitating factor identified.

A previous history of erythema multiforme and male sex has also been reported as risk factors, but pregnancy may contribute to development of erythema multiforme as well.

Postvaccination causes include Bacille Calmette-Guérin (BCG) vaccination, oral polio vaccine, vaccinia, and tetanus/diphtheria.

HSV and other infections

Infectious causes are more common in children and are implicated more commonly in erythema multiforme.

Erythema multiforme minor is regarded as being commonly triggered by herpes simplex virus (HSV) (types 1 and 2), and HSV is the most common cause in young adults; in fact, many instances of idiopathic erythema multiforme minor may be precipitated by subclinical HSV infection. Among other infections, Mycoplasma species appear to be a common cause.

Bacterial

Bacterial infections include borreliosis, catscratch disease, diphtheria, hemolytic streptococci, legionellosis, leprosy, Neisseria meningitidis, Mycobacterium avium complex, M pneumoniae,[12, 13] pneumococci, tuberculosis, Proteus/Pseudomonas/Salmonella/Staphylococcus/Yersinia species, Treponema pallidum,[14] tularemia, Vibrio parahaemolyticus, Vincent disease, and rickettsial infections. Chlamydial infections include lymphogranuloma venereum and psittacosis.

Viral

Viral infections include Adenovirus, coxsackievirus B5, cytomegalovirus (CMV), echoviruses, enterovirus, Epstein-Barr virus (EBV), hepatitis A / B / C viruses (HAV / HBV / HCV), HSV, influenza,[15] measles, mumps, paravaccinia, parvovirus B19, poliomyelitis, varicella-zoster virus (VZV), and variola.

Virus-drug interactions include CMV infection–terbinafine[16] and EBV infection–amoxicillin.[17]

Other

Fungal infections include coccidioidomycosis, dermatophytosis, and histoplasmosis.

Parasitic infections include Trichomonas species and Toxoplasma gondii.

Drugs

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.

Regarding medications, sulfa drugs are the most common triggers (30%). A slow acetylator genotype is a risk factor for sulfonamide-induced Steven-Johnson syndrome.[18]

The second most commonly involved agents are the anticonvulsants, including barbiturates,[19] carbamazepine,[19] hydantoin, phenytoin,[19] and valproic acid. Prophylactic anticonvulsants after surgery for a brain tumor combined with cranial irradiation may result in life-threatening Steven-Johnson syndrome.[20]

Causative antibiotics include penicillin, ampicillin, tetracyclines, amoxicillin, cefotaxime, cefaclor, cephalexin, ciprofloxacin,[21] erythromycin, minocycline, sulfonamides, trimethoprim-sulfamethoxazole, and vancomycin.

Antituberculoid agents such as rifampicin, isoniazid, thiacetazone, and pyrazinamide are also known offenders. Antipyretic agents as triggers include analgesics, especially aspirin as well as phenylbutazone, oxyphenbutazone, and phenazone.

Others drugs that may cause erythema multiforme include acarbose, albendazole, allopurinol,[19] arsenic, bromofluorene, quinine (Chinine), cimetidine, clofibrate, corticosteroids, diclofenac, didanosine, dideoxycytidine, diphosphonate, estrogen, etretinate, fluconazole, griseofulvin,[22] gabapentin, granulocyte-macrophage colony-stimulating factor (GM-CSF), hydralazine, indapamide, indinavir, lamotrigine,[19]

methazolamide, mefloquine, methotrexate, meprobamate, mercurials, minoxidil, nifedipine, nevirapine,[19] nitrogen mustard, nystatin, nonsteroidal anti-inflammatory drugs (NSAIDs), phenolphthalein, piroxicam,[19] pyritinol, progesterone, potassium iodide, sulindac, suramin, saquinavir, thiabendazole, thiouracil, terbinafine, theophylline, verapamil, and dihydrocodeine phosphate.[23]

Contact exposure

Contactants include ammoniated mercury, budesonide, bufexamac, capsicum, chloromethylnaphthalene, desoximetasone, dinitrochlorobenzene (DNCB), disperse blue 124, diphenylcyclopropenone, fire sponge (Tedania ignis), herbal medicines (eg, Alpinia galanga),[24] isopropyl-p -phenylenediamine of rubber, nickel, nitrogen mustard, oxybenzone, phenylbutazone, poison ivy,[25] proflavin, resin, rosewood, and triamcinolone acetonide.

Other etiologic factors

The following have also been reported as causes of erythema multiforme:

Flavorings and preservatives, such as benzoic acid and cinnamon[26]

Immunologic disorders, such as transient selective C4 deficiency of infancy,[27]

collagen diseases, vasculitides, sarcoidosis, non-Hodgkin lymphoma, leukemia, multiple myeloma, myeloid metaplasia, and polycythemia

Physical or mechanical factors, such as tattooing, radiotherapy, cold, and sunlight Foods, including salmon berries and margarine Malignancy Hormonal

EpidemiologyThe exact incidence of erythema multiforme (EM) in the United States is unknown; however, as many as 1% of dermatologic outpatient visits are for erythema multiforme. Globally, the frequency of erythema multiforme is estimated at approximately 1.2-6 cases per million individuals per year.

Before the human immunodeficiency virus (HIV) epidemic among young males, there was a slight female predominance of this disease. However, erythema multiforme is currently more common in younger males (male-to-female ratio, range of 3:2 to 2:1) (mainly second to fourth decades, but can include children and adolescents [20%][28] ). The condition is rare in children younger than 3 years and in adults older than 50 years.

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 (SLE), graft versus host disease (GVHD), and inflammatory bowel disease (IBD). Individuals undergoing radiation, chemotherapy, or neurosurgery for brain tumors are also at higher risk.

PrognosisMost cases of erythema multiforme (EM) are self-limited. In erythema multiforme minor, the lesions evolve over 1-2 weeks and ultimately subside within 2-3 weeks without scarring. However, the recurrence of erythema multiforme minor is common (up to one third of cases) and mostly preceded by apparent or subclinical herpes simplex virus (HSV) infection.

Erythema multiforme major has a mortality rate of less than 5% and is directly proportional to the total body surface area of sloughed epithelium. It usually has a more protracted course than erythema multiforme minor; clearing may require 3-6 weeks. Skin lesions usually heal with hyperpigmentation and/or hypopigmentation. Scarring is usually absent, except after secondary infection. Sepsis secondary to loss of the cutaneous barrier is the principle cause of death.

Advanced age, visceral involvement, increased serum urea nitrogen level, and previous bone marrow transplantation are poor prognostic factors. Surprisingly, although the incidence of erythema multiforme is increased among individuals with human immunodeficiency virus (HIV) infection (approaching 1 case per 1000 individuals per year), they do not appear to have a higher mortality rate.

Continuous and persistent erythema multiforme

Two additional rare clinical forms of erythema multiforme have been reported. Continuous erythema multiforme manifests as a prolonged course with overlapping attacks and may be associated with systemic administration of glucocorticoids.

Persistent erythema multiforme has a protracted clinical course over months, is commonly associated with atypical skin lesions, and is commonly resistant to conventional treatment. It has been reported in association with inflammatory bowel

disease (IBD), occult renal carcinoma, persistent or reactivated Epstein-Barr virus (EBV) infection, and HSV infection.

TreatmentFor all forms of erythema multiforme (EM), the most important treatment is usually symptomatic, including oral antihistamines, analgesics, local skin care, and soothing mouthwashes (eg, oral rinsing with warm saline or a solution of diphenhydramine, xylocaine, and kaopectate). Topical steroids may be considered. For more severe cases, meticulous wound care and use of Burrow or Domeboro solution dressings may be necessary.

The cause of the erythema multiforme should be identified, if possible. If a drug is suspected, it must be withdrawn as soon as possible. This includes all medications begun during the preceding 2 months. Discontinue all unnecessary medications. Studies have shown that prompt withdrawal of causative drugs will reduce the risk of death by about 30% per day.

Infections should be appropriately treated after cultures and/or serologic tests have been performed. The use of liquid antiseptics, such as 0.05% chlorhexidine, during bathing helps prevent superinfection. Topical treatment, including that for genital involvement, may be performed with a gauze dressing or a hydrocolloid.

Local supportive care for eye involvement is important and includes topical lubricants for dry eyes, sweeping of conjunctival fornices, and removal of fresh adhesions.

Suppression of herpes simplex virus (HSV) can prevent HSV-associated erythema multiforme, but antiviral treatment started after the eruption of erythema multiforme has no effect on the course of the erythema multiforme.

Prehospital and Emergency Department CareIn severe cases, prehospital personnel may need to treat respiratory complications and fluid imbalances aggressively, in the same manner as thermal burns.

Mild cases of erythema multiforme (EM) require only symptomatic treatment in the emergency department (ED), which may include analgesics or nonsteroidal inflammatory drugs (NSAIDs); cold compresses with saline or Burrow solution; topical steroids; and soothing oral treatments such as saline gargles, viscous lidocaine, and diphenhydramine elixir.

Aggressive monitoring and replacement of fluids and electrolytes are of paramount importance.

Provide supportive respiratory care, including suctioning and postural drainage, as needed. Use analgesics as needed to control pain, which may be severe.

Administer empiric antibiotics if clinical evidence of secondary infection exists. Most authorities advise against routine use of prophylactic antibiotics.

Avoid systemic corticosteroids in minor cases. In severe cases, their use is controversial, because these agents do not improve prognosis and may increase risk of complications.

HospitalizationErythema multiforme (EM) major may require hospitalization for the treatment of complications and sequelae (eg, severe mucous membrane involvement is present or with impaired oral intake, dehydration, or secondary infection) and to manage the patient's fluid and electrolytes. The most severe cases should be managed in intensive care or burn units.

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.

Care in a surgical specialty burn unit may provide the greatest likelihood of survival. Areas of denuded skin should be managed like thermal burns, although debridement is best avoided while lesions are still progressing. Eroded areas may be bathed q1-2d with saline or Burrow's solution and dressed with nonadherent dressings.

Treat patients for herpes simplex virus (HSV) or M pneumoniae -related erythema multiforme. Intravenous (IV) antibiotics may be necessary to treat secondary infections. Implement barrier isolation to decrease risk of infection.

Immediately withdraw all potentially causative drugs. The healing process usually takes about 2 weeks, during which time proper skin care is essential. Practice aseptic handling and avoid adhesive materials. Use topical agents such as 0.5% silver nitrate solution or 0.05% chlorhexidine solution to cleanse the skin. Warm these solutions before application. Avoid silver sulfadiazine because of its causative association.

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.

After the acute period of illness has passed and the patient has survived, mucous membrane sequelae may require surgical intervention.

Fluid resuscitation and nutritional support

Several issues make nutritional support critical. A liquid diet and IV fluid therapy may be necessary.

Fluid and electrolytes may be lost through the disrupted skin barrier, and 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. Oral antacids may be helpful for discrete oral ulcers.

Profuse diarrhea may result from gastrointestinal involvement, making oral or enteral feeding difficult. Parenteral nutrition may be appropriate.

Increased energy expenditure, such as from increased core body temperature, 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.

Fluid and electrolyte resuscitation are approximately 66-75% of that required for a similarly sized burn wound. 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. Change all catheters, peripheral or central, at regular intervals.

Monitor the adequacy of fluid resuscitation with the use of a urinary bladder catheter. Minimum urine output for adults is 0.5 mL/kg/h; for children, it is 1 mL/kg/h.

Pulmonary support

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).

Other supportive care

Maintain thermoregulation by keeping the environmental temperature at 30-32°C, administering only warmed fluids, and using heating lamps or warming blankets.

The use of a pressure support surface, an air or gel mattress, or a specialty bed is recommended to prevent pressure sores. Use antacids, proton pump inhibitors, or histamine 2 blockers to prevent stress ulceration.

Administer subcutaneous heparin to prevent the development of deep venous thrombosis (DVT).

ComplicationsMost patients with erythema multiforme (EM) have an uncomplicated course, with the exception of hosts who are immunocompromised and those with secondary bacterial infections of the skin or the mucosa. Healing of the mucosal areas is usually complete.

Scars and strictures of the esophageal, urethral, vaginal, and anal mucosa rarely occur. However, severe oral involvement may be accompanied by difficulty in consuming food and fluid and can result in dehydration, and vaginal and urethral erosions may cause urinary retention and phimosis. Hematocolpos is the result of genital lesions in teenage females. Severe scarring of the genitourinary tract may cause vaginal and urethral stenosis.

Severe eye complications (20%), such as purulent conjunctivitis, anterior uveitis, panophthalmitis, scarring of the conjunctivae, symblepharon, may result in permanent blindness. Other ocular sequelae may include:

Epiphora secondary to obstruction of the lacrimal ducts Sjögren-like sicca syndrome of dry eyes, punctate keratitis, corneal pannus, and

mucin deficiency in tears In-turned eyelashes, corneal scarring, corneal and conjunctival

neovascularization, epithelial proliferation with squamous metaplasia, photophobia, burning eyes, visual impairment

Other complications include the following:

Patchwork appearance of the skin, with hypopigmented regions and potential hypertrophic scarring

Pneumonia / acute respiratory distress syndrome (ARDS) Dehydration and electrolyte disturbances Possible gastrointestinal (GI) hemorrhage, nephritis, and renal failure

ConsultationsConsultation with the following specialists may be necessary:

Dermatologist: For diagnosis and management and for performance of skin biopsies, if indicated

Internal medicine specialist or a pediatric specialist: For evaluation of the underlying causes of disorders and systemic sequelae

Ophthalmologist: For early consultation in the evaluation and management of ocular involvement; daily examinations for signs of ocular involvement; if necessary, disruption of synechiae can be accomplished by administration of wetting or antibiotic eyedrops

Burn or trauma surgeon: For familiarity with caring for critically ill patients with burn wounds who have open wounds

Infectious disease specialists: For evaluation of intercurrent infections and treatment recommendations

Respiratory therapist: For tracheobronchial involvement Physical or occupational therapists Psychologists, psychiatrists, or social workers may be helpful.

Monitoring and Prevention The medical professional(s) who treated the patient during hospitalization should see the patient regularly and provide symptomatic relief, as needed. Such practitioners may include burn or trauma surgeons, ophthalmologists, nephrologists, infectious disease specialists, and gastroenterologists.

The affected skin should be protected from any pressure or shear forces. Otherwise, early institution of physical and occupational therapies is appropriate. To reduce the likelihood

of developing hyperpigmentation, recommend the use of sunscreens for 1 year after the incident has resolved.

Topical corticosteroids are useful for outpatient treatment of patients with limited disease.

Prophylaxis for recurrence of herpes-associated erythema multiforme (HAEM) should be considered in patients with more than 5 attacks per year; oral acyclovir may be helpful in reducing recurrence (see Medications). Prophylaxis may be required for 6-12 months or longer. If the patient's condition is unresponsive, continuous therapy with valacyclovir has been reported to be effective.[30]

Tamoxifen may prevent premenstrual erythema multiforme.

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.

Once erythema multiforme (EM) due to a drug 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. Chemically related compounds often share a common metabolic pathway that may be abnormal in the affected individual. Sulfonamide-containing ointments should also be avoided.

First-degree relatives of an affected patient have an increased risk of reactions to similar drugs

Patient EducationEducate patients with erythema multiforme (EM) about appropriate symptomatic treatment, and provide reassurance that disease is usually self-limited. In addition, advise patients of the significant risk of recurrence and emphasize the avoidance of any identified etiologic agent.