Chapter 40. Epidermal Necrolysis (Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis)

Toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS) are acute life-threatening mucocutaneous reactions characterized by extensive necrosis and detachment of the epidermis. Stevens and Johnson first reported two cases of disseminated cutaneous eruptions associated with an erosive stomatitis and severe ocular involvement.1 In 1956, Lyell described patients with epidermal loss secondary to necrosis and introduced the term toxic epidermal necrolysis.2 Both SJS and TEN are characterized by skin and mucous membrane involvement. Because of the similarities in clinical and histopathologic findings, risk factors, drug causality, and mechanisms, these two conditions are now considered severity variants of an identical process that differs only in the final extent of body surface involved.3–5 Therefore, it is better to use the designation epidermal necrolysis for both, as proposed by Ruiz-Maldonado (acute disseminated epidermal necrosis)6 and Lyell (exanthematic necrolysis).7

Epidermal necrolysis (EN) is rare. The overall incidence of SJS and TEN was estimated at 1 to 6 cases per million person-years and 0.4 to 1.2 cases per million person-years, respectively.8,9 EN can occur at any age, with the risk increasing with age after the fourth decade, and more frequently affects women, showing a sex ratio of 0.6. Patients infected with human immunodeficiency virus and to a lesser degree patients with collagen vascular disease and cancer are at increased risk.10–12 The overall mortality associated with EN is 20% to 25%, varying from 5% to 12% for SJS to more than 30% for TEN. Increasing age, significant comorbidity, and greater extent of skin involvement correlate with poor prognosis. In the United States, evaluation of death certificates suggested a seven time higher risk of dying from EN among blacks than whites.13

A prognosis score (SCORTEN) has been constructed for EN,14 and its usefulness has been confirmed by several teams.15–18 (See Table 40-1.)

The pathophysiology of EN is still unclear; however, drugs are the most important etiologic factors. More than 100 different drugs have been implicated,19–21 but fewer than a dozen “high-risk” medications account for about one half of cases in Europe (Table 40-2), as evidenced by two multinational case–control studies.12,22–25 These high-risk drugs are antibacterial sulfonamides, aromatic anticonvulsants, allopurinol, oxicam nonsteroidal anti-inflammatory drugs, lamotrigine, and nevirapine.26–27 The risk seems confined to the first 8 weeks of treatment. Slow dose escalation decreases the rate of rash with lamotrigine and nevirapine,28,29 but there is no evidence that it decreases the risk of EN.26 Oxcarbazepine, a 10-keto derivative of carbamazepine, which was considered to carry a lower risk, seems to significantly cross-react with carbamazepine.30 Many nonsteroidal anti-inflammatory drugs (primarily oxicam derivatives and diclofenac) were suspected to be associated with EN.12,31,32 A significant but much lower risk has also been reported for non-sulfonamide antibiotics such as aminopenicillins, quinolones, cephalosporins, and tetracyclines.22 Corticosteroids were significantly associated with a high relative risk, but confounding was not excluded.22

The role of infectious agents in the development of EN is much less prominent than for erythema multiforme. However, cases of EN associated with Mycoplasma pneumoniae infection, viral disease, and immunization have been reported, particularly in children.33,34 These rare observations underscore the fact that medications are not the only cause of EN, but there is still little evidence that infections can explain more than a very small percentage of cases.

Cases of EN have been reported after bone marrow transplantation. Some are an extreme form of acute graft-versus-host disease (see Chapter 28); others could be drug induced. The relationship between EN and graft-versus-host disease is difficult to assess because clinical and histological skin features are nearly indistinguishable.35 Lupus erythematosus (systemic LE or subacute cutaneous LE) is associated with an increased risk of EN.12,22 In such cases, drug causality is often doubtful and necrolysis might be an extreme phenotype of cutaneous lupus.36 Finally, radiotherapy in addition to treatment with antiepileptic drugs, such as phenytoin, phenobarbital, or carbamazepine, can trigger EN with lesions localized predominantly at sites of radiation treatment.37,38 In clinical practice, the causality of a medication can be clearly established in approximately 60% of cases and suspected in 20%. Other causes (infection, GVH, LE) are rarely apparent, about 20% of cases as idiopathic.39

Even if the precise sequence of molecular and cellular events is incompletely understood, several studies provided important clues to the pathogenesis of EN. The immunologic pattern of early lesions suggests a cell-mediated cytotoxic reaction against keratinocytes leading to massive apoptosis.39–41 Immunopathologic studies have demonstrated the presence within early lesions of cytotoxic cells including natural killer T cells (NKT) and drug-specific CD8+ T lymphocytes; monocytes/macrophages and granulocytes are also recruited.42–44 However, it is generally accepted that specific and nonspecific cytotoxic cells are too few within the lesions to explain the death of cells on the full thickness and large areas of the epidermis and mucous membranes. Amplification by cytokines has been suspected for years, especially for factors activating “death receptors” on cell membranes, especially antitumor necrosis factor (TNF) α and soluble Fas ligand (Fas-L).42,45 In the past decade it had been widely accepted that Fas-L was inducing the apoptosis of keratinocytes in EN,45,46 despite partial evidence and discordant findings.47–49 An important recent study has challenged this dogma by demonstrating the key role in EN of granulysin.50 Granulysin was present in the blister fluid of EN at concentrations much higher than those of perforin, granzyme B, or Fas-L. At such concentrations, only granulysin, and to a much lesser degree perforin, were able to kill human keratinocytes in vitro; Fas-L was not. Furthermore injection of granulysin in the dermis of normal mice resulted in clinical and histological lesions of EN.50

When combined, the above results strongly suggest that the effector mechanisms of EN have been deciphered. Cytotoxic T-cells develop and are usually specifically directed against the native form of the drug rather than against a reactive metabolite, contrarily to what has been postulated for 20 years. These cells kill keratinocytes directly and indirectly through the recruitment of other cells that release soluble death mediators, the principal being granulysin.50,51

These advances on understanding the final steps of the reaction point to inhibition of release and/or blockade of granulysin as major aims of therapeutic interventions.

Little is known on what are the initial and intermediate steps. We still do not understand why very few individuals develop a violent immune response to medications and why effector cells are especially directed to the skin and other epithelia. Actually, most drugs associated with a “high risk” for EN can also induce a variety of milder and more frequent reactions. Drug-specific CD8 cytotoxic T-lymphocytes were also often found in skin reactions with more benign phenotype.52 Hence, it is tempting to speculate on an abnormal regulation of immune response. Regulatory CD4+ CD25+ T cells have been demonstrated to be potentially important in the prevention of severe epidermal damage induced by reactive cytotoxic T lymphocytes in a mouse model of EN.53 Similar regulatory cells may play a role in drug eruptions in humans.54 Altered regulation of the immune response to medications in patients with EN could result from comorbidities that are frequent, for example, cancer, HIV infection, collagen vascular disease; from comedications, for example, corticosteroids; or from genetic background.

Genetic susceptibility plays an important role in the development of EN to a few “high-risk” medications. A strong association was observed in Han Chinese from Taiwan between the human leukocyte antigen HLA-B*1502 and EN induced by carbamazepine, and between HLA-B*5801 and EN induced by allopurinol.55,56 B*1502 association with carbamazepine-related cases was confirmed in several Asian countries,57,58 with the remarkable exceptions of Japan and Korea.59,60 The association between carbamazepine-induced EN and HLA-B*1502 was not present in European patients who do not have Asian ancestry.61 On the other hand, HLA-B*5801 was confirmed to be associated with allopurinol-related EN in Japan59 and Europe,62 but the strength of association was lower than in Taiwan.

Even in cases requiring immediate referral to specialized wards, the dermatologist will have a specific role in the management of patients with EN (Fig. 40-1).

History

EN clinically begins within 8 weeks (usually 4 to 30 days) after the onset of drug exposure for the first time. Only in very rare cases with prior reaction and inadvertent rechallenge with the same drug does it appear more rapidly, within a few hours. Nonspecific symptoms such as fever, headache, rhinitis, cough, or malaise may precede the mucocutaneous lesions by 1 to 3 days. Pain on swallowing and burning or stinging of the eyes progressively develop, heralding mucous membrane involvement. About one-third of cases begin with nonspecific symptoms, one-third with symptoms of mucous membrane involvement, and one-third with an exanthema. Whatever the initial symptoms are, their rapid progression, the addition of new signs, severe pain, and constitutional symptoms should alert one to the onset of a severe disease.

Cutaneous Lesions

The eruption is initially symmetrically distributed on the face, the upper trunk, and the proximal part of limbs.63 The distal portions of the arms as well as the legs are relatively spared, but the rash can rapidly extend to the rest of the body within a few days and even within a few hours. The initial skin lesions are characterized by erythematous, dusky red, purpuric macules, irregularly shaped, which progressively coalesce. Atypical target lesions with dark centers are often observed (Fig. 40-2A). Confluence of necrotic lesions leads to extensive and diffuse erythema. Nikolsky's sign, or dislodgement of the epidermis by lateral pressure, is positive on erythematous zones (Fig. 40-3 and eFig. 40-3.1). At this stage, the lesions evolve to flaccid blisters, which spread with pressure and break easily (see Fig. 40-2B). The necrotic epidermis is easily detached at pressure points or by frictional trauma, revealing large areas of exposed, red, sometimes oozing dermis (see Figs. 40-2C and 40-2D). In other areas, epidermis may remain.

Patients are classified into one of three groups according to the total area in which the epidermis is detached or “detachable” (positive Nikolsky): (1) SJS, less than 10% of body surface area (BSA); (2) SJS/TEN overlap, between 10% and 30%; (3) TEN, more than 30% of BSA (eFig. 40-3.2). Correct evaluation of the extent of lesions is difficult, especially in zones with spotty lesions. It is helpful to remember that the surface of one hand (palm and fingers) represents a little less than 1% of the BSA.

Mucous Membrane Involvement

Mucous membrane involvement (nearly always on at least two sites) is observed in approximately 90% of cases and can precede or follow the skin eruption. It begins with erythema followed by painful erosions of the oral, ocular, and genital mucosa. This usually leads to impaired alimentation, photophobia, conjunctivitis, and painful micturition. The oral cavity and the vermilion border of the lips are almost invariably affected and feature painful hemorrhagic erosions coated by grayish white pseudomembranes and crusts of the lips (Fig. 40-4). Approximately 80% of patients have conjunctival lesions,64,65 mainly manifested by pain, photophobia, lacrimation, redness, and discharge. Severe forms may lead to epithelial defect corneal ulceration, anterior uveitis, and purulent conjunctivitis. Synechiae between eyelids and conjunctiva often occur. There may be shedding of eyelashes (see Fig. 40-4B). Genital erosions are frequent, often overlooked in women, and may lead to synechiae.66

Shedding of nails occurs in severe forms.

Extracutaneous Symptoms

EN is associated with high fever, pain, and weakness. Visceral involvement is also possible, particularly with pulmonary and digestive complications. Early pulmonary complications occur in approximately 25% of patients and are essentially manifested by elevated respiratory rate and cough, which should prompt strict surveillance.67,68 Bronchial involvement in EN is not correlated with the extent of skin lesions or with the offending agent. In most cases chest radiographs are normal on admission but can rapidly reveal interstitial lesions that can progress to acute respiratory distress syndrome (ARDS). In all reported cases, when acute respiratory failure developed rapidly after the onset of skin involvement, it was associated with poor prognosis. In the case of respiratory abnormalities, fiberoptic bronchoscopy may be useful to distinguish a specific epithelial detachment in the bronchi from an infectious pneumonitis, which has a much better prognosis.

Gastrointestinal tract involvement is less commonly observed, with epithelial necrosis of the esophagus, small bowel, or colon manifesting as profuse diarrhea with malabsorption, melena, and even colonic perforation.69,70 Renal involvement has been reported. Proteinuria, microalbuminuria, hematuria, and azotemia are not rare. Proximal tubule damage can result from necrosis of tubule cells by the same process that destroys epidermal cells.71 Glomerulonephritis is rare.72

Laboratory Values

There is no laboratory test to support the diagnosis of EN. Laboratory examinations are essential to evaluation of severity and daily management as for all life-threatening conditions in intensive care units.

Evaluation of respiratory rate and blood oxygenation are among the first steps to take in the emergency room. Any alteration should be checked through measurement of arterial blood gas levels. Serum bicarbonate levels below 20 mM indicate a poor prognosis.14 They usually result from respiratory alkalosis related to the specific involvement of bronchi and more rarely from metabolic acidosis.

Massive transdermal fluid loss is responsible for electrolyte imbalances, hypoalbuminemia, and hypoproteinemia, and mild and transient renal insufficiency and prerenal azotemia are common. Raised blood urea nitrogen level is one marker of severity. Anemia is usual, and mild leukocytosis as well as thrombocytopenia may occur. Neutropenia is often considered to be an unfavorable prognostic factor but is too rare to have a significant impact on SCORTEN. Transient peripheral CD4+ lymphopenia is nearly always seen and is associated with decreased T-cell function. Mild elevation in levels of hepatic enzymes and amylase (most probably of salivary origin) are frequent but without impact on prognosis. A hypercatabolic state is responsible for inhibition of insulin secretion or insulin resistance, which results in hyperglycemia and occasionally overt diabetes. A blood glucose level above 14 mM is one marker of severity.14 Other abnormalities in laboratory values may occur, indicating involvement of other organs and complications such as sepsis.

Histopathology

Skin biopsy for routine histologic and possibly immunofluorescence studies should be strongly considered, especially if there are alternative diagnoses to consider. In the early stages, epidermal involvement is characterized by sparse apoptotic keratinocytes in the suprabasal layers, which rapidly evolves to a full-thickness necrosis and subepidermal detachment (Fig. 40-5). Apoptosis of epithelial cells may involve sweat glands and hair follicles. A moderately dense mononuclear cell infiltrate of the papillary dermis is observed, mainly represented by lymphocytes, often CD8+ and macrophages.73,74 Eosinophils seems to be less common in patients with the most severe form of EN. Results of direct immunofluorescence study are negative. Histopathology of involved mucous membranes, rarely performed, would show similar alterations.75

(Box 40-1)

Milder presentations of EN must be distinguished from erythema multiforme minor (EMM) (see Chapter 39). Early EN cases are often initially diagnosed as varicella. The rapid progression of skin lesions and the severity of mucous membrane involvement should raise the probability of EN.

The absence of mucous membrane involvement or its restriction to a single site must always raise the suspicion of an alternative diagnosis: staphylococcal scalded skin syndrome in infants; purpura fulminans in children and young adults; acute generalized exanthematous pustulosis, phototoxicity, or pressure blisters in adults. Thermal burns or scalding are occasionally an issue when a transient loss of consciousness occurs.

Linear immunoglobulin (Ig) A bullous disease and paraneoplastic pemphigus present with a less acute progression. Pathologic findings and a positive result on direct immunofluorescence testing are important for these diagnoses.

In all aspects, including pathology, generalized bullous fixed drug eruption (GBFDE) resembles EN. It may have a similar drug-related mechanism. However, the distinction is worthwhile because GBFDE has a reputation for much better prognosis, probably because of the mild involvement of mucous membranes and the absence of visceral complications. Prior attacks, rapid onset after drug intake, and very large, well-demarcated blisters are the hallmarks of GBFDE.

Toxic destruction of epithelia, whether through contact (fumigants) or ingestion (colchicine poisoning, methotrexate overdose), may result in clinical features of EN, but with skin erosions often predominating in the folds. In these rare cases, causality is generally obvious.

Overreporting of SJS is common. It usually arises from confusion between desquamation and detachment of epidermis, and also between mucous membranes and periorificial skin. Because of such confusion, patients with a desquamative rash and scaly lips are not rarely diagnosed with and reported as having SJS.

During the acute phase, the most common complication of EN is sepsis. The epithelial loss predisposes these patients to infections, which are the main causes of mortality.4,63 Staphylococcus aureus and Pseudomonas are the most frequent pathogens, but about one-third of positive blood cultures contain enterobacteriae not present on the skin, a finding that suggests bacterial translocation from gut lesions.76 Multisystem organ failure and pulmonary complications are observed in more than 30% and 15% of cases, respectively.77

A very important advance in EN is the recent understanding that sequelae are more frequent and more severe than previously thought.78 After the well-known risks of the acute stage, EN behaves as a chronic disease. More medical attention should be directed to that phase to better understand the frequency, mechanisms, and evolution of sequelae. Adequate management and prevention of sequelae are as important as saving the life during the acute phase.

A large European cohort has found that 90% of patients who survived EN suffered from sequelae at 1 year, with a mean of three different problems per patient and an important negative impact on the quality of life for about half of them (RegiSCAR group, unpublished data).

Symptoms suggesting posttraumatic stress disorder are not rare. Psychiatric consultation and/or psychological support are probably necessary in a majority of cases. Late ophthalmic complications are reported in 20% to 75% of patients with EN, with a credible figure of about 50% (Fig. 40-6).64,65,78 The relationship between the initial severity of ocular involvement and the development of late complications seems now to be well established. Late ophthalmic complications are mainly due to functional alteration of the conjunctival epithelium with dryness and abnormal lacrimal film. This leads to chronic inflammation, fibrosis, entropion, trichiasis, and symblepharon. Long-term irritation and deficiency of stem cells in the limbus may result in metaplasia of corneal epithelium with painful ulcerations, scarring, and altered vision. Such severe eye lesions occasionally develop in patients who had no patent ocular signs during the acute phase of EN.64

Hypopigmentation and/or hyperpigmentation are most frequent; residual hypertrophic or atrophic scars rarely occur. Nail changes, including change in pigmentation of the nail bed, ridging, dystrophic nails, and permanent anonychia, occur in more than 30% of cases (Fig. 40-7). Mouth sequelae are present in about one-third of patients who complain of dryness, altered taste, and late alterations of teeth.79

Vulvar and vaginal complications of EN are reported by about 25% of patients.66 Dyspareunia is not rare and is related to vaginal dryness, itching, pain, and bleeding. Genital adhesions may lead to the requirement for surgical treatment. Esophageal, intestinal, urethral, and anal strictures may also develop in rare cases. Chronic lung disease can be observed after EN, often attributed to bronchiolitis obliterans, and occasionally requires lung transplantation.68,80 Because these late complications and sequelae may develop insidiously, it is strongly suggested that all patients surviving EN have a clinical follow-up a few weeks after discharge and 1 year later, including examination by an ophthalmologist and by other organ specialist(s) as indicated by abnormal signs and symptoms.

The epidermal detachment progresses for 5 to 7 days. Then, patients enter a plateau phase, which corresponds to progressive reepithelialization. This can take a few days to a few weeks, depending on the severity of the disease and the prior general condition of the patient. During this period, life-threatening complications such as sepsis or systemic organ failure may occur. The overall hospital mortality rate of EN is 22–25%, varying from 5% to 12% for SJS to more than 30% for TEN. The prognosis is not affected by the type or dose of the responsible drug or the presence of human immunodeficiency virus infection (see Table 40-1).12,14,63,77

Prospective follow-up has shown an additional abnormally increased mortality in the 3-month period following hospital discharge, which seems to result from the negative impact of EN on prior severe chronic conditions, for example, malignancies (RegiSCAR, unpublished data).

EN is a life-threatening disease that requires optimal management: early recognition and withdrawal of the offending drug(s) and supportive care in an appropriate hospital setting.

Prompt withdrawal of offending agent(s) is associated with an increased rate of survival in patients with EN induced by drugs with short elimination half-lives.81 On the other hand, it is preferable to continue every important and nonsuspected medication. That will avoid reluctance on the part of the patient's physicians to prescribe them in the future. In case of doubt, all nonlife-sustaining drugs should be stopped, and particularly those administered within the previous 8 weeks.

Symptomatic Treatment

Only patients with limited skin involvement, a SCORTEN score of 0 or 1, and a disease that is not rapidly progressing can be treated in nonspecialized wards. Others should be transferred to intensive care units or burn centers.82 There is no “specific” treatment of demonstrated efficacy and supportive measures are the most important.5 Supportive care consists of maintaining hemodynamic equilibrium and preventing life-threatening complications. The aims are basically the same as for extensive burns.

EN is associated with significant fluid loss from erosions, which results in hypovolemia and electrolyte imbalance. Fluid replacement must be started as soon as possible and adjusted daily. Volumes of infusions are usually less than for burns of similar extent, because interstitial edema is absent. Peripheral venous lines are preferred when possible, because the sites of insertion of central lines are often involved in detachment of epidermis and prone to infection. The environmental temperature should be raised to 28°C to 30°C (82.4°F to 86°F). The use of an air-fluidized bed improves patient comfort.

Early nutritional support is preferentially provided by nasogastric tube to promote healing and to decrease the risk of bacterial translocation from the gastrointestinal tract. To reduce the risk of infection, aseptic and careful handing is required. Skin, blood, and urine specimens should be cultured for bacteria and fungi at frequent intervals. Prophylactic antibiotics are not indicated. Patients should receive antibiotics when clinical infection is suspected. Prophylactic anticoagulation is provided during hospitalization.

We do not recommend extensive and aggressive debridement of necrotic epidermis in EN because the superficial necrosis is not an obstacle to reepithelialization, and might even accelerate the proliferation of stem cells due to the inflammatory cytokines. This is the single noticeable divergence between authors of this chapter and the recommendations of US Burn centers.5 A few recent series suggest that debridement is necessary neither in superficial burns81 nor in EN. 84,85 There is no standard policy on wound dressings and the use of antiseptics. It is a matter of experience for each center. Skillfulness on the part of specialized nurses, careful manipulation, and an aggressive protocol of prevention and treatment of pain are essential.

Eyes should be examined daily by an ophthalmologist. Preservative-free emollients, antibiotic or antiseptic eye drops, and vitamin A are often used every 2 hours in the acute phase, and mechanical disruption of early synechiae is indicated. Early graft of cryopreserved amniotic membrane has been proposed as capable to decrease the rate of severe eye sequelae.64

The mouth should be rinsed several times a day with antiseptic or antifungal solution.

Specific Treatment in Acute Stage

Because of the importance of immunologic and cytotoxic mechanisms, a large number of immunosuppressive and/or anti-inflammatory therapies have been tried to halt the progression of the disease. None has clearly proved its efficacy. The low prevalence of the disease makes randomized clinical trials hard to perform.

Corticosteroids

The use of systemic corticosteroids is still controversial. Some studies found that such therapy could prevent the extension of the disease when administered during the early phase, especially as intravenous pulses for a few days.86 Other studies concluded that steroids did not stop the progression of the disease and were even associated with increased mortality and adverse effects, particularly sepsis. Thus, systemic corticosteroids cannot be recommended as the mainstay treatment of EN,5 but a large cohort study has suggested a possible benefit that should be explored by a prospective study.87

Intravenous Immunoglobulin

The proposal to use high-dose intravenous Ig was based on the hypothesis that Fas-mediated cell death can be abrogated by the anti-Fas activity present in commercial batches of normal human Ig.45 Benefits have been claimed by several studies and case reports,45,88–90 but refuted by several others.16,87,91,92 Thus, intravenous Ig cannot be considered the standard of care,5 especially after recent findings that the Fas-L/Fas pathway was not, or only marginally, involved in the mechanisms of EN.50 If used, a minimal precaution is to avoid preparations that are potentially nephrotoxic.

Cyclosporine A

Cyclosporine is a powerful immunosuppressive agent associated with biologic effects that may theoretically be useful in treatment of EN: activation of T helper 2 cytokines, inhibition of CD8+ cytotoxic mechanisms, and antiapoptotic effect through inhibition of Fas-L, nuclear factor-κB, and TNF-α. Several case reports and series suggested some efficacy of cyclosporine A in halting the progression of EN without worrisome side effects when administered early.93,94

Plasmapheresis or Hemodialysis

The rationale for using plasmapheresis or hemodialysis is to prompt the removal of the offending medication, its metabolites, or inflammatory mediators such as cytokines. A small series reported their efficacy and safety in treating EN.95–98 However, considering the absence of evidence and the risks associated with intravascular catheters, these treatments cannot be recommended.

Antitumor Necrosis Factor Agents

Anti-TNF monoclonal antibodies have been successfully used to treat a few patients. Because a prior randomized controlled trial of thalidomide, an anti-TNF agent, had to be interrupted due to significantly increased mortality,99 extreme caution is suggested in the use of anti-TNF agents to treat EN.

Treatment of Sequelae

Very promising treatments have now been developed for the ocular sequelae of EN, including gas permeable scleral lenses100,101 and grafting of autologous stem cells from contralateral limbus or mouth mucosa.102,103 With the exception of ocular sequelae, the literature contains only case reports related to treating sequelae. Photoprotection and cosmetic lasers may help resolve the pigmentation changes on the skin.

Primary prevention is only feasible in populations where a strong association has been established between a simple genetic maker and the risk of EN. That is the case for HLAB*1502 and EN induced by carbamazepine. The FDA has issued the recommendation to test patients from “Asian ancestry” for HLAB*1502 before prescribing carbamazepine. This recommendation should be refined to exclude persons of Japanese or Korean origin. In individuals of Han Chinese origin, alternative antiepileptic drugs can be carefully prescribed, although there may be an association of EN with phenytoin and HLAB*1502 as well.57 The present status of research on the pharmacogenetics of EN (RegiSCAR unpublished data) makes unlikely the finding of other genetic markers useful for primary prevention.

Secondary prevention is important for patients who experienced EN and are reluctant to take any medication. The most important issue is to evaluate drug causality. In vitro tests or patch tests to medications occasionally can be useful in the exploration of drug allergy. When used in EN patients, their sensitivity is low.104,105 Careful inquiry into all exposures to medications in the few weeks preceding the onset of the reaction leads to the identification of a probable culprit drug in approximately 70% of cases. The most useful clinical criteria are duration of treatment before onset (typically 4 to 30 days), absence of prior intake, and use of a drug known for being associated with a high risk.39

The few published cases of recurrent SJS or TEN were always due to inadvertent readministration of the same or a very closely related medication. Epidemiology and in vitro studies suggest that the list of possible cross-reactive medications is rather narrow, based on close chemical similarities. As an example, there is no evidence that patients who experienced SJS or TEN in reaction to an anti-infectious sulfonamide are at increased risk for reaction to sulfonamide-related diuretics or antidiabetic medications. Only anti-infectious sulfonamides should be contraindicated in this situation.

A list of the suspected medication(s) and molecules of the same biochemical structure must be given to the patient on a personal “allergy card.” It is also very useful to provide a list of drugs of common use that cannot be suspected. Because of recent indications of genetic susceptibilities to the development of EN, prescription of the offending agent to family members should also be avoided.