44 - EPIDERMAL NECROLYSIS (SJS AND TEN) Flashcards Preview

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Flashcards in 44 - EPIDERMAL NECROLYSIS (SJS AND TEN) Deck (31)
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1
Q

Widespread apoptosis of keratinocytes is provoked by what

A

Widespread apoptosis of keratinocytes is provoked by the activation of a cell-mediated cytotoxic reaction and amplified by cytokines, mainly granulysin.

2
Q

Define SJS and TEN

A

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute life-threatening mucocutaneous reactions characterized by extensive necrosis and detachment of the epidermis and mucosal epithelium (Table 44-1).

In 1922, 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 Because SJS and TEN share clinical pattern, histopathologic findings, etiology, risk factors, and mechanisms, they are considered as severity variants of one disease entity that differs only in the extent of skin detachment related to the body surface area. 3-5 Therefore, it seems more appropriate to use the designation epidermal (or epithelial) necrolysis for both, as proposed by RuizMaldonado (acute disseminated epidermal necrosis)6 and Lyell (exanthematic necrolysis).

3
Q

EPIDEMIOLOGY

A

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. 8-10 Whereas incidences as high as 5 or 6 cases per million per year derive from medical databases not primarily designed for epidemiologic analysis of rare diseases, 11 incidences of 1 to 2 cases per million per year were calculated using population-based prospective case registry data.12,13

EN can occur at any age, but the risk increases with age leading to the highest incidence in older adults after 65 years of age. 14 Women are more frequently affected, showing a sex ratio of 0.6. Patients infected with HIV and to a lesser degree patients with collagen vascular disease and cancer are at increased risk. 15,16 The overall mortality rate associated with EN is 22% to 27%, varying from approximately 10% for SJS to almost 50% for TEN. 17-19 Increasing age, significant comorbidity, and greater extent of skin detachment correlate with poor prognosis. A prognosis score (SCORTEN) has been constructed for EN, 20 and its usefulness has been confirmed by several teams 21-24 (Table 44-2).

4
Q

ETIOLOGY

A

The exact pathophysiology of EN is still unclear; however, drugs are the most important etiologic factors. More than 100 different drugs have been implicated, 25-31 but fewer than a dozen “high-risk” medications account for about half of cases in Europe (Table 44-3), as evidenced by two multinational casecontrol studies. 16,27-30 These high-risk drugs are antibacterial sulfonamides, aromatic antiepileptic drugs, allopurinol, oxicam nonsteroidal antiinflammatory drugs, lamotrigine, and nevirapine. 28-30 The risk seems confined to the first 8 weeks of treatment and most inducing medications revealed the first continuous exposure between 4 and 28 days before reaction onset. 28 Slow dose escalation decreases the rate of mild rashes to lamotrigine and nevirapine, 32,33 but there is no evidence that it decreases the risk of EN. 28,30 Oxcarbazepine, a 10-keto derivative of carbamazepine, which was considered to carry a lower risk, seems to significantly cross-react with carbamazepine. 34 Many nonsteroidal antiinflammatory drugs were suspected to be associated with EN, but there is a substantial difference in risk for EN among them, with oxicam derivatives showing the highest risk, acetic acid derivatives such as diclofenac a moderate, and propionic acid derivatives such as ibuprofen no increased risk. 16,28,35 A significant but much lower risk has also been reported for various groups of antibiotics such as cephalosporins, quinolones, tetracyclines, and aminopenicillins.28 Corticosteroids were significantly associated with an increased relative risk, but confounding could not be excluded. 28 Recent analysis of systematically ascertained registry data on EN using ALDEN (algorithm for causality assessment in EN) 36 in comparison with results of two case-control studies 16,28 revealed that over a period of more than 2 decades, the proportion of validated cases that could be explained by medications with a significant (high and moderate) risk was stable (65%–68%). For roughly one third of the cases, no patent drug cause could be identified, suggesting that many more cases than previously thought have to be considered as “non–drug related” or “idiopathic.”37 The role of infectious agents in the development of EN is much less prominent than for erythema multiforme (see Chap. 43). 5 However, cases of EN associated with Mycoplasma pneumoniae infection, viral disease, and immunization have been reported, particularly in children. 38 In many cases a clinical infection is present, but despite extensive laboratory workup, no specific viral or bacterial agent can be detected. 39 Cases of EN have been reported after bone marrow transplantation. Some are an extreme form of acute graft-versus-host disease (GVHD; see Chap. 129); others could be druginduced. The relationship between EN and GVHD is difficult to assess because clinical and histologic skin features are often indistinguishable. 40 Lupus erythematosus (systemic LE or subacute cutaneous LE) is associated with an increased risk of EN. 16,28 In such cases, drug causality is often doubtful and necrolysis might be an extreme phenotype of cutaneous lupus. Therefore, erosive LE has to be considered as a differential diagnosis of EN. 41,42 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.43,44

5
Q

Drugs and Recommendations in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

A
6
Q

PATHOGENESIS

A

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. 45,46 Immunopathologic studies have demonstrated the presence of cytotoxic cells, including natural killer T cells (NKT) and drugspecific CD8 + T lymphocytes in early lesions; monocytes and macrophages and granulocytes are also recruited. 47-49 CD94/NKG2C was identified as a killer effector molecule in patients with EN. 50 However, it is generally accepted that specific and nonspecific cytotoxic cells are too few within the lesions to explain fullthickness necrosis of extensive 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). 47,51 In the past decade, it had been widely accepted that Fas-L was inducing the apoptosis of keratinocytes in EN, 51,52 despite partial evidence and discordant findings. 53-55 An important study has

challenged this dogma by demonstrating the key role of granulysin in EN. 56 The cytolytic protein granulysin was present in the blister fluid of patients with 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 histologic lesions of EN. 57 Recently, interleukin (IL)-15 could be demonstrated to be associated with severity and mortality in EN. 58 When combined, these 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 many years. These cells kill keratinocytes directly and indirectly through the recruitment of other cells that release soluble death mediators, the principal being granulysin and probably also IL-15.56-58

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

Little is known on 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. Drugspecific CD8 cytotoxic T-lymphocytes were also found in milder skin like maculopapular eruption. 59 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. 60 Similar regulatory cells may play a role in drug eruptions in humans. 61 Altered regulation of the immune response to medications in patients with EN could result from comorbidities that are frequent (eg, cancer, HIV infection, collagen vascular disease), from comedications (eg, 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. 62,63 B ∗ 1502 association with carbamazepine-related cases was confirmed in several Southeast Asian countries 64,65 but not in Japan and Korea. 66,67 The association between carbamazepineinduced EN and HLA-B ∗ 1502 was not present in European patients without Asian ancestry. 68 On the other hand, HLA-B ∗ 5801 was confirmed to be associated with allopurinol-related EN in Japan 66 and Europe, 69 but the strength of association was lower than in Taiwan. A genome-wide association study on samples of European EN-patients confirmed the involvement of genetic variants located in the HLA region. No other locus reached genome-wide statistical significance in this large sample. If some loci outside HLA play a role in EN, their effect might be very small.

7
Q

Decisional tree for referral of a patient with epidermal necrolysis.

A
8
Q

Clinical history

A

EN clinically most often begins with unspecific prodromal symptoms such as sore throat, runny nose, cough, headache, fever, and malaise preceding the mucocutaneous lesions by 1 to 3 days. They are followed by the appearance of erythematous macules and atypical targets of the skin that may be confluent and on which blisters occur. Burning or stinging of the eyes, pain when swallowing, or urinating progressively develop, heralding mucous membrane involvement. The majority of cases begin with nonspecific symptoms followed either first by mucous membrane or by cutaneous involvement, but some cases may start with the specific lesions of skin and mucosa. 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.

A common problem is the fact that medications taken to treat the prodromal symptoms are often accused to have caused the reaction. This mainly concerns antipyretics, analgesics, and secretolytics, sometimes summarized as “cough and cold medicines.” When looking at the use of these medications more closely, they have usually been taken and tolerated before and were started after the onset of prodromal symptoms of EN (“protopathic bias”). Neither of these patterns is typical for exposure to medications causing EN, which have not been used previously and the exposure of which is the first continuous use started 4 weeks to 4 days before reaction onset. Furthermore, these substances do not belong to the drug groups for which epidemiologic studies have estimated an increased risk to induce EN.

9
Q

CUTANEOUS LESIONS

A

The eruption is initially symmetrically distributed on the face, the upper trunk, and the proximal part of limbs. 71 The distal portions of the arms as well as the legs are relatively spared, but the eruption 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, irregularly shaped purpuric macules, which progressively coalesce. Atypical target lesions with dark centers are often observed (Fig. 44-2A). Confluence of necrotic lesions leads to extensive and diffuse erythema. Nikolsky sign, or dislodgement of the epidermis by lateral pressure, is positive on erythematous zones (Figs. 44-3 and 44-4). At this stage, the lesions evolve to flaccid blisters, which spread with pressure and break easily (see Fig. 44-2B). The necrotic epidermis is easily detached at pressure points or by frictional trauma, revealing large areas of exposed, red, sometimes oozing dermis (see Figs. 44-2C and 44-2D). 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) SJSTEN overlap, between 10% and 30%; (3) TEN, more than 30% of BSA. 3,5 Correct evaluation of the extent of detachment 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.

10
Q

MUCOUS MEMBRANE INVOLVEMENT

A

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, genital, nasal, anal and sometimes tracheal or bronchial 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 hemorrhagic crusts of the lips (Fig. 44-5). Approximately 80% of patients have conjunctival lesions, 72,73 mainly manifested by pain, photophobia, lacrimation, redness, and discharge. Severe forms may lead to epithelial defect and corneal ulceration, anterior uveitis, and purulent conjunctivitis. Synechiae between eyelids and conjunctiva often occur. There may be shedding of eyelashes (Fig. 44-5B). Genital erosions are frequent, often overlooked in women, and may lead to synechiae.74,75

11
Q

What is nikolsky sign

A

dislodgement of the epidermis by lateral pressure

12
Q
A
13
Q

SYSTEMIC INVOLVEMENT

A

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. 76,77 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. 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. 78,79 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. 80 Glomerulonephritis is rare.81

14
Q

Laboratory findings

A

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

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

738

Massive transdermal fluid loss is responsible for electrolyte imbalances, hypoalbuminemia, and hypoproteinemia, and mild and transient renal insufficiency and prerenal azotemia are common. Increased blood urea nitrogen level is one marker of severity. Anemia is common, 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 may be a marker of severity.20 Other abnormalities in laboratory values may occur, indicating involvement of other organs and complications such as sepsis.

15
Q

Histologic appearance of epidermal necrolysis.

A

Skin biopsy for routine histologic and possibly immunofluorescence studies are strongly recommended, especially if there are alternative diagnoses to consider (see Fig. 44-3). The biopsy should be taken from a fresh lesion, preferably form the erythematous margin and not directly out of a blister because the latter carries the risk that epidermis and dermis are completely separated or partly lost. If similar lesions are present on the legs and elsewhere, the biopsy should preferentially not be taken from the legs below the knee. In the latter localization, changes could be superimposed by stasis dermatitis, complicating the correct histopathologic diagnosis.82

In the early stages, epidermal involvement is characterized by sparse apoptotic keratinocytes in the suprabasal layers (Fig. 44-6). In fully developed stages of the disease, when epidermal detachment and epidermolysis appear, in addition to the already mentioned changes subepidermal vesiculation secondary to extensive vacuolar alteration and confluent necrosis of keratinocytes develops. 82,83 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.83,84 Occasional eosinophilic granulocytes may be found. Variable numbers of extravasated erythrocytes are present. As the process develops rapidly, usually neither melanophages nor siderophages are found in the upper part of the dermis. The cornified layer remains unchanged. Results of direct immunofluorescence test are negative. Histopathology of involved mucous membranes show a similar pattern but are rarely performed.85

16
Q

DIFFERENTIAL DIAGNOSIS

A

Milder presentations of EN must be distinguished from erythema multiforme minus (without mucous membrane involvement) and majus (with mucous membrane involvement; EMM) (see Chap. 43). Early EN cases are often initially diagnosed as varicella, especially in children. The rapid progression of skin lesions and the severity of mucous membrane involvement should lead to considering potential 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 but also in adults with septicemia; purpura fulminans in children and young adults; and acute generalized exanthematous pustulosis, phototoxicity, tension or pressure blisters in adults. Thermal burns are occasionally an issue when a transient loss of consciousness occurs as well as in small children or older adults in nursing homes.71

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. 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 events, rapid onset after drug intake, and very large, well-demarcated blisters are the hallmarks of GBFDE.86

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 EN is common. It usually arises from confusion between desquamation and detachment of epidermis and 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 EN.

17
Q

COMPLICATIONS AND SEQUELAE

A

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. 4,71 Central intravenous lines are a source for infection and should be avoided in favor of peripheral lines if possible. Staphylococcus aureus and Pseudomonas spp. 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.87 Multisystem organ failure and pulmonary complications are observed in more than 30% and 15% of cases, respectively.88

A very important advance in EN is the recent understanding that sequelae (Table 44-5) are more frequent and more severe than previously thought. 89 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 patient’s life during the acute phase.

A large European cohort has found that 90% of patients who survived EN had sequelae 1 year after the acute stage of the disease, with a mean of three different problems per patient and an important negative impact on the quality of life for about half of them. A 5-year follow-up revealed similar data, demonstrating that many patients never got back to their normal activities before the reaction. 90 Symptoms suggesting posttraumatic stress disorder are not rare. Psychiatric consultation and psychological support have been considered to be helpful by affected patients and should be included into supportive care protocols. Late ophthalmic complications are reported in 20% to 75% of patients with EN, with a credible figure of about 50% (Fig. 44-7). 72,73,89 The relationship between the initial severity of ocular involvement and the development of late complications seems to be well established. However, late complications have also been observed in patients whose ocular involvement was considered to be mild during the acute stage of the disease. Late ophthalmic complications are mainly caused by 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.72

Hypopigmentation and hyperpigmentation of the skin are most frequent sequelae; 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. 44-8). Mouth sequelae are present in about one third of patients who complain of dryness, altered taste, and late alterations of teeth.91

Vulvar and vaginal complications of EN are reported by about 25% of patients. 74 Dyspareunia is not rare and is related to vaginal dryness, itching, pain, and bleeding. Genital adhesions may lead to the requirement for surgical treatment. 75 Esophageal, intestinal, urethral, and anal strictures may also develop, although rarely. Chronic lung disease can be observed after EN, often attributed to bronchiolitis obliterans, and occasionally requiring lung transplantation. 77,92 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.

18
Q
A
19
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20
Q

Course of epidermal necrolysis (EN).

A
21
Q

PROGNOSIS AND CLINICAL COURSE

A

The epidermal detachment progresses for 5 to 7 days (Figs. 44-9 and 44-10). 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 mortality rate associated with EN is 22% to 27%, varying from approximately 10% for SJS to almost 50% for TEN,17,18 but is highly dependent on the age of the patient and her or his underlying diseases. Thus, the mortality rate in children even with severe EN is very low compared with older adults. The prognosis is not affected by the cause of the reaction, whether drug or infection or unknown causality, type or dose of the responsible drug, or the presence of HIV infection (see Table 44-2).

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

22
Q

TREATMENT

A

EN is a life-threatening disease that requires optimal management: early recognition and withdrawal of the offending drug(s) in drug-induced cases and supportive care in an appropriate hospital setting (Table 44-6).

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. 93 At the same time, it is preferable to continue every important and nonsuspected medication. This is of medical benefit for the affected patient and may furthermore avoid reluctance of the patient’s physicians to prescribe them in the future. In case of doubt, all not life-sustaining drugs should be stopped when initiated and administered within the previous 8 weeks.

23
Q

SYMPTOMATIC TREATMENT

A

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. Depending on the local or national facilities, patients who do not need intensive care may remain in dermatology units or hospitals (eg, in many European countries), others should be transferred to ICUs or burn centers. 94 Although recent studies suggest that immunomodulating treatment with cyclosporine (ciclosporin) could be beneficial (see later), supportive measures are most important. 18,88,95,96 Supportive care consists of maintaining hemodynamic equilibrium and preventing life-threatening complications. The aims are similar to those for the treatment of 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 of skin detachment 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 should be 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. 96 A few recent series suggest that debridement is necessary neither in superficial burns 97 nor in EN.98,99 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.72

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

24
Q

SPECIFIC TREATMENT IN ACUTE STAGE

A

Because of the importance of immunologic and cytotoxic mechanisms, a large number of immunosuppressive and antiinflammatory therapies have been tried to halt the progression of the disease. The low prevalence of the disease makes randomized clinical trials hard to perform, so most publications on treatment are case reports and rather small case series.

25
Q

CORTICOSTEROIDS

A

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. 100 Other studies concluded that steroids did not stop the progression of the disease and were even associated with increased mortality and sepsis when administered for 2 to 3 weeks. Thus, systemic corticosteroids cannot be recommended as the mainstay treatment of EN, 96 but a large cohort study has suggested a benefit quoad vitam when steroids were given in a medium dose for a few days. 101 A recent systematic review revealed a beneficial effect on corticosteroids in the treatment of SJS and TEN. Although the potential effect on the progression of skin detachment could not be analyzed by that approach, the results on outcome (death versus survival) were favorable.102

26
Q

INTRAVENOUS IMMUNOGLOBULINS

A

The proposal to use high-dose intravenous immunoglobulin (IVIG) was based on the hypothesis that Fas-mediated cell death can be abrogated by the antiFas activity present in commercial batches of normal human Ig. 51 Benefits have been claimed by several studies, mainly case compilations with patients included in more than one study and case reports 51,103-105 but refuted by several others. 22,101,106-108 The large cohort study published in 2008 comparing the treatment in 281 patients with EN could not demonstrate a beneficial effect of IVIG. 101 Thus, IVIG could not be considered the standard of care in recent years, 96 especially after the finding that the Fas-L––Fas pathway was not, or only marginally, involved in the mechanisms of EN. 56 The recent systematic review mentioned did not find a favorable effect of IVIG, neither on the study nor on the individual patient level. 102 Taking these findings into account, we conclude that IVIG should not be used to treat patients with EN.

27
Q

CYCLOSPORINE A

A

Cyclosporine is a powerful immunosuppressive agent associated with biologic effects that are theoretically useful in the treatment of EN: activation of T helper cells and 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 the efficacy of cyclosporine A (CyA) in halting the progression of skin detachment in EN without worrisome side effects when administered early. 110,111 In the pilot study performed in the French Reference Center for EN, the initial dose of 3 mg of CyA per kilogram body weight was slowly tapered over 1 month (3 mg/kg body weight for 10 days followed by 2 mg/kg for 10 days and 1 mg/kg for 10 days). 111 However, in recent years, the protocol was modified to 3 mg/kg body weight for 10 days only, with the usual dose adjustment in cases with renal failure (personal communication). The recent systematic

review of EN treatment also saw positive effects of CyA, but the number of studies and patients treated were too small to demonstrate a significant finding.102 A recent study from Spain compared the treatments of EN in two large specialized units and concluded that the use of CyA was beneficial both in terms of halting disease progression and survival.112

These new studies are a real breakthrough concerning the immunomodulating treatment of EN. Because randomized double-blind, placebo-controlled trials are hardly feasible in rare and unexpectable conditions such as EN that may affect anyone at any time at any place, systematic surveillance of treatment modalities (eg, CyA use) is warranted.109

28
Q

PLASMAPHERESIS OR HEMODIALYSIS

A

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. 113-116 However, considering the absence of evidence and the risks associated with intravascular catheters, these treatments cannot be recommended.

29
Q

ANTITUMOR NECROSIS FACTOR AGENTS

A

Anti-TNF monoclonal antibodies have been successfully used to treat a few patients. Recently, a study comparing corticosteroids and etanercept reported improved clinical outcomes in patients with EN treated with the latter. Furthermore, decreased levels of TNF-α and granulysin were observed. 117 Nevertheless, because a prior randomized controlled trial of thalidomide, an anti-TNF agent, had to be interrupted because of significantly increased mortality, 118 extreme caution is suggested in the use of anti-TNF agents to treat EN.

30
Q

TREATMENT OF SEQUELAE

A

Very promising treatments have now been developed for the ocular sequelae of EN, including gas-permeable scleral lenses 119,120 and grafting of autologous stem cells from contralateral limbus or mouth mucosa. 121,122 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, but specific studies do not exist. This also accounts for nail disorders caused by EN.

31
Q

PREVENTION

A

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 HLA-B ∗ 1502 and EN induced by carbamazepine in persons of Southeast Asian ancestry. The US Food and Drug Administration has issued the recommendation to test patients of Han Chinese and Thai origin for HLA-B ∗ 1502 before prescribing carbamazepine. In Taiwan, testing of HLA-B ∗ 1502 before prescription of carbamazepine has led to a substantial reduction of EN-cases. 123 In Hong Kong, however, the screening policy was associated with prevention of carbamazepine-induced EN without reducing the overall burden of EN induced by antiepileptic medication, likely because clinicians preferred drugs not requiring a genetic test but that may also induce EN.124 In individuals of Han Chinese or Southeast Asian origin, alternative antiepileptic drugs can be carefully prescribed, although there may be an association of EN with phenytoin and HLA-B ∗ 1502 as well. 64 The present status of research on the pharmacogenetics of EN makes it rather unlikely to identify another genetic marker with such a clear and high association to be useful for primary prevention.70

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 patients with EN, their sensitivity is low. 125,126 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 67% of cases. The most useful clinical criteria are duration of treatment before onset (typically 4 to 28 days), absence of prior intake, and use of a drug known for being associated with a high risk.36

The few published cases of recurrent SJS or TENand so-called recurrent cases of SJS that are actually cases of EMM—were always caused by 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 EN in reaction to an antiinfective sulfonamide are at increased risk for reaction to sulfonamiderelated diuretics or antidiabetic medications. Only antiinfectious sulfonamides and sulfasalazine 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” or “allergy passport.” It may also be useful to provide a list of drugs of common use that cannot be suspected.

Decks in FITZPATRICK'S DERMATOLOGY 9TH EDITION Class (130):