Epidermal necrolysis

Stevens–Johnson Syndrome �Toxic Epidermal Necrolysis

1. Epidermal Necrolysis Stevens–Johnson Syndrome Toxic Epidermal Necrolysis Ext. Siwaporn Khureerung 25/4/58

2. Introduction Toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS) are acute life-threatening mucocutaneous reactions characterized by extensive necrosis and detachment of the epidermis . 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. Epidemiology 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. 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.

4. SCORTEN Prognostic Factors Points Age >40 years 1 Heart rate >120 beats/minute 1 Cancer or hematologic malignancy 1 Body surface area involved >10% 1 Serum urea level >10 mM 1 Serum bicarbonate level >20 mM 1 Serum glucose level >14 mM 1 SCORTEN Mortality Rate (%) 0-1 3.2 2 12.1 3 35.8 4 58.3 5 90

5.   Etiology Medications and the Risk of Epidermal Necrolysis High Risk Lower Risk Doubtful Risk No Evidence of Risk Allopurinol Sulfamethoxazole Sulfadiazine Sulfapyridine Sulfadoxine Sulfasalazine Carbamazepine Lamotrigine Phenobarbital Phenytoin Phenylbutazone Nevirapine Oxicam NSAIDs Thiacetazone Acetic acid NSAIDs (e.g.,  diclofenac ) Aminopenicillins Cephalosporins Quinolones Cyclins Macrolides Paracetamol (acetaminophen) Pyrazolone analgesics Corticosteroids Other NSAIDs (except aspirin) Sertraline Aspirin Sulfonylurea Thiazide diuretics Furosemide Aldactone Calcium channel blockers β Blockers Angiotensin-converting enzyme inhibitors Angiotensin II receptor antagonists Statins Hormones Vitamins

6. Pathogenesis As explained previously, drugs are the etiologic factor in the majority of SJS/TEN cases. However, it is still unknown, how a certain drug may actually induce epidermal necrosis. T cells, especially CD8 +  lymphocytes, have been identified to play an important role in the process that is most likely mediated by cytokines. CD8 +  T cells from the blister fluid of patients with TEN induced by co- trimoxazole were tested for their cytotoxic function and reacted without restimulation against the parent drug ( cotrimoxazole and sulfamethoxazole ), but not against the metabolite. This finding challenged the hypothesis that metabolites may be directly involved in the process of epidermal cell death. In addition, these cytotoxic T-cells killed autologous lymphocytes and keratinocytes in a drug-specific, perforin / granzyme -mediated pathway restricted to MHC class I. [19]  Later, the cytolytic protein granulysin , which is produced by drug-specific CD8 +  T cells and natural killer (NK) cells, was identified as the most important factor for the epidermal destruction. Its concentrations in the blister fluid of SJS/TEN patients were two to four orders of magnitude higher than those of other cytotoxic proteins such as perforin , granzyme B or soluble Fas ligand, and depleting granulysin reduced the cytotoxicity. Furthermore, the concentration of granulysin in the blister fluid was positively correlated with the clinical severity of the disease (i.e. was higher in TEN as compared with SJS). [20]

7. Recently, functionally active CD94/NKG2C +  cells were detected in the blister fluid but also in the peripheral blood of patients with SJS/TEN. This activating receptor might be involved in triggering cytotoxic T cells in the acute stage of the disease. [21] T-cell activation by drug antigens requires the interaction of the T-cell receptor (TCR) with the MHC on antigen-presenting cells. Thus, the drug may bind to the MHC molecule, which is recognized by the TCR leading to specific TCR activation, or the drug may bind first to a specific TCR that then interacts with the MHC. Both ways are possible, but drugs with a strong association to specific HLA alleles are more suggestive to interact primarily with the HLA molecule. [22]

8. A genetic predisposition for SJS/TEN has long been discussed. After preliminary data from Europe had suggested an association with certain HLA types more than 20 years ago, a research group from Taiwan was the first to demonstrate that 100% of Han-Chinese patients with SJS/TEN due to the use of carbamazepine were positive for the allele HLA-B*1502. [23]  This finding could not be confirmed in Europe showing that ethnicity matters more than previously thought in this context. [24]  For allopurinol-induced cases of SJS/TEN a 100% association with HLA-B*5801 could be demonstrated in a Han-Chinese population, whereas in the European population the association was present in no more than 55%. [25,26]  Strong associations such as those in Han-Chinese suggest that these alleles must be involved in the presentation of a specific drug antigen in a better way than other HLA alleles. [22]  Thus, the risk of SJS/TEN is not only related to the exposure with high-risk drugs, but also to a genetic predisposition. In more homogeneous ethnic groups with a high prevalence of reaction to a given medication strong genetic associations may be easier to detect. [27]

9. Clinical Findings Even in cases requiring immediate referral to specialized wards, the dermatologist will have a specific role in the management of patients with EN .

10. 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. 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 .

11. Early exanthematous phase with Nikolsky's sign. symmetrically distributed on the face, the upper trunk, and the proximal part of limbs. 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.

12. A .  Early eruption. Erythematous dusky red macules (flat atypical target lesions) that progressively coalesce and show epidermal detachment.  B . Early presentation with vesicles and blisters, note the dusky color of blister roofs, strongly suggesting necrosis of the epidermis.  C .  Advanced eruption. Blisters and epidermal detachment have led to large confluent erosions.  D .  Full-blown epidermal necrolysis characterized by large erosive areas reminiscent of scalding. Cutaneous Lesions

13. Blisters , erosions, and large areas of positive Nikolsky's sign on the back of a patient with TEN. One aim of local treatment is to protect “detachable” epidermis from being detached by using antishear dressings.

14. 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 It is helpful to remember that the surface of one hand (palm and fingers) represents a little less than 1% of the BSA.

15. Evolution at days 4 ( A ), 7 ( B ), and 17 ( C ) after onset of TEN. Note that repair of epidermis is delayed on previously detached areas versus “detachable” ones that remained on site at day 7.

16. 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 Approximately 80% of patients have conjunctival lesions,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. Genital erosions are frequent, often overlooked in women, and may lead to synechiae .

17. A.  Extensive erosions and necroses of the lower lip and oral mucosa.  B.  Massive erosions covered by crusts on the lips. Note also shedding of eyelashes. Mucous Membrane Involvement

18. Extracutaneous Symptoms EN is associated with high fever, pain, and weakness. Visceral involvement is also possible, particularly with pulmonary and digestive complications. P ulmonary complications occur in approximately 25% of patients manifested by elevated respiratory rate and cough. In most cases chest radiographs are normal on admission but can rapidly reveal interstitial lesions that can progress to acute respiratory distress syndrome (ARDS). It was associated with poor 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 .   Renal involvement ,Glomerulonephritis is rare.

19. 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.

20. Histologic appearance of toxic epidermal necrolysis .  A .   Eosinophilic necrosis of the epidermis in the peak stage, with little inflammatory response in the dermis. Note cleavage in the junction zone.  B .  The completely necrotic epidermis has detached from the dermis and folded like a sheet.

21.  Differential Diagnosisnof Epidermal Necrolysis Most Likely Limited EN (Stevens–Johnson syndrome) Erythema multiforme major Varicella Widespread EN Acute generalized exanthematous pustulosis Generalized bullous fixed drug eruption Consider Paraneoplastic pemphigus Linear immunoglobulin A bullous disease Pressure blisters after coma Phototoxic reaction Graft-versus-host disease Always Rule Out Staphylococcal scalded skin syndrome Thermal burns Skin necrosis from DIC or purpura fulminans Chemical toxicity (e.g., colchicine intoxication, methotrexate overdose)

22. Complications and Sequelae 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 .   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. Multisystem organ failure and pulmonary complications are observed in more than 30% and 15% of cases, respectively.

23. Posttraumatic stress disorder are not rare. Psychiatric consultation and/or psychological support are probably necessary in a majority of cases. 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.

24. Nail changes, including change in pigmentation of the nail bed, ridging, dystrophic nails, and permanent anonychia , occur in more than 30% of cases . Mouth sequelae are present in about one-third of patients who complain of dryness, altered taste, and late alterations of teeth. 79

25. Vulvar and vaginal complications are reported by about 25% of patients.Dyspareunia 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 .

26. Prognosis and Clinical Course 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 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).

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

28. Symptomatic Treatment There is no “specific” treatment of demonstrated efficacy and supportive measures are the most important. Supportive care consists of maintaining hemodynamic equilibrium and preventing life-threatening complications. The aims are basically the same as for extensive burns.

29. S ignificant fluid loss from erosions, which results in hypovolemia and electrolyte imbalance. Fluid replacement must be started as soon as possible and adjusted daily. Early nutritional support is preferentially provided by nasogastric tube to promote healing and to decrease the risk of bacterial translocation from the gastrointestinal tract. Prophylactic antibiotics are not indicated . Patients should receive antibiotics when clinical infection is suspected. Prophylactic anticoagulation is provided during hospitalization. Do not recommend extensive and aggressive debridement of necrotic epidermis in EN Eyes should be examined daily by an ophthalmologist. Mouth should be rinsed several times a day with antiseptic or antifungal solution.

30. 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.

31. Corticosteroids The use of systemic corticosteroids is still controversial.

32. 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 . Benefits have been claimed by several studies and case reports,but refuted by several others. Thus , intravenous Ig cannot be considered the standard of care ,especially after recent findings that the Fas-L/Fas pathway was not, or only marginally, involved in the mechanisms of EN.

33. Cyclosporine A Cyclosporine A 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.

34. 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.

35. 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,extreme caution is suggested in the use of anti-TNF agents to treat EN.

36. Treatment of Sequelae 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.

37. Prevention 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.