**1. Introduction**

Severe cutaneous adverse reactions (SCARs) are generally induced by drugs and encompass the conditions of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug induced eosinophilia and systemic syndrome (DRESS) also known as drug induced hypersensitivity syndrome (DIHS), and acute generalized exanthematous pustulosis (AGEP). These conditions, although rare, cause significant morbidity and are potentially fa‐ tal. It is therefore important for the treating physician to promptly recognize SCARs through the identification of their characteristic clinical features so that the offending drug is promptly withdrawn and supportive and adjunctive therapies are administered. SCARs are accompanied by particular abnormalities on routine laboratory investigations and skin biop‐ sy that enables confirmation of the diagnosis and provision of useful prognostic informa‐ tion. Data bases have been established, predominantly in Europe, since the 1980s to characterize the epidemiology of SCARs including the identification of drugs with the high‐ est relative risk and the latency between the commencement of drug intake and the onset of clinical manifestations. The pathogenesis of the various SCARs involves delayed T cellmediated inflammation in a genetically predisposed individual and in the case of DIHS, may involve viral factors. The emerging field of the genetic susceptibility to SCARs has raised the important issue of pharmacogenetic screening as a method of predicting an indi‐ vidual's risk of developing SCAR to a certain drug. The treatment of SJS/TEN is dependent on supportive care in a suitable settling such as a Burns Unit and the role of immunomodu‐ latory agents is not well defined and is not robustly supported in the literature by prospec‐ tive studies. The evidence for the use of immunomodulatory agents and ganciclovir is emerging in the treatment of DIHS/DRESS. AGEP usually has favourable prognosis if the offending drug is withdrawn but a course of corticosteroids may hasten recovery.

© 2013 Fernando; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **1.1. SJS/TEN**

Stevens-Johnson Syndrome (SJS), first described in 1922 as an acute mucocutaneous syndrome in two boys, and Toxic Epidermal Necrolysis (TEN), first described as a scalding eruption of the skin in 1956 in four patients, are now considered to lie along the spectrum of epidermal necrolysis. The terminology is based on the extent of epidermal detachment; SJS indicates that there is less than 10% detachment of the body surface area, TEN greater than 30%, and SJS/TEN overlap between 10 and 30%.

determine the extent of degranulation of cytotoxic T cells by flow cytometry or ELISA may

Severe Cutaneous Adverse Reactions http://dx.doi.org/10.5772/54820 47

The treatment of SJS involves the removal of the offending drug and supportive treatment depending on severity and availability in a burns unit to address the manifestations and complications of acute skin failure including monitoring of fluid-electrolyte balance, provision of enteral or parenteral nutrition, wound care and treatment of sepsis. In addition, supportive care of affected mucosal surfaces is required. This includes aggressive ocular lubrication, topical corticosteroids and topical antibiotics, hygienic mouthwashes and topical oral anaes‐ thetics, and monitoring for urinary retention. Large randomized trials on the benefits of immunomodulatory therapy is lacking but there is sufficient evidence to recommend the administration of intravenous immunoglobulin (IVIg) as it contains anti-FasL antibodies and as a result may halt further epidermal necrosis and hasten re-epithelialization. Cyclosporin due to its effects on cytotoxic T cell depletion has reported to be of benefit in a number of small studies. A number of early studies revealed that systemic corticosteroids may be not be beneficial in the treatment of SJS/TEN and in fact may be harmful by promoting sepsis but these conclusions may have been partly explained by the inadequate doses administered and the delay in initiating treatment. Recent studies have demonstrated benefit in the immediate use of high dose pulse methylprednisolone, especially in reducing the rate of ocular compli‐ cations. The application of amniotic membranes to the conjunctival surface may also prove beneficial in minimising ocular sequelae such as dry eye, cicatrization and in rare cases, corneal

The mortality rate of SJS/TEN is high; approximately 10% for SJS and 50% for TEN. A score for the evaluation of TEN (SCORTEN) has proven remarkably accurate in predicting mortality through identification of 6 risk factors; age > 40 years, presence of malignancy, heart rate > 120/ min, epidermal detachment > 10%, serum urea > 10 mmol/L (28 mg/dL), serum glucose > 14

DIHS/DRESS is also referred to as hypersensitivity syndrome and when caused by antiepi‐ leptic drugs it has been often referred to as anticonvulsant hypersensitivity. The condition is characterised by fever, rash, lymphadenopathy, eosinophilia and/or other leukocyte abnor‐ malities, and internal organ involvement such as hepatitis. Reactivation of human herpes virus (HHV)-6 is also considered by some groups to be an instrumental component of the condition. The rash typically begins as patchy erythematous macules that become confluent and pro‐ gresses especially if the causative drug is not withdrawn to an erythroderma or exfoliative dermatitis. The syndrome typically develops between 3 weeks and 3 months after the starting therapy and a limited number of drugs appear involved in its causation. They include anticonvulsants (phenytoin, carbamazepine, phenobarbital, lamotrigine, zonisaminde), allopurinol, sulphonamides (dapsone, sulphasalazine), antiretrovirals (abacavir, nevirapine), minocycline, strontium ranelate, and mexilitene. The precise incidence according to the latest

mmol/L (252 mg/dL) and serum bicarbonate < 20 mmol/L (20 mEq/L).

prove useful in the future.

perforation.

**2. DIHS/DRESS**

The clinical presentation is characterized by a rash featuring target-like lesions, and mucositis involving the ocular, oropharyngeal and genital surfaces. The patient is also systemically unwell with fever and malaise. The EuroSCAR case control study collected 379 cases of SJS/TEN between 1997 and 2001 from 6 countries encompassing over 100 million inhabitants. The estimated incidence is 1-2 per million per year. The drugs associated with the highest relative risk include allopurinol, antibacterial sulphonamides, oxicam non-steroidal antiinflammatory drugs (NSAIDs), aromatic anticonvulsants (phenytoin, carbamazepine, pheno‐ barbital), lamotrigine, and nevirapine. The latency between the intake of these high-risk drugs and the onset of clinical manifestations is 1 to 8 weeks. Other factors influencing risk include the presence of other diseases (HIV, malignancy, autoimmune disease, recent radiotherapy, acute infection within the last four weeks) and pharmacokinetic factors (dose of allopurinol commenced at 200-300 mg daily). Recently, genes conferring strong susceptibility to SJS/TEN have been identified, the most prominent of which are HLA-B\*1502 and carbamazepine in individuals of Asian ancestry, HLA-A\*3101 and carbamazepine in individuals from Northern European ancestry, and HLA-B\*5801 and allopurinol in various racial groups. A black box warning has been placed by the Food and Drugs Administration and Health Canada alerting physicians to not only to be aware of the risk of carbamazepine and SJS/TEN in Asians but to also screen at risk individuals for the susceptibility allele. Currently, this strategy has been limited by the lack of availability of cost-effective pharmacogenetic testing methods to the general physician.

The immunopathogenesis of SJS/TEN involves the release of granulysin by CD8 cytotoxic T cells and natural killer cells within the epidermis resulting in apoptosis of keratinocytes. Apoptosis may also result from the degranulation of perforin and granzyme by CD8 cytotoxic T cells and the ligation of Fas on keratinocytes by Fas-ligand (Fas-L). The source of Fas-L is still unclear with CD8 cells and keratinocytes proposed as candidates. Histologically, the resultant widespread apoptosis of keratinocytes results in necrosis of the epidermis and dermoepidermal separation at the level of the stratum spinosum. Direct immunofluorescence of skin biopsies in SJS/TEN is negative differentiating it from autoimmune vesiculobullous diseases.

The diagnosis is made clinically and confirmed histologically. Skin testing is contraindicated given the risk of precipitating a generalized reaction. In vitro tests are currently not widely available and relatively poor sensitivity. Lymphocyte transformation tests that assess the proliferative response of T cells to the drug have a sensitivity of 60-70% and are more likely to be positive if performed within 6 weeks of the onset of the disease. Cytotoxicity assays that determine the extent of degranulation of cytotoxic T cells by flow cytometry or ELISA may prove useful in the future.

The treatment of SJS involves the removal of the offending drug and supportive treatment depending on severity and availability in a burns unit to address the manifestations and complications of acute skin failure including monitoring of fluid-electrolyte balance, provision of enteral or parenteral nutrition, wound care and treatment of sepsis. In addition, supportive care of affected mucosal surfaces is required. This includes aggressive ocular lubrication, topical corticosteroids and topical antibiotics, hygienic mouthwashes and topical oral anaes‐ thetics, and monitoring for urinary retention. Large randomized trials on the benefits of immunomodulatory therapy is lacking but there is sufficient evidence to recommend the administration of intravenous immunoglobulin (IVIg) as it contains anti-FasL antibodies and as a result may halt further epidermal necrosis and hasten re-epithelialization. Cyclosporin due to its effects on cytotoxic T cell depletion has reported to be of benefit in a number of small studies. A number of early studies revealed that systemic corticosteroids may be not be beneficial in the treatment of SJS/TEN and in fact may be harmful by promoting sepsis but these conclusions may have been partly explained by the inadequate doses administered and the delay in initiating treatment. Recent studies have demonstrated benefit in the immediate use of high dose pulse methylprednisolone, especially in reducing the rate of ocular compli‐ cations. The application of amniotic membranes to the conjunctival surface may also prove beneficial in minimising ocular sequelae such as dry eye, cicatrization and in rare cases, corneal perforation.

The mortality rate of SJS/TEN is high; approximately 10% for SJS and 50% for TEN. A score for the evaluation of TEN (SCORTEN) has proven remarkably accurate in predicting mortality through identification of 6 risk factors; age > 40 years, presence of malignancy, heart rate > 120/ min, epidermal detachment > 10%, serum urea > 10 mmol/L (28 mg/dL), serum glucose > 14 mmol/L (252 mg/dL) and serum bicarbonate < 20 mmol/L (20 mEq/L).
