**2. DIHS/DRESS**

**1.1. SJS/TEN**

46 Skin Biopsy - Diagnosis and Treatment

general physician.

diseases.

SJS/TEN overlap between 10 and 30%.

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

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

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

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 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 case definition will be determined by RegiSCAR study, which comprises data collected from 6 European countries and the JSCAR Japanese registry. The incidence following phenytoin therapy is estimated to be 1 in 1000 to 10000 exposures.

**4. Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis**

lymphocytes and less apoptosis of keratinocytes [14].

TBSA is classified as SJS/TEN overlap.

**4.2. Epidemiology**

SJS and TEN were once considered as variants of erythema multiforme (EM), a condition first described by Ferdinand von Hebra in 1860 [1] as a mild and relapsing eruption of target lesions affecting the acral regions. Mucosal involvement occurs in up to 70% of cases of EM. In 1922, two American paediatricians, Albert Stevens and Frank Johnson, described two cases of fever, stomatitis, purulent conjunctivitis, and a generalized eruption of purple papules in boys aged 7 and 8 years, respectively [2]. Both cases were distinguished from EM by the prolonged high fever, and the generalized distribution and heavy terminal crusting of the skin lesions. Bernard Thomas proposed two categories of EM in 1950: erythema multiforme minor, as described by von Hebra, and erythema multiforme major, a severe form that encompassed SJS [3]. Alan Lyell, a Scottish dermatologist, termed the condition toxic epidermal necrolysis (TEN) after reporting four cases of an acute life threatening mucocutaneous disorder characterized by diffuse erythema followed by extensive epidermal detachment manifesting as blistering and sloughing of the skin [4]. Although SJS and TEN were initially considered distinct entities, it was later proposed that they form a continuum along the same disease process and differ mainly in the extent of involvement [5],[6]. It was also proposed that EM major and SJS are distinct conditions, with EM major characterised by acral target-like lesion typical of EM minor but with mucosal involvement. SJS was applied to cases of mucous membrane involvement and a more extensive eruption of atypical targetoid lesions, blisters or sloughing of the skin [7]. The distinction between EM and SJS are consistent with observations regarding differences in etiology, demography and histopathology and not just confined to variations in the severity of disease. Most cases of EM are related to infection especially those with recurrent disease, which is related to herpes simplex virus (HSV) infection [8]-[10] in contrast to SJS which usually is an idiosyncratic reaction to drugs [11]. EM typically affects young adults in their 20s and 30s although approximately 20% of cases involve children [12],[13] whereas SJS/TEN occurs at any age [11]. Histopathology in EM in contrast to SJS/TEN consists of a denser infiltrate of

Severe Cutaneous Adverse Reactions http://dx.doi.org/10.5772/54820 49

In 1993, a classification scheme was proposed that is widely but not universally adopted that arbitrarily defines SJS and TEN according to the extent of epidermal detachment [7]. In SJS, epidermal loss affects less than 10% of the total body surface area (TBSA) whereas TEN involves greater than 30% of the TBSA. Epidermal detachment between 10 and 30% of the

The epidemiology of SJS/TEN and other severe cutaneous adverse reactions (SCARs) has been more accurately determined in recent years due to registries that have been established mainly across Europe comprising cases that are reviewed by expert committees and based on predefined and validated criteria. A population-based registry was commenced in Germany in 1990 to collect all hospitalised cases of SJS, TEN and EM major [15]. An international casecontrol study was conducted between 1989 and 1995 in France, Germany, Italy and Portugal

**4.1. History and nosology**

DIHS has a relapsing remitting course lasting several weeks to months despite the withdrawal of the offending drug and this has been postulated to result from the sequential reactivation of herpes viruses analogous to that observed in graft versus host disease. The precise role of HHV-6 in DIHS is unclear. One theory is that HHV-6 triggers DIHS through its reactivation within T cells resulting in HHV-6 stimulated T cells cross-reacting with the culprit drug, following which there is sequential activation of heterologous herpes viruses. The alternative explanation is that drug specific T cells are activated resulting in reactivation of the viral genome and sequential reactivation of herpes viruses.

The histological features of DIHS are relatively non-specific and typically comprise a superfi‐ cial perivascular lymphocytic infiltrate. As the understanding of the disease mechanisms emerge, novel findings such as granulomatous inflammation have also been identified.

The diagnostic criteria consist of the typical clinical features and laboratory abnormalities. Confirmation of the role of the causative agent by skin testing is contraindicated because of the risk of a generalized reaction. The utility of LTTs is unclear as they are often negative early in the course of disease possibly as a result of regulatory T cell activation. LTTs may become positive after 5-7 weeks as the expanded regulatory T cell population are removed by apoptosis at the end of the immune response.

A prolonged course of oral corticosteroids is required to treat DIHS given the relapsing remitting nature of the condition. The mortality rate is estimated to be 10-20%.
