The reported incidence of EM varies, as it is often under-reported in mild cases. The annual incidence has been estimated between 0.01 and 1 % [14]. A review of world literature between 1975 and 2003 showed incidences of SJS ranging from 1.1 to 7.1 per million per year, and TEN was even rarer, at 0.4–1.2 per million per year. A more recent paper suggests that the incidence of SJS/TEN is around two per million annually [15]. Association with drugs was around 70 % in both SJS and TEN, with SJS having a higher association with infections at 10.4 % versus only 3.2 % in TEN. Mortality in EM is almost unheard of, whereas mortality of SJS was estimated to be 1–3 %, versus 10–70 % in TEN [16]. The incidence increases with age and there is at least a 1,000-fold higher risk in HIV/AIDS patients [17]. There have also been recent papers showing an association with lupus erythematosus [18, 19]. Mortality rate in children with SJS/TEN is estimated to be 7.5 %, with 95 % having mucous membrane lesions [20].

In certain ethnic groups, there have been very strong associations with certain HLA types and drug-induced SJS/TEN. HLA-B*1502 is strongly associated with carbamazepine reactions in those of Southeast Asian descent (i.e. Han Chinese, Thai), whilst HLA-A31 strongly associates with carbamazepine-induced adverse drug reactions in the Japanese population [16, 38, 39]. HLA-B*5801 is associated with reactions to allopurinol, SJS/TEN, and drug reaction with eosinophilia and systemic symptoms (DRESS) in Caucasians and Asians including the Japanese [21–25]. The association is so strong that the US FDA recommends genotyping of all Asians for the allele when considering carbamazepine in their management [26]. Allopurinol is the most common cause of SJS/TEN in Europe and Israel, with daily doses of more than 200 mg and short-term use of less than 8 weeks associated with higher risk [27]. Studies in the European population showed that 55 % of 27 patients with European ancestry who developed allopurinol-induced SJS/TEN carried the HLA-B*5801 allele, which was at par with observations in Han Chinese. A meta-analysis and systematic review done in 2011 by a group from Thailand included four studies with 55 SJS/TEN cases and 678 matched controls, as well as five studies with 69 SJS/TEN cases and 3,378 population controls. They found that SJS/TEN cases were significantly associated with the HLA-B*5801 allele in both groups of studies with matched control (OR 96.60, p < 0.001) and population control (OR 79.28, p < 0.001), with subgroup analysis for Asian and non-Asian population yielding similar findings [24]. Furthermore, it was observed that although certain HLA-B alleles are strong risk factors for drug-induced SJS/TEN, they are neither sufficient nor necessary to explain the disease [28].

With the advent of highly active antiretroviral therapy (HAART) for the treatment of HIV/AIDS, other HLA associations are now coming to light, in particular, HLA-B*5701 in association with SJS/TEN and other severe hypersensitivity reactions to abacavir in Caucasians. Nevirapine drug hypersensitivity is associated with HLA-B*3505 in the Thai population [22].

A review of 32 paediatric cases of EM, SJS, and TEN over a period of 8 years in a tertiary care centre in the USA found ibuprofen to have a statistically significant (p < 0.05) association with SJS/TEN, with 47 % of cases all given ibuprofen. It was found in association with 50 % of TEN cases, 56 % of SJS cases, and 30 % of EM cases. The most common cause of exfoliating disease was a combination of azithromycin and ibuprofen, followed by ibuprofen alone [29]. In a pooled analysis by Levi et al. published in April 2009, data on severe drug reactions in children less than 15 years of age was collected from two multicentre international case-control studies, the severe cutaneous adverse reaction (SCAR) and the multinational severe cutaneous adverse reaction (EuroSCAR) studies. There were 80 cases identified as having either SJS, SJS/TEN overlap, or TEN and 216 controls. There were strong associations with anti-infective sulphonamides, phenobarbital, carbamazepine, and lamotrigine. Significant associations were also found with valproic acid, nonsteroidal anti-inflammatory drugs, and paracetamol [20]. Table 29.2 lists the most common drugs associated with EM, SJS, and TEN as published in the 2009 British Society for Allergy and Clinical Immunology (BSACI) guidelines [30].

EM and some cases of SJS, especially those with recurrent episodes, have been strongly associated with activity of the herpes simplex virus (HSV) and Mycoplasma pneumoniae or drug-specific T-helper (Th) 1 lymphocytes. Gelatinase activity has also been demonstrated in EM lesions, with tissue levels and patterns similar to those in SJS/TEN [31, 32].

In severe drug reactions such as SJS/TEN, apoptosis of keratinocytes is a common histopathological feature, and this keratinocyte death is now known to be mediated by fatty acid synthase ligand (FasL), and a recent report showed that soluble FasL (sFasL) is a useful tool to differentiate viral exanthems from drug eruptions as it was found to be repeatedly negative in viral exanthems but present in SJS/TEN [33]. A Japanese study has found FasL gene polymorphisms associated with SJS/TEN cases [34]. The main pathomechanism is thought to be perforin-secreting CD8+ T lymphocyte coupled with FasL CD40L+Th1/Th2 lymphocyte activity [31, 35]. One of the newer concepts is granulysin expressed by cytotoxic T lymphocytes and natural killer cells being the key mediator for disseminated keratinocyte death as it was found in blister fluid of SJS/TEN patients, two to four orders of magnitude higher than perforin, granzyme B, or soluble FasL [36]. A recent Japanese study has revealed that CD14+ CD16+ cells of monocyte lineage play an important role in the epidermal damage associated with SJS/TEN, most probably by enhancing the cytotoxicity of CD8+ T cells [37].

Erythema multiforme (EM), as originally described by von Hebra in 1866, is a self-limited condition characterised by the sudden onset of red papules which evolve into target lesions and have a tendency to recur. EM is classified into “EM minor” and “EM major” in an attempt to separate the classical, mild disease described by von Hebra (EM minor), which is most often associated with herpes simplex virus (HSV) infection in almost 50 % of cases, and the more severe form with mucosal involvement usually attributed to Mycoplasma pneumoniae infections and drugs [2, 38]. To a lesser degree, there are a multitude of other infections reported in association with EM including those caused by other viruses (i.e. Epstein-Barr virus (EBV), vaccinia, and other herpesviruses), certain bacteria, mycobacteria, and fungi [14, 39].

Patients with EM may experience burning or itching at the site of the eruption, which usually appears symmetrically on the distal extremities, gradually progressing proximally. The involvement of the dorsal hands, as well as the extensor surfaces of the extremities, is common, as is involvement of the palms and soles. The individual lesions may start off as erythematous macules that later evolve into papules, plaques, and finally target lesions, which are only seen several days after the onset [38]. There are lesions of varying morphology coexisting, hence the term erythema “multiforme”. The target lesions initially described consisted of two distinct zones, an inner zone of acute epidermal injury with necrosis or blisters and an outer zone of erythema [1]. Recent descriptions of target lesions have mentioned three distinct zones, a dusky area of central necrosis, a middle zone of pale oedema, and an outer zone of erythema [38, 40]. Figure 29.1 shows typical target lesions in a patient with EM.

Differential diagnosis includes drug eruption, polymorphous light eruption, urticaria, urticarial vasculitis, and other viral exanthems. As EM is generally self-limiting, management rarely requires hospital admission. In a 10-year review of EM, SJS, and TEN in children, 300,000 records were reviewed and only 30 cases of EM required admission with no mortality reported [39]. In a Taiwanese review, 19 cases of EM were recorded in an 8-year period, and most of these cases were attributed to Mycoplasma pneumoniae infection (42.1 %), HSV (5.26 %), EBV (5.26 %), and adenovirus (5.26 %), without any mortality noted [41]. A similar pattern was also seen in a Swiss study of 42 cases of EM, where 30 cases were attributed to infections, 14 due to Mycoplasma pneumoniae, and 6 due to HSV infection [42].

EM usually resolves spontaneously in 3–5 weeks but has a tendency to recur [38]. This is usually the case when it is found in association with HSV infection. In these cases, there is a role for acyclovir prophylaxis.

SJS is mostly attributed to drugs, although a small proportion may be attributed to infection (i.e. HSV and Mycoplasma pneumoniae). The major pathological finding is keratinocyte apoptosis mediated by granulysin and FasL [36]. SJS is characterised by erythematous or purpuric macules, widespread blisters predominantly on the trunk, and involvement of at least two mucosal surfaces and less than 10 % detachment [7, 8]. The patient is often ill and may present with fever, malaise, headache, cough, and rhinorrhoea associated with the prodromal target lesions followed by skin detachment. Mucosal involvement occurs in almost 100 % of cases, whilst visceral involvement (gastrointestinal, tracheal, or bronchial erosions, glomerulonephritis, and hepatitis) occurs to a lesser degree in 8.1–61.5 % of cases [16]. Upon commencing treatment and withdrawal of the offending drug, re-epithelialisation occurs, and there may be resulting post-inflammatory hyperpigmentation and scaling, with the average course of the disease lasting 2–3 weeks [17]. Acute and late ocular complications have been found in up to 71 % [43]. Reported mortality is around 5 %, and there are reports that prompt withdrawal of the offending drug reduces the risk of death by 30 % per day, although this is generally in the case of drugs with short half-lives [44, 45].

Figure 29.2 shows a patient with TEN due to lamotrigine.

SJS/TEN overlap is characterised by epidermal detachment between 10 and 30 %, whilst TEN has greater than 30 % epidermal detachment. Both are Nikolsky sign positive. Almost all cases are due to drugs, most commonly anticonvulsants and antibiotics [39, 41, 44, 46]. Similar to SJS, there is a prodrome of fever, malaise, and mucositis followed by the onset of tender, purpuric target lesions and the extensive epidermal detachment that ensues within 24 h, but most erupt over a period of 2–15 days, with the skin being quite painful to touch. TEN does not affect the hairy part of the scalp. The exposed dermis looks red and raw, whilst the remaining epidermis in other areas is wrinkled [46]. Ocular involvement is found in 90–100 % of cases with SJS/TEN, with ocular involvement in the acute setting occurring more frequently in patients with epidermal detachment involving more than 10 % of the body surface area [43]. Laboratory abnormalities include elevated C-reactive protein, hepatic dysfunction, anaemia, and lymphopaenia, with neutropaenia having a worse prognosis. There is also inflammation of internal mucosal surfaces such as the gastrointestinal and respiratory tracts due to the massive release of proinflammatory cytokines into the systemic circulation. This can lead to metabolic imbalance, multiorgan failure, pulmonary embolism, and gastrointestinal haemorrhage [10, 46]. Figure 29.3 shows a Chinese male with HLA-B*1502 positivity who developed TEN due to carbamazepine.