Severe Cutaneous Adverse Reactions

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SCARs through the identification of their characteristic clinical features so that the offending drug is promptly withdrawn and supportive and adjunctive therapies are administered.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 AGEP usually has favourable prognosis if the offending drug is withdrawn but a course of corticosteroids may hasten recovery.


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 fatal. 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 biopsy that enables confirmation of the diagnosis and provision of useful prognostic information. Data bases have been established, predominantly in Europe, since the 1980s to characterize the epidemiology of SCARs including the identification of drugs with the highest 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 cell-mediated 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 individual's risk of developing SCAR to a certain drug. 120 sign, which is epidermal separation induced by gentle lateral pressure applied to the skin surface. The skin then sloughs rapidly over several days as a result of separation of large sheets of the epidermis from the dermis. Fulminant cases of TEN have been reported where total loss of the epidermis occurs within 24 hours. New lesions may continue to erupt for up to 4 weeks. However, the growth of a new epithelium occurs after several days and individual lesions are completely re-epithelialized after a mean of 3 weeks. Cicatrization of the mucous membranes may take longer to complete. At least two mucosal surfaces are involved in 90% of cases of SJS/TEN (Letko, Papaliodis et al. 2005). Oropharyngeal involvement causes severe pain and odynophagia as a result of erosion and crusting (Fig. 2). Ocular regions may show a purulent conjunctivitis, pseudomembrane formation and corneal ulceration as a result of sloughing of conjunctival and corneal epithelia (Fig. 3). Urethritis may result in dysuria and even urinary retention. Sloughing of the tracheal and bronchial epithelium occurs in up to 30% of cases and may result in hypoxia, bronchial hypersecretion, pulmonary edema and bronchiolitis obliterans and the need for mechanical ventilation (Lebargy, Wolkenstein et al. 1997). The gastrointestinal tract can also be involved resulting in per rectal bleeding (Sugimoto, Mizutani et al. 1998).  The mortality of SJS is generally below 10% whereas 30-50% of TEN patients die in the acute phase of the illness mostly as a result of skin failure. Infection and sepsis with multiorgan failure is the most common of death. The causative organisms are usually Staphylococcus aureus and Pseudomonas aeruginosa (Atiyeh, Dham et al. 2003). Fluid and electrolyte imbalances occur as a result of increased transepidermal water loss and impaired intake of nutrition due to odynophagia from stomatitis. Less common fatal complications include adult respiratory distress syndrome, pulmonary embolism and gastrointestinal haemorrhage Abood, Nickoloff et al. 2008). Mortality is accurately predicted by the SCORTEN scale (Table 1) and should be computed within 24 hours and 3 days following admission (Bastuji-Garin, Fouchard et al. 2000;Guegan, Bastuji-Garin et al. 2006).

SCORTEN
Mortality ( Chronic complications occur frequently following the acute phase of SJS/TEN. The most serious sequelae relate to the eye. The chronic ocular consequences are that of a cicatrization of the conjunctiva and symblepharon formation, severe dry eye, trichiasis, eyelid margin keratinization, and limbal stem cell deficiency, all of which combine to cause corneal ulceration and scarring and loss of vision. Patients may also experience chronic photophobia and eye pain. Skin sequelae include scarring, pigmentation abnormalities, and shedding of hair and nails. Vulvovaginal involvement can result in stenosis. Vulvar adenosis can occur in young women several years after resolution of the acute episode and can present with tender, erosive, haemorrhagic lesions. Phimosis can occur in men. Bronchopulmonary complications confer a poor prognosis and include chronic bronchitis, bronchiolitis obliterans, bronchiolitis obliterans with organizing pneumonia, and bronchiectasis. Oesophageal stricture and webbing has also been described and can result in dysphagia.

Pathogenesis
SJS/TEN results from the T-and NK-cell mediated extensive apoptosis of keratinocytes. The pharmaco-immune (p-i) concept, the mechanism by which the drug binds directly with the T cell receptor (TCR) causes activation of proapoptotic pathways. Granulysin is the major mediator of apoptosis in SJS/TEN. Apoptosis is also mediated through Fas-FasL interaction, and the release of granzyme and perforin.

The pharmaco-immune (p-i) concept
It is generally accepted that in SJS/TEN, the parent drug binds directly and non-covalently to the MHC and the TCR of primed effector and memory T cells (Pichler, Adam et al. 2010). Naïve T cells are not sufficiently stimulated by a p-i drug and additional signals are required (Pichler 2005). T cells may be primed by infection or autoimmune disease resulting in high cytokine levels such as IL-2 and IFN- resulting in increased expression of MHC and costimulatory molecules. This may provide an explanation for the increased incidence of drug hypersensitivity in inflammatory and infectious diseases. The drug may also bind to toll-like receptors resulting in the expression of costimulatory molecules by dendritic cells. For drugs such as cotrimoxazole, lamotrigine, and carbamazepine, the p-i concept may not be the sole mechanism involved; metabolites may also play a role through haptenization (Sanderson, Naisbitt et al. 2007).

Granulysin
A recent study by Chung et al using global gene expression profiling showed that granulysin RNA was the most significant cytotoxic molecule expressed in blister cells from patients with SJS/TEN. Granulysin protein concentrations were 2-4 times higher than perforin, granzyme B, and FasL and depleting granulysin reduced cytotoxicity (Chung, Hung et al. 2008). Granulysin is a cationic cytolytic protein produced by CTL, NK and NKT cells ( Fig. 4A) (Gamen, Hanson et al. 1998). The 15-kDa-precursor form, found in blister fluid, induced skin necrosis when injected into mice and exhibited significant cytotoxicity in vitro. This contrasted with the minimal cytotoxicity induced by perforin, granzyme B, and FasL (Chung, Hung et al. 2008). Granulysin is also a proinflammatory molecule that causes an increase in the expression of chemokines (RANTES/CCL5, MCP-1, MCP-3, MIP-1/CCL3) and cytokines (IL-1, IL-6, IFN-) resulting in the recruitment of T cells, monocytes and other inflammatory cells (Deng, Chen et al. 2005). Fig. 4. SJS/TEN is primarily mediated by cytotoxic T cells. The drug binds to the CD8 T cell receptor and MHC via the pi concept resulting in their proliferation, activation and infiltration of these effector cytotoxic T cells (CTLs) into the skin (A). These CTLs may also bind drug that also binds to MHC class I molecules expressed on keratinocytes. Apoptosis of keratinocytes in SJS/TEN is caused primarily by the release of granulysin (A), but the ligation of Fas by FasL (B), and the degranulation of perforin and granzyme (C) may also play a role.

Fas-FasL, perforin/ granzyme and TNF pathways
Viard et al, showed that the binding of FasL to Fas expressed on the surface of keratinocytes resulted in their apoptosis ( Fig. 4B) (Viard, Wehrli et al. 1998). The cytoplasmic death domain of Fas undergoes conformational changes and trimerization upon recognition of FasL. This results in the recruitment of the Fas-associated death domain (FADD), which binds to procaspase 8 resulting in triggering of the caspase cascade and apoptosis. The source of the FasL is unclear. Viard et al showed that the FasL was is present on the surface of keratinocytes and in the serum of patients with TEN but not on the surface of keratinocytes or in the serum of patients with maculopapular exanthems and normal controls (Viard, Wehrli et al. 1998). A further study demonstrated that FasL was not constitutively expressed on the surface of keratinocytes but are transported to the cell membrane after damage to the keratinocyte (Viard-Leveugle, Bullani et al. 2003). Abe et al, however, found that the source of FasL was PBMCs and not keratinocytes (Abe, Shimizu et al. 2003). Nassif et al showed that mononuclear cells from blister fluid induce cytotoxicity via perforin and granzyme B (Nassif, Bensussan et al. 2002). This cytotoxicity was blocked by inhibiting perforin/granzyme but not by inhibiting Fas. Perforin and granzyme are proteins stored in the granules of CTLs. Upon recognition of a target cell, the CTL releases perforin, which create 16-nm channels in the target cell membrane. Granzyme B, a protease passes through these channels to activate the caspase cascade (Fig. 4C). The loss of T regulatory cell function in the acute stage of SJS/TEN may further contribute to the epidermal damage caused by effector T cells (Takahashi, Kano et al. 2009). Posadas et al, showed that both Fas-FasL and perforin/granzyme pathways may be involved in SJS/TEN. They found a direct correlation between disease severity and levels of perforin and granzyme B in patients with maculopapular exanthems, SJS and TEN. FasL was detected in the PBMCs and blister fluid of patients in SJS and TEN but not in those in maculopapular exanthema, suggesting that Fas-FasL is involved in more severe reactions (Posadas, Padial et al. 2002). Nassif et al, also showed a potential role for cytokines in the pathogenesis of SJS/TEN. He found elevated levels of IFN-, soluble TNF, IL-10, soluble FasL in the blister fluid of TEN patients. Although they disputed the central role of FasL, they hypothesised that drug specific CTLs secrete IFN-, which activates keratinocytes to produce TNF, a cytokine that upregulates MHC class I molecules. This increases exposure of keratinocytes to CTL resulting in perforin/granzyme-mediated apoptosis. IL-10 serves to downregulate the inflammatory reaction (Nassif, Bensussan et al. 2004).

Risk factors for SJS/TEN 2.6.1 Genetic susceptibility
It was observed in the 1990s that the most commonly offending drugs vary among different ethnic populations. In Western countries, the most commonly implicated agents of SJS/TEN were NSAIDs and sulphonamides (Roujeau, Kelly et al. 1995). In contrast, carbamazepine was found to be the leading cause of SJS/TEN in Southeast Asian countries, including India, Malaysia, Singapore, Taiwan and Hong Kong (Hung, Chung et al. 2005a). Interestingly, carbamazepine in Western countries causes more cases of DIHS than SJS/TEN. Allopurinol is also a frequent case of SJS/TEN and DIHS but does not appear to have a racial bias (Hung, Chung et al. 2007 (Chung, Hung et al. 2004). These findings were replicated in an extended cohort of subjects of Chinese descent originating from separated geographic areas of China, Taiwan, and the United States (Hung, Chung et al. 2006). This association with carbamazepineinduced SJS/TEN, however, was not found in individuals with European (Lonjou, Thomas et al. 2006) and Japanese ancestries (Kaniwa, Saito et al. 2008), respectively, and therefore the allele appears relevant in the context of ethnicity. In a recent study comprising 12 patients of Northern European ancestry with carbamazepine-induced SJS/TEN, 5  (Hung, Chung et al. 2005b). The role of these HLA alleles in the pathogenesis of SCAR is unclear. Certain HLA alleles may bind to particular drugs more robustly than other alleles. Furthermore, the binding of the drug in SJS/TEN is MHC class I restricted, which is consistent with the prominent role of CD8 cells in the pathogenesis of the disease. If an allele has a functional effect that may play a role in the pathogenesis of disease, this association will be consistently observed across different populations. The differences observed between the Chinese and European studies may be partly explained by the fact that pharmacogenetic studies are likely to yield positive results when conducted in a population with a high frequency of such an allele . The risk of disease from a genetic polymorphism is influenced by its prevalence. The HLA-B*1502 allele frequency is 4.8 to 12.8% in Southeast Asians compared to 0-0.1% observed in Northern Europeans (Fig. 5). Therefore, HLA-B*1502 is of low prevalence in Caucasians and hence, if it is a true susceptibility allele, a very large sample size is required in this population to detect a significant odds ratio of sufficient power. In contrast, the allele frequency of HLA-A*3101 is 2-5% in Northern Europeans and the sample size required to demonstrate an association in a sufficiently powered study is less than that for the HLA-B*1502 allele. The HLA-B*5801 allele, in contrast to HLA-B*1502 is more evenly distributed among different racial groups ( Fig. 6) and hence, associations, albeit weaker, have been demonstrated in other ethnic groups such as the Southern Japanese (Kaniwa, Saito et al. 2008) and in whites ) (Lonjou, Borot et al. 2008). Another explanation is that HLA-B*1502, is a marker of a true disease contributing allele through strong linkage disequilibrium, which varies between populations. In other words, the same high-risk allele may have a different pattern of association with marker alleles and therefore HLA-B*1502 is in strong linkage disequilibrium in the Han Chinese population, but not in a European population. It is also plausible that SJS/TEN is a polygenic disorder, with many susceptibility and protective alleles in genes involved in the pathogenesis of the disease. Polymorphisms in the proapoptotic gene Fas-L, the toll-like receptor 3 gene, and in the IL-4 receptor/IL-13 signalling pathway have all been recently described in a Japanese study . Such alleles may also vary in different populations.  The FDA and Health Canada have issued warnings for carbamazepine stating that persons with ancestry in genetically at-risk populations should be screened for the presence of HLA-B*1502 prior to initiating treatment. Genetic screening for HLA-B*1502 i n a h i g h r i s k population such as the Han Chinese has a 100% sensitivity and 97% specificity and its presence confers a 7.7% positive predictive value for carbamazepine-induced SJS/TEN whereas its absence has a 100% negative predictive value (Hung, Chung et al. 2005a). A recent study demonstrated the benefit of genetic screening; in a Taiwanese population, screening for the HLA-B*1502 allele resulted in no cases of SJS/TEN in 4501 patients who were negative for the allele (Chen, Lin et al. 2011). The authors concluded that this would have prevented 10 cases of SJS/TEN. Despite the FDA recommendations, screening is not routinely performed partly because of the lack of availability of cost effective and rapid methods of detection (Fernando and Broadfoot 2010). However, many laboratories have now developed high resolution genetic testing using a sequence-specific primer assay method for the detection of this allele from whole blood samples and buccal swabs. The assay can be performed within 3-4 hours. Such a strategy has been very successful in virtually abolishing the incidence of HLA-B*5701-associated abacavir hypersensitivity in HIV-infected patients (Rauch, Nolan et al. 2006). Multiplexed PCRs can be utilized to assess multiple alleles.
It is important to note that the HLA-B*1502 allele does not predispose to carbamazepineinduced DIHS, maculopapular eruptions or other adverse reactions and continued vigilance for the symptoms of SCAR needs to be maintained if treatment is commenced (Hung, Chung et al. 2006). Currently, there is no recommendation for genetic screening prior to the commencement of allopurinol therapy. Although such a strategy is plausible, studies are required to determine the benefits of screening for the HLA*5801 allele in at risk populations.

Diseases
The EuroSCAR study showed that HIV infection conferred the highest risk of SJS/TEN; multivariate relative risk (

Pharmacokinetics
The EuroSCAR study revealed an increased risk of SJS/TEN at higher doses of allopurinol; adjusted odds ratio (OR) 36 [17-76] for doses ≥200 mg daily compared with an adjusted OR 3.0 [1.1-8.4] for doses <200 mg daily (Halevy, Ghislain et al. 2008). This study also revealed that the risk was mostly confined to short-term use (≤8 weeks, unadjusted OR 261 [36-∞]). Allopurinol is ideally commenced at a dose of 100 mg daily and increased by 100 mg increments until the desired serum uric acid level is attained. Previous reports have shown that allopurinol is often commenced at inappropriate doses (Stamp, Gow et al. 2000) and that higher doses are associated with an increased incidence of acute events (McInnes, Lawson et al. 1981). It is likely that the rapid accumulation of the chemically reactive metabolite oxypurinol when higher doses of allopurinol are commenced increases the risk of SJS/TEN (Kumar, Edward et al. 1996). This drug accumulation hypothesis is further supported by the 4.7 fold increased incidence of allopurinol-induced SCAR in renal insufficiency (Vazquez-Mellado, Morales et al. 2001). The established indications for allopurinol are treatment of hyperuricemia associated with chronic gout, acute uric acid nephropathy, recurrent uric acid stone formation, enzyme disorders of purine metabolism, and in the management of tumour lysis. Allopurinol is not indicated in the majority of patients with asymptomatic hyperuricemia (Dincer, Dincer et al. 2002). However, allopurinol is inappropriately prescribed in up to 86% of cases (Khoo and Leow 2000). A comparison of allopurinol exposure between the SCAR (1989)(1990)(1991)(1992)(1993) and EuroSCAR (1997EuroSCAR ( -2001 studies showed a 2-3 fold increase in exposure for both patients and control subjects, which may be attributed to the increased prescribing of the drug for the treatment of asymptomatic hyperuricemia. The authors of the EuroSCAR study postulate that up to 48 of the 56 cases of allopurinol-induced SJS/TEN could have been prevented if the treatment guidelines for prescribing allopurinol were followed. Lamotrigine when commenced at high doses can also overwhelm the detoxifying capacity resulting in an increased risk of SJS/TEN and DIHS (Schlienger, Shapiro et al. 1998). The incidence has reduced significantly as a result of the now conventional practice of gradually titrating the dose (Mockenhaupt, Messenheimer et al. 2005). Coadministration of certain drugs can predispose to SCAR by competition for the same enzyme-binding site. Reactions to lamotrigine are more common when given in combination with valproic acid as the addition of valproic acid inhibits the clearance of lamotrigine by competing for glucoronic acid conjugation (Yalcin and Karaduman 2000). The role of slow acetylation phenotypes of N-acetyltransferase was thought to confer susceptibility of sulphonamide-induced SJS/TEN in two small studies (Dietrich, Kawakubo et al. 1995;Wolkenstein, Carriere et al. 1995) but this needs confirmation in larger studies.

Diagnosis 2.7.1 Skin biopsy
A presumptive diagnosis of SJS/TEN is made clinically and is confirmed with a skin biopsy (Figs. 7 & 8). Early lesions demonstrate scattered necrotic keratinocytes in the epidermal layers at the level of the stratum spinosum and the basal cell layer. Later, full thickness epidermal necrosis is evident, which eventuates in the formation of subepidermal bullae.
The mononuclear predominantly T cell dermal infiltrate is generally sparse but dense infiltrates can also be present. Quinn et al, has shown an extensive infiltrate was associated with a 71% mortality rate, a moderate infiltrate with a 53% mortality, and a sparse infiltrate with a 27% mortality, respectively (Quinn, Brown et al. 2005). A fresh sample for direct immunofluoresence (DIF) reveals an absence of immunoglobulin and complement deposition. Cultures on blood, wounds and mucosal lesions should be performed to evaluate for superinfection. Serology may be performed for Mycoplasma pneumoniae if indicated.
A recent pilot study showed that serum granulysin levels may be raised early in the course of disease but rapidly wanes with progression of disease (Abe, Yoshioka et al. 2009). Further studies are required to determine whether this assay will prove to be a useful early diagnostic test for SJS/TEN.

Allergy testing
Skin tests and oral challenges are contraindicated in SJS/TEN because of the risk of inducing a recurrence of disease. Patch testing has not been investigated extensively. The biggest cohort comprised 22 patients and showed a poor sensitivity of only 9% (Wolkenstein, Chosidow et al. 1996). Lymphocyte transformation tests (LTTs) assess the proliferation of the patient's peripheral blood T cells cultured in the presence of a suspected drug for 6 days by measuring the incorporation of 3 H-thymidine during DNA synthesis. The result is expressed as a stimulation index, which is the ratio of cell proliferation with antigen and without antigen. The sensitivity of LTTs in SJS/TEN is greatly improved if the test is performed within 1 week of the onset of disease but becomes negative by 6 weeks (Kano, Hirahara et al. 2007). This may be attributed to loss of regulatory T cell function in the acute phase, which is then restored upon recovery (Takahashi, Kano et al. 2009). Recently, a new cytotoxicity assay combining the measurement of expression of the degranulation marker, CD107a, using flow cytometry and the release of the serine protease, granzyme B by Elispot after incubating the patient's peripheral blood mononuclear cells with the suspected drug for 3 days (Zawodniak, Lochmatter et al. 2010). The test has very good specificity with all of the 16 controls having a negative test and good sensitivity with 10 of the 12 patients having a positive result. One role of these in vitro tests is to determine the culprit drug when more than one drug is suspected.

Differential diagnosis
SJS/TEN is differentiated from other conditions on the basis of the acute onset of disease, the presence of targetoid and vesiculobullous lesions, sloughing of the epidermis, severe mucosal involvement, the histologic finding of full thickness epidermal necrosis, and a negative DIF. In EM major, erosive mucous membrane involvement is present but in contrast to SJS, the patient has typical target lesions mainly affecting the extremities and it is often induced by acute or recurrent HSV infection. The clinical manifestations of druginduced maculopapular exanthems (MPE) are variable and often polymorphic and lesions may have a target-like appearance. Fever may be present but mucosal involvement is absent. The histopathology typically shows an interface dermatitis with hydropic degeneration of the basal cell layer. Some exanthems may progress to more severe reactions such as SJS/TEN or DIHS. Generalized bullous fixed drug eruption (GBFDE) features large brownish violaceous patches upon which flaccid blisters arise. These blisters affect only a small percentage of the TBSA. Mucosal involvement is rare and fever is absent. Most patients report a history of a similar local reaction or fixed drug eruption. Staphylococcal scalded skin syndrome (SSSS) usually affects children under the age of 5 years and patients present with fever, erythema and painful skin, followed by blistering, which is typically accentuated in areas of friction and around orifices. SSSS is caused by the systemic distribution of epidermolytic toxins produced by certain strains of Staphylococci. These toxins cause separation at the level of the stratum granulosum, the upper layer of the epidermis, resulting in very superficial detachment of the skin and blistering. Mucous membrane involvement is rare. The condition usually but not always follows local or systemic staphylococcal infection. Adults are less susceptible as improved renal function allows for better clearance of the toxins. However SSSS has been described in adults who are immunosuppressed or in renal failure. Toxic shock syndrome (TSS) is caused by elaboration of toxins produced by Staphylococcus aureus and Streptococcus pyogenes that act as superantigens, which bind to the variable regions of  chains of antigen receptors on subsets of T cells and cross-link them to the MHC molecules of antigen-presenting cells. This results in activation of large numbers of T cells (5-30%) and the massive release of cytokines including IL-2, TNF, lymphotoxin and IL-1. TSS is characterised by fever, diffuse red macular rash, hypotension and involvement of ≥3 organs: renal failure, hepatitis, thrombocytopenia, encephalopathy, mucous membrane hyperemia, gastrointestinal involvement with vomiting and diarrhoea.  Desquamation occurs after 1-2 weeks and predominantly affects the palms and soles. Approximately 50% of cases are menstrually related due to the prolonged application of absorbent tampons. Notably, 50% of cases of TSS are not associated with menstruation. Nonmenstrual cases of TSS usually complicate the use of barrier contraceptives, surgical and postpartum wound infections, burns, cutaneous lesions, osteomyelitis, and arthritis. Although most cases of TSS occur in women, about 25% of non-menstrual cases occur in men.
Autoimmune bullous diseases such as drug-induced linear IgA bullous dermatosis, druginduced pemphigus, and paraneoplastic pemphigus need to be considered in the differential diagnosis of SJS/TEN. These conditions, in contrast to SJS/TEN, usually have a chronic course and are characterized by acantholysis on histopathology and immunoglobulin deposition on DIF. Bullous pemphigoid (BP) is a chronic disease that is typified by a tense bullous eruption that primarily affects individuals in the fifth through seventh decades of life. Acute graft versus host disease (AGVHD) shares many of the same clinical, pathologic and immunologic features as SJS/TEN. Both conditions are mediated by cytotoxic T cells, which results in epidermal necrosis and keratinolysis (Schulz and Sheridan 2006). Furthermore, bone marrow transplantation patients receive medications that can trigger SJS/TEN. AGVHD generally occurs 4 weeks after stem cell transplantation. Patients describe a sensation of skin pain and itching followed by a morbilliform rash that in severe cases becomes generalized with diffuse areas of epidermal necrosis. Mucositis is usually present. AGVHD frequently begins acrally and spreads proximally in contrast to TEN, which begins on the trunk and spreads distally. Also, the early exanthem of AGVHD has a folliculocentric distribution. AGEP is characterized by fever and as the disease progresses, widespread erosions mimicking SJS/TEN may be evident. Mucous membrane involvement is unusual and if present is mild.
2.9 Treatment 2.9.1 Supportive care Immediate discontinuation of the culprit drug is mandatory to reduce mortality. As the management of TEN is similar to that of extensive burns, a transfer to a burns unit reduces morbidity and mortality. The unit has expertise in providing analgesia, ensuring adequate enteral or parenteral nutrition, maintaining fluid and electrolyte balance, and managing wounds. Ophthalmologic consultation is important in SJS/TEN and the combination of aggressive lubrication, topical antibiotics, topical corticosteroids, and lysis of adhesions may attenuate the acute ocular manifestations. However, these measures have only a modest effect on the long term ocular complications. Recently, the application of amniotic membranes has proved effective in preserving visual acuity and an intact ocular surface (Shammas, Lai et al. 2010). The benefit may be derived from creating a physical barrier between inflamed and denuded mucosal surfaces that minimizes the formation of adhesions. The membrane may also have antiinflammatory and antifibrotic effects. Other supportive measures include hygienic mouthwashes and topical oral anaesthetics, and monitoring for urinary retention.

Corticosteroids
The role of corticosteroids in the treatment of SJS/TEN is controversial. Corticosteroids given 48 hours or more prior to admission are associated with an increase incidence of infection, length of hospital admission, and mortality in children and adults (Rasmussen 1976;Ginsburg 1982;Engelhardt, Schurr et al. 1997). A study in 1986 of 30 patients with TEN with an average TBSA involvement > 80% were equally divided into those receiving supportive care alone and those receiving dexamethasone at varying doses (Halebian, Corder et al. 1986). Although the incidence of sepsis was not significant different between the groups, the survival following onset of sepsis was less in the corticosteroid treated group. The use of corticosteroids doubled the rate of mortality (66% versus 33%). Corticosteroids do not prevent SJS/TEN from occurring and have no effect on arresting disease progression (Samimi and Siegfried 2002). A retrospective analysis of 379 patients from the EuroSCAR study found no benefit from corticosteroids or IVIg compared to supportive care alone (Schneck, Fagot et al. 2008).
The poor outcomes may have resulted from inadequate doses and the delay in the initiation of corticosteroid therapy. In a prospective study of 16 children with SJS in 1997, 10 received methylprednisolone (4 mg/kg/daily) within 3 days of the onset of rash whilst 6 received supportive care only; corticosteroids were associated with decreased length of fever and duration of skin eruption (Kakourou, Klontza et al. 1997). The use of pulsed IV corticosteroids has also been shown in retrospective analyses to reduce mortality. The initiation of IV methylprednisolone 500-1000 mg/daily for 3-4 days may also prevent ocular complications of cicatrization and preservation of visual acuity (Araki, Sotozono et al. 2009). The benefits of early pulsed therapy with IV corticosteroids need to be further evaluated in randomised control trials. The current level of evidence suggests that high dose corticosteroids may be beneficial if commenced early in the course of disease with vigilant monitoring for emergence of infection. However, further evaluation in randomised control trials are required to confirm these benefits

Intravenous immunoglobulin (IVIg)
The rationale for the use of IVIg is based on its ability in vitro to block Fas and subsequently FasL-mediated apoptosis of keratinocytes. The beneficial role of IVIg in SJS/TEN has been demonstrated in retrospective studies. The largest such study to date comprised 48 patients with TEN recruited from centres across Europe and the United States. Treatment with IVIg resulted in a more rapid cessation of epidermal detachment and a survival rate of 88%. The authors subsequently recommended a dose of 1 g/kg/daily for 3 days (Prins, Vittorio et al. 2003). Studies have also demonstrated benefit when investigators have compared the rates of mortality following the use of IVIg with the pre-treatment estimate using SCORTEN (Campione, Marulli et al. 2003;Metry, Jung et al. 2003;Yang, Xu et al. 2009). Despite the initial preponderance of evidence favouring the use of IVIg in SJS/TEN, a few published reports have not demonstrated any benefit. Most of these studies comparing the use of IVIg with supportive care alone used doses less than the recommended 2-3 g/kg. The largest restrospective analysis on the use of IVIg derived from the EuroSCAR study found no additional benefit from IVIg administered at a dose of 1.9 g/kg when compared to the use of supportive measures alone. This study involved the use of lower than recommended doses of IVIg and the patients from the IVIg group tended to have a greater TBSA involvement (Schneck, Fagot et al. 2008). Randomized control studies are required using sufficient doses of IVIg to characterize its benefit in not only reducing mortality but also arresting the rate of progression and hastening the rate of re-epithelialization. However, the evidence thus far, would suggest that it should be at least considered as part of the adjunctive therapy in the treatment of SJS/TEN.

Cyclosporine
Cyclosporine inhibits CD8 activation and subsequent release of granulysin, granzyme and perforin as well as inhibiting the proapoptotic effect of NF-B. Several case and case series reports have shown arrest of disease progression and shorter time to re-epithelialization with doses varying from 3-10 mg/kg/daily for a period ranging from 8 days to several weeks. One study showed that outcomes for 10 patients treated with cyclosporine was superior to 6 patients treated with cyclophosphamide and corticosteroids with respect to re-epithelialization, disease progression and death (Arevalo, Lorente et al. 2000). However, randomised control studies are required to better define its benefits, the appropriate dose and duration of therapy. Furthermore, no studies have been published to date evaluating the efficacy of using both IVIg and cyclosporine but may be worthwhile considering as different pathways involved in the pathogenesis of SJS/TEN are targeted.

Other pharmacotherapies
Plasmapheresis and N-acetylcysteine-induced detoxification of drugs have demonstrated benefit in a small number of studies but larger randomized control studies are required to elucidate their role in the management of SJS/TEN. However, thalidomide, a potent inhibitor of TNF, was found in a double blinded randomised placebo controlled to be lethal in 10 of 12 patients as compared with 3 of 10 control subjects (Wolkenstein, Latarjet et al. 1998). The exact mechanism underlying these fatalities is unknown but the drug is firmly contraindicated in SJS/TEN.

Restricted use of related medications
In addition to the restricted use of the same medication, structurally similar drugs should also be avoided. The aromatic anticonvulsants carbamazepine, phenytoin and phenobarbitol cross react with one another. Cross reactivity resulting in SJS/TEN can also occur across different classes of beta-lactam antibiotics, such as penicillins, cephalosporins and carbapenems. Administration of a structurally related drug can also result in different reactions. One case report described a patient with ceftriaxone-induced TEN who developed immediate anaphylaxis following the administration of piperacillin/tazobactam (Lam, Randhawa et al. 2008). The risk of SJS/TEN with structurally distinct agents within the same class of drug is less clear. For example, the cross reactivity between a priopionic acid NSAID and an enolic acid NSAID is unknown. The safest practice is to restrict all NSAIDs following NSAID-induced SJS/TEN.

Nosology
The term hypersensitivity syndrome has been used for decades to describe a cutaneous drug reaction accompanied by involvement of internal organs. In 1938, Merritt and Putnam described a toxic reaction to phenytoin characterized by exfoliative dermatitis, fever and eosinophilia (Merritt and Putnam 1938). This was distinguished from those patients who developed a mild, morbilliform rash. The anticonvulsant hypersensitivity syndrome was named in 1988 by Shear and Spielberg to refer the similar cutaneous and systemic manifestations of idiosyncratic reactions to a range of anticonvulsant medications including phenytoin, phenobarbitol and carbamazepine (Shear and Spielberg 1988). In 1996, Bocquet et al introduced the term drug reaction with eosinophilia and systemic symptoms (DRESS) to distinguish it from drug-induced pseudolymphoma and other drug reactions that are not associated with eosinophilia (Bocquet, Bagot et al. 1996). Finally, Shiohara et al proposed the term drug induced hypersensitivity syndrome (DIHS) to include patients who may not have marked eosinophilia but have other evidence of leukocyte abnormalities, internal organ involvement and evidence of HHV-6 reactivation (Suzuki, Inagi et al. 1998;Shiohara, Inaoka et al. 2006).

Epidemiology
The incidence of DIHS is estimated to be between 1 in 1000 and 1 in 10000 to phenytoin (Gennis, Vemuri et al. 1991). The true incidence remains to be determined because of the variable presentations and the lack of universally accepted criteria. The JSCAR and RegiSCAR studies will provide more accurate reporting on the basis of stringent criteria. Preliminary data from the RegiSCAR study suggests that it affects males and females equally with a mean age of 47.4 years (range 3-84 years) ).
The rash evolves, especially if the causative drug is not withdrawn into a severe exfoliative dermatitis (Fig. 10) or erythroderma with edematous, follicular and purpuric lesions. Cheilitis (Fig. 9), pharyngeal erythema and oral ulceration may occur but severe stomatitis is not present. Tender lymphadenopathy in more than two sites and bilateral swelling of salivary glands with xerostomia is evident early in the course of disease.
Hepatosplenomegaly is a common finding. Leukocytosis with atypical lymphocytes and eosinophilia (60-70% of cases) is a prominent feature of this syndrome although the eosinophilia may not be observed for 1-2 weeks. Thrombocytopenia and anemia may also be present. Hypogammaglobulinema is noted at the onset of disease with the nadir occurring several days after the withdrawal of the causative drug (Kano, Inaoka et al. 2004). An overshoot in the IgG level occurs 1-2 weeks after the nadir before returning to normal on full recovery. Internal organ involvement is summarised in  Table 4. Internal organ involvement in DIHS The onset of symptoms is variable with patients developing 2-3 symptomatic features followed by stepwise development of other manifestations. In most cases, withdrawal of the drug is not followed by rapid resolution of symptoms. Many patients may continue to deteriorate and show periodic relapses for weeks after the withdrawal of the causative drug.

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Severe Cutaneous Adverse Reactions 137 Fig. 9. Facial erythema and edema with labial ulceration in a young woman with DIHS/DRESS. Fig. 10. Exfoliative dermatitis involving the hand in a young woman with DIHS/DRESS who had continued to ingest the culprit drug for 4 weeks when this image was taken.
Several reports have described the occurrence of autoantibody formation and autoimmune diseases up to 4 years after the acute resolution of DRESS (Aota and Shiohara 2009) and these include type 1 diabetes mellitus, autoimmune thyroid disease, scleroderma GVHD, SLE, and bullous pemphigoid. One of the likely explanations for the occurrence of autoimmune disease is the depletion of regulatory T cells upon recovery of disease. Abacavir, an HIV nucleoside analogue reverse transcriptase inhibitor causes a potentially lifethreatening hypersensitivity syndrome in approximately 5-8% of recipients within 6 weeks of therapy. The clinical and laboratory features of this syndrome differs from typical cases of DIHS/DRESS in that there is a predilection for the gastrointestinal system with nausea, abdominal pain, diarrhoea, and the respiratory tract with cough, pharyngitis and shortness of breath. Headache, myalgia and/or arthralgia may also be present. Eosinophilia is present in < 10% of cases and liver function test abnormalities are detected in < 20% of cases (Peyriere, Dereure et al. 2006). Also, the manifestations resolve within 72 hours rather than having a protracted relapsing course and the role of herpetic viruses in this condition is unknown.

Differential diagnosis
Viral infections such as EBV, CMV, and measles can be distinguished by the absence of eosinophilia, hypogammaglobulinemia, and supportive serology. In children, DIHS is differentiated from Kawasaki's disease by the absence of a bulbar conjunctivitis, strawberry tongue, coronary aneurysms, hypoalbuminemia and thrombocytosis. Serum sickness is characterized by urticarial lesions and the absence of internal organ involvement. Atopic erythroderma with bacterial infection does not usually involve hepatitis or nephritis. Druginduced pseudolymphoma from carbamazepine or phenytoin is distinguished from DIHS by the absence of internal organ involvement and the prompt resolution of symptoms when the drug is withdrawn. Cutaneous B and T cell lymphomas have an indolent course and characteristic histopathology.

Pathology
The histopathology of DIHS is relatively non-specific and consists of a lymphocytic infiltrate that is superficial, perivascular, dense and diffuse. Eosinophils may be present but is often absent. The presence of loose rather than discrete granulomatous aggregates of histiocytes have been recently reported (Figs. 11 & 12) (Fernando, Henderson et al. 2009). HHV-6 and DNA from other herpes viruses may be detected in skin lesions by PCR or in situ hybridization (Suzuki, Inagi et al. 1998).

Drug allergy testing 3.6.1 Patch tests
Santiago et al recently studied the utility of patch testing in DIHS and found a positive reaction in 32% of the 56 patients. Patch testing was performed between 6 weeks and 6 months after healing of the lesion and at least one month after corticosteroids were ceased. They found that 76% of the 17 patients with carbamazepine-induced DIHS were patch test positive but none of the 19 allopurinol-sensitive patients were positive to allopurinol and its metabolite, oxypurinol. No systemic reactions occurred during or after testing (Santiago, Goncalo et al. 2010). Hence patch testing may prove useful once the reagent and timing of such testing is optimized. Patch testing has, however, proven to be very useful in confirming suspected cases for abacavir hypersensitivity with a higher degree of specificity than can be confirmed clinically (Phillips, Wong et al. 2005).

Lymphocyte transformation tests (LTTs)
LTTs are usually negative up to 3 weeks after the onset of DIHS but most patients are positive at 5-7 weeks and have persistent responses even at 1 year. Treatment with corticosteroids did not affect the results (Kano, Hirahara et al. 2007). One possible explanation for the negative LTT result during the acute phase of DIHS is the expansion T regulatory cells with a naïve phenotype (CD4CD25FoxP3), which then are depleted by apoptosis during the recovery phase. These regulatory T cells are capable of suppressing proliferation of memory T cells in LTTs (Takahashi, Kano et al. 2009).

Pathogenesis
The pathogenesis of DIHS is still to be fully elucidated. The precise role of HHV-6 in DIHS is unclear. The initiating event may be the reactivation of one or more herpetic viruses, which is clinically unapparent (Fig. 13). Virus-stimulated T cells may then cross react with drugderived hapten-protein conjugates that are presented by dendritic cells to naïve antigenspecific CD4 T-cells with the subsequent differentiation into effector/memory CD4 cells. These dendritic cells may also activate CD8 T-cells by cross-presentation. The expansion of effector CD4 T-cells with their production of IFN- and other cytokines results in recruitment and activation of macrophages. Failure to eradicate the antigenic stimulus, in this instance due to the continued ingestion of the drug, causes persistent cytokine release and promotes differentiation of macrophages into epithelioid cells, which secrete large amounts of TNF promoting their fusion to form multinucleate giant cells (Fernando, Henderson et al. 2009). Analogous to that observed in GVHD, longitudinal real-time PCR analyses of viral loads in blood samples drawn from patients with DIHS show that various herpetic viruses are sequentially activated as a result of massive T cell stimulation, B cell loss and hypogammaglobulinemia (Hirahara, Kano et al. 2010); Activation of Epstein-Barr virus or HHV-6 extends to the sequential activation of HHV-7, cytomegalovirus and varicellazoster virus (Kano, Inaoka et al. 2004). The frequent deterioration or several exacerbations that occur despite continuation of the drug may at least be partly explained by sequential reactivation of herpetic viruses and the immune response to viral replication. An alternative explanation is that drug specific T cells are activated resulting in reactivation of the viral genome and sequential reactivation of herpes viruses (Fig. 14). Genetic susceptibility may also play a role as all patients with allopurinol-induced DIHS in a Han Chinese population harboured the HLA-B*5801 allele compared with 15% of control subjects (Hung, Chung et al. 2005b (Mallal, Nolan et al. 2002). There is a discrepancy in the association of HLA-B*5701 and abacavir hypersensitivity across various racial groups The association was confirmed in a separate cohort of HIV-infected white Americans and was also found to confer susceptibility in Hispanics but not in blacks (Hughes, Mosteller et al. 2004). No association was found in a cohort of Korean patients (Park, Choe et al. 2009). The racial variation may be partly explained by the differences in MHC haplotypes across different racial groups. The Caucasian 57.1 ancestral haplotype, which confers susceptibility to abacavir hypersensitivity possibly as a result of strong linkage disequilibrium with other candidate genetic factors such as cellular chaperones (e.g. heat shock proteins), inflammatory cytokines (e.g. TNF), and proteins involved in the stress response (e.g. MHC class I chain-related genes, MIC-A and MIC-B). African populations do not demonstrate this haplotype (Cao, Hollenbach et al. 2001). However, in a recent study by Saag et al, all 42 white patients with immunologically confirmed (i.e. positive patch tests) hypersensitivity to abacavir reactions were HLA-B*5701 positive (sensitivity 100%, OR 1945 [110-34,352]) but in addition all 5 black patients with immunologically confirmed hypersensitivity reactions were HLA-B*5701 positive (sensitivity 100%,045]. Screening for the HLA-B*5701 has eliminated immunologically confirmed cases of abacavir hypersensitivity (Mallal, Phillips et al. 2008).

Treatment
Early recognition of the syndrome with cessation of the causative drug is essential in improving patient outcomes. No randomized controlled trials have been conducted to determine the appropriate adjunctive therapy for DIHS. Oral corticosteroids at 1 mg/kg/daily is commenced and tapered over at least 6-8 weeks to prevent relapse of various cutaneous and visceral manifestations of the syndrome. If symptoms deteriorate despite corticosteroid therapy then IVIg, plasma exchange (Higuchi, Agatsuma et al. 2005), rituximab or a combination of these modalities could be considered although the evidence for their use is currently scant.

Nosology
In 1980, Beylot et al introduced the term acute generalized exanthematous pustulosis (AGEP) to describe acute pustular reactions with distinct clinical and histological features thereby differentiating it from pustular psoriasis (Beylot, Bioulac et al. 1980).

Demography
AGEP is rare with an incidence of 1-5 cases per million per year (Sidoroff, Halevy et al. 2001). The EuroSCAR study comprising 97 validated cases of AGEP recruited from Austria, France, Israel, Italy and the Netherlands, revealed a mean age (SD) of 56 (21) years and a female preponderance with a male/female ratio of 0.8 (Sidoroff, Dunant et al. 2007). The predominance in women was shown to be even greater in case series reports from Taiwan (68.7% of 16 cases) (Chang, Huang et al. 2008), and Israel (76.9% of 13 cases) (Davidovici, Dodiuk-Gad et al. 2008). AGEP has been reported in children, with the largest pediatric series of 20 cases from China (Zhang, Chen et al. 2008).

Clinical features
The clinical manifestations are characterized by fever and a pruritic or burning edematous erythema followed by the rapid appearance of dozens of small (< 5 mm) non-follicular sterile pustules (Fig. 15). The skin lesions are often accentuated in the intertriginous areas. There is usually an accompanying marked neutrophilia (7 x 10 9 /L) and in a third of cases, a mild eosinophilia. A mild non-erosive mucous membrane involvement occurs in 20% of cases. Internal organ involvement is uncommon and usually is confined to a slight reduction in creatinine clearance and mild elevation of aminotransferases. The clinical course is characterized by spontaneous resolution of skin and systemic manifestations over a period of up to 15 days once the offending agent is withdrawn. AGEP has a favourable prognosis; the reported mortality rate is up to 5% and poor outcomes usually result from secondary infection in the elderly or those patients with significant comorbidities.

Etiology
AGEP is caused by drugs in at least 90% of cases. According to the EuroSCAR study, the agents conferring the highest risk are pristinamycin, aminopenicillins, hydroxychloroquine, antibacterial sulphonamides, terbinafine and diltiazem (Sidoroff, Dunant et al. 2007). The latent period is short (usually 1-5 days) with the EuroScar study demonstrating that it may vary for different drugs. For antibiotics, including sulphonamides, the median latent period was 1 day, and for other drugs it was 11 days (Sidoroff, Dunant et al. 2007). Contact sensitivity has been implicated in a few case reports. Causative agents include mercury, and bufexemac, a potent topical NSAID. Neither of these agents was implicated in the 97 cases of AGEP in the EuroScar study. The role of infectious agents in AGEP has been suggested in various case reports due to the absence of an inciting drug. The organisms include coxsackie B4, cytomegalovirus, parvovirus B19, Chlamydia pneumoniae, and Escherichia coli. No significant risk for infection was found in the EuroScar study although the study was not designed to identify potential causative organisms. Spider bites were suggested as a cause AGEP in a series of three cases from Israel, presumably as a result of the venom's ability to induce IL-8 and GM-CSF (Davidovici, Pavel et al. 2006). Finally, as illustrated in two recent cases, AGEP may develop without preceding medication or disease (Birnie and Litlewood 2008).

Pathogenesis
The pathogenesis of AGEP has been elucidated by patch (Schaerli, Britschgi et al. 2004) and in vitro tests (Girardi, Duncan et al. 2005) and initially involves activation, expansion and subsequent migration of drug-specific CD4 and CD8 cells to the skin. The initial influx of CD8 cytotoxic T cells results in apoptosis of keratinocytes and the formation of subcorneal vesicles. The infiltrating CD4 cells release CXCL-8, which results in recruitment of neutrophils, and granulocyte macrophage-colony stimulating factor (GM-CSF), which prevents apoptosis of neutrophils. This results in the conversion of vesicles into pustules. CD4 cells also release IFN-, which stimulates keratinocytes to secrete CXCL-8, as well as RANTES and IL-5, which contributes to the eosinophilia observed in some patients (Britschgi, Steiner et al. 2001). Resident Langerhans' cells may present drug antigens to CD4 cells and keratinocytes may act as antigen presenting cells to CD8 cells thereby augmenting the neutrophil-mediated inflammatory response. Genetic susceptibility to AGEP has not been robustly examined and therefore remains largely unknown.

Diagnostic tests
A pustular smear should be performed to exclude an infectious aetiology. A full blood count will reveal a neutrophilia. A skin biopsy may show (spongiform or non-spongiform) subcorneal and/or intradermal pustules, edema of the papillary dermis, perivascular infiltrates with neutrophils and exocytosis of some eosinophils and focal necrotic keratinocytes (Fig. 16). The typical changes of psoriasis such as acanthosis and papillomatosis are usually absent. Patch testing may be useful in confirming the association between AGEP and the culprit drugs. In a controlled study, patch tests were positive in half of the 14 cases of AGEP (Wolkenstein, Chosidow et al. 1996). Readings should not be restricted to 24 and 48 hours after the application of the drug but should also be determined at 96 and 120 hours to maximise sensitivity. Pustule formation is often observed in positive patch tests in cases of AGEP. The test can be conducted one month after resolution of the disease. The risk of AGEP with patch testing is considered to be low but not negligible (Mashiah and Brenner 2003). A small number of studies have supported a role for LTT, IFN- release, lymphokine macrophage migration inhibition factor release assays but these in vitro tests are not widely available and its value remains to be determined in large cohorts. Fig. 16. A moderate power view of a skin biopsy from a patient with AGEP shows spongiform subcorneal pustules, edema of the papillary dermis and perivascular infiltrates with neutrophils and exocytosis of some eosinophils.

Differential diagnosis
AGEP, which is characterized by non-follicular pustules can be readily distinguished from diseases with follicular pustulosis such as bacterial folliculitis, furunculosis, acneiform eruptions, pustular contact dermatitis, dermatophyte infection, viral exanthema with primary vesiculation and secondary postulation, impetigo, Sweet syndrome and SSSS. Other diseases are not as easily differentiated from AGEP. Generalized pustular psoriasis 146 (Zumbusch psoriasis) is characterized by pustules that slowly develop on areas of psoriasis accompanied by the histological changes of psoriasis on skin biopsy. There is also usually a family history of psoriasis. Sneddon-Wilkinson disease (subcorneal pustulosis) and subcorneal IgA dermatosis are characterized by the subacute development of larger pustules than those that erupt in AGEP and maybe associated with hyopyon formation. A diagnostic score was devised to validate the diagnosis of AGEP based on the morphology, course of disease, and histology, and assist in the differentiation from similar diseases (Sidoroff, Halevy et al. 2001).

Treatment
As AGEP is a self-limiting disease with a favourable prognosis. Cessation of the causative agent and supportive treatment is usually all that his required. In the pustular phase, supportive measures consist of moist dressings with drying and disinfecting solutions to avoid superinfection. In the postpustular desquamation phase, emollients are used to optimise preservation of skin barrier function. In a study of nine cases from Israel, all of who made a full recovery, seven received supportive care alone and the other two received corticosteroids (Tamir, Wohl et al. 2006). It remains to be established whether oral or parenteral corticosteroids hasten the resolution of disease. A brief course of systemic corticosteroids may be considered in patients with severe and widespread inflammation of the skin.

Conclusion
SCARs such as SJS/TEN, DIHS/DRESS, and AGEP are idiosyncratic and specific types of reactions that have distinct clinical, laboratory and histological features. The definition of DIHS/DRESS has not been universally adopted and will need to be clarified once the role of herpetic viruses and characteristic histological features are known. The early identification of these reactions and the subsequent prompt withdrawal of therapy and the implementation of supportive and adjunctive therapies are crucial in minimising morbidity and rates of mortality. Multicentre randomized studies are required to adopt the most suitable therapies for these potentially life-threatening conditions. The emergence in the understanding of HLA susceptibility genes will enable patients to be screened for the risk of developing a SCAR and will hopefully be more widely performed once cost effective and rapid methods of detection are widely available to the prescribing doctor.