The reasons why a drug administered parentally or orally commonly targets the skin have not be fully defined. Most of DISI (>90%) is benign MPE (Hunziker et al., 1997). Reactions initially appear on the upper extremities and trunk then spread more widely (Roujeau, 2005). Usually reactions are detected in the first two weeks after drug treatment; however, reactions with a later onset have been reported.
22 All types of DISI differ in the effector cell phenotype and cytokine secretion profile of activated T-cells. CD8+ T-cells are thought are thought to be dominant in TEN, whereas CD4+ T-cells dominate in MPE and AGEP. Research studies on skin have revealed that IL-5 is the main cytokine in MPE. IL-5 is important as it is involved in the recruitment of eosinophils to the site of inflammation (Pichler et al., 1997). IFN-γ and IL-8 are released by drug-specific T-cell in pateints with AGEP (Britschgi et al., 2001; Roujeau, 2006). IFN-γ upregulates MHC class II on keratinocytes surface making them more prone to T-cell mediated killing, while IL-8 is involved in the recruitment of neutrophils to the site of inflammation (Friedmann et al., 1994; Roujeau, 2006). Patients with SJS/TEN have high levels of granulysin in their blister fluids (Nassif et al., 2004b; Chung et al., 2008), together IFN-γ and TNF-α, which collectively induce keratinocyte cytotoxicity(Friedmann et al., 1994).
DRESS is also known as hypersensitivity syndrome (HSS). DRESS begins later than other types of DISI and can be seen even after 2-6 weeks after treatment initiation. Liver involvement can increase the mortality rate of DRESS up to 10% (Roujeau, 2005). Drug-specific T-cells that release high levels of IFN-γ and IL-5 are detected in the blood of patients with DRESS (Naisbitt et al., 2003b). Viral reactivation is frequently observed in the course of DRESS; thus, it can be utilised as a diagnostic criterion (Suzuki et al., 1998; Tohyama et al., 1998). Still, it is not fully understood what role this reactivation has in the pathophysiology of the disease and whether it is a consequence or cause of the clinical manifestations. Reactivation of human herpes virus 6 (HHV-6) is detected by increasing levels of particular viral DNA and IgG. However, this usually is not measurable until many weeks after symptoms appear (Shiohara et al., 2006). Thus, it is likely that viral reactivation is caused by T-cell activation. Transient increases in virus-specific immunoglobulins against HHV-7, Epstein-Barr virus (EBV) and cytomegalovirus (CMV) have also been detected in patients with DRESS (Aihara et al., 2001; Descamps et al., 2003; Picard et al., 2010). Cells from skin lesions have been analysed and found to contain high levels of HHV-6 DNA and express viral antigen at an early stage (Suzuki et al., 1998). Therefore it is still theoretically possible that certain clinical manifestations result from virus-specific T-cells expansion (Shiohara et al., 2006).
23 SJS/TEN is the most serious form of DISI. The main characteristic is blistering skin lesions. Nowadays, it is believed that both SJS and TEN are involved within the same disease spectrum with different degree of skin detachment and this difference is being used to delineate each type (Bastuji-Garin et al., 1993; Mockenhaupt, 2011). SJS and TEN have a high mortality rate with approximately 10% and >30%, deaths reported respectively. Death usually happens as a consequence of pulmonary symptoms or sepsis. Treatment often requires a specialist from burns unit with expertise in dealing with extensive skin loss. Table 1.3 illustrates the common characteristics of SJS/TEN and DRESS.
TEN is a CD8+ T-cell mediated reaction (Schwartz et al., 2013). Histopathology shows that keratinocyte death in the epidermis initially results from apoptosis, which subsequently leads to necrosis and skin detachment (Paul et al., 1996). NK T-cells are also involved in the pathogenesis as the skin lesions contain high numbers of these cells (Chung et al., 2008). Blister fluid contains high levels of the soluble mediator granulysin and granulysin levels have been shown to correlate with clinical severity (Chung et al., 2008). Therefore, measurement of granulysin levels in the serum of patients with TEN can be used as an early diagnostic marker (Abe et al., 2009).
24
Symptom Drug-induced skin injuries
SJS TEN DRESS
Mucous membrane >90% >90% <30%
Erosions Several sites Several sites Mouth and lips Detachment of epidermis Yes <10% of
BSA Yes >30% of BSA No Hyperkeratosis/desquamation No No Usual Neutropenia NO 30% No Eosinophilia No No 90% Atypical lymphocytes No No 30-40%
Respiratory tract Bronchial Erosions/ARDS
Bronchial Erosions/ARDS
Interstitial pneumonitis
Liver Hepatitis 10% Hepatitis 10% Hepatitis 60%
Heart No No Myocarditis
Lymph node enlarged No No Usual
Viral reactivation Occasional Occasional Frequent
Table 1.3- Features of the most serious DISI. (BSA) body surface area, (ARDS) acute respiratory distress syndrome. Adapted from (Bachot and Roujeau, 2001).
25 1.6 Drug-induced liver injury (DILI)
Drug-induced liver injury is a rare but serious health problem with an incidence rate of 1 in 10,000 and 1 in 100,000 (Holt and Ju, 2006). DILI is one of the main causes for the withdrawal of newly marketed drugs. Identifying hepatotoxic drugs during the development process is not easy, because reactions are not predictable in pre- clinical animal models or in in vitro humanised experimental systems (Kaplowitz, 2005). This is particularly applicable with the idiosyncratic reactions that are thought to involve the immune system (Holt and Ju, 2010). DILI is usually seen when the drug is marketed and exposed to several thousand patients (Watkins, 2005). Cautious monitoring is needed, because liver injury is often not seen until weeks or even months after the initiation of drug treatment (Wilke et al., 2007).