The skin is one of the most frequently involved organs by drug side effects, with
the incidence of adverse cutaneous drug reactions situated between 0.1 – 1% of patients
during pre-marketing clinical trials, and post-marketing analyses suggest that their
incidence can be as high as 1 – 8% for certain types of drugs (NSAIDS, antibiotics,
antiepileptics). Adverse cutaneous drug reactions are benign in nature in over 98%
of cases and present most frequently as maculo-papular eruptions or urticaria. However,
studies suggest that roughly a third of drug eruptions require hospital management
and are considered as severe, although fortunately only 2% of cutaneous drug eruptions
are really life-threatening; this is the case for Stevens-Johnson syndrome (SJS) and
toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP),
and drug rash with eosinophilia and systemic symptoms (DRESS)/drug induced hypersensitivity
syndrome (DIHS). It is estimated that between
2 and 5% of all hospital costs are related to adverse drug eruptions, and – cutaneous
adverse drug eruptions representing 20 – 30% of all drug eruptions – the burden of
these on the health care system is considerable.
Although the pathomechanism of adverse cutaneous drug eruptions remains incompletely
understood, great progress in this field of medicine has been made in the past few
years. Improvements range from the clinical classification that is essential for a
better understanding to the identification of genetic susceptibilities to certain
drugs, and consequently the development of the first preventive genetic screening
measures for selected patient groups and drug classes.
Here I will present the clinical characteristics of the different types of adverse
cutaneous drug reactions and then focus on progress made in understanding the pathogenesis
of two of the severe forms, notably toxic epidermal necrolysis and acute generalized
exanthematous pustulosis.
Toxic epidermal necrolysis (TEN) is an immune-mediated reaction that selectively affects
the skin and mucous membranes. It is triggered by drug-intake resulting in massive
keratinocyte apoptosis and necroptosis within 2 – 4 weeks and extensive skin detachment
resembling a severe burn. Compelling evidence suggests that TEN is associated with
an impaired capacity to detoxify reactive intermediate drug metabolites. According
to the current research data available, the immune response in TEN is dependent, at
least for certain types of drugs, on HLA-restricted drug presentation, and consequently
a genetic susceptibility has been reported, as evidenced by the identification of
specific drug-related HLA alleles as major susceptibility genes for the development
of TEN. The current model for the pathogenesis of TEN thus suggests that in an individual
with particular predisposing factors (including but not always HLA type), exposure
to certain types of drugs results in an immune
reaction to the drug or one of its metabolites, and subsequent massive keratinocyte
death mediated by FasL (CD95L) and/or granulysin and/or perforin-granzyme B and/or
annexin A1. Interestingly, however, amongst individuals with a predisposing HLA type,
only a minority develop TEN upon the selected drug intake (the positive predictive
value of HLA-B*15 : 02 for carbamazepine-induced TEN is only 5.6%). These above facts
suggest that factors other than HLA type and adaptive immunity are involved in the
pathogenesis of TEN. While we and others have identified key molecular cell death
mechanisms in TEN, early events driving the immune response and leading to cell death
remain largely unknown.
Acute generalized exanthematous pustulosis (AGEP) is a severe adverse cutaneous drug
reaction (ADR) caused mainly by antibiotics, antimalarials, and antifungals, characterized
by a disseminated eruption of sterile non-follicular pustules on the background of
a widespread erythematous skin eruption accompanied with fever and peripheral blood
neutrophilia. The pathophysiology of AGEP remains unclear. However, as for most other
ADR, AGEP is currently considered as a T cell-mediated disease in which T cell- and
keratinocyte-derived IL-8 has been proposed to be responsible for the recruitment
of neutrophils to the intraepithelial pustules. Using an unbiased approach we could
recently demonstrate selective and significative IL-36α and γ upregulation in lesional
skin of AGEP patients when compared to MPR. Keratinocytes and macrophages were found
to be the source of IL-36γ in AGEP patients. In vitro, causative drugs were shown to have the ability to specifically induced
IL-36γ release either directly by peripheral blood monocytes, or indirectly in
presence of autologous peripheral blood mononuclear cells by keratinocytes of patients
with AGEP. Such culprit drug induction of IL-36γ secretion in vitro was specific for
AGEP and not observed for MPR. These results demonstrate a new pathogenetic mechanism
for the development of AGEP whereby strong and selective IL-36γ secretion by monocytes/macrophages
and keratinocytes in response to culprit drug exposure drives neutrophil infiltration
of the skin which is the clinical hallmark of AGEP.
Identification of key molecular signaling pathways involved in the pathogenesis of
severe adverse cutaneous drug reactions such as TEN and AGEP opens new perspectives
for the development of targeted treatments.
