Severe cutaneus

adverse drug
reactions
 Writer: Department of
Journal Dermatology,
Wen-Hung
Identity Chang Gung
Chuang Wei Memorial
Ro Lan DAO Hospital,
Taiwan. 2015.
1. Introduction

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 DRUG ERUPTIONS
Skin eruptions that are induced by
drugs.
Several severe phenotypes:
> Steven Johnson Synd
> Toxic epidermal necrolysis
> Severe cutaneous adverse drug
reactions (SCAR)

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 ▫ CLASSIFICATION &
“ CLINICAL MANIFEST
 Severe drug eruptions often belong to type IV
hypersensitivity and mediated by CD4 and CD8 T
lymphocytes.
 Drug induced hypersensitivity can cause rash or eruptions
ranging from mild (maculopapular exanthema), fixed drug
eruptions, acute generalized exanthematous pustulosis and
SCAR (such as DIHS, DRESS, SJS, and TEN)
 MPE (Maculopapular exanthema)  mild skin rashes.
 FDE (Fixed drug eruption)  classified by the
development of one or more local annular without
hyperpigmentation.
 AGEP (Acute generalized exanthematous pustulosis) 
rapid development of many numerous pustules,
located in epidermis.
 TEN(toxic epidermal necrosis)  Full thickness
epidermal necrosis.
 DIHS (drug induced hypersensitivity synd)  less / no
skin detachment and mucocutaneous involvement, but
internal organ involved.
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 ▫ Immune mediated mechanism
“
 Immunological changes of DIHS/DRESS are characterized
by leukocytosis with atypical lymphocytosis or eosinophilia.
 Massive elevations of eosinophil-associated cytokines like
IL-4, IL-5 and IL-13, which are responsible for maturation and
differentiation of eosinophils, have been reported in DIHS
patients.
 Like SJS/TEN, the pathogenesis of DIHS is involved in T-
cell-mediated responses.

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 ▫ Immune mediated mechanism
“
 Like SJS/TEN, the pathogenesis of DIHS is involved in T-
cell-mediated responses.
 This increase of the CD4+ T cells is reported to be associated
with the severity of clinical symptoms, such as the extent of
skin rash and reactivations of virus.
 Several cytokines have also been reported to be elevated in
DIHS patients.

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 ▫ Immune mediated mechanism
“
 More recently, we have identified that granulysin acts as the
significant “killer” and is responsible for the disseminated
keratinocyte death.
 The expression level of granulysin rises when the CTL and
NK cells are activated.
 Granulysin also serves as a chemoattractant for T
lymphocytes, monocytes and other inflammatory cells by
activating the pro-inflammatory.`

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 ▫ Therapeutic Strategies
“
 Identification and early withdrawal of the offending drug is
the most important step for the management of SCAR.
 Although there is no consensus for the therapeutics of SCAR,
systemic corticosteroids are the most commonly used
worldwide.
 Corticosteroids function as the non-specific
immunosuppressant to decrease SJS/TEN progression.
 However, the efficacy of systemic corticosteroids for
SJS/TEN are still controversial.
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 ▫ Therapeutic Strategies
“
 Other common treatments of SJS/ TEN include intravenous
Ig (IVIG), cyclosporin and biologic anti-TNF-a agents (e.g.
etanercept and infliximab).
 However, the clinical benefits of IVIG and cyclosporin for
SJS/TEN treatment remain controversial, or there are no
case–control studies for using biologic anti-TNF-a agents
due to the paucity of cases of SJS/TEN.

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 ▫ Therapeutic Strategies

“
For DIHS treatments, systemic corticosteroids are commonly
used for patients with DIHS.
 Although systemic corticosteroids have been known as the
standard treatment for DIHS,
 Hence, a potential drug development for therapeutics and an
international collaboration of clinical trials for SJS/TEN as well
as DIHS still need further exploration.

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 “ ▫ Prevention of SCAR
 Because of the high morbidity, mortality and long-term
sequelae of SCAR, prevention and early diagnosis has
become one of the most important goals in SCAR research.
 There have been some prospective studies showing that
pre-emptive genetic screening is effective to prevent SCAR,
including HLAB*1502 screening for CBZ-induced SJS/TEN,
HLA-B*5701 screening for hypersensitivity to abacavir and
HLA-B*5801 for allopurinol-induced SCAR.

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 ▫ Prevention of SCAR
“
 Identification of strong genetic markers for specific drug-
related hypersensitivity reactions and implementation of
genetic tests before prescriptions is an important way to
prevent SCAR.
 In addition to genetic screening, avoidance of administrating
specific drugs to patients with risk factors is also an
important way to prevent SCAR.

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 ▫ Conclusion
“
 In this article, we have summarized the important
mechanistic studies of SCAR.
 The pathogenic mechanisms of SCAR are complex.
 It has been known that drug antigen presentation, genetic
factors, immune/cell death mechanism and environmental
or non-genetic factors are all involved.

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