SEVERE DRUG REACTIONS AND REACTIONS TO CHEMOTHERAPEUTIC AGENTS

Mar
2014
Vol. 33. No. 1

Introduction

Severe drug eruptions are associated with significant morbidity
and mortality. Though rare, severe adverse drug rashes
represent a clinical problem for which a dermatologist’s expertise
is critical. The intent of this issue of Seminars in Cutaneous
Medicine and Surgery is to provide key updates on our understanding
of this clinical problem, including new insights into the pathophysiology
underlying severe drug reactions and side effects of
chemotherapy. This collection of work also offers a synthesis of
evidence supporting key diagnostic and therapeutic interventions
that arise when evaluating and managing a patient suspected of
having a severe drug eruption.
The series begins with an update on the epidemiology of drug
eruptions by Drs Ddiuk-Gad, Laws, and Shear. In this informative
review, the authors outline the most current epidemiologic characterization
of drug hypersensitivity reactions with a focus on the
most severe cutaneous adverse reactions, or SCARs. They provide
evidence describing the prevalence of systemic complications associated
with key categories of SCARs. In addition, characteristics
such as onset of timing, clinical features, medications, and prognosis
are discussed. Together, this information starts off this series
with a clear perspective on the problem at hand, including a
detailed picture of the clinical scenarios in which SCARs develop
and who is most at risk.
In the next article, Dr. Mockenhaupt provides a comprehensive
analysis of the clinical characteristics, pathogenesis, diagnostic and
therapeutic management considerations for Stevens-Johnson syndrome
and toxic epidermal necrolysis. Her expert article relies on
literature search and her extensive clinical experience stemming
from a multicenter collaboration whose mission is to study SCARs.
This collaboration is truly visionary, serving as the gold standard for
advancing our understanding of both the diagnostic and therapeutic
considerations of SCARs in an evidence-based fashion.
The complex interplay between genetic determinants of immune
responses and drug metabolism with medication pharmacology is
presented in the next article by Drs Kinnebrew, Harp, and Shinkai.
This conceptual framework provides a useful construct to consider
key factors that conspire to give rise to SCARs. The highlight of
this article is the concept of the critical interplay between genetic
factors that determine an individual’s susceptibility to mount a hypersensitivity
reaction to a medication or medication metabolite,
the likelihood of generating immunogenic metabolites through
genetically predetermined drug metabolism pathways, and drug
characteristics that, taken together, contribute to a drug hypersensitivity
reaction. This article explores the relevance of emerging
information of antigen presentation pathways, especially specific
HLA (human leukocyte antigen) haplotypes, that increase an individual’s
susceptibility to develop a SCAR. Though we are still far
from identifying the relative contributions of each of these three
factors, better understanding of these causes will clearly pave the
road towards the practical application of pre-exposure pharmacogenetic
testing in the future of personalized medicine.
In their 2-part series, authors Kyllo and Anadkat (Part 1), and
Choi (Part 2) review the rapidly expanding spectrum of cutaneous
reactions to cancer therapeutics. In an era in which novel targets
for cancer intervention are being rapidly defined, and numerous
new therapies are developed for the se lective targeting for the
treatment of cancer, we have witnessed the emergence of an incredibly
diverse spectrum of predictable cutaneous side effects
stemming from targeted chemotherapeutic agents. The authors
beautifully review these, discussing practical management strategies
and highlight what is perhaps most fascinating about these adverse
reactions to cancer therapeutics: what the known molecular
targets of these therapies and adverse reactions teach us about the
basic biology of skin, nails, and hair.
In the last article, authors Ahronowitz and Fox explore the broad
array of drug-induced dermatoses with an extensive synthesis of
the literature detailing common, less common, and rare medications
associated with each process. This article provides an incredible
resource that extends beyond the scope of SCARs to offer an
essential consideration of medications as a cause of dermatoses
including drug-induced lupus, blistering disorders, lichenoid reactions,
and neutrophilic dermatitides.
In closing, we are proud to bring this collection of work together
to provide an up-to-date synthesis and review of key concepts that
we view as essential information for all dermatologists on adverse
drug eruptions. Though our current understanding of this field is
expanding at a tremendous rate, we feel that this series of papers
serves as a strong foundation for conceptualizing the fundamental
principals of drug reaction management that will hopefully provide
a durable resource for years to come.

Stevens-Johnson syndrome and toxic epidermal necrolysis: clinical patterns, diagnostic considerations, etiology, and therapeutic management

Maja Mockenhaupt, MD, PhD

Severe cutaneous adverse reactions are associated
with significant morbidity and mortality. They may be
life-threatening for the affected patient and difficult to
treat. Such conditions include toxic epidermal necrolysis
(TEN), Stevens-Johnson syndrome (SJS), acute generalized
exanthematous pustulosis and drug reaction with
eosinophilia and systemic symptoms. Due to the fact
that prognosis, etiology and treatment of the various
reactions differ, a clear diagnosis based on the specific
clinical pattern is important. This review will focus on the
clinical presentations, pathogenesis, and important diagnostic
and therapeutic considerations in the management
of SJS and TEN.

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