Vol. 33. No. 1


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.

Dermatologic adverse events to chemotherapeutic agents, Part 1: cytotoxic agents, epidermal growth factor inhibitors, multikinase inhibitors, and proteasome inhibitors

Milan J. Anadkat, MD | Rachel L. Kyllo, BS

Dermatologic toxicities have profound effects on patients
receiving chemotherapy for cancer treatment. Cytotoxic
chemotherapies are associated with a number of nonspecific
dermatologic adverse events including alopecia, mucositis,
and onychodystrophy. Targeted therapies including
epidermal growth factor inhibitors, multikinase inhibitors,
and proteasome inhibitors are associated with different
skin reactions that are class-specific. In Part 1 of this
review, we examine the presentations of the most common
dermatologic adverse events associated with the above
drugs and discuss the strategies used for their prevention
and treatment.


Dermatologic adverse events to chemotherapeutic agents, Part 2: BRAF inhibitors, MEK inhibitors, and ipilimumab

Jennifer Nam Choi, MD

The advent of novel targeted chemotherapeutic agents
and immunotherapies has dramatically changed the
arena of cancer treatment in recent years. BRAF inhibitors,
MEK inhibitors, and ipilimumab are among the newer
chemotherapy drugs that are being used at an increasing
rate. Dermatologic adverse events to these medications
are common, and it is important for dermatologists and
oncologists alike to learn to recognize and treat such
side effects in order to maintain both patients’ quality of
life and their anticancer treatment. This review describes
the cutaneous side effects seen with BRAF inhibitors (eg,
maculopapular eruption, photosensitivity, squamoproliferative
growths, melanocytic proliferations), MEK inhibitors (eg,
papulopustular eruption), and ipilimumab (eg, maculopapular
eruption, vitiligo), with a mention of vismodegib
and anti-PD-1 agents.


Epidemiology of severe drug hypersensitivity

Neil H. Shear, MD | Philip M. Laws, MDChB | Roni P. Dodiuk-Gad, MD

Epidemiological studies of severe drug hypersensitivities
are important to understanding the morbidity and
mortality of this heterogeneous group of disorders. These
insights also allow greater identification of at-risk patient
groups. However, epidemiological studies of drug hypersensitivity
reactions are challenging due to the variable
diagnostic criteria applied and incomplete data sets
studied. We review the epidemiology of severe drug hypersensitivity
reactions with a particular focus on severe
cutaneous adverse reactions (SCARs). SCAR diseases
include: Stevens-Johnson syndrome, toxic epidermal
necrolysis, drug rash eosinophilia and systemic symptoms,
serum-sickness–like reaction and acute generalized
exanthematous pustulosis.


Severe cutaneous adverse reactions: impact of immunology, genetics, and pharmacology

Joanna L. Harp, MD | Kanade Shinkai, MD | Melissa A. Kinnebrew, PhD

Severe cutaneous adverse reactions, though rare, represent
a mucocutaneous presentation of adverse drug
responses associated with significant morbidity and mortality.
Here, we review the recent literature highlighting the
roles of selective immune responses, genetic factors, and
drug metabolism in increasing susceptibility of a given
patient to these rare and severe reactions. Further understanding
of these factors and their relative contributions to
a severe drug reaction may hold important implications
for future patient-specific pharmacogenomic and immunologic
profiling in an effort to personalize prescribing patterns
by clinicians. Emerging concepts, such as the role of
viral reactivation and the presence of overlapping clinical
features in severe drug eruptions, are also discussed.


Severe drug-induced dermatoses

Iris Ahronowitz, MD | Lindy P. Fox, MD

A variety of common dermatoses are known to have
drug-induced variants. This article discusses the clinical
presentation, time frames, reported culprit medications,
pathophysiology and management of drug-induced
lupus, cutaneous vasculitis, pemphigus, pemphigoid,
linear IgA bullous dermatosis, Sweet’s syndrome, erythema
nodosum, pyoderma gangrenosum, pseudolymphoma,
lichen planus, and psoriasis.