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Updates in Clinical Dermatology
Series Editors: John Berth-Jones · Chee Leok Goh · Howard I. Maibach
HaurYuehLee
DanielCreamerEditors
Drug
Eruptions
Updates in Clinical Dermatology
Series Editors
JohnBerth-Jones, University Hospitals Coventry & Warwickshire
NHS Trust, Coventry,UK
CheeLeokGoh, National Skin Centre, Singapore,Singapore
HowardI.Maibach, Department of Dermatology, University of
California San Francisco Department of Dermatology, ALAMEDA
CA,USA
Updates in Clinical Dermatology aims to promote the rapid and ecient
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transfer of medical research into clinical practice. It is published in four
volumes per year. Covering new developments and innovations in all elds of
clinical dermatology, it provides the clinician with a review and summary of
recent research and its implications for clinical practice. Each volume is
focused on a clinically relevant topic and explains how research results impact
diagnostics, treatment options and procedures as well as patient management.
e reader-friendly volumes are highly structured with core messages,
summaries, tables, diagrams and illustrations and are written by internationally
well-known experts in the eld. A volume editor supervises the authors in
his/her eld of expertise in order to ensure that each volume provides cuttingedge information most relevant and useful for clinical dermatologists.
Contributions to the series are peer reviewed by an editorial board.
Haur Yueh Lee • Daniel Creamer
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Editors
Drug Eruptions
Editors
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Haur Yueh Lee
Department of Dermatology
and Allergy Centre
Singapore General Hospital
Singapore, Singapore
Daniel Creamer
Department of Dermatology
King’s College Hospital
London, UK
ISSN 2523-8884 ISSN 2523-8892 (electronic)
Updates in Clinical Dermatology
ISBN 978-3-031-09387-6 ISBN 978-3-031-09388-3 (eBook)
https://doi.org/10.1007/978-3-031-09388-3
© Springer Nature Switzerland AG 2022
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or
part of the material is concerned, specically the rights of translation, reprinting, reuse of
illustrations, recitation, broadcasting, reproduction on microlms or in any other physical way,
and transmission or information storage and retrieval, electronic adaptation, computer software,
or by similar or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this
publication does not imply, even in the absence of a specic statement, that such names are
exempt from the relevant protective laws and regulations and therefore free for general use.
The publisher, the authors, and the editors are safe to assume that the advice and information in
this book are believed to be true and accurate at the date of publication. Neither the publisher nor
the authors or the editors give a warranty, expressed or implied, with respect to the material
contained herein or for any errors or omissions that may have been made. The publisher remains
neutral with regard to jurisdictional claims in published maps and institutional afliations.
This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
This book is dedicated to
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Prof. Jean-Claude Roujeau (1944–2021)
Dermatologist, clinician-scientist, and doyen of cutaneous
adverse drug reactions
Preface
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Introduction
An adverse drug reaction (ADR) is an unwanted, detrimental response to a
medication which is independent of its therapeutic action. Recognition that a
medicine’s benet is offset by potential side effects is a paradox all doctors
must bear in mind as they write a prescription. This consideration represents
an important aspect of the clinical encounter and one which informs the formulation of a treatment strategy. Indeed, concern about adverse effects can
have a deep inuence on prescribing practices, as physicians attempt to ‘Do
No Harm’. While the inherent risks of any medication need to be assessed by
the clinician, the patient must have condence that their doctor is aware of
potential side effects and will advise and guide them appropriately. The study
of adverse drug reactions is thus an essential theme in clinical therapeutics.
Cutaneous eruptions induced as a side effect to drugs account for 15–20%
of all ADRs, with presentations which range from mild to severe. This book
addresses the subject of cutaneous drug side effects and aims to summarise
current knowledge in both the pathogenetic and clinical domains.
Clinical Approach toaPatient withaCutaneous ADR
In a patient presenting with new signs and symptoms in the skin, the clinician
must consider whether the dermatosis might be caused by a medication. A
distinction needs to be made between the aggravation of a pre-existing skin
disorder by a drug (e.g. rosacea destabilised by glucocorticoids) and the
induction of a primary eruption as manifestation of a drug side effect (e.g.
drug-induced exanthem). The former situation is not uncommon and is an
important consideration in clinical dermatology; however it is the specic
drug-induced dermatoses which constitute the eld of cutaneous ADRs.
As in any medical consultation, history-taking is imperative when making
an assessment of a potential cADR. There are several contextual features
which heighten a clinician’s concern about a drug aetiology. The incidence of
cutaneous drug reactions increases with the number of drugs taken, while the
prevalence of cADRs increases with advancing age. Individuals with complex medical problems and who are in-patients appear to be at greater risk for
a drug reaction. The presence of an ongoing systemic infection (particularly
vii
viii
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herpesvirus infections) may also have a permissive effect on cutaneous drug
reactions, irrespective of the anti-microbial medications they are receiving.
Studies have demonstrated that female patients tend to be more likely to suffer a cADR.
In many instances a cADR will present as an acute eruption, that is an
inammatory rash which develops suddenly and progresses swiftly to become
widespread. These drug reactions are commonly accompanied by symptoms
of pruritus or cutaneous soreness, while constitutional symptoms of systemic
inammation (such as fever and malaise) are typically a component of the
severe cADRs. Drug reaction with eosinophilia and systemic symptoms
(DRESS) is one of the severe cutaneous adverse reactions which is, as its
name indicates, a disorder with signicant systemic as well as skin involvement. However, some cADRs are not explosive in onset, do not become generalised, and are not associated with systemic features. In these disorders, the
evolution of skin signs may be insidious and slowly progressive.
Many cADRs have a clinical presentation which is identical to a non-druginduced dermatosis. The morphology and distribution of weals in druginduced urticaria is indistinguishable from that seen in idiopathic urticaria.
Therefore, assessment of the physical signs alone is not sufcient to implicate
a drug aetiology. Nonetheless some cADRs do have both a specic morphology and a characteristic distribution. An example is the ‘atypical’ target seen
in drug-induced SJS/TEN which can be differentiated morphologically from
the ‘classic’ target of HSV-induced erythema multiforme. In drug-induced
SJS/TEN, atypical target lesions tend to be concentrated on the face and central upper torso whereas in erythema multiforme the eruption favours acral
skin. An understanding of disease-specic patterns is helpful in the approach
to a patient suspected of having a drug hypersensitivity dermatosis.
The analysis of skin biopsies also plays a key role in the assessment of
drug-induced skin disease. As with the physical signs, the dermatopathology
of cADRs is rarely pathognomic but requires careful consideration in the
context of the complete clinical picture. Common patterns of inammation
are seen in drug eruptions, but variations in cytology or histology can help the
pathologist to implicate a drug trigger.
Preface
Drug Causality inCutaneous ADRs
It is important to state that a cADR can only be diagnosed if the patient has
taken a medicine prior to the eruption’s onset. Although patently obvious, this
fundamental premise lies at the heart of diagnosing a cADR and of identifying the causative medication. Moreover, the critical therapeutic manoeuvre in
all these disorders is discontinuation of the offending drug, an action which
almost always results in resolution. Therefore, the clinical presentation must
be appraised in the context of the patient’s drug history.
When identifying a culprit medication it is important to recognise that the
process of attribution is, by and large, an intuitive process undertaken by the
Preface
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ix
clinician without assistance from laboratory investigations. Although there
are biological assays which can be used (outlined in the following chapters)
imputation of the causative agent normally involves consideration and integration of three variables: clinical phenotype of cADR, drug timelines, and
relative notoriety of possible culprits.
To attribute a cADR to a certain drug one must establish that the medication under consideration is likely to cause the reaction pattern. A crucial question is: does our knowledge of this drug’s toxicity prole conform with the
patient’s eruption? Pharmacovigilance studies have given us insight into the
side effect potential of most medications. In the context of dermatology this
information is rened so that we now have an understanding of the type(s) of
cADR caused by a particular drug.
The temporal relationship between drug administration and onset of the
cADR is central in imputation of the culprit. Has the reaction occurred following the administration of the drug (challenge)? Is there a clinical improvement with withdrawal of the drug (dechallenge)? Has the reaction recurred
following re-exposure to the drug (re-challenge)? The time lag between rst
administration of the culprit medication and onset of the cADR is called the
latency period and reects patho-mechanisms underlying the specic drug
eruption. This ‘incubation’ time is fairly constant for each of the cADR syndromes and helps to identify the trigger when the patient is receiving more
than one medication. A drug which has been taken for longer or shorter than
the typical latency period is unlikely to be the culprit. When a cADR is being
considered, all the patients’ medications must be noted along with the length
of time each has been taken. Marrying up drug timelines with latency period
of the reaction is a key task in pinpointing the guilty agent.
Along with an understanding of latency, clinicians need to be aware that
every drug carries a greater or lesser potential to cause cADRs. This is the
concept of relative notoriety. It sometimes stated that ‘any drug can cause any
reaction’, an aphorism which is theoretically true but unhelpful in practice. In
the clinical setting, the majority of reactions are caused by a relatively
restricted number of medications. Drugs which feature as common triggers in
the cADR syndromes include the aromatic anticonvulsants, antibiotics,
sulfur- containing drugs, and allopurinol. While some drugs have the potential
to induce many of the cADR syndromes, other fastidious agents have a propensity to trigger just one or two of the drug eruption phenotypes. Figure1
illustrates the principles in drug causality analysis.
As new drugs are launched the scope of cutaneous side effects will expand
both in terms of clinical phenotypes and in the numbers of potential culprit
agents. At the present time, it is the targeted anti-cancer therapies which have
been unveiled as an important new source of cutaneous toxicity. These drugs
use completely new mechanisms to alter cancer biology and consequently
reveal novel pathways for drug-induced skin injury. The ongoing explosion in
pharmaco-therapeutics will add to the ways drugs cause rashes and in so
doing will diversify the practice of clinical dermato-toxicology.
x
Onset of
Amoxicillin
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Reaction
Latency Period
Toxic
Epidermal
Necrolysis
Preface
- 8 wks
Aspirin
Nifedipine
Drug exposures
Fig. 1 Illustrates the principles in drug causality analysis. In a case of toxic epidermal necrolysis, the latency period is
typically between 1 week to 8 weeks. Drugs which fall outside of this latency period, or are stopped prematurely, are
unlikely to be causative. In this example, only allopurinol and paracetamol satisfy the latency, however, allopurinol is
the most likely culprit drug based on its notoriety
Famotidine
Allopurinol
Paracetamol
2 wks- 2 wks- 4 wks- 6 wks
Frusemide
Classication oftheCutaneous ADRs
Traditionally, adverse drug reactions have been classied as Type A or Type
B reactions. Type A reactions are predictable, dose-dependent, occur in all
individuals and arise out of the pharmacological activity of the drug. A typical example would be skin purpura or bleeding arising from warfarin overdose. Type B reactions, on the other hand, are thought to be idiosyncratic,
unpredictable, and not dose-dependent. Drug hypersensitivity reactions are
responsible for the majority of type B reactions. Whilst this is a simple and
straightforward approach, improved understanding has shown that many type
B reactions, though immune-mediated, may be dose-dependent and/or require
a threshold dose before the reaction is initiated. Likewise, the mechanisms of
various drug hypersensitivity reactions are being claried and so are no longer considered idiosyncratic. Similarly, in certain ethnic groups, severe reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis can be
predicted and prevented.
In an attempt to improve on the above categorisation, two complementary
approaches to the classication of drug eruptions are proposed:
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