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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2758_Библиотеки_им_академика_М_И_Перельмана
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Preface
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1. Mechanistic Classication.
2. Phenotypic Classication.
Mechanistic Classication
The various chapters in this book illustrate the breadth of drug-induced skin
reactions. Not all of the mechanisms behind these drug reactions are known;
however, they can be broadly categorised into drug hypersensitivity and nonhypersensitivity reactions (Fig.2).
Drug Hypersensitivity Reactions
Drug hypersensitivity reactions are classied according to the underlying
immune mechanisms, as described by Gell and Coombs. Type I reactions are
Ig-E mediated and occur within 1–6h after drug intake. The presentation of
type I reactions includes urticaria, angioedema, and anaphylaxis. Type II
Drug Eruptions
Drug Hypersensitivity
Immediate
E.g. Urticaria, Angioedema,
Anaphylaxis
Delayed
E.g. Exanthem, SJS/TEN, DRESS,
AGEP, serum sickness
Non-drug Hypersensitivity
"Off-target"
E.g. Papulopustules - EGFR-inhibitors
Skin Function Perturbation
E.g. Minocycline- induced pigmentation
Drug induced
autoimmunity/inflammation
DPP4 inhibitors - Bullous Pemphigoid
Others
E.g. Drug induced pruritus
Fig. 2 Classication of cutaneous adverse drug reactions
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reactions are Ig-G mediated, present typically as blood dyscrasias such as
haemolytic anaemia, thrombocytopenia, or neutropenia. The skin is not
involved in type II reactions. In type III reactions, the mediators are antigenantibody complexes and may present as serum sickness or vasculitis. Lastly,
type IV reactions are T cell mediated and can be further subdivided into four
subtypes, a–d, depending on the cytokines and accompanying cells involved
(see chapter “Mechanisms of Drug Hypersensitivity”). Type IV reactions
typically affect the skin and present as exanthematous drug eruptions, drug
reaction with eosinophilia and systemic symptoms (DRESS), StevensJohnson syndrome/toxic epidermal necrolysis (SJS/TEN), and acute generalised exanthematous pustulosis (AGEP).
Drug hypersensitivity syndromes can also be classied into immediate
and non-immediate (delayed) reactions based on the time interval between
drug exposure and the onset of symptoms. Type I reactions are considered
immediate reactions due to their short latency from drug ingestion, typically
<1–6h whereas types II, III, and IV are considered delayed reactions due to
their longer latency periods of days, or even weeks.
Non-hypersensitivity
The mechanism behind non-drug hypersensitivity reactions is not well
dened. Mechanisms vary and cutaneous involvement arises from a range of
drug-induced biological processes. These include ‘off-target’ effects of the
drug (e.g. papulopustular eruption with EGFR inhibitors), perturbation of a
normal skin function (e.g. drug-induced pigmentation or photosensitivity),
and drug-induced inammatory or autoimmune pathways (e.g. drug-induced
cutaneous lupus erythematosus). This classication, though arbitrary, is practical since in vitro and in vivo tests (described in chapter “In Vitro Drug
Allergy Testing”) are less likely to be useful in determining drug causality in
non-hypersensitive reactions.
Preface
Phenotypic Classication
Cutaneous adverse drug reactions can also be broadly classied into two
groups according to clinical threat or severity. The severe cutaneous adverse
reactions (SCAR) are categorised based on prominent systemic involvement,
considerable morbidity, and a signicant mortality risk, whereas benign cutaneous adverse reactions (BCAR) tend not to have a systemic component and
carry a negligible morbidity/mortality. Entities classied as SCARs include
(1) Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), (2)
drug reaction with eosinophilia and systemic symptoms (DRESS), and (3)
acute generalised exanthematous pustulosis (AGEP). The mortality risk for
such reactions ranges from 1 to 5% in AGEP, 5 to 10% in DRESS, and 25%
in SJS/TEN.However, the initial presentation of these SCARs may be similar
to an exanthematous drug reaction; therefore serial evaluation of the patient
is necessary to monitor for progression and for the appearance of red ags
heralding a more severe phenotype (Table1). These red ags include constitutional symptoms such as fever, u-like symptoms, and lethargy. If at pre-
Preface
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Table 1 Red ags which suggest a severe cutaneous adverse drug reaction
Constitutional symptoms: malaise, fever, sore throat, rhinorrhoea, odynophagia
Mucosal involvement: kerato- conjunctivitis, erosions of oral/lip/anogenital mucosae
Facial oedema
Target-like lesions, blisters, erosions, pustules
Lymphadenopathy
Organomegaly
Eosinophilia, atypical mononuclear cells, other blood dyscrasias
Deranged liver function tests, impaired renal function, other visceral dysfunction
sentation mucositis (at any site), skin tenderness, purpura, blisters, or erosions
are present then an early, evolving SJS/TEN must be considered. In patients
with DRESS, a widespread dermatosis and facial oedema are usually prominent, while eosinophilia and internal organ involvement should be actively
sought with appropriate laboratory evaluation.
In the severe cutaneous adverse drug reactions the patient should never be
re-exposed to, or re-challenged with, the causal drug since there is a substantial risk of provoking a fatal reaction. This rule need not be adhered to in
benign skin reactions when an approach of ‘treating-through’ may be considered, a decision which should follow careful risk/benet analysis. In particular this policy can be adopted if the culprit drug is essential to the patient’s
health and there is no other drug alternative available.
In the ensuing chapters of this book the diverse presentation of drug eruptions will be discussed. These range from self-limiting and benign reaction
patterns to those that are severe and life-threatening. Despite advances in our
understanding of the mechanisms of adverse drug reactions, the diagnosis
remains clinical. Appreciation of the varied clinical presentations, typical
latency, and the common putative drugs will enable clinicians to recognise
and diagnose such reactions, institute timely measures such as drug withdrawal and specic treatments as well as determine if subsequent allergological evaluation is required or appropriate.
Singapore, Singapore HaurYuehLee
London, UK DanielCreamer
30th Oct 2022
Contents
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Part I General Considerations
Pharmacogenetics of Cutaneous Adverse Drug Reactions . . . . . . . . . 3
Vincent Lai Ming Yip and Munir Pirmohamed
Mechanisms of Drug Hypersensitivity . . . . . . . . . . . . . . . . . . . . . . . . . 35
Chih-Jung Chang, Chun-Bing Chen, and Wen-Hung Chung
Histopathology of Cutaneous Adverse Drug Reactions . . . . . . . . . . . . 53
Nicolas Ortonne
Skin Tests in Evaluating Drug Eruptions . . . . . . . . . . . . . . . . . . . . . . . 65
Margarida Gonçalo
In Vitro Drug Allergy Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Ying Xin Teo and Michael R. Ardern-Jones
Part II Reaction Patterns
Drug-Induced Urticaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Karen J. L. Choo, Alison V. Sears, and Clive Grattan
Exanthematous Drug Eruptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Colleen Gabel and Daniela Kroshinsky
Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis . . . . . . 111
Saskia Ingen-Housz-Oro, Tu-anh Duong, and Olivier Chosidow
Acute Generalised Exanthematous Pustulosis . . . . . . . . . . . . . . . . . . . 127
Chantal Cotter and Daniel Creamer
Drug Reaction with Eosinophilia and Systemic
Symptoms (DRESS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Sarah Walsh
Fixed Drug Eruptions and Generalized Bullous Fixed
Drug Eruptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Yung-Tsu Cho and Chia-Yu Chu
Lichenoid Drug Eruptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
Yee Kiat Heng and Yen Loo Lim
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Drug-Induced Connective Tissue Disorders . . . . . . . . . . . . . . . . . . . . . 165
Stephen J. Mounsey and Emma Benton
Drug-Induced Vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
John Stack
Drug-Induced Autoimmune Bullous Diseases . . . . . . . . . . . . . . . . . . . 181
Michael Benzaquen, Michael Hertl, and Luca Borradori
Other Drug-Induced Inflammatory Skin Reactions . . . . . . . . . . . . . . 191
Chai Zi Teng, Shashendra Aponso, and Haur Yueh Lee
Drug-Induced Photosensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
Sally H. Ibbotson
Drug-Induced Pruritus Without Primary Rash . . . . . . . . . . . . . . . . . . 211
Rachel Shireen Golpanian, Gil Yosipovitch,
and Roni P. Dodiuk-Gad
Drug-Induced Nail Changes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
Chia-Chun Ang and Eckart Haneke
Drug-Induced Hair Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
Leila Asfour, David Rutkowski, and Matthew Harries
Drug-Induced Pigmentary Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 247
Tan WeiXuan Colin, Yiping Emily Gan, and Alain Taieb
Contents
Part III Special Drug Categories
Immediate and Delayed Reactions to Beta-Lactams . . . . . . . . . . . . . . 263
María José Torres Jaén and Adriana Ariza Veguillas
Hypersensitivity Reactions to Iodinated Radiocontrast Media . . . . . 275
Knut Brockow
Cutaneous Adverse Reactions to Biologic Agents . . . . . . . . . . . . . . . . 283
Karen J. L. Choo and Yi Wei Yeo
Cutaneous Reactions to Oncologic Targeted Therapy . . . . . . . . . . . . . 303
Chia-Yu Chu
Cutaneous Reactions to Oncologic Immunotherapy . . . . . . . . . . . . . . 317
Rachel Choi and Jonathan Leventhal
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
Contributors
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Chia-ChunAng, M Med (Int Med), FAMS Department of Dermatology,
Singapore General Hospital, Singapore, Singapore
Shashendra Aponso, MD, MRCP (UK) Department of Dermatology,
Singapore General Hospital, Singapore, Singapore
Michael R. Ardern-Jones, BSc, MBBS, DPhil FRCP Department of
Dermatology, University Hospitals Southampton NHS Foundation Trust,
Southampton, UK
Adriana Ariza Veguillas, PhD Allergy Research Group, Instituto de
Investigación Biomédica de Málaga-IBIMA, Málaga, Spain
LeilaAsfour, MB ChB, BSc, MRCP Department of Dermatology, Sinclair
Dermatology Clinical Trial Centre, Victoria, VIC, Australia
The Dermatology Centre, University of Manchester, Salford Royal Hospital,
Northern Care Alliance NHS Foundation Trust, Salford, Greater Manchester,
UK
EmmaBenton, MB ChB, FRCP St John’s Institute of Dermatology, Guy’s
& St Thomas’ NHS Trust, London, UK
Michael Benzaquen, MD Department of Dermatology, Inselspital—
University Hospital of Bern, Bern, Switzerland
LucaBorradori, MD Department of Dermatology, Inselspital—University
Hospital of Bern, Bern, Switzerland
KnutBrockow, MD Department of Dermatology and Allergy Biederstein,
Faculty of Medicine, Technical University of Munich, Munich, Germany
Chih-JungChang, PhD Xiamen Chang Gung Hospital, School of Medicine,
Medical Research Center and Xiamen Chang Gung Allergology Consortium,
Xiamen, China
Huaqiao University, Quanzhou, Fujian, China
Chun-Bing Chen, MD Chang Gung Memorial Hospital, Linkou, Taipei,
Taiwan
Department of Dermatology, Drug Hypersensitivity Clinical and Research
Center, Taoyuan, Taiwan
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RachelChoi, BA Department of Dermatology, Yale New Haven Hospital,
New Haven, CT, USA
Karen J. L. Choo, MB ChB, MRCP Department of Dermatology and
Allergy Centre, Singapore General Hospital, Singapore, Singapore
OlivierChosidow, MD, PhD Department of Dermatology, Henri Mondor
Hospital, Creteil, France
Yung-Tsu Cho, MD Department of Dermatology, National Taiwan
University Hospital and National Taiwan University College of Medicine,
Taipei, Taiwan
Chia-Yu Chu, MD, PhD Department of Dermatology, National Taiwan
University Hospital and National Taiwan University College of Medicine,
Taipei, Taiwan
Wen-HungChung, MD, PhD Chang Gung Memorial Hospital, Linkou,
Taipei, Taiwan
Department of Dermatology, Drug Hypersensitivity Clinical and Research
Center, Taoyuan, Taiwan
Chantal Cotter, MB Bch, BAO Department of Dermatology, King’s
College Hospital, London, UK
Contributors
DanielCreamer, MD, FRCP Department of Dermatology, King’s College
Hospital, London, UK
Roni P. Dodiuk-Gad, MD Dermatology Department, Bruce Rappaport
Faculty of Medicine, Emek Medical Center, Technion—Institute of
Technology, Haifa, Israel
Department of Medicine, University of Toronto, Toronto, ON, Canada
Tu-anh Duong, MD, PhD Department of Dermatology, Henri Mondor
Hospital, Creteil, France
ColleenGabel, MD Department of Internal Medicine, Beth Israel Deaconess
Medical Center, Boston, MA, USA
Yiping Emily Gan, MRCP (UK), M Med (Int Med) Department of
Dermatology, KK Women’s and Children’s Hospital, Singapore, Singapore
RachelShireenGolpanian, BA Dr. Phillip Frost Department of Dermatology
and Miami Itch Center, University of Miami, Miami, FL, USA
Margarida Gonçalo, MD, PhD Department of Dermatology, University
Hospital and Faculty of Medicine, University of Coimbra, Coimbra, Portugal
CliveGrattan, MD, MA, FRCP St. John’s Institute of Dermatology, Guy’s
and St Thomas’ NHS Foundation Trust, London, UK
Eckart Haneke, MD, PhD Department of Dermatology, Inselspital—
University of Bern, Bern, Switzerland
Contributors
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Matthew Harries, MB ChB, PhD, FRCP The Dermatology Centre,
University of Manchester, Salford Royal Hospital, Northern Care Alliance
NHS Foundation Trust, Salford, Greater Manchester, UK
Yee Kiat Heng, MBBS, MRCP (UK), M Med (Int Med) National Skin
Centre, Singapore, Singapore
Michael Hertl, MD Department of Dermatology, University Hospitals
Marburg, Marburg, Germany
SallyH.Ibbotson, MD Photobiology Unit, Ninewells Hospital & Medical
School, University of Dundee, Dundee, UK
SaskiaIngen-Housz-Oro, MD Department of Dermatology and Reference
Center for Toxic Bullous Dermatoses and Severe Drug Reactions Toxibul,
APHP, Henri Mondor Hospital, Creteil, France
DanielaKroshinsky, MD, MPH Department of Dermatology, Massachusetts
General Hospital, Harvard Medical School, Boston, MA, USA
HaurYuehLee, MBBS, MRCP, MMED (INT MED), FAMS Department
of Dermatology and Allergy Centre, Singapore General Hospital, Singapore,
Singapore
Jonathan Leventhal, MD Department of Dermatology, Yale New Haven
Hospital, New Haven, CT, USA
YenLooLim, MBBS, MRCP (UK), FRCP (Edin) National Skin Centre,
Singapore, Singapore
StephenJ.Mounsey, MBBS, MPharm St. John’s Institute of Dermatology,
Guy’s Hospital, London, UK
Nicolas Ortonne, MD, PhD Department of Pathology, Henri Mondor
Hospital and Paris Est Creteil University, Creteil, France
MunirPirmohamed, FBPhS, FFPM, F Med Sci Department of Molecular
and Clinical Pharmacology, University of Liverpool, Liverpool, UK
David Rutkowski, BSc, MPhil, MRCP (Derm) Department of
Dermatology, Northern Care Alliance NHS Group, Salford, UK
The Dermatology Centre, University of Manchester, Salford Royal Hospital,
Northern Care Alliance NHS Foundation Trust, Salford, Greater Manchester,
UK
AlisonV.Sears, MB ChB, BSc Hons St. John’s Institute of Dermatology,
Guy’s and St Thomas’ NHS Foundation Trust, London, UK
JohnStack, MB BCh BAO, MD, MRCPI Department of Rheumatology,
Mater Misericordiae University Hospital, Dublin, Ireland
School of Medicine, University College Dublin, Dublin, Ireland
AlainTaieb, MD, PhD University of Bordeaux, INSERM U1035, Bordeaux,
France
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ChaiZiTeng, MD, MRCP (UK) Department of Dermatology, Singapore
General Hospital, Singapore, Singapore
YingXinTeo, MB BChir Department of Dermatology, University Hospitals
Southampton NHS Foundation Trust, Southampton, UK
MaríaJoséTorresJaén, MD, PhD Allergy Research Group, Instituto de
Investigación Biomédica de Málaga-IBIMA, Málaga, Spain
Allergy Unit, Hospital Regional Universitario de Málaga, Málaga, Spain
Centro Andaluz de Nanomedicina y Biotecnología-BIONAND, Málaga,
Spain
Departamento de Medicina, Universidad de Málaga, Málaga, Spain
Sarah Walsh, MB BCh BAO, BMedSci, MRCP Department of
Dermatology, King’s College Hospital NHS Foundation Trust, London, UK
Tan WeiXuan Colin, MBBS, MRCP (Edinburgh) Department of
Dermatology, KK Women’s and Children’s Hospital, Singapore, Singapore
YiWeiYeo, MBBS, MRCP Department of Dermatology, Singapore General
Hospital, Singapore, Singapore
VincentLaiMingYip, BSc (Hons), MB ChB (Hons), PhD Department of
Molecular and Clinical Pharmacology, University of Liverpool, Liverpool,
UK
Contributors
Gil Yosipovitch, MD Dr. Phillip Frost Department of Dermatology and
Miami Itch Center, University of Miami, Miami, FL, USA
Part I
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General Considerations
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