Advances in Diagnosis and Management of Cutaneous

Adverse Drug Reactions Current and Future Trends

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Contents

Part I Introduction
1 Introduction: Classification, Terminology, Epidemiology,
and Etiology of Cutaneous Adverse Drug Reactions����������������������������    3
Maja Mockenhaupt

Part II Pathomechanisms of Cutaneous Adverse Drug Reactions

2 Immunology of Cutaneous Adverse Drug Reactions����������������������������   23
Chuang-Wei Wang and Shuen-Iu Hung
3 Pharmacogenomics and Cutaneous Adverse Drug Reactions ������������   39
Ren-You Pan, Chun-Bing Chen, and Wen-Hung Chung
4 Viral Reactivation in Cutaneous Adverse Drug Reactions������������������   55
Tetsuo Shiohara, Yoko Kano, Yoshiko Mizukawa, and Yumi Aoyama
5 Using Technology to Learn About Immunology of Cutaneous
Adverse Drug Reactions��������������������������������������������������������������������������   67
Ryan J. Schutte and David A. Ostrov

Part III Clinical Perspectives of Cutaneous Adverse Drug Reactions

6 Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis
(Epithelial Necrolysis)������������������������������������������������������������������������������   77
Jean-Claude Roujeau
7 Drug Reaction with Eosinophilia and Systemic
Symptoms (DRESS) ��������������������������������������������������������������������������������   87
Sylvia H. Kardaun
8 Acute Generalized Exanthematous Pustulosis�������������������������������������� 105
Sima Halevy
9 Urticarial Reactions to Drugs ���������������������������������������������������������������� 123
Daniel F. Carr

vii
viii Contents

10 Dermatologic Adverse Events from Cancer Treatments���������������������� 131

Jennifer Wu, Alina Markova, and Mario E. Lacouture
11 Cutaneous Adverse Drug Reactions in Pediatric Population�������������� 175
Ilan Fridental and Yaron Finkelstein
12 Cutaneous Drug Reactions in the Elderly �������������������������������������������� 185
James W. S. Young
13 Cutaneous Adverse Drug Reactions in Human
Immunodeficiency Virus Infection �������������������������������������������������������� 197
Rannakoe J. Lehloenya and Jonny Peter
14 Cutaneous Adverse Drug Reactions from Antituberculosis
Treatment�������������������������������������������������������������������������������������������������� 207
Jonny Peter and Rannakoe J. Lehloenya

Part IV Approach to the Patient with a Cutaneous Adverse

Drug Reaction
15 Practical Approach to Diagnosis and Management
of Cutaneous Adverse Drug Reactions�������������������������������������������������� 219
Cristina Olteanu, Neil H. Shear, and Roni P. Dodiuk-Gad
16 Histopathology of Severe Drug Eruptions �������������������������������������������� 227
Mari Orime and Riichiro Abe
17 Evaluation of Drug Safety Literature: A Guide
for the Practicing Dermatologist������������������������������������������������������������ 237
Sandra R. Knowles and Jackie Campbell
18 In Vitro and In Vivo Tests in Cutaneous Adverse Drug Reactions������ 247
Annick Barbaud
19 Pharmacovigilance of Cutaneous Adverse Drug Reactions ���������������� 265
Lois La Grenade, Maja Mockenhaupt, and Elizabeth Phillips

Part V Epilogue
20 Future Directions and Unmet Research Needs in Cutaneous
Adverse Drug Reactions�������������������������������������������������������������������������� 275
Elizabeth Ergen, Jason Trubiano, Jonny Peter, and Elizabeth Phillips
21 Atlas of Cutaneous Adverse Drug Reactions���������������������������������������� 283
Alina G. Bridges and Kevin Brough
Acknowledgments

We have the greatest appreciation for our leading editorial assistant, Dr. Cristina
Olteanu. She was a dominant player in editing of this book. She participated in all
of the editing process including planning of the book outline to the last stages of
editing and formatting. Dr. Olteanu invested hundreds of hours in reading the chap-
ters submitted, conducting editing, and correspondence with the authors. Her voice
and contribution can be seen in each chapter of the book. Her job description was
editorial assistant, but we felt she was actually working as an editor. There are not
enough words to express our gratitude to her dedication, professionalism, and hard
work in creating this important project. Above all, she was a great companion to
work with in the challenging road in creating this book.
We would also like to thank our editorial assistant, Dr. Rena Hashimoto, for her
detailed review of the chapters and editing of the book. Her dedication to the team
and time invested in this project is truly invaluable.
This book is a result of fruitful international contributions of global opinion lead-
ers in the field of adverse drug reactions. We are deeply grateful and honoured to
have the privilege of gathering their knowledge into the first edition of this book
with the united mission of advancing the field. We hope that this book will serve as
a teaching resource to various fields in medicine including dermatology, immunol-
ogy, paediatrics, and family medicine.
We would like to thank our publisher Springer Nature; the Responsible Editors,
Cameron Wright and Jo Grant. Commissioning Editor, Nitin Joshi; and the Project
Coordinator, Prasad Gurunadham.
We would like to express our gratitude to our patients for sharing with us their
medical experience of having cutaneous adverse drug reactions, which both inspired
us and contributed tremendously to our sense of responsibility in pursuing the
advancement of this field.
Last but not least, we thank our dear families for their unconditional support,
love, and encouragement to dedicate ourselves to this important project.

ix
Editorial Team

Lead Editors

Neil H. Shear, MD, FRCPC

Sunnybrook Health Sciences Centre, University of
Toronto Medical School, Toronto, ON, Canada

Roni P. Dodiuk-Gad, MD
Department of Dermatology, Emek Medical Center,
Afula, Israel
Bruce Rappaport Faculty of Medicine, Technion-
Institute of Technology, Haifa, Israel
Sunnybrook Health Sciences Centre, University of
Toronto Medical School, Toronto, ON, Canada

xi
xii Editorial Team

Editorial Assistants

Cristina Olteanu, MD
University of Alberta, Edmonton, AB, Canada

Rena Hashimoto, MD
Department of Dermatology, Keio University
Hospital, Tokyo, Japan
 Part I
Introduction
Introduction: Classification, Terminology,
Epidemiology, and Etiology of Cutaneous 1
Adverse Drug Reactions

Maja Mockenhaupt

Abbreviations

ADR Adverse drug reactions

AGEP Acute generalized exanthematous pustulosis
BSA Body surface area
cADR Cutaneous adverse drug reactions
DIHS Drug-induced hypersensitivity syndrome
DRESS Drug reaction with eosinophilia and systemic symptoms
E(E)M Erythema (exsudativum) multiforme
EMM EM majus
EN Epithelial necrolysis
FDE Fixed drug eruption
GBFDE Generalized bullous fixed drug eruption
HSS Hypersensitivity syndrome
MPE Maculopapular exanthema
NSAIDs Nonsteroidal anti-inflammatory drugs
SCAR Severe cutaneous adverse reactions
SJS Stevens–Johnson syndrome
TEN Toxic epidermal necrolysis
WHO World Health Organization

M. Mockenhaupt (*)
Dokumentationszentrum schwerer Hautreaktionen (dZh), Department of Dermatology,
Medical Center and Medical Faculty—University of Freiburg, Freiburg, Germany
e-mail: [email protected]

© Springer Nature Singapore Pte Ltd. 2019 3

N. H. Shear, R. P. Dodiuk-Gad (eds.), Advances in Diagnosis and Management
of Cutaneous Adverse Drug Reactions, https://doi.org/10.1007/978-981-13-1489-6_1
4 M. Mockenhaupt

Key Points
• Epidemiologic studies on cADR are important to evaluate their impact in derma-
tology and health care in general as well as their burden for affected patients.
• For milder, non-life-threatening ADR, only rough incidence estimates exist,
whereas for severe cADR incidence rates have been calculated.
• A clear clinical diagnosis and classification are of major importance in the field
of cADR before causality can be assessed in the individual case and before epi-
demiologic investigations can be done.
• The time latency between the beginning of drug use and reaction onset differs
considerably among the reaction types. In SCAR the inducing agent has not been
used before and resembles the first continuous use of the medication.
• Antibiotics are the most frequent inducers of MPE or AGEP, but they have a
lower risk to cause SJS/TEN or DRESS.
• “High-risk” drugs for SJS/TEN are allopurinol, anti-infective sulfonamides, cer-
tain antiepileptic drugs, nevirapine, and oxicam-NSAIDs, some of which may
also cause DRESS.

1.1 Introduction

Based on the definition of the World Health Organization (WHO), an adverse drug
reaction (ADR) is “a response to a medicine which is noxious and unintended, and
which occurs at doses normally used in man” (World Health Organization 1972). Most
ADR (up to 80%) are dose-dependent and predictable, whereas the remaining 20%
occur independently of the doses taken and are not predictable. These may be immu-
nologically mediated reactions, which are often referred to as “drug allergy” and which
either involve IgE or T-cells. In contrast, non-immunologically mediated reactions are
also called “idiosyncratic” (Johansson et al. 2004). A review of all published epidemio-
logical studies quantifying ADR in Europe showed that the median percentage of hos-
pital admissions due to ADR was 3.5%, whereas the median percentage of patients that
experienced ADR while hospitalized was 10.1% (Bouvy et al. 2015). Only very limited
data is available for ADR that occur and are treated outside the hospital.
Since a large proportion of ADR affects the skin, epidemiological studies have
been performed in relation to cutaneous manifestations. However, these studies often
comprise various cutaneous ADR of different mechanisms and clinical appearance.
Except for anaphylaxis of different etiologies, systematic large-scale epidemiological
studies have only been performed for severe cutaneous adverse reactions (SCAR)
allowing to obtain reliable data on incidence and demography. In contrast, few studies
on the epidemiology of milder cutaneous ADR have been undertaken and published.

1.2 Classification and Terminology

The majority of adverse drug reactions affecting the skin are nonserious and not
life-threatening eruptions. However, many patients with such a reaction are admit-
ted to the hospital, because in the beginning a serious and life-threatening condition
is suspected or cannot be excluded.
1 Introduction: Classification, Terminology, Epidemiology, and Etiology 5

1.2.1 Nonserious Cutaneous ADR

Milder, non-life-threatening cutaneous ADR include maculopapular exanthema

(MPE), fixed drug eruption (FDE), morbilliform eruption, urticaria, purpura, vascu-
litis, and many other clinical manifestations. These reactions, except perhaps FDE,
are not exclusively caused by medications but can also be induced by various kinds
of infections. In some of them, infections even seem to be the more likely etiology,
e.g., in urticaria or vasculitis, whereas others almost obligatory occur when both
certain infections and specific medications are present, e.g., EBV infection and ami-
nopenicillins leading to MPE (Bork 2009). The clinical pattern of these frequently
occurring, less severe conditions is known by many physicians, but it may be diffi-
cult to differentiate in the early phase whether the eruption is benign or whether it
may be the beginning of a severe condition. Therefore, the entire skin of the patient
has to be inspected, and signs for severity have to be looked for. Such danger signs
are, e.g., little crusts in SJS/TEN, even before skin detachment is obvious, and
mucosal symptoms like burning or soreness reported by the patient before lesions
are seen. Fever and constitutional symptoms are often a marker for a more severe
type of ADR (Paulmann and Mockenhaupt 2016). The patient should be examined
again the next day, since the clinical pattern may progress or change rapidly. To
confirm the clinical diagnosis, the evaluation by a dermatologist and the result of a
skin biopsy are needed. Whether a drug caused a specific reaction or not is some-
times difficult to determine, and a detailed medication history has to be obtained.
Further allergy work-up, such as skin tests, may follow 2–4 months after the skin
eruption has resolved (see Chap. 18).

1.2.2 Serious Cutaneous ADR

These life-threatening conditions are also called severe cutaneous adverse reactions
(SCAR). They include Stevens–Johnson syndrome (SJS) and toxic epidermal
necrolysis (TEN), but also acute generalized exanthematous pustulosis (AGEP) and
drug reaction with eosinophilia and systemic symptoms (DRESS) (Paulmann and
Mockenhaupt 2016). The precondition for these studies and the analysis of data
were a clinical consensus definition of skin reactions in the spectrum of SJS/TEN
(Bastuji-Garin et al. 1993). In addition, well-defined diagnostic scores were elabo-
rated for DRESS and AGEP (Kardaun et al. 2013; Sidoroff et al. 2007).

1.2.2.1 SJS/TEN
These reactions are characterized by erythematous skin and extensive detachment
of epidermis as well as hemorrhagic erosions of mucous membranes (Fig. 1.1)
(Mockenhaupt 2009). SJS and TEN are considered as a single disease entity of dif-
ferent severity but with common causes and mechanisms. The differentiation is
made based on the extent of skin detachment, that is, limited to less than 10% of the
body surface area (BSA) in SJS, widespread with more than 30% of the BSA in
TEN, and in-between defined as SJS/TEN overlap (Fig. 1.1) (Bastuji-Garin et al.
1993; Auquier-Dunant et al. 2002). Nikolsky sign is positive revealing a “wet”
ground when the necrotic epidermis is slightly pushed away (Salopek 1997). The
6 M. Mockenhaupt

a d

b e

c f

Fig. 1.1 Clinical pictures of patients with SJS/TEN (a–c), GBFDE (d), DRESS (e), and AGEP (f)

histopathology shows subepidermal blistering and necrotic keratinocytes either in

wide dissemination or full-thickness necrosis of the epidermis, which is due to
extensive apoptosis (Ziemer and Mockenhaupt 2011). Recently, the denomination
of “epidermal” or “epithelial necrolysis” (EN) has been suggested for SJS/TEN (see
Chap. 6).
Based on the almost identical histopathology of SJS/TEN and erythema (exsuda-
tivum) multiforme (E(E)M), SJS/TEN is often thought to be part of a broader EM
spectrum (Mockenhaupt 2009). For decades EM with mucosal involvement (EM
majus, EMM) was considered as Stevens-Johnson syndrome leading to false assess-
ment of the etiology, which in EMM are predominantly infections and not medica-
tions (Auquier-Dunant et al. 2002; Schröder et al. 1999). However, a consensus
definition allows differentiating SJS from EMM based on the clinical presentation
(Bouvy et al. 2015; Fagot et al. 2001).
Besides EMM, multiforme-like drug eruption is often confused with SJS/TEN in
the initial state or EMM. Histologically, it reflects what used to be called the dermal
type of EM. Clinically, it is less severe, and blisters may be due to edema with
mucous membranes spared (Ziemer and Mockenhaupt 2011; Ziemer et al. 2007).
Another important differential diagnosis is generalized bullous fixed drug eruption
(GBFDE), which is usually characterized by well-defined round or oval patches of
dusky violaceous or brownish color. Blisters develop on these patches, but typically
1 Introduction: Classification, Terminology, Epidemiology, and Etiology 7

skin detachment does not affect more than 10% of the BSA (Kauppinen 1972;
Lipowicz et al. 2013). However, the reaction may also present with diffuse erythema
and blisters, which will show demarcation during the course. Nikolsky sign is posi-
tive on the areas with marked erythema but not beyond. Patients with GBFDE rarely
have fever and mucosal involvement, but may present with periorificial erosions.
Previous eruptions are frequent in patients’ history and support the clinical diagno-
sis, which histologically shows the same features as SJS/TEN (Table 1.1, Fig. 1.1).
Only in repeated events the skin biopsy may reveal pigment changes, which are
rarely present in the histopathology of an acute reaction (Ziemer and Mockenhaupt
2011).

1.2.2.2 DRESS
For many years the term drug hypersensitivity syndrome summarized numerous
severe drug reactions (Shear and Spielberg 1988). However, about 20 years ago,
efforts were made to separate a specific entity of “drug hypersensitivity syndrome”
from other ADR (Bocquet et al. 1996), which was later renamed in Europe as drug

Table 1.1 Comparison of main features in SJS/TEN, GBFDE, DRESS, and AGEP
Features/diagnosis SJS/TEN GBFDE DRESS AGEP
Fever +++ (+) +++ +++
Facial edema − − +++ ++
Pustules − − + +++
Blisters +++ ++ +a +a
Target lesions/macules +++ − ± ±
Mucosal involvement +++ ± ± ±
Histological findings Epidermal Epidermal Lymphocytic Subcorneal
necrosis necrosis infiltrate pustules
Lymph node enlargement − − +++ +
Lymph node histology − − Lymphoid −
hyperplasia
Hepatitis + − +++ ++
Other organ involvements +b − +++c +
Neutrophils (in the ↓ ↓ (↑) ↑↑↑
peripheral blood)
Eosinophils (in the − − ↑↑↑ ↑
peripheral blood)
Atypical lymphocytes − − ++ +
Time between beginning of 1–4 weeks 1–2 days 2–8 weeks 1–2 days
drug use and reaction onset 9–11 days
Typical duration of the 2–3 weeks 1–2 weeks Several weeks 1 week
reaction (skin, mucosa)
Previous event (of the − ++ − −
same type)
a
Tension blisters due to edema
b
Tracheobronchial necrosis, tubular nephritis
c
Interstitial nephritis, interstitial pneumonia
8 M. Mockenhaupt

reaction with eosinophilia and systemic symptoms (DRESS) and in Japan as drug-­
induced hypersensitivity syndrome (DIHS) (Kardaun et al. 2013; Shiohara et al.
2012). DRESS/DIHS is characterized by a highly variable skin eruption, multi-­
organ involvement, lymphocyte activation (lymph node enlargement, lymphocyto-
sis, atypical lymphocytes), eosinophilia, and frequent virus reactivation (Table 1.1,
Fig. 1.1) (Kardaun et al. 2013; Shiohara et al. 2012). The histopathology of a skin
biopsy reflects the skin pattern and is thus as variable as the clinical lesions (Ziemer
and Mockenhaupt 2011). However, it should be performed to exclude potential dif-
ferential diagnoses. From a skin perspective, a wide range of differential diagnoses
have to be considered, especially due to the fact that the cutaneous lesions may vary
from macular, papular, pustular, purpuric, urticarial to infiltrated plaques and even
erythroderma. Cutaneous edema frequently leads to tension blisters, which may
raise the suspicion of SJS/TEN (Paulmann and Mockenhaupt 2016).
The main features such as skin eruption, fever, and organ involvement can also be
attributed to a wide range of infections and to concomitant and underlying diseases.
Therefore, each symptom has to be thoroughly investigated for its relation to the reac-
tion. Since the various signs and symptoms may develop consecutively over time, they
may be easily overlooked, especially when they are asymptomatic like eosinophilia
and atypical lymphocytes or sometimes increased liver enzymes. Obvious symptoms
and visible skin lesions may occur at different time points in the course of the disease
than elevated specific laboratory values (Paulmann and Mockenhaupt 2016; Kardaun
et al. 2013). In order to make a correct diagnosis, a score was developed that has to be
applied very strictly. In order to give a score point for liver involvement, liver enzymes
need to be elevated at least twofold on at least two different dates. Similar rules define
kidney involvement and lymphadenopathy can only be considered a relevant criterion
of DRESS when present in different body sites. Unfortunately, the score is frequently
applied inappropriately leading to a milder eruption with, e.g., slightly elevated liver
enzymes or eosinophilia being called DRESS (Paulmann and Mockenhaupt 2016;
Kardaun et al. 2007) (see Chap. 7).

1.2.2.3 AGEP
Acute generalized exanthematous pustulosis is characterized by the sudden occur-
rence of dozens of sterile, non-follicular pinhead-sized pustules on edematous ery-
thema predominantly in the main body folds. The reaction is frequently accompanied
by fever and leukocytosis, especially neutrophilia. The pustules appear within only
a few hours and resolve within a few days leaving a typical post-pustular desquama-
tion. Complications are rare but may occur in patients with underlying diseases and
overall poor medical condition (Table 1.1, Fig. 1.1) (Sidoroff et al. 2007).
The histopathology reveals subcorneal and/or intraepidermal pustules, a some-
times pronounced edema in the papillary dermis and perivascular infiltrates consist-
ing of neutrophils and some eosinophils. In the pustular stage, the most difficult
differential diagnosis is generalized pustular psoriasis, which in the acute stage
rarely displays psoriatic changes such as acanthosis in the histopathology (Ziemer
and Mockenhaupt 2011). Several reports have been published suggesting that AGEP
may turn into TEN, because Nikolsky phenomenon appeared positive. When
1 Introduction: Classification, Terminology, Epidemiology, and Etiology 9

pustules are confluent, this may indeed imitate a Nikolsky-like pattern, but the
intraepidermal subcorneal separation does not change to the subepidermal blister-
ing with necrotic keratinocytes in SJS/TEN.
The presence of pustules frequently leads to a misdiagnosis of an infectious con-
dition and explains how an ADR may be overlooked. A diagnostic score has been
elaborated to standardize the diagnosis of AGEP (Sidoroff et al. 2007) (see Chap. 8).

1.3 Epidemiology and Etiology

1.3.1 Epidemiological Studies on Cutaneous ADR

Most published reports of adverse drug reactions are summaries related to observa-
tions in a specific setting in a certain time period, e.g., a teaching hospital over a
period of 10 years (Bouvy et al. 2015). Most often various types of ADR are com-
prised, sometimes differentiated in cutaneous and non-cutaneous. However, rarely a
differentiation is made between serious and nonserious cutaneous ADR. Since seri-
ous cutaneous ADR are rare, the vast majority of reactions reported in the literature
represent milder, non-life-threatening reactions (Bork 2009).
Studies monitoring cutaneous ADR, e.g., the Boston Collaborative Drug
Surveillance Program, provided important information on the type of reaction and
the potentially culprit medications, but they were not designed to estimate incidence
or prevalence of the reactions. In later years, two prospective studies have been
undertaken to investigate the epidemiology of cutaneous ADR in a hospital setting.
The first study from France analyzed cutaneous ADR due to systemic drugs in a
specific hospital over a period of 6 months. All patients were examined and clini-
cally diagnosed by a dermatologist, whereas medication intake was reviewed by a
pharmacologist. Based on 48 inpatients with a diagnosis of cADR, the prevalence
was calculated as 3.6 per 1000 hospitalized patients (Fiszenson-Albala et al. 2003).
The second study from Mexico was a prospective cohort study over 10 months and
revealed a prevalence of 7 per 1000 hospitalized patients with cADR (35/4765 inpa-
tients) (Hernández-Salazar et al. 2006). Among 55,432 admissions in a period of
7 months, 2682 cases of ADR, both cutaneous and non-cutaneous, were identified
by a mandatory electronic reporting system for immunologically mediated drug
reactions in South Korea. After review by allergists, 532 were classified as “signifi-
cant drug hypersensitivity reactions,” 100 of these were new events, of which 70%
had cutaneous manifestations. The overall incidence of ADR was estimated as 1.8
per 1000 hospital admissions (Park et al. 2008).

1.3.2 Epidemiological Studies on Serious Cutaneous ADR

Several epidemiologic studies on severe cutaneous adverse reactions (SCAR) were

undertaken in Europe in the past 25–30 years. First, two hospital-based retrospec-
tive studies were performed in France and Germany over a period of 5 years in the
10 M. Mockenhaupt

1980s (Roujeau et al. 1995; Schöpf et al. 1991). Second, a prospective population-­
based registry on severe skin reactions was initiated in Germany in 1990 with the
aim to ascertain all hospitalized cases of SJS/TEN (Rzany et al. 1996). In parallel,
an international case-control study on severe cutaneous adverse reactions—also
called SCAR study—was conducted in France, Germany, Italy, and Portugal
between 1989 and 1995 (Roujeau et al. 1995). This study was followed by the
European ongoing case-control surveillance of SCAR—also referred to as
EuroSCAR—which was undertaken in Austria, France, Germany, Israel, Italy, and
the Netherlands from 1997 to 2001 (Mockenhaupt et al. 2008). Besides SJS/TEN,
acute generalized exanthematous pustulosis (AGEP) was investigated (Sidoroff
et al. 2001). The European registry on SCAR to drugs and collection of biological
samples—also called RegiSCAR—was established in 2003 and initially collected
cases of SJS/TEN, AGEP, and DRESS in the same six countries as the EuroSCAR
study, but later expanded to further countries such as Taiwan, the United Kingdom,
South Africa, and Spain (Sekula et al. 2013). These epidemiologic studies first
established clinical networks for active and prospective case ascertainment.
For the German Registry, a population-based approach was chosen with a net-
work of approximately 1700 hospitals including all hospitals and departments that
are likely to treat patients with SJS/TEN, such as departments of dermatology and
pediatrics, burn units, and departments of internal medicine with intensive care
facilities. Potential cases are reported by phone, fax, or e-mail to the registry center.
When the inclusion criteria are met, a visit of the patient by a trained investigator in
the reporting/treating hospital is scheduled.
In order to achieve a high coverage rate, all departments receive quarterly letters
addressed to a nominated contact person. Prepaid postcards asking whether cases of
SCAR occurred in the past 3–4 months that have not yet been reported are added to
these letters and should be returned. A high percentage of postcards is returned to
the registry center, but departments that do not respond over a certain period of time
receive a reminder phone call. Due to such active and systematic ascertainment, the
registry is considered to be exhaustive for detection of SJS/TEN cases in Germany
(Paulmann and Mockenhaupt 2016; Roujeau et al. 1995).
For the SCAR- and EuroSCAR-studies, cases from the German Registry were
included, whereas specific networks were established in the other participating
countries. These were not operating nationwide but followed the same rules for case
ascertainment. However, only prospectively ascertained and directly interviewed
community cases of SJS/TEN (i.e., patients who developed the reaction in the com-
munity and were admitted due to SCAR) were included. For the case-control analy-
sis, three control patients were matched on age, gender, region, and date of interview
to each case patient. Controls were patients hospitalized for acute conditions includ-
ing acute infections, trauma, and abdominal emergencies, which were not related to
an underlying chronic disease. Both cases and controls were validated and checked
for appropriateness of diagnosis and eligibility, and inappropriate controls were
excluded (Roujeau et al. 1995; Mockenhaupt et al. 2008; Sidoroff et al. 2001).
In the current RegiSCAR project, reactions developing in patients already hospi-
talized for another disease are also included (so-called in hospital cases). In addition
1 Introduction: Classification, Terminology, Epidemiology, and Etiology 11

to SJS/TEN, further reactions such as DRESS and AGEP and most recently GBFDE
are included in the study. Initially, the networks of the German Registry and the
EuroSCAR study were used for the RegiSCAR project, but the network expanded
to new research teams in further countries, as described above. Within RegiSCAR a
cohort of SJS/TEN patients was followed for long-term sequelae and quality of life
after the reaction; a cohort of DRESS patients is still investigated. Furthermore,
blood samples are taken and stored centrally for pathophysiologic and genetic
investigations (Sekula et al. 2013).
All patients with SCAR included in these studies were/are seen and interviewed by
a trained health-care professional (physician, pharmacist, study nurse, biologist) using
a standardized questionnaire. The interview includes questions regarding the current
illness, demographic data, recent and past medical history, recent infections, as well
as detailed information on medication use. All collected cases are reviewed by a der-
matologic expert committee with no information on exposures using clinical data,
photographs, and histopathology for clinical case validation. Cases are classified as
“definite,” “probable,” or “possible” severe skin reactions or are excluded based on the
consensus definition for SJS/TEN and the specific score systems for AGEP and
DRESS (Bastuji-Garin et al. 1993; Kardaun et al. 2013; Sidoroff et al. 2007).

1.3.3 Incidence and Demographic Data

1.3.3.1 SJS/TEN
The retrospective studies performed in the 1980s provided incidence estimates of
1.2 per 1 million inhabitants per year for TEN in France and of 0.93 per 1 million
per year in Germany, although data were not primarily collected for that purpose
(Schöpf et al. 1991; Roujeau et al. 1990). Incidences between 1.4 and 6 per million
person years were reported for SJS and TEN in other countries (Strom et al. 1991).
The huge variation among incidence rates may be caused by various factors, such as
smaller reference populations, different diagnostic criteria, methodological issues,
e.g., the use of automated data bases with variable coding to identify cases.
Over the past 25 years, the prospective population-based registry in Germany has
calculated an incidence of one to two cases of SJS/TEN per 1 million population per
year (varying between 1.53 and 1.89) (Mockenhaupt 2009; Rzany et al. 1996).
Approximately one third of cases developed in the hospital, while the other two
thirds in the community, i.e., the reaction itself, led to hospital admission. SJS/TEN
occurring in the hospital reveals more underlying diseases in the affected patient, a
higher number of drugs before reaction onset, and an overall poorer prognosis (data
of the German Registry).
SJS/TEN occurs in all age groups. In the German Registry, the average age of
patients with validated SJS/TEN was 53.4 years (1–94 years) for over 2200 patients.
Thirty-six percent of SJS patients were ≤40 years of age, whereas 75% of the
patients with SJS/TEN overlap and 72% of the patients with TEN were >40 years of
age. In contrast, 83% of the patients with EM majus were ≤40 years of age
(Paulmann and Mockenhaupt 2016).
12 M. Mockenhaupt

Among patients with SJS/TEN in Europe, about 5% have been shown to be HIV
infected, with a lower percentage in recent years. Although the distribution of age
and gender differs from that of non-HIV-infected patients, mortality rate and out-
come are comparable (Bork 2009; Mockenhaupt et al. 2008).
The reason for death in patients with SJS/TEN is often difficult to determine, but
death within 6 weeks after the onset of the reaction is considered to be related to the
reaction. Thus, 9% of the patients with SJS, 29% of patients with SJS/TEN overlap,
and 48% of those with TEN, altogether almost 25%, died in that large cohort
(Mockenhaupt 2009).
In recent years the average age of patients with SJS/TEN observed by the German
Registry has increased as well as the mortality rate, probably reflecting the increas-
ing age of patients in an older general population, accompanied by a higher rate of
underlying diseases. Based on the RegiSCAR cohort study, risk factors for death in
the acute stage of the disease are large amount of skin detachment, old age, and
renal failure, whereas death in the first year after SJS/TEN is related to preexisting
conditions such as hepatic insufficiency and active malignant disease (Sekula et al.
2013).

1.3.3.2 GBFDE
Few studies beyond case reports have so far been undertaken for generalized bullous
fixed drug eruption (GBFDE), and incidence data are not available. In fact, the con-
dition is rarely recognized as a specific entity and often not separated from SJS/
TEN, although it was distinguished from the latter already in 1971 (Kauppinen
1972). Although usually considered to be less severe, a case-control study compar-
ing cases of GBFDE and cases of SJS/TEN with a comparable amount of skin
detachment demonstrated that mortality was rather high in elderly patients (22%)
(Lipowicz et al. 2013). Repeated episodes are common and may lead to more exten-
sive skin involvement and finally to an increased risk of death.

1.3.3.3 DRESS
For decades, a wide variety of adverse reactions had been reported under the denom-
ination of hypersensitivity syndrome (HSS), and no epidemiologic studies were per-
formed on the disease until recently. That may explain why no reliable incidence
data are available for what is nowadays called DRESS or DIHS. The published data
suggest an incidence of “anticonvulsant HSS” that varies between 1 in 1000 and
1 in 10,000 exposed patients (Shear and Spielberg 1988).
Of the 201 potential DRESS cases collected within RegiSCAR, 117 were finally
validated as “probable” and “definite.” The female/male ratio was 66/51, and women
were significantly younger than men with a median age of 41.5 years compared to
51 years of men. Generalized exanthema was present in all patients, and further
main features were eosinophilia (95%), visceral involvement (91%) predominantly
of the liver (75%), high fever (90%), atypical lymphocytes (67%), mild mucosal
involvement (56%) and lymphadenopathy (54%).