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Anti-IgE Therapy in Asthma and Allergy
 Anti-IgE Therapy in
Asthma and Allergy
Syed Hasan Arshad, DM, MRCP
Director of the David Hide Asthma and Allergy Centre, Isle of Wight,
UK and Director of Clinical Trials, Department of Medical
Specialties, Southampton General Hospital, Southampton, UK

K Suresh Babu, MD, DNB

Clinical Research Fellow, Respiratory, Cell and Molecular Biology
Research Division, University of Southampton School of Medicine,
Southampton, UK

Stephen T Holgate, BSc, MD, DSc, FRCP, FRCPath,

FIBiol, CBiol, FmedSci
Medical Research Council Professor of Immunopharmacology at
the University of Southampton, Southampton General Hospital,
Southampton, UK
The views expressed in this publication are
those of the authors and not necessarily
those of Martin Dunitz Ltd.

© 2001 Martin Dunitz Ltd, a member of

the Taylor & Francis group

First published in the United Kingdom in 2001 by

Martin Dunitz Ltd
The Livery House
7–9 Pratt Street
London NW1 0AE

Tel: +44 (0) 207 482 2202

Fax: +44 (0) 207 267 0159
E-mail: [email protected]
Website: http://www.dunitz.co.uk

This edition published in the Taylor & Francis e-Library, 2002.

All rights reserved. No part of this publication may

be reproduced, stored in a retrieval system, or
transmitted, in any form or by any means, electronic,
mechanical, photocopying, recording, or otherwise,
without the prior permission of the publisher or in
accordance with the provisions of the Copyright,
Designs and Patents Act 1988 or under the terms of
any licence permitting limited copying issued by the
Copyright Licensing Agency, 90 Tottenham Court Road,
London W1P 0LP.

A CIP record for this book is

available from the British Library.

ISBN 1 84184 0904 (Print Edition)

Distributed in the USA, Canada and Brazil by:

Blackwell Science Inc.

Commerce Place, 350 Main Street
Malden MA 02148, USA
Tel: 1 800 215 1000

Cover image: Interactions between CD4 T cells and B cells

that are important in IgE synthesis. Adapted with permission
from Busse WW, Lemanske RF. Advances in immunology: asthma.
NJEM 2001;344:353. Copyright © 2001
Massachusetts Medical Society. All rights reserved.

ISBN 0-203-42170-1 Master e-book ISBN

ISBN 0-203-44590-2 (Adobe eReader Format)

Contents

Preface vii
1. What is asthma and allergy? 1
2. What is immunoglobulin E? 10
3. Synthesis and regulation of IgE 18
4. Allergic inflammation and the role of IgE 24
5. Current management of asthma and allergy 31
6. Anti-IgE as a therapeutic strategy 37
7. Efficacy and safety of anti-IgE in asthma 44
8. Efficacy and safety of anti-IgE in allergic rhinitis 51
9. Future prospects for IgE in the treatment of allergic 56
disorders
Further reading 60
Index 63

v
Preface

The discovery by Prausnitz and Küstner in 1921 of reagin, the

circulating substance that could passively transfer the immediate
allergic response from one individual to another, stimulated a
50-year search for the molecular basis of this phenomenon.The
identification of reagin as IgE independently by Ishizakas and
Johansson in the late 1960s provided the rational basis for dis-
eases such as rhinitis, asthma and food allergy and a legitimate
target for novel therapeutics. Almost 25 years were to pass
before it was clearly shown that a monoclonal antibody directed
against that part of the IgE molecule that is encrypted by the
high- and low-affinity IgE receptors on effector cells could dra-
matically remove circulating and tissue IgE by forming small com-
plexes that are easily cleared without cross-linking IgE on the
surface of effector cells and, therefore, failing to produce anaphy-
lactic responses. The fully humanized monoclonal antibody
omalizumab (Xolair™) has these properties. It has been clearly
demonstrated that when administered at 2–4 weekly intervals
this therapy has markedly beneficial effects on multiple outcome
measures in allergic asthma.
This pocketbook provides an illustrative summary of the role of
IgE in asthma and allied allergic disorders and the effects of anti-
IgE treatment. With little new having been introduced into the
armamentarium for asthma therapy in the last three decades
other than improvements in β2-adrenoceptor agonists, corticos-
teroids and cysteinyl leukotriene antagonists, the introduction of
omalizumab is likely to provide a new way of treating allergic

vii
disorders with effects that extend beyond a single affected organ
and tissue. Its precise role in treatment guidelines will need to be
carefully evaluated, but its clear efficacy and safety provide
a clear statement about the importance of IgE across the full
spectrum of allergic disease.

Syed Hasan Arshad

K Suresh Babu
Stephen T Holgate
March 2001

viii
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What is asthma and
allergy? 1
What is asthma?
Asthma is a chronic inflammatory disease of the airways and
manifests clinically as intermittent cough and wheezing in
response to exposure to allergenic and non-allergenic stimuli.
The severity of asthma varies widely among individuals. In most
patients the symptoms are mild and intermittent. However, in
some patients it is a life-threatening disease which severely
affects their quality of life.
The National Heart, Lung, and Blood Institute (NHLBI)/World
Health Organization (WHO) expert panel report defines asthma
as (Figure 1):
a chronic inflammatory disorder of the airways in which many cells
and cellular elements play a role, in particular, mast cells,
eosinophils,T lymphocytes, neutrophils, and epithelial cells. In
susceptible individuals, this inflammation causes recurrent
episodes of wheezing, breathlessness, chest tightness, and cough,
particularly at night and/or in the early morning.These symptoms
are usually associated with widespread but variable airflow
limitation that is at least partly reversible either spontaneously
or with treatment.The inflammation also causes an associated
increase in airway responsiveness to a variety of stimuli.

1
 Environmental
influences (e.g.
allergen exposure)

Intermittent cough,
Asthma Variable
Inflammation wheezing and chest
genes bronchoconstriction
tightness

Specific
(allergenic) and
nonspecific
stimuli

Bronchial
hyper-responsiveness

Figure 1 Development of allergic inflammation in asthma and relationship to

bronchial hyper-responsiveness and symptoms.

Pathophysiology of asthma
Clinical features
Episodic cough and wheeze with chest tightness and difficulty in
breathing are characteristic symptoms.These symptoms are usu-
ally most marked in the morning or at night.The cough is usually
dry but may be productive of mucoid sputum. In some patients,
cough is the only symptom. Most mild-to-moderate asthmatics
wheeze on exposure to exogenous triggers, but in severe
asthma, persistent wheezing may occur.
In mild asthma, physical examination may be entirely normal.
However, in more severe forms, breathlessness may be apparent
and chest auscultation may reveal inspiratory and/or expiratory
wheezing. During an exacerbation the patient is breathless,
apprehensive and restless.Tachycardia and tachypnoea is almost
always present, and speech may be difficult. Wheezing may be

2
heard without stethoscope, but in most severe forms the chest
may be silent.
On lung function tests, a typical obstructive-type defect is often
noted with a prominent reduction in forced vital capacity in one
second (FEV1).The variable bronchoconstriction can be demon-
strated from diurnal and day-to-day variability in the peak expira-
tory flow rates (Figure 2).

Pathology
The clinical features of asthma are due to the airway narrowing
causing obstruction to airflow.This narrowing results from the
underlying inflammation, and has three elements:
■ Excessive bronchial smooth muscle contraction
■ Thickening of bronchial wall
■ Excessive secretions in the lumen

Excessive bronchial smooth muscle contraction

Inflammatory mediators such as histamine, bradykinin,
prostaglandins and leukotrienes act directly on their specific

600

500

400
l/min

300

200

100

0
am pm am pm am pm am pm am pm am pm am pm
Days

Figure 2 Diurnal and day-to-day variability in peak flow is characteristic of

asthma.

3
receptors to cause bronchoconstriction. Stimulation of the
cholinergic receptors causes bronchoconstriction, whereas
adrenaline acting on the β2-receptors has the opposite effect.The
physiological role of non-adrenergic, non-cholinergic nerves is
unclear.
In asthma, the smooth muscles contract easily and excessively
following exposure to inflammatory mediators, perhaps due to
the heightened sensitivity of their receptors.This feature is called
bronchial hyper-responsiveness and can be demonstrated in the
laboratory by inhalation of stimuli such as histamine or metha-
choline.

Thickening of the bronchial wall

Thickening of the bronchial wall is due to inflammatory and
fibrotic changes. Increased microvascular permeability allows
plasma exudation into the mucosa, causing oedema, and cellular
infiltration of eosinophils, mast cells and mononuclear cells.This
causes swelling of the airway wall and loss of elastic recoil pres-
sure, contributing to airway narrowing and hyper-responsiveness.
As the epithelium is damaged, the myofibroblasts lying beneath
the epithelium proliferate and lay down collagen, causing thicken-
ing of the basement membrane (Figure 3). Other changes include
hypertrophy and hyperplasia of airway smooth muscle, increase
in goblet cell numbers and remodelling of the airway connective
tissue. These changes may lead to irreversible obstruction in
chronic asthma.

Excessive secretions in the lumen

Bronchial biopsy in asthmatic patients shows that the epithelium
is fragile, and damaged epithelial cells are found in the sputum.
Increased mucous secretion, with exuded protein and cell debris,
comprises the mucous plug. Impaired ciliary function encourages
retention of thick mucus in the lumen. During severe exacerba-
tion, the lumen of the airway is blocked by thick mucus, plasma
proteins and cell debris (Figure 4).

4
Figure 3 Thickening of the basement membrane with deposition of collagen
may lead to irreversible obstruction in chronic asthma.

Figure 4 Cross-section through airways showing mucosal oedema and mucous

plugging. During severe exacerbation, the lumen of the airway is blocked by
thick mucus, plasma proteins and cell debris.

5
What is allergy?
Allergy is defined as an inappropriate or harmful immune
response to foreign substances that are otherwise not harmful
to the body. These substances are called allergens, and the
immune response is mediated largely, though not exclusively, by
the antibody IgE. Common sources of allergens include house
dust mites, airborne pollens of grass, trees and weeds, domestic
pets, mould spores and foods. IgE-mediated allergic disorders
include allergic asthma, allergic rhinoconjunctivitis, atopic der-
matitis, and some forms of occupational, food, drug and insect
venom allergy.Atopy, the genetic propensity to produce IgE, is a
prerequisite for the development of these disorders, and can
usually be confirmed by positive responses on skin prick test (or
the presence of specific IgE in the serum) to common allergens.
Allergens are introduced into the body through respiratory, gas-
trointestinal or conjunctival mucosa, with the exception of insect
stings or drug allergies, where they may be injected through the
skin. Initial exposure causes sensitization and production of IgE
antibodies, specific to the allergen. Subsequent exposures may
lead to immune reaction and disease. Clinical manifestations of
this reaction depend on the organ involved. For example, in the
airways this reaction causes asthma, whereas in the nasal and
conjunctival mucosa, it may cause rhinoconjunctivitis.

Epidemiology of asthma and allergy

Natural history
Sensitization to food allergens, such as cows’ milk and eggs is
common in early childhood, and is associated with a high preva-
lence of eczema and food allergic reactions. By the age of 4
years, the majority of children tolerate food allergens, but many
of these children develop allergies to inhalant allergens such as
house dust mite and pollen, with a concomitant increase in the
prevalence of asthma and hay fever in later childhood. This is

6
termed ‘allergy march’. Nearly 50% of children and adolescents
‘grow out’ of asthma and rhinitis as they approach adulthood.
However, young adults may develop asthma or rhinitis for the
first time. A family history of similar disorders is a common
denominator in these individuals.

Prevalence of allergy
Prevalence of atopy, as defined by the presence of positive skin
test or specific IgE to one or more allergens, ranges from 30% to
50% in various studies. However, not all atopic individuals develop
allergic disease. More than a quarter of the population develop
one or more allergic disorders (Figure 5).These range from mild
hay fever to life-threatening asthma or systemic anaphylaxis.
The International Study of Asthma and Allergy in Childhood
(ISAAC), using standardized questionnaires, obtained comparable

Infancy (n=1167)
1–2 years (n=1174)
2–4 years ( n=1218)
Cumulative (n=1060)
45
40
35
30
Per cent

25
20
15
10
5
0
Asthma Eczema Rhinitis Food Any
intolerance disorder

Allergic disorders

Figure 5 Prevalence of allergic disorders in early childhood. Data from a whole

population birth cohort study. Reproduced with permission from Tariq et al (1997).

7
information on the prevalence of asthma and allergy from differ-
ent parts of the world.This confirmed a high prevalence of these
disorders in most developed countries. Serial studies in the same
population have confirmed a rise in the prevalence of asthma and
other allergic disorders during the last few decades.

Asthma
In the ISAAC study, the prevalence of self-reported ever asthma
in children in the industrialized world was around 20–30%. Using
more stringent criteria of current wheezing and bronchial hyper-
responsiveness, the prevalence of asthma varies between 8% and
15%.An estimated 17.8 million people suffer from this disease in
the USA alone.The direct cost of asthma in the USA was esti-
mated to be around $11 billion. Indirect cost is more difficult to
estimate accurately, but this is substantial in terms of lost pro-
ductivity and school days.The cost is enormous, though 80% of
the resources are consumed by 20% of the asthmatic population,
who have more severe disease.

Allergic rhinitis
The prevalence of seasonal allergic rhinitis (hay fever) is said to
be around 10–12%, and a similar figure is quoted for perennial
allergic rhinitis.As with asthma, the prevalence of allergic rhinitis
is increasing.The cost of allergic rhinitis is high, primarily because
of the high prevalence of this disease. It was estimated to be in
excess of $3 billion in the USA in 1996. Indirect cost of loss of
work productivity and reduced performance and learning, is
additional.

Atopic eczema
The prevalence rates of atopic eczema in early childhood range
from 10%–12%. In the vast majority, atopic eczema improves,
although in nearly 50% some eczema lesions persist into adult-
hood. Moderate to severe atopic eczema has a major impact on
the quality of life of children and their parents.

8
Food allergy
Food allergy is defined as adverse reactions to food with an
immunological basis. Cows’ milk, eggs, fruits, nuts, fish and wheat
are the commonest food allergens. Common symptoms of food
allergy include urticaria/angioedema, vomiting, diarrhoea, and,
rarely, anaphylactic shock.Allergy to cows’ milk (3–4%) and eggs
(2–3%) is common in infancy but rarely persists beyond 3 years
of age. Peanut allergy affects around 0.5% of the population of all
ages.

Anaphylaxis
Less than 0.1% of the unselected population report ever having
an anaphylactic episode in their life. Common causes of anaphyl-
axis include drugs, insect venom, latex and foods, especially nuts.
However, patients with severe food, drug or latex allergy live in
constant fear of an inadvertent exposure and subsequent, poten-
tially life-threatening, reaction.

9
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