Transcript Anti-IgE: Beyond Asthma

Anti-IgE: Beyond Asthma
Michael S. Blaiss, MD
Clinical Professor of Pediatrics and Medicine
University of Tennessee Health Science Center
Memphis, Tennessee
Introduction
Omalizumab (Xolair®) anti-IgE is approved
throughout the world for the treatment of
allergic asthma
Obviously, IgE is involved in the pathogenesis
of many other atopic conditions beyond
asthma
Purpose: Review studies looking at
omalizumab treatment in other disorders
Omalizumab-Other
Conditions
Allergic rhinitis
Immunotherapy
Mastocytosis Indolent
and systemic
Drug allergy
Nasal
polyposis/sinusitis
Insulin allergy
Latex allergy
Idiopathic anaphylaxis
Chronic
urticaria/angioedema
Idiopathic,
autoimmune,
cholinergic, cold
induced
Eosinophilic
gastrointestinal
diseases
ABPA
Atopic dermatitis
Urticaria
Courtesy of David Khan, MD
Epidemiology of Urticaria
Overall limited data, particularly in US
Acute urticaria
20% in 1969 (Champion et al, England)1
19% in 2004 (Gaig et al, Spain)2
Chronic urticaria2
147 of 5003 (2.9%) patients reported a history of CU
0.6% prevalence (active disease)
CU = chronic urticaria; GP = general practitioner.
1. Champion RH, et al. Br J Dermatol.1969;81:588-597.
2. Gaig P, et al. J Invest Allergol Clin Immunol. 2004;14:214-220.
3. Paul E, et al. Hautarzt. 1991;42:366-375.
Autoimmune Theory of Chronic Urticaria
1983
History of Autoimmunity in CIU1
1986
1988
1991
1993
Functional IgG anti-FcεRlα
antibodies in CIU subjects6
Histamine releasing activity (HRA)
in CIU sera with anti-IgE properties5
IgG anti-IgE in CIU with ELISA4
+ ASST (Autologous serum skin test) in 7/12 CIU subjects3
An association of CIU with thyroid autoimmunity2
1. Brodell LA, et al. Ann Allergy Asthma Immunol. 2008;100:291-297. 2. Leznoff A, et al. Arch Dermatol. 1983;119:636-640.
3. Grattan CE, et al. Br J Dermatol. 1986;114:583-590. 4. Gruber BL, et al. J Invest Dermatol. 1988;90:213-217.
5. Grattan CE, et al. Clin Exp Allergy. 1991;21:695-704. 6. Hide M, et al. N Engl J Med. 1993;328:1599-1604.
Stepwise Approach
to Chronic Urticaria Therapy
Step 1
Second-generation antihistamine
Step 2
Higher-dose second-generation antihistamine
Step 3
Second-generation antihistamine + first-generation
antihistamine (hydroxyzine or doxepin taken at bedtime up
to 150 mg qhs)
Step 4
Antihistamines + leukotriene-receptor antagonist
Step 5
Anti-inflammatory alternative therapy (eg, dapsone,
sulfasalazine, hydroxychloroquine)
Step 6
Immunosuppressant alternative therapy (eg, tacrolimus,
cyclosporine, mycophenolate)
Step 7
Biologic therapy (eg, omalizumab)
Step 8
Other alternative therapies (eg, phototherapy,
anticoagulants)
Chronic Autoimmune
Urticaria and Omalizumab
Rationale for omalizumab
in CAU
Omalizumab is a recombinant humanized mAb
that selectively binds to IgE
It inhibits the binding of IgE to the high affinity IgE
receptor (FceRI) on the surface of mast cells and
basophils
It reduces the number of FceRI receptors on basophils
It reduces free IgE in the serum
May block the initial antigen presentation
Reduces the additional production of IgE
Reduces the numbers of inflammatory cells such as
eosinophils, B lymphocytes, and T-helper and T
cytotoxic lymphocytes
J Allergy Clin Immunol 2008;122:569-73
Methods
Twelve patients with CAU, identified by
basophil histamine release assay and
autologous skin test, with persistent symptoms
for at least 6 weeks despite antihistamines
Treated with placebo for 4 weeks followed by
omalizumab (≥0.016mg/kg/IU mL-1 IgE per
month) every 2 or 4 weeks for 16 weeks
Urticaria Activity Score (Pruritus severity,
Interference with sleep, interference with daily activity)
What happens after
omalizumab therapy was
stopped?
Kaplan et al investigated the post-treatment
clinical course over the 2 years following
discontinuation of omalizumab (4 month trial)
Of the 7 complete responders, 5 had no
recurrence, one experienced a mild
exacerbation 6 months later that
spontaneously resolved, and one experienced
intermittent urticaria treated with as-needed
hydroxyzine.
What happens after omalizumab
therapy was stopped? (cont)
Of the 4 patients with a partial response:
One had mild urticaria for 6 months which then
worsened requiring prednisone and diphenhydramine
for 1 year and is now treated with cetirizine
Two have had continuous mild urticaria for 2 years
treated with cetirizine, and hydroxyzine respectively
One worsened immediately after omalizumab was
stopped
Required cyclosporine therapy for 1 1/2 years and is now
treated with cetirizine
MAINTENANCE OF REMISSION WITH LOW-DOSE
OMALIZUMAB IN LONG-LASTING, REFRACTORY
CHRONIC URTICARIA
Italian report in Annals of Allergy, Asthma, and
Immunology in January 2010
Two patients with refractory CU and highly atopic
respond to omalizumab and able to decrease dose to
every 28 days without relapse
Quick remission in both patients in 72 hours
JACI 2011
Study
In this multicenter, randomized, double-blind,
placebo-controlled study patients with CU
(male/female, 18-70 years of age) with IgE
autoantibodies against TPO who had persistent
symptoms (wheals and pruritus) despite standard
antihistamine therapy
Randomized to receive either omalizumab (75-375
mg, dose determined by using the approved
asthma dosing table) or placebo subcutaneously
once every 2 or 4 weeks for 24 weeks
Other Types of Urticaria
At least 2 cases in solar urticaria (Waibel
et al. JACI 2010)
Cold-induced urticaria (Boyce JACI 2006)
Cholinergic urticaria (Otto et al. Allergy
Asthma Proc 2009)
JACI 2011
Methods
Phase IIa prospective, DB, placebo controlled dose
ranging study in patients with chronic urticaria not
responsive to antihistamines using single dose of
omalizumab
75mg, 300 mg, and 600 mg omalizumab
Change in UAS from baseline to 4 weeks
Atopic Dermatitis and
Omalizumab
Atopic Dermatitis
AD involves many different components of the
immune system
In the acute phase, there is emphasis of a Th2
immune response leading to the production of IL-4
and IL-13 (triggering production of IgE by B
lymphocytes), IL-5 (important for recruitment and
activation of eosinophils), and IL-6.
Chronic AD is characterized by a switch from Th2
cells to Th1 cells with the subsequent up-regulation
of interferon (IFN) and IL-5
Atopic Dermatitis
Various antigen-presenting cells are also
involved in this immunologic process
Langerhans cells, dendritic cells, and macrophages
Langerhans cells are increased in number in chronic
AD lesions, express FcRII and FcRI (high affinity) IgE
receptors, and have been found to be carrying IgE
antibodies
Dermal dendritic cells and inflammatory dendritic
epidermal cells also have an affinity to anti-FcRI
receptors
Studies
In one study by Krathen and Hsu, three
patients with chronic severe lichenified AD and
other atopic comorbidities who were followed
for 4 months on 450 mg of omalizumab dosed
every 2 weeks had no improvement at 4
months
It was noted that these patient’s pretreatment
serum IgE levels ranged from 5440 to 24,000
IU/mL.
Krathen RA, and Hsu S. Failure of omalizumab for treatment of
severe adult atopic dermatitis. J Am Acad Dermatol 53:338 –340,
2005.
Studies
Three nonasthmatic patients aged 10–13 years
old, presented by Lane et al
Their pretreatment serum IgE levels ranged
from 1990 to 6120 IU/mL.
This study showed clinical improvement in
severity of AD with dosing of omalizumab as
high as 450 mg given every 2 weeks over a 22week period
Lane JE, Cheyney PA, Lane TN, et al. Treatment of recalcitrant
atopic dermatitis with omalizumab. J Am Acad Dermatol 54:
68–72, 2006
Study
The primary objective of this study was
to examine the efficacy of omalizumab
for the treatment of AD in 21 patients
aged 14–64 years with IgE levels ranging
from 18 to 8396 IU/mL, with the majority
of patients having food allergy as the
trigger for their AD
Results
Although improvement was noted in all
three subgroups, a more profound
improvement in SCORAD scores was
noted in those patients with lower
pretreatment serum IgE levels compared
with those patients with high or very
high IgE levels
Clinical improvement seen as early as
one month
Conclusions
Omalizumab has demonstrated efficacy for
allergic asthma and rhinitis
Data continues to accumulate of it’s benefit
in two common skin conditions-chronic
autoimmune urticaria and atopic dermatitis
Though definitely not a first-line treatment
in either condition, it gives another option
in patients when these disorders are
recalcitrant to other medications