Unanswered questions: Anti-IgE as a practical tool in asthma management with observations and warnings from clinical experience
Bob Lanier, M.D.
Clinical Professor
Department of Pediatrics
University of North Texas
6407 Southwest Blvd
Fort Worth, Texas 76132
Abstract
Moderate to severe allergic asthmatics represent a
challenging group of patients that have unmet needs with regards to asthma
management. Current guidelines have
resulted in significant improvements in asthma outcomes yet do not affect the
underlying disease process. Omalizumab
is the first biologic agent introduced to specifically manage allergic disease
by specifically targeting IgE. It is a
recombinant DNA-derived humanized monoclonal IgG1 antibody with unique
anti-human IgE binding specificities. But the mechanism of action as
down regulation of FceR1 receptors in the
presence of low free IgE is incomplete.
Some severe allergic asthmatic patients respond almost immediately,
others take months, some never respond. Other unexplained phenomena include the presence
of positive skin tests for much longer than three months – some for years raising
the possibility of anaphylaxis with concomitant allergy immunotherapy. Indicating that some
patients may have exquisitely sensitive B cell production. Current
guidelines for anti-IgE use in asthmatics may require reexamination as data
from broad clinical experience is gathered.
Introduction
The development of
asthma is a multi-factorial process involving genetics, and environmental
exposure. Allergic asthma occurs in
patients with sensitivities to allergens such as house dust mite, animal dander
and cockroaches. Of the patients with
asthma, most have evidence of IgE-mediated sensitivity to airborne allergens
[1]. This is especially true in
children, where over 85% of asthmatic children show positive skin test to one or
more airborne allergens [2,3]. With improved knowledge of the mechanisms of
allergy, inflammation and asthma novel treatments have been developed.
IgE and allergy
Development of
allergic asthma is driven by the production of IgE antibodies that are specific
to a given allergen. In the case of
asthma important allergens include house dust mite, animal dander, cockroaches
and alternaria.
Once allergen specific IgE has been produced it binds via the Fc segment to the high affinity receptor,
Mechanism of action of anti-IgE
The effect of
anti-IgE is produced as a function of complexing
free IgE to reduce mast cell implacement. As total free IgE drops below 10 ng/ml, down regulation of IgE receptors on
circulating basophils, skin mast cells, IgE+ bronchial mast cells, Langerhans cells, and circulating
(precursor) dendritic cells occurs (
4,5). This effect on dendritic
cells may lead to a reduction in allergen presentation, and TH2 activation and
proliferation. (6,7).
Eosinophils, T and B cells are also reduced in
the submucosa.
In addition to the high-affinity
Effect of anti-IgE on
asthma
The efficacy of anti-IgE in severe asthma has been established in both short and long term studies. 525 subjects with severe allergic asthma requiring daily inhaled corticosteroids were randomized to receive placebo or omalizumab subcutaneously every 2 or 4 weeks, with stable inhaled corticosteroid doses for the initial 16 weeks of treatment and tapered during a further 12-week treatment period. Treatment resulted in significantly fewer asthma exacerbations per subject and in lower percentages of subjects experiencing an exacerbation than placebo treatment during the stable steroid and during the steroid reduction phase. Inhaled steroid reduction was significantly greater with omalizumab treatment than with placebo and ICS discontinuation was more likely with anti-IgE treatment. Improvements in asthma symptoms and pulmonary function occurred along with a reduction in rescue beta-agonist use. (9) In the longer term study, 460 patients continued 24-week, double-blind extension phase to a previous 28-week core study for 16 weeks in addition to their existing ICS therapy followed by a 12-week phase in which controlled attempts were made to gradually reduce ICS therapy (10). Both placebo and active patients were maintained on the lowest sustainable dose of BDP. The use of other asthma medications was permitted during the extension phase. Omalizumab-treated patients experienced significantly fewer exacerbations vs placebo during the extension despite a sustained significant reduction in their use of ICS.
Anomalies in asthma –
do patients with low total IgE levels respond ?
Physicians in the process of evaluating potential candidates for anti-IgE are frustrated with the current provisions requiring a minimum IgE level of <30 IU before application of this new treatment. 11 female patients with moderate to very severe asthma and IgE levels less than 34 IU and their unexpectedly encouraging progress with anti-IgE injections are presented in figure 1(11). “Wow” response refers to a dramatic improvement, primarily in activity, as judged by patients. These patients, except for discernable prick puncture skin tests would historically be classified as intrinsic asthmatics. IgE levels are predictive for the incidence of asthma, but not the severity. The current literature suggests that the sickest asthmatics with the highest level of IgE tend to be the best responders. (12). However, clinical trials excluded individuals with total IgE levels below 30 KU/Il, and may have excluded a host of legitimate responders. It is possible a clone of IgE may produce significant disease while not elevating the total level.
Warnings about
concomitant treatment with Allergy Immunotherapy and anti-IgE
Much recent speculation involves the use of anti IgE as a
protective mechanism since this drug is understood to bind free IgE and down
regulate the high affinity receptors.(13,14) Three
asthmatic patients are presented from a cohort of 58 who experienced an
anaphylactic reaction to their pollen Specific Antigen Immunotherapy in spite
of pre-treatment with omalizumab for over 6-12 months (15).
Omalizumab treated patients consistently retain positive
skin tests to pollens and molds, although in many cases the reactivity is less
after 
3-6 months (16).
While studies suggest omalizumab reduces the incidence of anaphylaxis
and has been proven to inhibit nasal responses on challenge, the possibility
for life threatening allergic reactions still exist in patients receiving
SIT. Concomitant use of SIT and
Omalizumab should not suggest a change in the practice parameters for doses and
frequency of SIT and should not lull practitioners into a sense of false
security.
Summary
Omalizumab, in practice is a highly effective and indeed
life-altering drug in many asthmatic patients, but not all. Profiling for this intensive therapy has not
been well estanlished, but clinical evidence is
beginning to mount that some asthmatics below the total IgE level discussed in
the package insert may respond well.
1. Burrows B, Marinez
FD, Halonen M, et al.
Association of asthma with serum IgE levels and
skin-test reactivity to allergens.
N Engl J Med 1989;320:271-7.
2. Martinez FD, Wright AL, Taussing
LM, et al. Asthma and wheezing in the first six years of
life. The Group Helath Medical Associates. N E N Engl J Med
1995;332:133-8.
3. Platts-Mills TAE. The role of immunoglobin E in allergy and asthma. Am J Respir Crit Care Med 2001;164:S1-5.
4. Anti-immunoglobulin
E treatment with omalizumab in allergic diseases: an update on
anti-inflammatory activity and clinical efficacy.
5. Macglashan D, Miura K. Loss of receptors and IgE in
vivo during treatment with anti-IgE antibody.J
Allergy Clin Immunol. 2004 Dec;114(6):1472-4. Loss of syk kinase
during IgE-mediated stimulation of human basophils.J
Allergy Clin Immunol.
2004 Dec;114(6):1317-24.
6. Corren J, Diaz-Sanchez D, Saxon A, Deniz
Y, Reimann J, Sinclair D, Davancaze
T, Adelman D.Effects of omalizumab, a humanized monoclonal anti-IgE
antibody, on nasal reactivity to allergen and local IgE synthesis.Ann
Allergy Asthma Immunol. 2004 Sep;93(3):243-8.
7. Holgate S, Casale T, Wenzel S, Bousquet
J, Deniz Y, Reisner C.
The anti-inflammatory effects of
omalizumab confirm the central role of IgE in allergic inflammation.J Allergy Clin Immunol. 2005 Mar;115(3):459-65
8 Broide DH. Molecular and Cellular
mechanisms of allergic disease. J
Allergy Clin Immunol 2001;108:S65-71
9..Busse W, Corren J,
Lanier BQ, McAlary M, Fowler-Taylor A, Cioppa GD, van As A, Gupta N Omalizumab, anti-IgE
recombinant humanized monoclonal antibody, for the treatment of severe allergic
asthma. J Allergy Clin Immunol. 2001 Aug;108(2):184-90.
10..Lanier BQ, Corren J, Lumry W, Liu J, Fowler-Taylor A, Gupta N.
Omalizumab is effective in the
long-term control of severe allergic asthma. Ann
Allergy Asthma Immunol. 2003 Aug;91(2):154-9.
11. Lanier, BQ Observations of anti-IgE treated patients in Clinical Practice, Abstract, World Allergy Organziation, Berlin 2005
12. Bousquet J, Wenzel S, Holgate S, Lumry W, Freeman P, Fox H. Predicting response to omalizumab, an anti-IgE antibody, in patients with allergic asthma. Chest. 2004 Apr;125(4):1378-86.
13. Hamelmann E, Rolinck-Werninghaus
C,
114. Wahn U, Hamelmann E.
Anti-IgE therapy combined with specific immunotherapy: pro.Arb
Paul Ehrlich Inst Bundesamt Sera Impfstoffe
Frankf A M. 2003;(94):269-71
15. Lanier BQ, Anaphylaxis to immunotherapy in Omalizumab treated patients, Abstract, World Allergy Organization Meeting, Berlin 2005.
16. Lanier, BQ The effect of Omalizumab on Prick Puncture
skin tests at six months, Abstract, ACAAI, 2004
Figure 1
Response and Characteristics of patients entering Omalizumab
treatment below 34 KU/IL
Figure 2
|
Pateint ID |
VC |
JV |
WE |
|
+ ST @ 6 months |
reduced |
same |
Reduced (on AH) |
|
SIT content |
HD,MC |
Grass, MC |
MC,RW,HD |
|
IgE baseline |
19 |
125 |
215 |
|
IgE 6 months |
30 |
493 |
910 |
|
Conc @ event |
|
|
|
|
Duration SIT prior to event |
6 months |
12 months |
Day ( RUSH) |
|
Months of Omalizumab before event |
6 months |
12 months |
6 months |
|
Symptoms of event |
Wheeze, itch, angio |
Angio,sneeze, congestion |
Wheeze,sneeze, congestion |
|
Intervention |
Epi x3 AH |
Epix2 AH |
Epix2 AH |
|
Resolution |
30 mins |
120 mins |
20mins |
|
Serum markers |
Not done |
Not done |
Not done |
Characteristics of three patients experiencing anaphylaxis following pre-treatment with anti-IgE