DEFINITION:

Medical procedure that uses controlled exposure to

known allergens to reduce the severity of allergic
disease.
Mechanism:
1. B cell response
 Gradual increase of allergen-specific IgG antibodies -- especially
IgG4 (blocking antibody):
Intercept and neutralize allergen before it bound to cell-surface IgE.
Form IgG-antigen-IgE complex and inhibition of IgE receptor triggering.
 Decreased allergen-specific IgE antibodies.
 Increase IgA and IgM antigen-specific B lymphocytes.
May limit antigen penetration into the body from mucosa.
2. T cell response:
 Moving immune system from CD4+Th2 cell to Th1 cell
pathway.
 Alter cytokine production:
Increase IL-10 which has numerous potential antiallergic properties
against mast cells, T cells, and eosinophils..
Clinical indications for SCIT in asthma:
Symptoms of allergic asthma (specially if
associated with allergic rhinitis) after natural
exposure to aeroallergens
AND Demonstrable evidence of clinically relevant
specific IgE by skin test or serum level
AND At least one of the following:
1. Poor response to pharmacotherapy, allergen
avoidance, or both .
2. Unacceptable adverse effects of medications .
3. Wish to reduce or avoid long-term pharmacotherapy
and the cost of medication.
4. Coexisting allergic rhinitis and asthma .

 Patients sensitive to a single allergen

versus those who are polysensitized
benefit more from immunotherapy.
 The effectiveness of SCIT has been for the following
allergens:
Tree pollens.
Grass pollens .
Weed pollens .
Animal danders (cat and dog).
Dust mites .
Molds .
Cockroach.
Symptom improvement and/or reduction of the need
for symptomatic drugs in allergic rhinitis and asthma.

Long-lasting effect once discontinued.

Prevention of the onset of new skin sensitizations.

Prevention of the onset of asthma.

The administration of SCIT to children with allergic rhinitis can help
prevent the subsequent development of allergic asthma .
76 trials with 3,188 patients
Significant improvement in asthma symptom
scores.
Significant reduction of allergen specific BHR
Some reduction also in non-specific BHR.

Abramson, Weiner and Puy

Cochrane Database Systematic Review 2003
Systemic Reactions:
1. Non-specific reactions (likely non-IgE-mediated), discomfort, nausea, headache,
arthralgia.

2. Mild systemic reactions; mild rhinitis/asthma (PEFR > 60%), responding to β
2
agonists/antihistamines.

3. Non-life-threatening systemic reactions; urticaria, angioedema, severe asthma (PEFR

< 60%). Responding well to treatment.

4. Anaphylaxis; itching, urticaria, bronchospasm, with hypotension, requiring

intensive care.

 Estimated risk for fatal reactions less than 1 per 2 million injections
Uncontrolled asthma.
Severe asthma.
Use of betablockers.
Patients with autoimmune disease
 Immunodeficiency
Pregnant women.
 Serious immunopathologic diseases and
immunodeficiencies.
 Malignancies.
 Severe psychological disorders.
 Treatment with beta blockers, even when administered
topically.
 Poor compliance.
 Severe or uncontrolled asthma by pharmacotherapy
(FEV1< 70%).
 Significant cardiovascular diseases.
 Children under 5 years (relative contraindication).
Use upper outer surface
of arm.
Ensure sterile technique.
Use 1ml syringe and
orange needle.
Inject at 45º by deep
subcutaneous route.
Record any local
/systemic reaction.
Oral immunotherapy (OIT): allergen immediately swallowed,
as drops, tablets or capsules.

Sublingual immunotherapy (SLIT): allergen kept under the

tongue for 1-2 minutes, then swallowed .

Local nasal (LNIT): allergen sprayed into the nostrils as

aqueous solution or dry powder.

Local bronchial (LBIT): allergen inhaled with a deep

inspiration.
Bronchial and oral route are not recommended for
clinical use, due to insufficient demonstration of
efficacy and the occurrence of side effects.

Nasal IT (NIT) and Sublingual IT (SLIT): “Based on

the available literature, local nasal immunotherapy
and sublingual immunotherapy can be considered as
viable alternatives to subcutaneous administration”.

WHO Position Paper 1998

NIT
May be indicated in carefully selected adult patients
with rhinitis caused by pollen and possibly by mites.
Potential candidates are patients who:
1. Cannot be properly controlled by standard
pharmacotherapy.
2. Have experienced previous systemic
reactions induced by subcutaneous allergen
immunotherapy.
3. Who refuse injections.
ARIA 2001
NIT requires a careful administration technique, and
premedication with cromolyn is suggested.

It acts only on rhinitis symptoms, and seems not to

have a long lasting effect.

For these reasons, its use is progressively declining.

 SLIT-Swallow:

• SLIT is effective in rhinitis caused by pollens and

mites.

• There are few studies showing additional efficacy on

asthma symptoms.

• More studies about efficacy in children are required.

• The long-lasting effect has been demonstrated in
children with mite-induced asthma.

Di Rienzo et al Clin Exp Allergy 2003

• The preventive effect on new skin sensitizations

has been demonstrated.

Marogna et al Allergy 2004

In post-marketing studies, the overall rate of side
effects of SLIT (all grades) ranges between 3% and 8%
of patients.

The most frequently reported side effects are local

(gastrointestinal); oral itching/swelling, nausea,
stomach-ache.

The side effects are usually mild and treatment

discontinuation is rarely required.
Gastrointestinal side effects are dose-
dependent.

No life-threatening side effect or fatality has

ever been reported since the introduction of
SLIT in 1986.

The occurrence of systemic effects in

controlled trials does not differ from the
placebo treated patients.
SLIT may be indicated in pollen and mite
induced rhinitis and asthma in adults and
children, using maintenance dosages 5 -100
times higher then injection IT.
ARIA, JACI, 2001

 SLIT reduces both symptom and medication scores in

pediatric patients with allergic rhinitis.
Annals of Allergy Asthma and Immunology 2006.
Specific immunotherapy does not take the position of
being an ultimate treatment principle. It should be
part of the global treatment, and should be used in
the early phase of disease.

Modified from JACI 2001

Allergoids/polymerized extracts.
Creation of an allergoid by treatment with
formaldehyde and polymerization with
glutaraldehyde both reduce allergenicity of the
extract while retaining immunogenicity.
Recombinant allergens with site-directed mutagenesis
and deletion.
Although this produces a consistent extract, there
is no reduction in allergenicity and hence limited
advantage over natural allergen extracts.
Allergen-derived peptides.
 Peptides too small to react with IgE but with retention of
the T lymphocyte epitopes. Thus, reduced allergenicity
with retained immunogenicity is achieved.

Immunostimulatory sequences.
Unmethylated segments that characterize bacterial and
viral DNA react with the Toll-like receptor9 of APC.
These Synthetic DNA chains, when covalently
linked to allergens, have the advantage not only of
directing the response to the allergen toward a regulatory
and TH1 bias but also of interfering with the reactionof
IgE with the allergen, thus reducing its allergenicity.
Most asthmatic patients have elevated circulating IgE
concentrations when levels are adjusted for age .
 Allergic sensitization results from the formation of
specific IgE in response to common inhalant
allergens.
 IgE is produced by B lymphocytes under the
direction of two cytokines: interleukin (IL)-4 and the
closely related IL-13, which are produced by several
cell types, including Th2 cells, a subset of T-helper
lymphocytes prevalent in atopy .
Stimulated B cells mature into plasma cells that
secrete allergen-specific IgE, which binds to high
affinity receptors (Fc-epsilon-RI) on the surface of
mast cells, basophils, and other cells .

Cross-bridging of these IgE molecules on mast cells

and basophils by protein allergens results in their
activation, with release of preformed mediators such
as histamine, and increased synthesis of lipid
mediators such as PG and LTs .
Release of mast cell mediators results in broncho-
constriction and plasma exudation.

Thus, IgE plays a central role in the mechanism of

immediate bronchoconstriction in allergic asthmatic
patients after inhalation of allergen.
OMALIZUMAB 
is a recombinant humanized IgG1 monoclonal
antibody that binds IgE with high affinity and has
been developed for the treatment of allergic diseases .
It is approved for use in patients 12 and older with
moderate to severe persistent asthma, allergic
sensitization to an allergen that is present year round
(a perennial allergen), and symptoms that are
inadequately controlled with the maximal doses of
inhaled therapy.
Binds to the third constant domain of the IgE heavy
chain (C-epsilon-3), forming complexes that are
subsequently cleared by the hepatic RES.
 This binding inhibits interaction of circulating IgE with
both high and low-affinity IgE receptors on mast cells,
basophils, and other cell types.
The antibody is specific to IgE and does not bind to IgG
or IgA.
 It cannot bind to IgE receptors or to IgE already
attached to Fc-epsilon-RI, and therefore does not
activate mast cells or basophils .
Omalizumab therapy also causes a marked down-
regulation of Fc-epsilon-RI on the surface of basophils
and mast cells, although the time course of this
change may differ in the two cell types.
Approved indications in
asthma
 The Food and Drug Administration in the United
States “in 2003” approved Omalizumab for
subcutaneous use in:
Patients with moderate-to-severe persistent asthma.
Demonstrable sensitivity to a perennial aeroallergen
And incomplete symptom control with inhaled
corticosteroid treatment
Patient selection
 Clinical predictors of a positive response included :
1. Impaired baseline lung function.
2. And frequent exacerbations despite high dose
inhaled corticosteroid therapy.
3. Relatively high proportion of allergen-specific IgE
relative to total IgE.
However, among patients fulfilling these criteria, it is
not possible to predict which patients will
experience benefit.
Pretreatment testing
  Total serum IgE levels should be between 30 and 700
international units/mL (IU/mL).
Sensitization to a perennial aeroallergen (eg, dust
mite, animal danders, cockroach, molds) must be
demonstrated by positive skin testing or in vitro IgE
testing.
Baseline FEV1, peak flow, or other pulmonary
function testing is recommended.
Effect
Larger median dose reduction in inhaled
glucocorticoids.

Higher percentage of patients able to discontinue

inhaled glucocorticoids.

Fewer exacerbations during both the stable-steroid

and steroid-withdrawal phases .
Cost 
Several analyses have questioned the cost-
effectiveness of omalizumab therapy.
 The cost is $10,000 to $12,000 per year for patients
who require one vial (150 mg) every four weeks (the
minimum dose), and incrementally higher for those
requiring more, which far exceeds that of other
asthma therapies.
Dose &route of administration 
Omalizumab is approved for administration by subcutaneous
injection.

Initial trials demonstrated that aerosolized omalizumab was

ineffective in protecting against allergen challenge and had no
effect on circulating IgE .

 In contrast, parenteral use of the antibody significantly reduced

the concentration of circulating free IgE and affected markers of
asthma severity. Intravenous omalizumab induced a rapid and
sustained fall in free serum IgE of 96 percent following a 100 mg
dose.
 OMALIZUMAB is administered by sc injection every
two to four weeks in a dose that is determined by
body weight and the levels of serum IgE (0.016 mg/kg
per IU/mL of IgE per month).
It should not be initiated in the setting of an acute
exacerbation of asthma, nor should it be self-
administered.
Therapy requires a dose of 150 to 375 mg injected
subcutaneously every two to four weeks.
 Peak serum concentration is reached in 7-8 days .
 No more than 150 mg should be administered at a
single site, to prevent local reactions.
The elimination half-life of the drug is one to four
weeks after subcutaneous administration.
Monitoring therapy 
 No specific laboratories are suggested for monitoring
patients who are responding clinically to anti-IgE
therapy.
Total serum IgE levels increase 3-6 fold in all
individuals on therapy (due to the presence of
omalizumab: IgE immune complexes) and are not
useful for monitoring clinical response .
 Free serum IgE levels decrease dramatically, although
measurement of free IgE is not available outside of
research settings .
Duration of treatment 
A minimum of 12 weeks of treatment is needed to
determine the efficacy of anti-IgE therapy .
 Long-term dosing should be adjusted for changes in
body weight.
 Reductions in the omalizumab dose below the
recommended formula (0.016 mg/kg per IU/mL of IgE
per month) are likely to result in a loss of efficacy.
ADVERSE EFFECTS 
To date, all studies have indicated that omalizumab is
generally well tolerated. However, there are case reports
and series of adverse reactions, including the following:
Anaphylaxis :
 Anaphylaxis and anaphylactoid reactions that could not
be ascribed to any other agent developed in approximately
two in 1000 patients receiving omalizumab.
 The mechanism(s) in these reactions is not known,
although a hypersensitivity reaction to the additive
polysorbate 20 was implicated in a report of two cases.
Anaphylaxis after omalizumab may occur after any
dose.
39 % occurred with the first dose and 19 %, with the
second dose.
 The reaction occurred after one of the first three
doses in 68 % of cases .
 Approximately 70 % of reported cases occurred
within 2 hrs of administration, although anaphylactic
events beginning as late 4 days after the injection
have also been reported .
 Injection site reactions:
Injection site reactions appeared in approximately 44 % of
omalizumab and placebo treated patients. These were mostly
described as mild to moderate and ranged in size from 1.5 to 3
cm. Most local reactions occurred within one hour of injection
and lasted for 3 to 14 days.
 Serum sickness :
A small number of case reports describe serum sickness-like
reactions following administration . One case proved fatal .
 Urticarial rash :
 An urticarial skin rash has been reported to develop in
approximately 1 % of patients .
The relationship between this limited reaction and risk for
anaphylaxis has not been studied
 Unclear association with cardiovascular disease :
An FDA interim safety analysis reported that there was an
apparent increase among certain cardiovascular disorders in
patients receiving Xolair® compared to the placebo group.
These disorders included IHD, cardiomyopathy, arrhythmias,
and embolic and thrombotic events.
The FDA did not suggest stopping the drug and did not alter the
prescribing information.
 Unclear association with malignancy:
In preclinical and clinical studies done by the FDA in 2003
there was a numeric excess of malignancies among omalizumab-
exposed subjects that may be omalizumab-related."
The effects of extended treatment have not been examined.
A five year study is currently underway to evaluate longer term
safety and efficacy .
Churg-Strauss syndrome
Cases of Churg-Strauss syndrome developing in
temporal relationship with the use of omalizumab
have been reported, although the coincident
reduction in glucocorticoid therapy must also be
considered as a possible contributing factor in
expression of the disease .
Susceptibility to parasitic infection
This issue warrants further investigation.
OTHER NOVEL STRATEGIES TO REDUCE IgE 

Anti-CD23 
 CD23 is the low affinity IgE receptor (Fc-epsilon-RII),
present on the surface of many cell types, including B
lymphocytes, monocytes, macrophages, & dendritic
cells.
A monoclonal antibody to CD23 has been developed,
and was shown to decrease serum total IgE in patients
with allergic asthma in a phase I, placebo-controlled
trial .
 Cytokine modulators 
IgE synthesis is suppressed by inhibition of the cytokines IL-4 or
IL-13, which are needed for class switching.
IgE production is also inhibited by the cytokines interferon-
gamma and IL-12, which switch the balance from Th2 towards Th1.
 Anti-IL-4 antibody:
Failed in clinical trials & had non significant effects on serum IgE
levels.

 IL-12:
Reduces circulating eosinophils in asthma, but the effect on
circulating IgE is not known
 Interferon-gamma:
does not appear to be effective in the treatment of asthma, at least
when given by inhalation, and its effects on IgE are not known .
 SUMMARY
Most asthmatic patients are atopic and have elevated
circulating IgE concentrations when levels are
adjusted for age.
IgE plays a central role in the mechanism of
immediate bronchoconstriction in allergic asthmatic
patients after inhalation of allergen.
Omalizumab is a recombinant humanized IgG1
monoclonal antibody that binds circulating IgE,
forming immune complexes that inhibits interaction
of IgE with IgE receptors on mast cells, basophils, and
other cell types.
Randomized trials of patients with moderate and
severe persistent asthma showed that anti-IgE
therapy significantly reduces severe exacerbations.
Many patients can also significantly reduce their need
for inhaled glucocorticoids .
Omalizumab is approved for use as an add-on therapy
in patients with inadequately controlled moderate-to-
severe asthma despite the use of ICS therapy at
appropriate doses.
Omalizumab is administered by sc injection under
medical supervision.
No specific lab tests are suggested for monitoring patients
who are responding clinically to anti-IgE therapy.
Total serum IgE levels are not helpful because these do not
distinguish free IgE from IgE complexed to the drug, and
total IgE levels typically increase three to six-fold on
therapy.
Omalizumab is generally well tolerated.
Anaphylaxis occurs in approximately 2 in 1000 patients,
and can develop after any dose, including the first one, or
have delayed onset or protracted course.
Professional allergy societies in the United States have
proposed that patients be observed for two hours after
each of the first three injections, and for 30 minutes after
each subsequent injection.
Other adverse effects include an urticarial skin rash in
approximately 1 percent of patients, and mild
injection site reactions occur in 44 percent.
Other novel strategies to reduce the effects of IgE in
atopic disease include monoclonal antibodies to
CD23, the low affinity IgE receptor, and cytokine
modulators designed to decrease IgE production.
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