Sublingual Immunotherapy for Treatment of Food Allergy
11
November

By Adem Lewis / in , , , , , , , , , , , , , , , , , , , , , , , , , /


Thank you for inviting me to share the
scientific information about a treatment option that is available now, using
allergy extracts that all allergists have in their offices. You will see that this
form of treatment provides a margin of safety if an allergic food is eaten, and
there are minimal safety concerns with the treatment itself. I hope this
information will help expand your treatment option discussion with your
own allergist. My father was a real pioneer in the use of sublingual
immunotherapy or allergy drops for treating not only airborne allergies, but
also food allergies. We have, over the last almost 50 years, treated a hundred
and fifty-five thousand patients with this form of immunotherapy. Back in 2000
we decided that we would put together the La Crosse Method Protocol, which
summarized all of the experience that we had in our clinic as well as research
that had been done on sublingual immunotherapy. We did this in an effort
to provide more patients the benefit of sublingual immunotherapy by sharing our
experience with our colleagues. We also felt that with the large clinical
experience that we hadm we should set a standard of care for this form of
immunotherapy. In our clinic, we treat patients’ airborne allergies as well as
their food allergies. The first study that we’re going to look at is looking
at actual patients in our clinic that were treated for not only their airborne
allergies but also their food allergies. They were all selected because they had
very severe peanut allergy. They had a history of reactions, along with a peanut
specific IgE over 15. Actually, on average, those peanut specific IgE was 95.7. With
these criteria, the estimated risk with an accidental exposure or ingestion of
peanut would be that 95% of them would have a serious
reaction if they ate peanuts. We then send out a validated questionnaire to
these patients and there was a 60% response rate in this highly motivated
group. Despite their best efforts, 31% of them had eaten peanut
since beginning sublingual immunotherapy. In this very high-risk group, however, 73%
of them did not require emergency room evaluation, 86% of them did not need
epinephrine and there were no hospitalizations or ICU admissions. One
of them mother’s wrote that she had been going through her son’s backpack at the
end of the day and found a wrapper for a granola bar that contained peanuts.
She went running into the other room to ask him had he actually eaten the
granola bar, which he had, but he had eaten it that morning. Because he had
developed no symptoms in the intervening day, she did not feel it was necessary to
give him epinephrine or go to the emergency room. When I talk to families
in our clinic and ask them what their goals of treatment are, typically
they respond to me that the their main goal is really decreasing the risk of a
severe reaction if their child eats an allergic food. I would add that I also
think it’s important that this be done with minimal risk from the treatment
itself. In this presentation we’re going to talk about two forms of immunotherapy.
One is sublingual immunotherapy, which is typically done using a liquid extract
delivered under the tongue, or oral immunotherapy, which is done typically
using a powder and it is then swallowed. With either form of immunotherapy, you
start with a very small amount of the food or antigen
and gradually increase until you reach a maintenance dose. The main difference
between sublingual immunotherapy and oral immunotherapy is where we place the
extract is very important. The area under the tongue is an immunologically
privileged site. There are very high concentrations of dendritic cells, which
are the cells that take that up the extract and communicate with the immune
system to provide systemic protection. Because we’re putting the extract in
this unique site, we only require milligram amounts to get the effect,
where with oral immunotherapy using a powder, markedly higher doses are
required. We’re going to be looking at three randomized double-blind
placebo-controlled trials looking specifically at peanut. Randomized
double-blind placebo-controlled means that subjects in a research trial are
randomly assigned to either active or placebo treatment. It is double-blind,
meaning that the patient’s, the families, the researchers, have no idea which group
the patient is in. This is considered one of our best scientific types of research
designs to make sure that the researchers bias isn’t impacting the
results. Unfortunately, with food immunotherapy, there are no blood or skin
tests that can tell us with certainty of immunotherapy as effective, so we have to
use graded oral food challenges to determine efficacy. This is true with all
of the food immunotherapy trials. We give gradually increasing amounts until a
person has a reaction. We then refer to all of those doses
added up to be the cumulative tolerated dose.A recent study helped us get a real sense of what the thresholds are that provide a margin of safety with accidental
exposure. This first study looked at patients who had a baseline threshold
for peanut of less than 100 milligrams, or 1/3 of a peanut, with immunotherapy. If
we can achieve a threshold of 300 milligrams, the risk of reaction from
accidental exposure drops 100 fold. If 1000 milligrams, or roughly 3 peanuts,
are achieved, this drops the risk another 70 fold. Let’s look at the first
randomized double-blind placebo-controlled trial. This was a
project that was started about 15 years ago. I approached one of our
leading food allergy researchers in the country, we put our heads together,
and by using the clinical experience that we had at Allergy Associates of La
Crosse along with his research experience, we were able to develop a
protocol that has been used in all of the following sublingual immunotherapy
peanut trials. Let’s look at study 1. There were 18 children. The maintenance
dose was 2 milligrams a day and they were treated for 12 months.
Safety was very good. The main side effect was just mouth ithching that was
self-limited and resolved without treatment. After 12 months of treatment,
the placebo group could only tolerate 85 milligrams of peanut, where the active
treatment group was able to tolerate over 1,700 milligrams of peanut. This is
far above the 1,000 milligram threshold that decreases the risk of a serious
reaction with ingestion by at least 170 fold. These encouraging results prompted
the next study which is a randomized double-blind placebo controlled multicenter trial. These were selected food allergy research
groups appointed by the National Institutes of Health as being our best
research facilities for immunotherapy trials. There were 40
patients, five different sites, safety was very good. In the first group, they used a
1.3 milligram maintenance dose. Again, the main side effect was just mouth itching.
At the end of 44 weeks, the patient had gone from being able to tolerate only 3.5
milligrams of peanut, which is about 1/100 of a peanut, to at 44 weeks
achieving almost 500 milligrams, and at 68 weeks, almost a thousand milligrams.
They then also did a crossover arm where they looked at 3.7 milligrams as the maintenance dose. Safety was the same and the results were
the same. We now have results of an open trial
that was done using the same basic protocol but treated the children for
four years. There were 55 patients. They used a four milligram, once daily
maintenance dose and after 48 months they were able to tolerate 2,900
milligrams of peanut. This is in a group of children that were able to tolerate
less than 1 milligram of peanut at the start of the study. To me, this shows the
power of immunotherapy, specifically sublingual immunotherapy, that we were
able to use a dose that is roughly 1/100 of a peanut once a day and were able to
achieve a tolerance of 9 peanuts, which is certainly higher than an accidental
ingestion likely would be. Clinically we also have seen that the longer
you treat the patients, the better the results. Safety, again, in all of these
studies, has been very good. I’d now like to look at the final study which is
a sublingual immunotherapy versus oral immunotherapy randomized double-blind
placebo-controlled trial. There were 21 patients in the sublingual group of, as
always, very small amounts of antigen are required. They use 3.7 milligrams
as the maintenance dose where with the oral immunotherapy group, 2,000
milligrams was required for their maintenance dose. The safety
showed marked differences in the sublingual group. The main side effect,
still, was mouthing, but in the oral immunotherapy group, the incidence of
side effects not only of mouth itching were much higher, but even with serious side effects such as effects on breathing or such severe
gastrointestinal symptoms that patients had to withdraw because of the severity
of the symptoms. In the trial, the only epinephrine that was required were
for patients in the oral immunotherapy group. No patients in the sublingual
immunotherapy group required epinephrine for the side effects. When we look at the
success of immunotherapy, there still is no question that with oral immunotherapy
you can achieve markedly higher doses than you can can with sublingual
immunotherapy, but the safety profile is markedly better with sublingual
immunotherapy. The level that is achieved with sublingual immunotherapy
is still a clinically meaningful amount, meaning an amount that we know would
decrease the risk at least one hundredfold. I believe I have shown you
that the scientific evidence of efficacy has been showed in several national
institutes of house sponsored studies, meaning non industry studies. The
protocols that are presented in the studies are available for use by your
allergist now. All of the studies have all of the information regarding dosing,
frequency of dose increases, and maintenance doses that your allergist
can can review and find in great detail from these published studies. The peanut
extract that was used in all of the previous studies is the FDA approved
extract that we use for skin testing and is readily available to your allergist
to use in an off-label manner. Unfortunately, there are not many
allergists who offer sublingual immunotherapy for food allergies and
they’re even fewer who offer this form of treatment for patients with severe
food allergies. Through Allergychoices with our La Crosse Method Protocol, we
have shared this information with about 2,000 doctors over the last several
years. This is a protocol that not only treats for peanut allergy, but for all of
the food allergies as well as airborne allergies at the same time. If your
allergist would be interested in finding out more, please have them contact us. We
will freely share our protocol with them. So in summary, if the goals of treatment
of severe food allergies are to decrease the risk of severe reactions with an
accidental exposure, and the treatment having minimal risk from the treatment
itself, then I think sublingual immunotherapy fulfills all of these
criteria. Thank you.


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