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Current Standards of Care & Advances in Immunotherapy

A Roundtable Discussion:

Sublingual Immunotherapy (SLIT)

Listen to the Podcast


Oral vs. sublingual

Dr. Nelson:  Oral and sublingual therapies are often mentioned together, and they shouldn’t be.  Oral was tried for inhalant allergy back 25 or 30 years ago and was found not be effective.  The major problem is the variable delivery of the antigen through the digestive processes in the stomach so you don’t get consistent dosing. The doses also were associated with a very high occurrence of gastrointestinal side effects as well as intermittent systemic reactions.  So that has been abandoned and what’s being done in Europe is strictly sublingual where the dose is much smaller, there’s no digestive process to overcome and gastrointestinal side effects are minimal.

Status in the United States

Dr. Bernstein:  Although there is as yet no FDA approval for sublingual, there are sublingual tablet products for grass allergen currently in development in the United States.  At this meeting [of the College] Dr. Nelson will be reporting the results of a seasonal grass allergy study14 in adults. There’s also one completed in pediatric patients15 showing that this timothy grass tablet given pre-seasonally for 16 weeks and then co-seasonally was effective in reducing seasonal nasal and eye symptoms as well as reducing medication requirements in treated patients versus placebo.

Dr. Nelson:  Right now in the United States, development is limited to those allergens for which there’s a standardized preparation – ragweed, cat and house dust mites in addition to grass.

SLIT versus SCIT

Dr. Lanier:  Subcutaneous immunotherapy has always had the potential for long-term remission, not necessarily just symptom control.  The sublingual studies right now aren’t very old.  Do we know at this point if we actually induce a long-term remission with SLIT?  If you now have medications that may cost a penny a day, it’s difficult to compare that to something that may be vastly more expensive if there’s not a differentiation between symptom control and remission.

Dr. Blaiss:  There are data, at least with the timothy grass allergen immunotherapy tablet, showing that after three years of treatment there’s a disease modifying effect for at least two years after treatment is stopped.  There’s a report16 out of the United Kingdom looking at the cost-effectiveness of this particular tablet that showed it was cost-effective over time and saved money for the UK health care system.

Dr. Nelson:  Dr. Canonica from Italy shared with us a study17 which is in press but not yet published.  It’s a 10-year study of sublingual immunotherapy looking at treatments for three, four or five years and the duration of remission after that.  It appears that with four years of treatment you get the optimal result, which was a continuing remission for the group as a whole for about four years or so after treatment was discontinued.  The interesting thing is, when there was a recurrence of symptoms, they got a much more rapid response when they reinstituted sublingual immunotherapy than they got initially.  It required just a small booster series of treatments to get patients back under control.

Dr. Finegold:  Looking at the data for SLIT versus SCIT, I have to come away impressed that almost everything that SCIT does, SLIT is doing.  In some cases the SLIT studies are done even better than what was done originally with SCIT because times are different now.  However, a potential obstacle with SLIT in the United States is that we don’t have a CPT code.  If the tablet is considered a drug and not a medical procedure, we may not need a code.

Dr. Cox:  From the collective literature it appears that sublingual immunotherapy has a similar persistent long-lasting effect such as we have seen with subcutaneous immunotherapy.  We don’t have a huge database of long-term efficacy studies to rely on for either therapy approach, but it appears to be similar.

Adverse events with SLIT

Dr. Finegold:  There’s some caution to be exercised with sublingual.  Even though there are absolutely no fatalities, there are a lot of people who have problems with itching in the mouth, angioedema and one interesting case study of a patient who had an ulcer on the bottom of her tongue that looked pretty severe.  It was from keeping the tablet there too long, apparently. 

Dr. Bernstein:  I think there have been about six cases of anaphylaxis reported.

Dr. Cox:  The problem with anaphylaxis and case reports is how you define anaphylaxis, but there have been six studies published with anaphylaxis in the title.  There also have been two case reports in a letter to the editor in JACI, of reaction that appeared to meet the definition of anaphyalaxis, although they were not defined as such. These were patients who had systemic reactions to subcutaneous immunotherapy that prompted discontinuation of treatment.  They were placed on sublingual solution and both had systemic reactions, at least one of which would meet the definition of anaphylaxis, and had to discontinue.  And there also have been two case reports of patients who had to discontinue subcutaneous immunotherapy and had systemic reactions to first grass tablet dose. 

Dr. Bernstein: The data presented at this meeting from a really well-powered large study14 of the timothy grass tablet reported only one mild systemic reaction in over 400 people.  Also, the study did not exclude asthmatics and they found no severe asthmatic responses.  Another interesting finding was that asthma symptom scores did seem to be significantly reduced to some extent.

Dr. Blaiss:  We also saw the safety in the pediatric data15 with the grass allergen immunotherapy tablet.  No severe anaphylactic reactions occurred.  Most of the reactions were local and they appeared to be in the first few days of treatment.

Special patient populations and SLIT

Dr. Finegold:  We need to introduce the idea of the polysensitized patient since that is what we usually treat in the United States.  The question is, how applicable will a single grass tablet be for these patients?

Dr. Cox:  Studies do suggest that polysensitized patients will respond to monotherapy. In the U.S. studies14,15 presented at this meeting, most of the patients were polysensitized.  And the same was shown in the European studies18, as well.

Patient compliance

Dr. Wallace:  I think compliance is another issue we need to bring up in comparing the two types of treatments because the dosing interval is very different.  The dosing interval for subcutaneous eventually will become four weeks for one treatment while with SLIT it’s much more frequent, usually daily.  One has to question if patients will be compliant.

Dr. Nelson:  When the patient comes in for injection you can monitor compliance. If patients fail to come in you can call and remind them or do something to stimulate compliance.  On the other hand, you don’t know about compliance with sublingual. A recent study19 from Italy using manufacturers’ data on refills showed that it fell precipitously over the course of a year down to about 15 percent.  Dr. Pajno did another Italian study20, a prospective, where they brought people in once, twice or three or four times a year.  It had a huge impact on adherence.  Far and away the people who were brought back for a return visit every three months were most adherent.

Dosing schedule

Dr. Bernstein:  One of the other disadvantages of this, at least looking at some of the studies, is patients took the tablets every day on a year-round basis. I think it would be much more acceptable to the patients if they could dose this pre-seasonally, even on a consecutive year basis.  I’m not aware of much data looking at this.

Dr. Cox:  There is a U.S. company that has a grass tablet looking at dosing two months versus four months before season. 

Dr. Nelson:  There is a fairly large study21 by a European investigator named Ott with well over 200 subjects and its very interesting because it’s a four-year study:  three years of treatment and one year of follow up.  They instituted therapy with a one-day buildup on the first day of the grass pollen season, treated only through the season for an average of about 87 days per year for three years, stopped and followed up for a year afterward.  The data look just as good as the data with daily grass tablets for three years.

Dr. Cox:  Did they get treatment effect in the first year? 

Dr. Nelson:  They showed significant improvement the first year even though treatment was initiated the first day of the grass pollen season.  They showed better results the second and even better in the third season, which was very encouraging. 

Dose response

Dr. Wallace:  We’ve known for years that using extremely low dose sublingual immunotherapy is not effective.  We know that we have to use a much higher dose with sublingual than we do with subcutaneous to achieve results.  But do we know the absolute lowest level that is effective? Because the studies with SLIT are very wide ranging and I’d like to hear some comments from the group on that.

Dr. Nelson:  The review22 that Linda headed on the studies of sublingual immunotherapy up to 2005, showed a remarkable result in that there was the same likelihood of a successful study when they administered about the same amount of allergen as you would give by injection or when they administered 500 times that amount.  So very clearly there are studies in the literature which report very favorable outcomes with doses down to the cumulative dose that you give by injection.  There is a suggestion, however, that as you get into the low dose range the evidence of efficacy may not appear until the second year of treatment.  It may be that you have to go to a higher dose to get a fairly rapid response.  If you can wait two years to get better, you may be able to use lower doses.  Not the homeopathic doses that have been used in the past in the United States, but doses that are about equal to that given by injection.

Dr. Bernstein:  What’s nice about the tablet studies being done now is they usually start with Phase I studies in allergic patients.  They look for what the best dose is, at least in terms of safety, and then also look at efficacy as they go into Phase II studies.  So there’s some very nice dose response data that you can look at and really pinpoint what dose is safest and also efficacious.

SLIT and asthma prevention

Dr. Nelson:  The Italian investigator, Novembre,23 took a group of children allergic to grass and followed them for three years in one untreated group and one treated group.  The outcome was to determine the development of asthma in children who previously had only rhinitis.  In the first year there was no difference, but in the second and third year there were virtually no additional cases of asthma in the actively treated group.  There was continual recurrence of new asthma cases in the untreated group, so it was quite significant by the end of three years.

Dr. Bernstein:   Did they see prevention of new sensitizations?

Dr. Nelson:  No, but prevention of new sensitivities has been shown in a number of other studies4,5 in monosensitized patients. 

Unmet needs and SLIT

Dr. Blaiss:  One of the major advantages in the pediatric population is, obviously, SLIT is not an injection.  One of the biggest problems I have in my patient population is the parents may want the injections but the child puts up a fight.  This gives us another option that can be very beneficial for that child.

Dr. Cox:  When you look at the general population of allergic patients – pediatrics and adults – we’re only treating 2 to 6 percent with immunotherapy, which is the only disease-modifying treatment that can lead to lasting clinical benefit after discontinuation.  I think one of the reasons is that in most of our patients’ over-scheduled lives it’s very inconvenient to come into an office on a regular basis over a period of time.  I think we can expand that 2 to 6 percent to a larger percentage of patients that might benefit from this treatment. Practically speaking, most of the patients that we would consider for this new therapy are those who have seasonal allergic rhinitis and maybe one or two bad seasons.  Usually that’s not the person who wants to be on subcutaneous immunotherapy, which is a commitment to year-round therapy. So I think sublingual will take up that niche because those patients currently are not being treated with immunotherapy.

Needed research/unanswered questions

Dr. Nelson:  All but one of the controlled studies that have been done with SLIT are single antigen studies.  The one exception involved grass and birch, but it was not placebo-controlled.  So I think we can say that there is no good evidence yet that you can administer multiple allergen mixes sublingually and get the same efficacy that you can when you administer a single agent.  And that’s very critical because there isn’t a large American population that needs treatment with just a single allergen extract.  Multiple sensitivities is the rule. 

Dr. Wallace:  In reviewing the literature, most of the studies on SCIT multiple allergen therapy go back more than 20 years, and they were not large studies.  So, we’re basing the evidence of improvement on our clinical experience much more than on research studies, even in SCIT.  Idealistically we’d have some long-term studies of multiple allergens in both forms of therapy as a fair comparison.

Dr. Finegold:  As SLIT emerges and, hopefully, becomes available in the United States, it’s important to remember that we are still giving patients something they are allergic to, so this should not be something that is over-the-counter or easily accessible to patients.  Allergists are the people who should be prescribing the drug and monitoring these patients.

Dr. Cox:  To add to that, there are some factors that might increase the patient’s risk for an adverse reaction that I don’t quite understand.  In the European guidelines24 it advises against giving SLIT to patients who have mouth ulcers or some dental inflammation, gastroenteritis or increased asthma symptoms.  We need more information about what guidelines to give patients.  For example, how long can they go between treatments without you having to do something or having them contact you?

Dr. Bernstein:  Studies also are needed to look at the safety and efficacy of SLIT in the treatment of asthmatic patients.  We know from our experience with SCIT that severe uncontrolled asthmatics are at high risk for systemic reactions.   I’m not sure we know it is entirely safe to treat similar patients with sublingual.  So certainly we need those types of studies.  An ideal study would probably look at the efficacy of SLIT in preventing cat-induced asthma, which is a big problem in treating allergic asthmatic patients.  Also we need to monitor safety.  We need long-term surveillance studies to monitor systemic reactions that may occur as we expand the populations of patients receiving this therapy.

Dr. Blaiss:  Another concern is whether SLIT patients should be prescribed an auto injector of epinephrine.  It’s not done in Europe, but should it be done in the United States if SLIT is approved?

Dr. Nelson:  The critical study would be a good head-to-head efficacy comparison between SCIT and SLIT.  Clearly, what would continue SCIT as a very viable part of the allergy practice would be if it could be shown to be more rapidly effective and more effective than SLIT.  Then you could select those patients who were willing to undergo the inconvenience of SCIT in return for more rapid or more complete relief of symptoms. But that really needs to be demonstrated.


Other Topics:  

Perspectives Article published in the November 2011 issue of Annals of Allergy, Asthma and Immunology.


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