Harold Nelson discussed New Approaches to Immunotherapy (IT) during the 2012 meeting of the Canadian Society of Allergy and Clinical Immunology (CSACI):
Subcutaneous Immunotherapy (SCIT)
IT is the only disease-modifying therapy for allergic conditions, and it is still under-used. Significant proportion of patients who would benefit from disease modifying therapy such as immunotherapy do not receive it.
Suboptimal extracts, safety concerns, and inconvenience all barriers to more appropriate IT use.
There is a 90% reduction in systemic reactions with alum-precipitated vs. aqueous grass extracts. New alum-precipitated extracts if introduced in the U.S. would have to receive all new approval. This is likely to be cost prohibitive.
Omalizumab reduces rates of systemic reactions in the setting of rush or cluster IT schedule. However, it must be given for 3 months prior to IT. Omalizumab is expensive and cost is an an issue.
Sublingual Immunotherapy (SLIT)
SLIT appears to be effective and disease-modifying, but there are some important unanswered questions. There are many unanswered SLIT questions - optimal doses for allergens other than grass; relative efficacy compared with SCIT; use of mixes of allergens.
Duration of SLIT
The optimal duration of sublingual immunotherapy (SLIT) is 3-4 years - similar to subcutaneous (SCIT).
A period of 3 yrs of HDM SLIT is effective for 7 yrs. The benefits adds to only 1 additional year if the duration is 4 or 5 yrs of therapy. There is a clear decrease in new sensitizations compared to untreated controls (similar for 3,4 and 5 yrs of SLIT).
There is a clear reduction (open study) in persistent asthma with 3 yrs of SLIT (there was little change in intermittent asthma). SLIT is beneficial for asthma control (Marogna Annals of Allergy 2008; 101: 206).
SLIT requires 5 yrs of treatment (similar to SCIT). SLIT is shown to reduce new sensitization in the monosensitized patient; and it can be given at home. A 15-year prospective study of SLIT showed that if treated for 3 years, patients relapse at 7 years post-treatment (Marogana et al JACI 2010; 126: 969-75). 4 years of SLITis better than 3 years for persistent benefits after discontinuation of therapy.
SLIT for birch in monosensitized patients showed benefits that were clearer with 2 to 3 yrs of therapy; 1 yr was not enough (Marogna et al JACI 2005; 115: 1184-8).
Local side effects are very common with ALK tablet grass IT. However, systemic reactions are rare.
In the U.S., the first dose of grass tablet IT will be given in an MD office, and an epinephrine autoinjector must be prescribed.
70% of adults and 62% of children receiving oral grass tablet immunotherapy have oral side effects. They are mostly gone in 1 hour though. 50% of patients or more will experience mouth itching or throat irritation upon initiation of SLIT - it usually lasts less than 60 minutes.
SLIT-related mouth edema occurs in 10%, and it persists on average for 30 days following initiation of SLIT.
Anaphylactic reactions to SLIT are exceedingly rare and will usually get published because of their rarity. No deaths have been reported. Anaphylaxis can occur, generally early - most often with the 1st dose; therefore administer 1st SLIT dose in MD office.
Dr. Nelson assumes the U.S. patients receiving SLIT will go home with an adrenaline autoinjector. The 1st dose will definitely be given in MD office.
Doses of SLIT and SCIT
Dr. Nelson discussed optimal dosing of SLIT. Higher doses provide earlier relief but lesser doses may eventually be effective.
The optimal SLIT dosing is unclear for most allergens, it depends on protein size and other variables. The dose-response with SLIT is unclear, even with 1-50 x SCIT cumulative dosing, there are similar efficacy outcomes.
Comparison of SLIT vs SCIT in HDM-allergic kids (a study from Turkey, 2012): SCIT was better for rhinitis and asthma symptoms and medication use. SCIT appears to be better than SLIT - it might be related to a dosing issue (Yukselen et al. Int Arch Allergy Immunol 2012; 157: 288-298). SLIT and SCIT are both better than placebo; SCIT better than SLIT but not statistically significant (Khinchi et al. Allergy 2004; 59: 45-53).
The average SCIT contains of 8-10 unrelated allergens in the U.S. SCIT prescriptions. SCIT is more effective than SLIT at least in the first year of therapy.
Harold Nelson has studied mulitple allergen administration via SLIT - he compared grass vs. grass plus up to 9 other allergens. His study suggests that timothy grass monotherapy SLIT is more effective than multiple allergens. Adding more allergens diluted grass-specific benefits. There is a tendency towards ineffectiveness with multiple allergens in SLIT (Amar, JACI 2009).
Many prescribers are using off-label SLIT formulations with multiple allergens in drops. There are no studies of efficacy to support this practice.
There is a high (40-50%) discontinuation rate in children 4 and under, it is better tolerated in 5-6 year olds.
Pre- and co-seasonal SLIT may work as well as perennial therapy for pollens.
Grass SLIT tablets are more effective than drops, there is probably a greater protein gradient across the non-absorptive sublingual mucous membrane. This gradient issue may impact effectiveness of multi-allergen mixes for SLIT.
Oralair grass tablet 100 IR is not effective; 300 IR and 500 IR are equally effective at reducing rhinitis symptoms during grass season.
New IT forms
Grass transcutaneous IT patch was found to be safe and effective in in small Italian study. Agostinis article in the journal Allergy showed success with transdermal grass patch IT and it was safe. There were only 15 patients though. A Swiss study (Senti JACI 2011) used patches but also abraded the skin. It was also successful but increased adverse reactions.
Dr. Nelson reviewed the open access PNAS study of low-dose intralymphatic study by Senti from 2008 using 3 ultrasound-guided lymph node injections. Intralymphatic IT (3 inguinal injections) had comparable outcomes to SCIT (but it was faster, with much lower doses).
Birch rBet v 1 extracts are very effective compared to natural or purified extracts.
Cat peptide IT had decreased allergenicity but optimized immunogenicity. A Canadian cat peptide study used 4 or 8 injections followed by cat exposure. It was successful and now they are conducting a phase III study.
Immunostimulatory sequences CpG-ragweed therapy for 6 injections was comparable to traditional SCIT.
Bacteriophage-coated CpG treatment alone (with no allergen) for HDM allergy improved symptoms and medication use, but patients had flu-like adverse events.
The future approaches to immunotherapy will be limited to extracts that are standardized to begin with (G/R/DM and Cat).
Twitter summary made possible by @allergydoc4kidz @DrAnneEllis @IgECPD4
Three allergists did a great job posting updates from the 2012 meeting of the Canadian Society of Allergy and Clinical Immunology (#CSACI): @allergydoc4kidz @DrAnneEllis @IgECPD4. Compared to year 2011, this represents 300% growth in Twitter use by the Canadian allergists. The AAAAI has a larger audience and not surprisingly 30 allergists posted Twitter updates from the 2012 #AAAAI meeting. I used the website “All My Tweets” to review the updated from each allergist, for example: http://www.allmytweets.net/#@IgECPD4
For comparison, here are the tweets from the 2011 and 2012 #CSACI meetings: http://allergynotes.blogspot.com/search/label/CSACI
Comments from Twitter:
@IgECPD4: Newest Twitter Summary by @DrVes from #CSACI Meeting. Today's Topic: Newer forms of Allergen Immunotherapy
Lisa Phelps @Lisa_tweeting: Check out this twitter summary on #immunotherapy from #CSACI http://bit.ly/ULXM6z . Great stuff @allergydoc4kidz @DrAnneEllis @IgECPD4
UkAllergy.com @Allergy_London: ukallergy.com recommends! Check out this twitter summary by @DrVes on #immunotherapy from #CSACI bit.ly/ULXM6z