Sublingual immunotherapy (SLIT) – indications, mechanism, and efficacy Position paper prepared by the Section of Immunotherapy, Polish Society of Allergy

Marek Jutel 1,  
Wroclaw Medical University, Wrocław, Poland
Chair of Clinical Immunology, Department of Clinical Immunology, University of Medicine, Lublin, Poland
Department of Pneumonology, Allergology and Clinical Immunology, Poznan University of Medical Sciences, Poland
Chair of Pediatrics, Department of Pediatrics, Jagiellonian University Medical College, Krakow, Poland
Department of Lung Diseases and Rheumatology, University of Medicine, Lublin, Poland
Chair and Department of Internal Medicine, Allergy, Clinical Immunology, Medical University of Silesia, Katowice, Poland
I Department of Pediatrics, Allergy and Pulmonology, Szczecin, Poland
Icahn School of Medicine at Mount Sinai Hospital, New York, US
Department of Prevention of Envinronmental Hazards and Allergology, Medical University, Warszawa, Poland
Ann Agric Environ Med 2016;23(1):44–53
UP-DATING COMMENTARY In view of the fact that the manuscript was accepted for publication in October 2013 and published in March 2016, the authors consider it necessary to add short comments and present the most important conclusions according to studies published in the interim. 1. Availability of allergen extracts: At the present time, two allergen extracts (Staloral 300 and Oralair manufactured by Stallergenes, France) for sublingual immunotherapy are unavailable in Europe. 2. SLIT to house dust mites: The III phase trial confirmed the efficacy and favourable safety profile of both 6 SQ-HDM and 12 SQ-HDM in adults with HDM-induced AR. The treatment effect was present from 14 weeks of treatment onward [Demoly P, Emminger W, Rehm D, Backer V, Tommerup L, Kleine-Tebbe J. Effective treatment of house dust mite–induced allergic rhinitis with 2 doses of the SQ HDM SLIT-tablet: Results from a randomized, double-blind, placebo-controlled phase III trial. J Allergy Clin Immunol 2016; 137: 444–51]. HDM-sensitized asthmatic children treated for at least 3 years with either SCIT or SLIT showed sustained clinical improvement. [Karakoc-Aydiner E, Eifan AO, Baris S, Gunay E, Akturk E, Akkoc T, Bahceciler NN, Barlan IB. Long-Term Effect of Sublingual and Subcutaneous Immunotherapy in Dust Mite-Allergic Children With Asthma/Rhinitis: A 3-Year Prospective Randomized Controlled Trial. J Investig Allergol Clin Immunol. 2015; 25: 334–42]. 3. SLIT in asthma: Lack of data for important outcomes, such as exacerbations and quality of life and use of different unvalidated symptom and medication scores, limits the ability to draw a clinically useful conclusion. Very few serious adverse events have been reported, but most studies have included patients with intermittent or mild asthma; therefore, comment on the safety of SLIT for those with moderate or severe asthma is impossible. SLIT is associated with increased risk of all adverse events [Normansell R, Kew KM, Bridgman AL. Sublingual immunotherapy for asthma. Cochrane Database Syst Rev. 2015 Aug 28;8:CD011293]. 4. SLIT in atopic dermatitis: The quality of the evidence was low mainly due to the differing results between studies, lack of blinding in some studies, and relatively few studies reporting participant-centred outcome measures. There is limited evidence that SIT may be an effective treatment for people with atopic eczema [Cochrane Database Syst Rev. 2016 Feb 12;2:CD008774. Specific allergen immunotherapy for the treatment of atopic eczema. Tam H 1 , Calderon MA, Manikam L, Nankervis H, García Núñez I, Williams HC, Durham S, Boyle RJ. [Epub ahead of print]. 5. SLIT in food allergy: In a long-term study, peanut SLIT induced a modest level of desensitization, decreased immunologic activity over 3 years in responders, and had an excellent long-term safety profile. However, most patients discontinued therapy by the end of year 3, and only 10.8% of subjects achieved sustained unresponsiveness. At this time, SLIT for allergy is limited by the low maximum dose of food allergen than can be delivered as drops. In the future, SLIT for food allergy may be optimized by using an alternative delivery vehicle, e.g. dissolvable tablets as well as administration in the areas of higher density of Langerhans cells, such as vestibular and buccal mucosa compared with sublingual mucosa [Burks AW, Wood RA, Jones SM, Sicherer SH, Fleischer DM, Scurlock AM, Vickery BP, Liu AH, Henning AK, Lindblad R, Dawson P, Plaut M, Sampson HA; Consortium of Food Allergy Research. Sublingual immunotherapy for peanut allergy: Long-term follow-up of a randomized multicenter trial. J Allergy Clin Immunol. 2015; 135: 1240–8.e1–3]. 6. SLIT in HIV-positive patients: Preliminary data showed that SLIT therapy in viro-immunological controlled HAART (highly active antiretroviral therapy) treated HIV positive patients was efficacious, safe and well tolerated [Iemoli E, Borgonovo L, Fusi A, Magni C, Ricci ED, Rizzardini G, Piconi S. Sublingual allergen immunotherapy in HIV-positive patients. Allergy. 2016; 71: 412–5]. 7. Quality of SLIT products: For more than half of the products, SLIT was not “high dose” as has originally beenrecommended. When reviewing the low- and high-dose products with respect to efficacy in clinical trials included in a meta-analysis on SLIT, some low-dose extracts showed efficacy [Larenas-Linnemann DE, Mösges R. Dosing of European sublingual immunotherapy maintenance solutions relative to monthly recommended dosing of subcutaneous immunotherapy. Allergy Asthma Proc. 2016; 37: 50–6.]. Substantial variations regarding allergen content were found among 5 SLIT-HDM products. Therefore, it can be necessary to guarantee the quality of the SLIT-HDM products and to demonstrate their effectiveness before they are marketed [Moreno Benítez F, Espinazo Romeu M, Letrán Camacho A, Mas S, García-Cózar FJ, Tabar AI. Variation in allergen content in sublingual allergen immunotherapy with house dust mites. Allergy. 2015; 70:1413–20]. 8. Optimal dosage: The results of a multicentre trial of sublingual liquid birch pollen preparation indicate that, within the studied dose range, SB 40 000 AUN/ml is the most optimal effective and safe dose [Pfaar O, van Twuijver E, Boot JD, Opstelten DJ, Klimek L, van Ree R, Diamant Z, Kuna P, Panzner P. A randomized DBPC trial to determine the optimal effective and safe dose of a SLIT-birch pollen extract for the treatment of allergic rhinitis: results of a phase II study. Allergy. 2016; 71:99–107]. 9. Simultaneous administration of more than one allergen extract: In a 4-week sequential SLIT-tablet dosing schedule followed by simultaneous intake of timothy grass and ragweed tablets was well tolerated [Maloney J, Berman G, Gagnon R, Bernstein DI, Nelson HS, Kleine-Tebbe J, Kaur A, Li Q, Nolte H. Sequential Treatment Initiation with Timothy Grass and Ragweed Sublingual Immunotherapy Tablets Followed by Simultaneous Treatment Is Well Tolerated. J Allergy Clin Immunol Pract. 2016 Jan 2. pii: S2213–2198(15)00647–9. Epub ahead of print]. 10. Comparability of SLIT vs SCIT: The comparisons for grass pollen immunotherapy products indicate comparable reductions in allergic rhinoconjunctivitis symptoms and supplemental medication use for SLIT tablets and SCIT in the first pollen season [Nelson H, Cartier S, Allen-Ramey F, Lawton S, Calderon MA. Network meta-analysis shows commercialized subcutaneous and sublingual grass products have comparable efficacy. J Allergy Clin Immunol Pract. 2015; 3: 256–266.e3, Larenas-Linnemann D. Patient selection for subcutaneous versus sublingual immunotherapy. Curr Opin Allergy Clin Immunol. 2015; 15: 588–95]. 11. Side effects and safety aspects: Eosinophilic esophagitis as a potential side effect due to SLIT was reported in case reports [Miehlke S, Alpan O, Schröder S, Straumann A. Induction of eosinophilic esophagitis by sublingual pollen immunotherapy. Case Rep Gastroenterol. 2013; 7: 363–8]. In-seasonal initiation or switchover of immunotherapy with tablet sublingual immunotherapy could potentially induce serious adverse reactions, including anaphylaxis [Hsiao KC, Smart J. Anaphylaxis caused by in-season switchover of sublingual immunotherapy formulation. Pediatr Allergy Immunol. 2014; 25: 714–5]. 12. A new position paper on sublingual immunotherapy was published [Canonica GW 1 , Cox L, Pawankar R, Baena-Cagnani CE, Blaiss M, Bonini S, Bousquet J, Calderón M, Compalati E, Durham SR, van Wijk RG, Larenas-Linnemann D, Nelson H, Passalacqua G, Pfaar O, Rosário N, Ryan D, Rosenwasser L, Schmid-Grendelmeier P, Senna G, Valovirta E, Van Bever H, Vichyanond P, Wahn U, Yusuf O. Sublingual immunotherapy: World Allergy Organization position paper 2013 update. World Allergy Organ J. 2014; 7: 6].
SLIT (sublingual immunotherapy) induces allergen-specific immune tolerance by sublingual administration of a gradually increasing dose of an allergen. The mechanism of SLIT is comparable to those during SCIT (subcutaneous immunotherapy), with the exception of local oral dendritic cells, pre-programmed to elicit tolerance. In the SLIT dose, to achieve the same efficacy as in SCIT, it should be 50–100 times higher with better safety profile. The highest quality evidence supporting the efficacy of SLIT lasting 1 – 3 years has been provided by the large scale double-blind, placebo-controlled (DBPC) trials for grass pollen extracts, both in children and adults with allergic rhinitis. Current indications for SLIT are allergic rhinitis (and conjunctivitis) in both children and adults sensitized to pollen allergens (trees, grass, Parietaria), house dust mites (Dermatophagoides pteronyssinus, Dermatophagoides farinae), cat fur, as well as mild to moderate controlled atopic asthma in children sensitized to house dust mites. There are positive findings for both asthma and new sensitization prevention. Severe adverse events, including anaphylaxis, are very rare, and no fatalities have been reported. Local adverse reactions develop in up to 70 – 80% of patients. Risk factors for SLIT adverse events have not been clearly identified. Risk factors of non-adherence to treatment might be dependent on the patient, disease treatment, physician-patient relationship, and variables in the health care system organization.
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