The Future of Sublingual Immunotherapy in the United States

  • Nicole Pleskovic
  • Ashton Bartholow
  • Deborah A. Gentile
  • David P. SkonerEmail author
Rhinitis (JJ Oppenheimer and J Corren, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Rhinitis


Sublingual immunotherapy (SLIT) is a safe and effective treatment for allergic rhinitis (AR) and allergic rhinoconjunctivitis (ARC). The Food and Drug Administration (FDA) in the USA has approved three SLIT tablets for the treatment of AR and ARC in relation to pollen. Specifically, Grastek® and Oralair® are two formulations approved to treat patients suffering with AR/ARC to grass pollen, and Ragwitek™ is a formulation approved to treat patients suffering with AR/ARC to ragweed pollen. Although these approvals provide support for physicians to prescribe SLIT, barriers to prescribing SLIT still remain such as FDA approval for additional formulations, a standard dose and dosing schedule, and cost/insurance coverage. In order to further support the use of SLIT, research is currently being conducted to expand the indication for SLIT to other common comorbidities to AR/ARC. For example, allergic asthma, food allergies, and atopic dermatitis are other diseases which are being explored. The future of SLIT in the USA is unknown; however, education will be necessary for both providers and patients.


Sublingual immunotherapy Allergic rhinitis Allergic rhinoconjunctivitis Allergen immunotherapy 


Compliance with Ethics Guidelines

Conflict of Interest

Nicole Pleskovic and Ashton Bartholow declare that they have no competing interests. Deborah A. Gentile reports that she was a speaker for Merck & Co. and Greer. David P. Skoner reports grants from Greer Laboratories, Novartis, Merck & Co., Genentech, GlaxoSmithKline, Sunovion, and Teva, and was a speaker or consultant for Merck & Co., Sunovion, Mylan, Teva, GlaxoSmithKline, Genentech, Novartis, and Sunovion.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Gentile D, Bartholow A, Valovirta E, Scadding G, Skoner D. Current and future directions in pediatric allergic rhinitis. J Allergy Clin Immunol Pract. 2014;1:214–26.CrossRefGoogle Scholar
  2. 2.
    Tran NP, Vickery J, Blaiss MS. Management of rhinitis: allergic and non-allergic. Allergy Asthma Immunol Res. 2011;3:148–56.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Lin SY. Sublingual immunotherapy: current concepts for the U.S. practitioner. Int Forum Allergy Rhinol. 2014;4:S55–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Brehler R, Klimek L, Kopp MV, Christian Virchow J. Specific immunotherapy-indications and mode of action. Dtsch Arztebl Int. 2013;110:148–58.PubMedCentralPubMedGoogle Scholar
  5. 5.
    Linkov G, Toskala E. Sublingual immunotherapy: what we can learn from the European experience. Curr Opin Otolaryngol Head Neck Surg. 2014;22:208–10.PubMedCrossRefGoogle Scholar
  6. 6.
    Canonica GW, Bousquet J, Casale T, et al. Sub-lingual immunotherapy world allergy organization position paper. WAO J. 2009;2:233–81.Google Scholar
  7. 7.•
    Kim JM, Lin SY, Suarez-Cuervo C, et al. Allergen-specific immunotherapy for pediatric asthma and rhinoconjunctivitis: a systematic review. Pediatrics. 2013;131:1155–67. The authors performed a meta-analysis to study SLIT and the therapy’s effectiveness and safety in asthmatics, rhinitis, conjunctivitis, and children.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Nelson HS. Subcutaneous immunotherapy versus sublingual immunotherapy: which is more effective? J Allergy Clin Immunol Pract. 2014;2:144–9.PubMedCrossRefGoogle Scholar
  9. 9.•
    Didier A, Wahn U, Horak F, Cox LS. Five-grass-pollen sublingual immunotherapy tablet for the treatment of grass-pollen-induced allergic rhinoconjunctivitis: 5 years of experience. Expert Rev Clin Immunol. 2014;10:1309–24. This article summarizes all key parts of grass pollen SLIT including the formulations Oralair® and Grazax™/Grastek® from their efficacy, safety, research trials, and cost-effectiveness.PubMedCrossRefGoogle Scholar
  10. 10.••
    Creticos PS, Corren J, Feldweg AM. Sublingual immunotherapy for allergic rhinoconjunctivitis and asthma. UpToDate. 2014. This article evaluates SLIT completely—from the background to different formulations. It is an all-encompassing article highlighting delivery formulations, doses, and concomitant diseases. The article also goes into detail regarding the FDA-approved SLIT formulations.Google Scholar
  11. 11.
    Tucker MH, Tankersley MS. Perception and practice of sublingual immunotherapy among practicing allergists. Ann Allergy Asthma Immunol. 2008;101:419–25.PubMedCrossRefGoogle Scholar
  12. 12.
    Sikora JM, Tankersley MS. Perception and practice of sublingual immunotherapy among practicing allergists in the United States: a follow-up survey. Ann Allergy Asthma Immunol. 2013;110:194–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Ryan MW, Marple BF, Leatherman B, et al. Current practice trends in allergy: results of a United States survey of otolaryngologists, allergist-immunologists, and primary care physicians. Int Forum Allergy Rhinol. 2014;4:789–95.PubMedCrossRefGoogle Scholar
  14. 14.••
    Leatherman B, Skoner DP, Hadley JA, et al. The Allergies, Immunotherapy, and RhinoconjunctivitiS (AIRS) survey: provider practices and beliefs about allergen immunotherapy. Int Forum Allergy Rhinol. 2014;4:779–88. The AIRS surveys collected important knowledge of both providers and patients about AR/ARC and immunotherapy. The article highlights the view of providers on allergen immunotherapy.PubMedCrossRefGoogle Scholar
  15. 15.
    Elenburg S, Blaiss MS. Current status sublingual immunotherapy in the United States. World Allergy Organ J. 2014;7:24.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Durham SR, Nelson HS, Nolte H, et al. Magnitude of efficacy measurements in grass allergy immunotherapy trials is highly dependent on pollen exposure. Allergy. 2014;69:617–23.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Nelson HS. Sublingual immunotherapy: the U.S. experience. Curr Opin Allergy Clin Immunol. 2013;13:663–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Bartholow A, Pleskovic N, Drori J, Skoner DP. Review of the use of sublingual allergen immunotherapy in children. Pediatr Allergy Immunol Pulmonol. 2014;27:3–7.CrossRefGoogle Scholar
  19. 19.
    Cox L. Sublingual immunotherapy for aeroallergens: status in the United States. Allergy Asthma Proc. 2014;35:34–42.PubMedCrossRefGoogle Scholar
  20. 20.
    Nelson HS. Is sublingual immunotherapy ready for use in the United States? JAMA. 2013;309:1297–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Larenas-Linnemann D, Esch R, Plunkett G, et al. Maintenance dosing for sublingual immunotherapy by prominent European allergen manufacturers expressed in bioequivalent allergy units. Ann Allergy Asthma Immunol. 2011;107:448–58.PubMedCrossRefGoogle Scholar
  22. 22.
    Bousquet J, Khaltaev N, Cruz AA, Denburg J, et al. Allergic rhinitis and its impact on Asthma (ARIA) 2008 update. Eur J Allergy Clin Immunol. 2008;63:Supplement 86, 8–160.Google Scholar
  23. 23.
    Compalati E, Braido F, Canonica GW. Sublingual immunotherapy: recent advances. Allergol Int. 2013;62:415–23.PubMedCrossRefGoogle Scholar
  24. 24.
    Aboshady OA, Elghanam KM. Sublingual immunotherapy in allergic rhinitis: efficacy, safety, adherence, and guidelines. Clin Exp Otorhinolaryngol. 2014;7:241–9.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Di Bona D, Plaia A, Scafidi V, Leto-Barone MS, Di Lorenzo G. Efficacy of sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: a systematic review and meta-analysis. J Allergy Clin Immunol. 2010;126:558–66.PubMedCrossRefGoogle Scholar
  26. 26.
    Corp MS& D. Biologic License Application (BLA) for Timothy grass pollen allergen extract tablet for sublingual use. FDA Brief Doc. 2013.Google Scholar
  27. 27.
    Nakonechna A, Hills J, Moor J, Dore P, Abuzakouk M. Grazax sublingual immunotherapy in pre–co-seasonal and continuous treatment regimens: is there a difference in clinical efficacy? Ann Allergy Asthma Immunol. 2015;114:63–76.CrossRefGoogle Scholar
  28. 28.
    Passalacqua G, Garelli V, Sclifo F, Canonica GW. Sublingual immunotherapy for allergic rhinitis and conjunctivitis. Immunotherapy. 2013;5:257–64.PubMedCrossRefGoogle Scholar
  29. 29.
    Canonica GW, Cox L, Pawankar R, et al. Sublingual immunotherapy: World Allergy Organization position paper 2013 update. World Allergy Organ J. 2014;7:6.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Meltzer EO, Bukstein DA. The economic impact of allergic rhinitis and current guidelines for treatment. Ann Allergy Asthma Immunol. 2011;106:S12–6.PubMedCrossRefGoogle Scholar
  31. 31.•
    Dranitsaris G, Ellis AK. Sublingual or subcutaneous immunotherapy for seasonal allergic rhinitis: an indirect analysis of efficacy, safety, and cost. J Eval Clin Pract. 2014;20:225–38. This is a valuable meta-analysis performed on Oralair®, Grazax™, and SCIT. It examines and compares the efficacy, safety, and cost of the three medications.PubMedCrossRefGoogle Scholar
  32. 32.
    Incorvaia C, DiRienzo A, Celani C, Makri E, Frati F. Treating allergic rhinitis by sublingual immunotherapy: a review. Ann Ist Super Sanita. 2012;48:172–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Hankin CS, Cox L, Bronstone A, Wang Z. Allergy immunotherapy: reduced health care costs in adults and children with allergic rhinitis. J Allergy Clin Immunol. 2013;131:1084–91.PubMedCrossRefGoogle Scholar
  34. 34.•
    Hankin CS, Cox L. Allergy immunotherapy: what is the evidence for cost saving? Curr Opin Allergy Clin Immunol. 2014;14:363–70. This article consisted of a cost-analysis of SLIT, tablets and drops, SCIT, and symptomatic drug treatment.PubMedCrossRefGoogle Scholar
  35. 35.
    Bender BG, Oppenheimer J. The special challenge of nonadherence with sublingual immunotherapy. J Allergy Clin Immunol Pract. 2014;2:152–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Anolik R, Schwartz AM, Sajjan S, Allen-Ramey F. Patient initiation and persistence with allergen immunotherapy. Ann Allergy Asthma Immunol. 2014;113:101–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Maloney J, Durham S, Skoner D, et al. Safety of sublingual immunotherapy Timothy grass tablet in subjects with allergic rhinitis with or without conjunctivitis and history of asthma. Allergy. 2015;70:302–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med. 2010;181:116–24.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Lin SY, Erekosima N, Kim JM, et al. Sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: a systematic review. JAMA. 2013;309:1278–88.PubMedCrossRefGoogle Scholar
  40. 40.
    Nowak-Wgrzyn A, Sampson HA. Future therapies for food allergies. J Allergy Clin Immunol. 2011;127:558–73.CrossRefGoogle Scholar
  41. 41.
    Boyce JA, Assa’ad A, Burks AW, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol. 2010;126:S1–S58.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Kim EH, Bird JA, Kulis M, et al. Sublingual immunotherapy for peanut allergy: clinical and immunologic evidence of desensitization. J Allergy Clin Immunol. 2011;127:640–646.e1.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Fleischer DM, Burks AW, Vickery BP, et al. Sublingual immunotherapy for peanut allergy: a randomized, double-blind, placebo-controlled multicenter trial. J Allergy Clin Immunol. 2013;131:119–127.e1-e7.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Enrique E, Pineda F, Malek T, et al. Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J Allergy Clin Immunol. 2005;116:1073–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Narisety SD, Frischmeyer-guerrerio PA, Keet CA, et al. A randomized, double-blind, placebo-controlled pilot study of sublingual versus oral immunotherapy for the treatment of peanut allergy. J Allergy Clin Immunol. 2015;135:1275–82.Google Scholar
  46. 46.
    Burks AW, Wood RA, Jones SM, et al. Sublingual immunotherapy for peanut allergy: long-term follow-up of a randomized multicenter trial. J Allergy Clin Immunol. 2015;1–12.Google Scholar
  47. 47.
    Leung DYM, Boguniewicz M, Howell MD, Nomura I, Hamid QA. New insights into atopic dermatitis. J Clin Invest. 2004;113:651–7.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Qin YE, Mao JR, Sang YC, Li WX. Clinical efficacy and compliance of sublingual immunotherapy with Dermatophagoides farinae drops in patients with atopic dermatitis. Int J Dermatol. 2014;53:650–5.PubMedCrossRefGoogle Scholar
  49. 49.
    Sánchez-Borges M, Asero R, Ansotegui IJ, et al. Diagnosis and treatment of urticaria and angioedema: a worldwide perspective. World Allergy Organ J. 2012;5:125–47.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.•
    Nettis E, Colanardi MC, Soccio AL, et al. Double-blind, placebo-controlled study of sublingual immunotherapy in patients with latex-induced urticaria: a 12-month study. Br J Dermatol. 2007;156:674–81. This study showed the effects or house dust mite SLIT in adults with allergic rhinitis. The 300IR and 500IR levels show a significant improvement in symptoms after 1 year of treatment, and this effectiveness was maintained in the second year without the therapy.PubMedCrossRefGoogle Scholar
  51. 51.
    Bergmann K-C, Demoly P, Worm M, Fokkens W, Carrillo T. Efficacy and safety of sublingual tablets of house dust mite allergen extracts in adults with allergic rhinitis. Am Acad Allergy Asthma Immunol. 2013;133:1608–14.Google Scholar
  52. 52.
    Cingi C, Bayar Muluk N, Ulusoy S, et al. Efficacy of sublingual immunotherapy for house dust mite allergic rhinitis. Eur Arch Oto-Rhino-Laryngology. 2014.Google Scholar
  53. 53.
    Trebuchon F, Lheritier-Barrand M, David M, Demoly P. Characteristics and management of sublingual allergen immunotherapy in children with allergic rhinitis and asthma induced by house dust mite allergens. Clin Transl Allergy. 2014;4:15.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Aydogan M, Eifan AO, Keles S, et al. Sublingual immunotherapy in children with allergic rhinoconjunctivitis mono-sensitized to house-dust-mites: a double-blind-placebo-controlled randomised trial. Respir Med. 2013;107:1322–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Yukselen A, Kendirli SG, Yilmaz M, Altintas DU, Karakoc GB. Two year follow-up of clinical and inflammation parameters in children monosensitized to mites undergoing subcutaneous and sublingual immunotherapy. Asian Pac J Allergy Immunol. 2013;31:233–41.PubMedCrossRefGoogle Scholar
  56. 56.
    Nelson HS. Update on house dust mite immunotherapy: are more studies needed? Curr Opin Allergy Clin Immunol. 2014;14:542–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Calderon MA, Casale TB, Nelson HS, Demoly P. An evidence-based analysis of house dust mite allergen immunotherapy: a call for more rigorous clinical studies. Am Acad Allergy Asthma Immunol. 2013;132:1322–36.Google Scholar
  58. 58.
    Casale TB, Stokes JR. Future forms of immunotherapy. J Allergy Clin Immunol. 2011;127:8–15.PubMedCrossRefGoogle Scholar
  59. 59.
    Swamy RS, Reshamwala N, Hunter T, et al. Epigenetic modifications and improved regulatory T-cell function in subjects undergoing dual sublingual immunotherapy. J Allergy Clin Immunol. 2012;130:215–224.e7.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Amar SM, Harbeck RJ, Sills M, Silveira LJ, O’Brien H, Nelson HS. Response to sublingual immunotherapy with grass pollen extract: monotherapy versus combination in a multiallergen extract. J Allergy Clin Immunol. 2009;124:150–156.e5.PubMedCrossRefGoogle Scholar
  61. 61.
    Kavuru M, Melamed J, Gross G, et al. Salmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment of asthma: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2000;105:1108–16.PubMedCrossRefGoogle Scholar
  62. 62.
    Creticos PS, Esch RE, Couroux P, et al. Randomized, double-blind, placebo-controlled trial of standardized ragweed sublingual-liquid immunotherapy for allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2014;133:751–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Antico A. Long-term adherence to sublingual tablet: literature review and suggestions for management strategies based on patients’ needs and preferences. Clin Exp Allergy. 2014;44:1314–26.PubMedCrossRefGoogle Scholar
  64. 64.
    Devillier P, Dreyfus J-F, Demoly P, Calderón MA. A meta-analysis of sublingual allergen immunotherapy and pharmacotherapy in pollen-induced seasonal allergic rhinoconjunctivitis. BMC Med. 2014;12:71.PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Skoner D, Blaiss M, Dykewicz M, et al. The Allergies, Immunotherapy, and RhinoconjunctivitiS (AIRS) survey: patients’ experience with allergen immunotherapy. Allergy Asthma Proc. 2014;35:219–26.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Nicole Pleskovic
    • 1
  • Ashton Bartholow
    • 1
  • Deborah A. Gentile
    • 1
    • 2
  • David P. Skoner
    • 1
    • 2
    • 3
    Email author
  1. 1.Division of Allergy, Asthma and Immunology, Department of MedicineAllegheny General HospitalPittsburghUSA
  2. 2.Temple University School of MedicinePhiladelphiaUSA
  3. 3.Department of MedicineAllegheny General HospitalPittsburghUSA

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