Skip to main content

Allergen Immunotherapy and Atopic Dermatitis: the Good, the Bad, and the Unknown

Abstract

Purpose of Review

In light of the recent advancements in atopic dermatitis treatment, this review aims to summarize the utility and efficacy of allergy immunotherapy in atopic dermatitis patients. We examine its mechanism, pathophysiology, cost-efficacy, and current guidelines for clinical practice.

Recent Findings

The literature supports the use of allergy immunotherapy in atopic conditions such as allergic rhinitis and asthma but insufficient evidence exists to suggest its efficacy in atopic dermatitis. The use of allergy immunotherapy has been shown to provide long-term cost savings in both the USA and the European Union in certain populations but differences in prescribing patterns and manufacturing make it difficult to study its impact on a larger, generalizable scale.

Summary

Conflicting meta-analyses data and conclusions highlight the need for better, higher quality research to better understand allergy immunotherapy utility in atopic dermatitis.

This is a preview of subscription content, access via your institution.

Abbreviations

AIT:

Allergy immunotherapy

AD:

Atopic dermatitis

AR:

Allergic rhinitis

EASI:

Eczema Area and Severity Index

FLG:

Filaggrin

QALY:

Quality adjusted life years

SCIT:

Subcutaneous immunotherapy

SLIT:

Sublingual immunotherapy

SCORAD:

SCORing Atopic Dermatitis

References

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

  1. Leung DYM, Bieber T. Atopic dermatitis. Lancet. 2003;361(9352):151–60. https://doi.org/10.1016/s0140-6736(03)12193-9.

    Article  PubMed  Google Scholar 

  2. •• Werfel T, Allam JP, Biedermann T, Eyerich K, Gilles S, Guttman-Yassky E, et al. Cellular and molecular immunologic mechanisms in patients with atopic dermatitis. J Allergy Clin Immunol. 2016;138(2):336–49. https://doi.org/10.1016/j.jaci.2016.06.010 Excellent paper summarizing the immunological mechanisms in AD pathogenesis.

    CAS  Article  PubMed  Google Scholar 

  3. Novak N, Bieber T. Allergic and nonallergic forms of atopic diseases. J Allergy Clin Immunol. 2003;112(2):252–62.

    Article  Google Scholar 

  4. Werfel T, Breuer K, Rueff F, Przybilla B, Worm M, Grewe M, et al. Usefulness of specific immunotherapy in patients with atopic dermatitis and allergic sensitization to house dust mites: a multi-centre, randomized, dose–response study. Allergy. 2006;61(2):202–5.

    CAS  Article  Google Scholar 

  5. Frischmeyer-Guerrerio PA, Rasooly M, Gu WJ, Levin S, Jhamnani RD, Milner JD et al. IgE testing can predict food allergy status in patients with moderate to severe atopic dermatitis. Ann Allergy Asthma Immunol. 2019;122(4):393-+. doi:10.1016/j.anai.2019.01.001.

    Article  Google Scholar 

  6. Fleischer DM, Bock SA, Spears GC, Wilson CG, Miyazawa NK, Gleason MC, et al. Oral food challenges in children with a diagnosis of food allergy. J Pediatr. 2011;158(4):578–83.e1.

    Article  Google Scholar 

  7. Ring J, Zink A, Arents BWM, Seitz IA, Mensing U, Schielein MC, et al. Atopic eczema: burden of disease and individual suffering - results from a large EU study in adults. J Eur Acad Dermatol Venereol. 2019;33(7):1331–40. https://doi.org/10.1111/jdv.15634.

    CAS  Article  PubMed  Google Scholar 

  8. Williams H, Robertson C, Stewart A, Ait-Khaled N, Anabwani G, Anderson R, et al. Worldwide variations in the prevalence of symptoms of atopic eczema in the international study of asthma and allergies in childhood. J Allergy Clin Immunol. 1999;103(1):125–38. https://doi.org/10.1016/s0091-6749(99)70536-1.

    CAS  Article  PubMed  Google Scholar 

  9. Silverberg JI, Simpson EL. Association between severe eczema in children and multiple comorbid conditions and increased healthcare utilization. Pediatr Allergy Immunol. 2013;24(5):476–86. https://doi.org/10.1111/pai.12095.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Bieber T. Atopic dermatitis. N Engl J Med. 2008;358(14):1483–94. https://doi.org/10.1056/NEJMra074081.

    CAS  Article  PubMed  Google Scholar 

  11. Lee HH, Patel KR, Singam V, Rastogi S, Silverberg JI. A systematic review and meta-analysis of the prevalence and phenotype of adult-onset atopic dermatitis. J Am Acad Dermatol. 2019;80(6):1526-+. https://doi.org/10.1016/j.jaad.2018.05.1241.

    Article  PubMed  Google Scholar 

  12. Hanifin JM, Tofte SJ. Update on therapy of atopic dermatitis. J Allergy Clin Immunol. 1999;104(3):S123–S5. https://doi.org/10.1016/s0091-6749(99)70054-0.

    CAS  Article  PubMed  Google Scholar 

  13. Paller AS, Kabashima K, Bieber T. Therapeutic pipeline for atopic dermatitis: end of the drought? J Allergy Clin Immunol. 2017;140(3):633–43. https://doi.org/10.1016/j.jaci.2017.07.006.

    Article  PubMed  Google Scholar 

  14. Wollenberg A, Barbarot S, Bieber T, Christen-Zaech S, Deleuran M, Fink-Wagner A, et al. Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part II. J Eur Acad Dermatol Venereol. 2018;32(6):850–78.

    CAS  Article  Google Scholar 

  15. Andersen YM, Egeberg A, Ban L, Gran S, Williams HC, Francis NA, et al. Association between topical corticosteroid use and type 2 diabetes in two European population-based adult cohorts. Diabetes Care. 2019;42(6):1095–103.

    CAS  Article  Google Scholar 

  16. Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med. 2011;365(14):1315–27. https://doi.org/10.1056/NEJMra1011040.

    CAS  Article  PubMed  Google Scholar 

  17. Yang H, Wang J, Zhang X, Zhang Y, Qin ZL, Wang H, et al. Application of topical phosphodiesterase 4 inhibitors in mild to moderate atopic dermatitis a systematic review and meta-analysis. Jama Dermatol. 2019;155(5):585–93. https://doi.org/10.1001/jamadermatol.2019.0008.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Bäumer W, Hoppmann J, Rundfeldt C, Kietzmann M. Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007;6(1):17–26.

    Article  Google Scholar 

  19. Dastidar SG, Rajagopal D, Ray A. Therapeutic benefit of PDE4 inhibitors in inflammatory diseases. Curr Opin Investig Drugs. 2007;8(5):364–72.

    CAS  PubMed  Google Scholar 

  20. Jimenez JL, Punzón C, Navarro J, Muñoz-Fernández MA, Fresno M. Phosphodiesterase 4 inhibitors prevent cytokine secretion by T lymphocytes by inhibiting nuclear factor-kappaB and nuclear factor of activated T cells activation. J Pharmacol Exp Ther. 2001;299(2):753–9.

    CAS  PubMed  Google Scholar 

  21. Hamilton JD, Ungar B, Guttman-Yassky E. Drug evaluation review: dupilumab in atopic dermatitis. Immunotherapy. 2015;7(10):1043–58. https://doi.org/10.2217/imt.15.69.

    CAS  Article  PubMed  Google Scholar 

  22. Holm JG, Thomsen SF. Omalizumab for atopic dermatitis: evidence for and against its use. G Ital Dermatol Venereol. 2019;154(4):480–7. https://doi.org/10.23736/s0392-0488.19.06302-8.

    Article  PubMed  Google Scholar 

  23. Kupczyk M. Future directions of application and development of allergen immunotherapy. Alergol Polska-Polish J Allergol. 2018;5(2):80–4. https://doi.org/10.5114/pja.2018.76676.

    Article  Google Scholar 

  24. Hotze M, Baurecht H, Rodríguez E, Chapman-Rothe N, Ollert M, Fölster-Holst R, et al. Increased efficacy of omalizumab in atopic dermatitis patients with wild-type filaggrin status and higher serum levels of phosphatidylcholines. Allergy. 2014;69(1):132–5.

    CAS  Article  Google Scholar 

  25. • Owens S, Liu H, Sun K, Venturanza M, Kuligowski M, Howell M, editors. Ruxolitinib cream significantly modulates inflammatory profiles of atopic dermatitis patients. J Investig Dermatol; 2019: ELSEVIER SCIENCE INC STE 800, 230 PARK AVE, NEW YORK, NY 10169 USA. Study showing the efficacy of ruxolitinib in reducing itch, reveling novel mechanism involved in itch.

  26. Uermosi C, Zabel F, Manolova V, Bauer M, Beerli RR, Senti G. IgG-mediated down-regulation of IgE bound to mast cells: a potential novel mechanism of allergen-specific desensitization (vol 69, pg 338, 2014). Allergy. 2014;69(8):1118. https://doi.org/10.1111/all.12460.

    Article  Google Scholar 

  27. •• Larche M, Akdis CA, Valenta R. Immunological mechanisms of allergen-specific immunotherapy. Nat Rev Immunol. 2006;6(10):761–71. https://doi.org/10.1038/nri1934 Detailed overview of mechanisms of allergy immunotherapy in atopic disorders.

    CAS  Article  PubMed  Google Scholar 

  28. Stanic B, van de Veen W, Wirz OF, Ruckert B, Morita H, Sollner S, et al. IL-10-overexpressing B cells regulate innate and adaptive immune responses. J Allergy Clin Immunol. 2015;135(3):771–U299. https://doi.org/10.1016/j.jaci.2014.07.041.

    CAS  Article  PubMed  Google Scholar 

  29. Frankland A. High and low dosage pollen extract treatment in summer hay fever and asthma. Allergy. 1955;9(3):183–7.

    CAS  Article  Google Scholar 

  30. Patel P, Salapatek AMF. Pollinex((R)) Quattro: a novel and well-tolerated, ultra short-course allergy vaccine. Expert Rev Vaccines. 2006;5(5):617–29. https://doi.org/10.1586/14760584.5.5.617.

    CAS  Article  PubMed  Google Scholar 

  31. Penagos M, Compalati E, Tarantini F, Baena-Cagnani R, Huerta J, Passalacqua G, et al. Efficacy of sublingual immunotherapy in the treatment of allergic rhinitis in pediatric patients 3 to 18 years of age: a meta-analysis of randomized, placebo-controlled, double-blind trials. Ann Allergy Asthma Immunol. 2006;97(2):141–8. https://doi.org/10.1016/s1081-1206(10)60004-x.

    CAS  Article  PubMed  Google Scholar 

  32. Pajno GB, Caminiti L, Vita D, Barberio G, Salzano G, Lombardo F, et al. Sublingual immunotherapy in mite-sensitized children with atopic dermatitis: a randomized, double-blind, placebo-controlled study. J Allergy Clin Immunol. 2007;120(1):164–70. https://doi.org/10.1016/j.jaci.2007.04.008.

    CAS  Article  PubMed  Google Scholar 

  33. Cox LS, Hankin C, Lockey R. Allergy immunotherapy adherence and delivery route: location does not matter. J Allergy Clin Immunol. 2014;2(2):156–60.e2.

    Article  Google Scholar 

  34. Sade K, Berkun Y, Dolev Z, Shalit M, Kivity S. Knowledge and expectations of patients receiving aeroallergen immunotherapy. Ann Allergy Asthma Immunol. 2003;91(5):444–8.

    Article  Google Scholar 

  35. Abramowicz M, Kruszewski J, Chcialowski A. Evaluation of the placebo effect in the trials of allergen immunotherapy effectiveness: meta-analysis of randomized and placebo-controlled trials. Postepy Dermatologii I Alergologii. 2018;35(6):620–5. https://doi.org/10.5114/ada.2018.77614.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Incorvaia C, Berto P, Ariano R, Elia R, Frati F. Cost-effectiveness of allergen immunotherapy. J Aller Ther S. 2012;6:2.

    Google Scholar 

  37. Petersen KD, Gyrd-Hansen D, Dahl R. Health-economic analyses of subcutaneous specific immunotherapy for grass pollen and mite allergy. Allergol Immunopathol. 2005;33(6):296–302.

    CAS  Article  Google Scholar 

  38. Hankin CS, Cox L, Lang D, Levin A, Gross G, Eavy G, et al. Allergy immunotherapy among Medicaid-enrolled children with allergic rhinitis: patterns of care, resource use, and costs. J Allergy Clin Immunol. 2008;121(1):227–32.

    Article  Google Scholar 

  39. Berto P, Bassi M, Incorvaia C, Frati F, Puccinelli P, Giaquinto C, et al. Cost effectiveness of sublingual immunotherapy in children with allergic rhinitis and asthma. Eur Ann Allergy Clin Immunol. 2005;37(8):303–8.

    CAS  PubMed  Google Scholar 

  40. Pearson SD, Rawlins MD. Quality, innovation, and value for money: NICE and the British National Health Service. Jama. 2005;294(20):2618–22.

    CAS  Article  Google Scholar 

  41. Bachert C, Vestenbaek U, Christensen J, Griffiths UK, Poulsen PB. Cost-effectiveness of grass allergen tablet (GRAZAX (R)) for the prevention of seasonal grass pollen induced rhinoconjunctivitis - a Northern European perspective. Clin Exp Allergy. 2007;37(5):772–9. https://doi.org/10.1111/j.1365-2222.2007.02706.x.

    CAS  Article  PubMed  Google Scholar 

  42. Canonica GW, Poulsen PB, Vestenbaek U. Cost-effectiveness of GRAZAX (R) for prevention of grass pollen induced rhinoconjunctivitis in Southern Europe. Respir Med. 2007;101(9):1885–94. https://doi.org/10.1016/j.rmed.2007.05.003.

    CAS  Article  PubMed  Google Scholar 

  43. Hankin CS, Cox L. Allergy immunotherapy: what is the evidence for cost saving? Curr Opin Allergy Clin Immunol. 2014;14(4):363–70. https://doi.org/10.1097/aci.0000000000000084.

    CAS  Article  PubMed  Google Scholar 

  44. •• Mahler V, Esch RE, Kleine-Tebbe J, Lavery WJ, Plunkett G, Vieths S, et al. Understanding differences in allergen immunotherapy products and practices in North America and Europe. J Allergy Clin Immunol. 2019;143(3):813–30. https://doi.org/10.1016/j.jaci.2019.01.024 Provides an in-depth discussion of AIT in US vs. EU regulations, diagnostics, and practice patterns.

    Article  PubMed  Google Scholar 

  45. Slater JE, Menzies SL, Bridgewater J, Mosquera A, Zinderman CE, Ou AC, et al. The US Food and Drug Administration review of the safety and effectiveness of nonstandardized allergen extracts. J Allergy Clin Immunol. 2012;129(4):1014–9.

    Article  Google Scholar 

  46. Golden DB, Demain J, Freeman T, Graft D, Tankersley M, Tracy J, et al. Stinging insect hypersensitivity: a practice parameter update 2016. Ann Allergy Asthma Immunol. 2017;118(1):28–54.

    Article  Google Scholar 

  47. Roberts G, Pfaar O, Akdis C, Ansotegui I, Durham S, Gerth van Wijk R, et al. EAACI guidelines on allergen immunotherapy: allergic rhinoconjunctivitis. Allergy. 2018;73(4):765–98.

    CAS  Article  Google Scholar 

  48. Pfaar O, Bachert C, Bufe A, Buhl R, Ebner C, Eng P, et al. Guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases. Allergo J Int. 2014;23(8):282–319.

    Article  Google Scholar 

  49. Virchow JC, Backer V, Kuna P, Prieto L, Nolte H, Villesen HH, et al. Efficacy of a house dust mite sublingual allergen immunotherapy tablet in adults with allergic asthma: a randomized clinical trial. Jama. 2016;315(16):1715–25.

    CAS  Article  Google Scholar 

  50. Sánchez Caraballo JM, Cardona VR. Clinical and immunological changes of immunotherapy in patients with atopic dermatitis: randomized controlled trial. ISRN Allergy. 2012;2012.

  51. • Tam HH, Calderon MA, Manikam L, Nankervis H, Núñez IG, Williams HC, et al. Specific allergen immunotherapy for the treatment of atopic eczema: a Cochrane systematic review. Allergy. 2016;71(9):1345–56. https://doi.org/10.1111/all.12932 Recent meta-analysis on AIT efficacy in AD.

    CAS  Article  PubMed  Google Scholar 

  52. Bae JM, Choi YY, Park CO, Chung KY, Lee KH. Efficacy of allergen-specific immunotherapy for atopic dermatitis: a systematic review and meta-analysis of randomized controlled trials. J Allergy Clin Immunol. 2013;132(1):110–7.

    Article  Google Scholar 

  53. •• Ridolo E, Martignago I, Riario-Sforza GG, Incorvaia C. Allergen immunotherapy in atopic dermatitis. Expert Rev Clin Immunol. 2018;14(1):61–8 Great source of updated guidelines and recommendations for AIT.

    CAS  Article  Google Scholar 

  54. • Boguniewicz M, Fonacier L, Guttman-Yassky E, Ong PY, Silverberg J, Farrar JR. Atopic dermatitis yardstick: Practical recommendations for an evolving therapeutic landscape. Ann Allergy Asthma Immunol. 2018;120(1):10–22.e2. https://doi.org/10.1016/j.anai.2017.10.039 Updates on AD management with practical information based on disease severity and impact on quality of life.

    Article  PubMed  Google Scholar 

  55. Eichenfield LF, Ahluwalia J, Waldman A, Borok J, Udkoff J, Boguniewicz M. Current guidelines for the evaluation and management of atopic dermatitis–a comparison of the Joint Task Force Practice Parameter and American Academy of Dermatology Guidelines. Alergol Polska-Polish J Allergol. 2017;4(4):158–68.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Anna De Benedetto.

Ethics declarations

Conflict of Interest

Dr. De Benedetto has served on advisory board for Regeneron & Sanofi and Allakos. She has been an investigator for Novartis, Kiniksa, Alchem, Regeneron and Sanofi. Drs. Rizk and Rodenas declare no conflicts of interest relevant to this manuscript.

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.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Allergic Skin Diseases

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rizk, P., Rodenas, M. & De Benedetto, A. Allergen Immunotherapy and Atopic Dermatitis: the Good, the Bad, and the Unknown. Curr Allergy Asthma Rep 19, 57 (2019). https://doi.org/10.1007/s11882-019-0893-z

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11882-019-0893-z

Keywords

  • Atopic dermatitis
  • Allergy immunotherapy
  • AIT efficacy
  • Treatment