American Journal of Clinical Dermatology

, Volume 19, Issue 2, pp 145–165 | Cite as

Are Biologics Efficacious in Atopic Dermatitis? A Systematic Review and Meta-Analysis

  • Igor Snast
  • Ofer Reiter
  • Emmilia Hodak
  • Rivka Friedland
  • Daniel Mimouni
  • Yael Anne Leshem
Systematic Review

Abstract

Background

Current systemic treatments for atopic dermatitis (AD) offer limited efficacy and are often restricted by safety concerns. Biologics may address the unmet need for improved AD therapeutics.

Objective

The aim of this study was to evaluate the efficacy and safety of biologic agents in AD.

Methods

A systematic review and meta-analysis of studies evaluating AD patients treated with biologics was performed. The primary outcome was the Eczema Area and Severity Index (EASI)-75 response, while secondary outcomes were SCOring Atopic Dermatitis (SCORAD)-75, EASI-50, SCORAD-50, Investigator Global Assessment 0/1 responses, change in responses from baseline, and adverse events.

Results

We included 13 randomized controlled trials (RCTs) and 10 observational studies evaluating nine biologics. High-quality evidence was available for dupilumab, nemolizumab and ustekinumab. Pooling five studies, at weeks 12–16 dupilumab 300 mg every week to every 2 weeks achieved EASI-75 responses of 55%, superior to placebo [relative risk (RR) 3.3, 95% confidence interval (CI) 2.9–3.6]. Nemolizumab had similar EASI-75 responses as placebo, but significantly improved pruritus. In online reports, lebrikizumab demonstrated superior EASI-50 responses versus placebo (RR 1.3, 95% CI 1.04–1.7), while tralokinumab had superior SCORAD-50 responses versus placebo, with borderline significance (RR 1.7, 95% CI 0.97–3.1). In two RCTs each, omalizumab and ustekinumab were comparable with placebo, while antithymic stromal lymphopoietin receptor, infliximab, and rituximab lacked adequate evidence of efficacy. All medications had a comparable safety profile to placebo.

Limitations

Lack of RCTs and the use of variable outcome measures limited conclusions.

Conclusion

Dupilumab is currently the only biologic with robust evidence of efficacy in AD. Nemolizumab, lebrikizumab, and tralokinumab show promise but further data are needed. Longer follow-up and larger studies will establish their safety profile.

Notes

Compliance with ethical standards

Funding

No funding was received for this study.

Conflict of interest

Igor Snast, Ofer Reiter, Emmilia Hodak, Rivka Friedland, and Daniel Mimouni report no conflicts of interest. Yael Anne Leshem has received speaker honorarium and advisory board participation fees from Sanofi, Israel, and consulting fees from Regeneron, USA, and Genentech, USA.

Supplementary material

40257_2017_324_MOESM1_ESM.pdf (1.1 mb)
Supplementary material 1 (PDF 1178 kb)

References

  1. 1.
    Silverberg JI, Hanifin JM. Adult eczema prevalence and associations with asthma and other health and demographic factors: a US population-based study. J Allergy Clin Immunol. 2013;132:1132–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet. 1998;351:1225–32.Google Scholar
  3. 3.
    Ring J, Alomar A, Bieber T, Deleuran M, Fink-Wagner A, Gelmetti C, et al. Guidelines for treatment of atopic eczema (atopic dermatitis) Part II. J Eur Acad Dermatol Venereol. 2012;26:1176–93.CrossRefPubMedGoogle Scholar
  4. 4.
    Roekevisch E, Spuls PI, Kuester D, Limpens J, Schmitt J. Efficacy and safety of systemic treatments for moderate-to-severe atopic dermatitis: a systematic review. J Allergy Clin Immunol. 2014;133:429–38.CrossRefPubMedGoogle Scholar
  5. 5.
    Schmitt J, Schäkel K, Fölster-Holst R, Bauer A, Oertel R, Augustin M, et al. Prednisolone vs. ciclosporin for severe adult eczema. An investigator-initiated double-blind placebo-controlled multicentre trial. Br J Dermatol. 2010;162:661–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Boguniewicz M, Leung DYM. Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev. 2011;242:233–46.CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Lebwohl MG, Del Rosso JQ, Abramovits W, Berman B, Cohen DE, Guttman E, et al. Pathways to managing atopic dermatitis: consensus from the experts. J Clin Aesthet Dermatol. 2013;6:S2–18.PubMedCentralPubMedGoogle Scholar
  8. 8.
    Dupixent (dupilumab) FDA Approval History. Drugs.com. https://www.drugs.com/history/dupixent.html. Cited 17 Apr 2017.
  9. 9.
    Hamilton JD, Ungar B, Guttman-Yassky E. Drug evaluation review: dupilumab in atopic dermatitis. Immunotherapy. 2015;7:1043–58.CrossRefPubMedGoogle Scholar
  10. 10.
    Hamilton JD, Suárez-Fariñas M, Dhingra N, Cardinale I, Li X, Kostic A, et al. Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol. 2014;134:1293–300.CrossRefPubMedGoogle Scholar
  11. 11.
    Holm JG, Agner T, Sand C, Thomsen SF. Omalizumab for atopic dermatitis: case series and a systematic review of the literature. Int J Dermatol. 2017;56:18–26.CrossRefPubMedGoogle Scholar
  12. 12.
    Han Y, Chen Y, Liu X, Zhang J, Su H, Wen H, et al. Efficacy and safety of dupilumab for the treatment of adult atopic dermatitis: a meta-analysis of randomized clinical trials. J Allergy Clin Immunol. 2017;140:888–91.CrossRefPubMedGoogle Scholar
  13. 13.
    Blauvelt A, de Bruin-Weller M, Gooderham M, Cather JC, Weisman J, Pariser D, et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet. 2017;389:2287–303.CrossRefPubMedGoogle Scholar
  14. 14.
    Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Le Cleach L, Doney E, Katz KA, Williams HC, Trinquart L. Research techniques made simple: workflow for searching databases to reduce evidence selection bias in systematic reviews. J Investig Dermatol. 2016;136:e125–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375:2335–48.CrossRefPubMedGoogle Scholar
  17. 17.
    Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Ottawa Hospital Research Institute. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Cited 12 Feb 2017.
  19. 19.
    Ioannidis JPA, Trikalinos TA. The appropriateness of asymmetry tests for publication bias in meta-analyses: a large survey. CMAJ. 2007;176:1091–6.CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Nast A, Jacobs A, Rosumeck S, Werner RN. Efficacy and safety of systemic long-term treatments for moderate-to-severe psoriasis: a systematic review and meta-analysis. J Investig Dermatol. 2015;135:2641–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Beck LA, Thaçi D, Hamilton JD, Graham NM, Bieber T, Rocklin R, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014;371:130–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Thaçi D, Simpson EL, Beck LA, Bieber T, Blauvelt A, Papp K, et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. Lancet. 2016;387:40–52.CrossRefPubMedGoogle Scholar
  23. 23.
    Blauvelt A, Simpson E, Wu R, Akinlade B, Graham N, Pirozzi G, et al. The effect of dupilumab on vaccine antibody responses in adults with moderate-to-severe atopic dermatitis: a randomized, double-blind, placebo-controlled trial. Eur J Allergy Clin Immunol. 2016;71(Suppl. 102):95–117.Google Scholar
  24. 24.
    Simon D, Hösli S, Kostylina G, Yawalkar N, Simon H-U. Anti-CD20 (rituximab) treatment improves atopic eczema. J Allergy Clin Immunol. 2008;121:122–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Khattri S, Brunner PM, Garcet S, Finney R, Cohen SR, Oliva M, et al. Efficacy and safety of ustekinumab treatment in adults with moderate-to-severe atopic dermatitis. Exp Dermatol. 2017;26:28–35.CrossRefPubMedGoogle Scholar
  26. 26.
    Jacobi A, Antoni C, Manger B, Schuler G, Hertl M. Infliximab in the treatment of moderate to severe atopic dermatitis. J Am Acad Dermatol. 2005;52:522–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Lebrikizumab opens new door in atopic dermatitis therapy. http://www.mdedge.com/edermatologynews/article/115736/atopic-dermatitis/lebrikizumab-opens-new-door-atopic-dermatitis. Cited 12 Feb 2017.
  28. 28.
    A study of intravenous MK-8226 in participants with moderate-to-severe atopic dermatitis (MK-8226-003). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01732510?term=MK-8226-003&rank=1. Cited 13 Feb 2017.
  29. 29.
    Lacombe Barrios J, Bégin P, Paradis L, Hatami A, Paradis J, Des Roches A. Anti-IgE therapy and severe atopic dermatitis: a pediatric perspective. J Am Acad Dermatol. 2013;69:832–4.CrossRefPubMedGoogle Scholar
  30. 30.
    Kim DH, Park KY, Kim BJ, Kim MN, Mun SK. Anti-immunoglobulin E in the treatment of refractory atopic dermatitis. Clin Exp Dermatol. 2013;38:496–500.CrossRefPubMedGoogle Scholar
  31. 31.
    Vigo PG, Girgis KR, Pfuetze BL, Critchlow ME, Fisher J, Hussain I. Efficacy of anti-IgE therapy in patients with atopic dermatitis. J Am Acad Dermatol. 2006;55:168–70.CrossRefPubMedGoogle Scholar
  32. 32.
    Sheinkopf LE, Rafi AW, Do LT, Katz RM, Klaustermeyer WB. Efficacy of omalizumab in the treatment of atopic dermatitis: a pilot study. Allergy Asthma Proc. 2008;29:530–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Iyengar SR, Hoyte EG, Loza A, Bonaccorso S, Chiang D, Umetsu DT, et al. Immunologic effects of omalizumab in children with severe refractory atopic dermatitis: a randomized, placebo-controlled clinical trial. Int Arch Allergy Immunol. 2013;162:89–93.CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    Belloni B, Ziai M, Lim A, Lemercier B, Sbornik M, Weidinger S, et al. Low-dose anti-IgE therapy in patients with atopic eczema with high serum IgE levels. J Allergy Clin Immunol. 2007;120:1223–5.CrossRefPubMedGoogle Scholar
  35. 35.
    Heil PM, Maurer D, Klein B, Hultsch T, Stingl G. Omalizumab therapy in atopic dermatitis: depletion of IgE does not improve the clinical course: a randomized, placebo-controlled and double blind pilot study. J Dtsch Dermatol Ges. 2010;8:990–8.PubMedGoogle Scholar
  36. 36.
    Zink A, Gensbaur A, Zirbs M, Seifert F, Suarez IL, Mourantchanian V, et al. Targeting IgE in severe atopic dermatitis with a combination of immunoadsorption and omalizumab. Acta Derm Venereol. 2016;96:72–6.CrossRefPubMedGoogle Scholar
  37. 37.
    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;69:132–5.CrossRefPubMedGoogle Scholar
  38. 38.
    Ramírez del Pozo ME, Contreras E, López Tiro J, Gómez Vera J. Omalizumab (an anti-IgE antibody) in the treatment of severe atopic eczema. J Investig Allergol Clin Immunol. 2011;21:416–7.PubMedGoogle Scholar
  39. 39.
    Ruzicka T, Hanifin JM, Furue M, Pulka G, Mlynarczyk I, Wollenberg A, et al. Anti-interleukin-31 receptor A antibody for atopic dermatitis. N Engl J Med. 2017;376:826–35.CrossRefPubMedGoogle Scholar
  40. 40.
    Saeki H, Kabashima K, Tokura Y, Murata Y, Shiraishi A, Tamamura R, et al. Efficacy and safety of ustekinumab in japanese patients with severe atopic dermatitis: a randomised, double-blind, placebo-controlled, phase 2 study. Br J Dermatol. 2017;177:419–27.CrossRefPubMedGoogle Scholar
  41. 41.
    Leshem YA, Hajar T, Hanifin JM, Simpson EL. What the Eczema Area and Severity Index score tells us about the severity of atopic dermatitis: an interpretability study. Br J Dermatol. 2015;172:1353–7.CrossRefPubMedGoogle Scholar
  42. 42.
    Chopra R, Vakharia PP, Sacotte R, Patel N, Immaneni S, White T, et al. Severity strata for EASI, mEASI, oSCORAD, SCORAD, ADSI and BSA in adolescents and adults with atopic dermatitis. Br J Dermatol. doi: 10.1111/bjd.15641.Google Scholar
  43. 43.
    Phase 2 study to evaluate the efficacy and safety of tralokinumab in adults with atopic dermatitis. Study results. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/results/NCT02347176?sect=X70156&cond=tralokinumab&draw=1&rank=7#outcome1. Cited 11 Aug 2017.
  44. 44.
    Oyama S, Kitamura H, Kuramochi T, Higuchi Y, Matsushita H, Suzuki T, et al. Cynomolgus monkey model of interleukin-31-induced scratching depicts blockade of human interleukin-31 receptor A by a humanized monoclonal antibody. Exp Dermatol. doi: 10.1111/exd.13236.Google Scholar
  45. 45.
    Walsh GM. Tralokinumab, an anti-IL-13 mAb for the potential treatment of asthma and COPD. Curr Opin Investig Drugs. 2010;11:1305–12.PubMedGoogle Scholar
  46. 46.
    Presta LG, Lahr SJ, Shields RL, Porter JP, Gorman CM, Fendly BM, et al. Humanization of an antibody directed against IgE. J. Immunol. 1993;151:2623–32.PubMedGoogle Scholar
  47. 47.
    Zaghi D, Krueger GG, Callis Duffin K. Ustekinumab: a review in the treatment of plaque psoriasis and psoriatic arthritis. J. Drugs Dermatol. 2012;11:160–7.PubMedGoogle Scholar
  48. 48.
    Comeau MR, Ziegler SF. The influence of TSLP on the allergic response. Mucosal Immunol. 2010;3:138–47.CrossRefPubMedGoogle Scholar
  49. 49.
    Mease PJ. Tumour necrosis factor (TNF) in psoriatic arthritis: pathophysiology and treatment with TNF inhibitors. Ann Rheum Dis. 2002;61:298–304.CrossRefPubMedCentralPubMedGoogle Scholar
  50. 50.
    Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358:676–88.CrossRefPubMedGoogle Scholar
  51. 51.
    Nygaard U, Hvid M, Johansen C, Buchner M, Fölster-Holst R, Deleuran M, et al. TSLP, IL-31, IL-33 and sST2 are new biomarkers in endophenotypic profiling of adult and childhood atopic dermatitis. J Eur Acad Dermatol Venereol. 2016;30:1930–8.PubMedGoogle Scholar
  52. 52.
    Hershey GKK. IL-13 receptors and signaling pathways: an evolving web. J Allergy Clin Immunol. 2003;111:677–90 (quiz 691).CrossRefPubMedGoogle Scholar
  53. 53.
    Corry DB, Kheradmand F. Induction and regulation of the IgE response. Nature. 1999;402:B18–23.CrossRefPubMedGoogle Scholar
  54. 54.
    Kim JE, Kim JS, Cho DH, Park HJ. Molecular mechanisms of cutaneous inflammatory disorder: atopic dermatitis. Int J Mol Sci. 2016;17(8):E1234.CrossRefPubMedGoogle Scholar
  55. 55.
    Milgrom H, Fowler-Taylor A, Vidaurre CF, Jayawardene S. Safety and tolerability of omalizumab in children with allergic (IgE-mediated) asthma. Curr Med Res Opin. 2011;27:163–9.CrossRefPubMedGoogle Scholar
  56. 56.
    Chan S, Cornelius V, Chen T, Radulovic S, Wan M, Jahan R, et al. Atopic Dermatitis Anti-IgE Paediatric Trial (ADAPT): the role of anti-IgE in severe paediatric eczema: study protocol for a randomised controlled trial. Trials. 2017;18:136.CrossRefPubMedCentralPubMedGoogle Scholar
  57. 57.
    Noda S, Suárez-Fariñas M, Ungar B, Kim SJ, de Guzman Strong C, Xu H, et al. The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization. J Allergy Clin Immunol. 2015;136:1254–64.CrossRefPubMedGoogle Scholar
  58. 58.
    Renert-Yuval Y, Guttman-Yassky E. Systemic therapies in atopic dermatitis: the pipeline. Clin Dermatol. 2017;35:387–97.CrossRefPubMedGoogle Scholar
  59. 59.
    Schmitt J, Spuls PI, Thomas KS, Simpson E, Furue M, Deckert S, et al. The Harmonising Outcome Measures for Eczema (HOME) statement to assess clinical signs of atopic eczema in trials. J Allergy Clin Immunol. 2014;134:800–7.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Igor Snast
    • 1
  • Ofer Reiter
    • 1
  • Emmilia Hodak
    • 1
    • 2
  • Rivka Friedland
    • 3
  • Daniel Mimouni
    • 1
    • 2
  • Yael Anne Leshem
    • 1
    • 2
  1. 1.Department of DermatologyBeilinson Hospital, Rabin Medical CenterPetah TikvaIsrael
  2. 2.Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  3. 3.Schneider Children’s Medical CenterPetah TikvaIsrael

Personalised recommendations