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

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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.

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References

  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.

    Article  PubMed  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  6. Boguniewicz M, Leung DYM. Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev. 2011;242:233–46.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    PubMed Central  PubMed  Google Scholar 

  8. Dupixent (dupilumab) FDA Approval History. Drugs.com. https://www.drugs.com/history/dupixent.html. Cited 17 Apr 2017.

  9. Hamilton JD, Ungar B, Guttman-Yassky E. Drug evaluation review: dupilumab in atopic dermatitis. Immunotherapy. 2015;7:1043–58.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Ottawa Hospital Research Institute. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Cited 12 Feb 2017.

  19. Ioannidis JPA, Trikalinos TA. The appropriateness of asymmetry tests for publication bias in meta-analyses: a large survey. CMAJ. 2007;176:1091–6.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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. 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. 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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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. 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. Walsh GM. Tralokinumab, an anti-IL-13 mAb for the potential treatment of asthma and COPD. Curr Opin Investig Drugs. 2010;11:1305–12.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  48. Comeau MR, Ziegler SF. The influence of TSLP on the allergic response. Mucosal Immunol. 2010;3:138–47.

    Article  CAS  PubMed  Google Scholar 

  49. Mease PJ. Tumour necrosis factor (TNF) in psoriatic arthritis: pathophysiology and treatment with TNF inhibitors. Ann Rheum Dis. 2002;61:298–304.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  52. Hershey GKK. IL-13 receptors and signaling pathways: an evolving web. J Allergy Clin Immunol. 2003;111:677–90 (quiz 691).

    Article  CAS  PubMed  Google Scholar 

  53. Corry DB, Kheradmand F. Induction and regulation of the IgE response. Nature. 1999;402:B18–23.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  58. Renert-Yuval Y, Guttman-Yassky E. Systemic therapies in atopic dermatitis: the pipeline. Clin Dermatol. 2017;35:387–97.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Dermatology, Beilinson Hospital, Rabin Medical Center, 4941492, Petah Tikva, Israel

    Igor Snast, Ofer Reiter, Emmilia Hodak, Daniel Mimouni & Yael Anne Leshem

  2. Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel

    Emmilia Hodak, Daniel Mimouni & Yael Anne Leshem

  3. Schneider Children’s Medical Center, Petah Tikva, Israel

    Rivka Friedland

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  1. Igor Snast
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  2. Ofer Reiter
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  3. Emmilia Hodak
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  6. Yael Anne Leshem
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Correspondence to Daniel Mimouni.

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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.

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Snast, I., Reiter, O., Hodak, E. et al. Are Biologics Efficacious in Atopic Dermatitis? A Systematic Review and Meta-Analysis. Am J Clin Dermatol 19, 145–165 (2018). https://doi.org/10.1007/s40257-017-0324-7

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