Kim Blakely, BSc, PhD1; Melinda Gooderham, MD, MSc, FRCPC2,4, Kim Papp, MD, PhD, FRCPC3,4

1University of Toronto, Faculty of Medicine, Toronto, ON, Canada
2Skin Centre for Dermatology, Peterborough, ON, Canada
3SK. Papp Clinical Research, Waterloo, ON, Canada
4Probity Medical Research, Waterloo, ON Canada

Conflict of interest:
Dr. Gooderham and Dr. Papp have both attended advisory board meetings and been involved in clinical research on dupilumab for Sanofi and Regeneron.

ABSTRACT
Atopic dermatitis results when aberrant barrier function and immune activation occur within the skin. Standard therapies for atopic dermatitis have fallen short, prompting efforts to discover novel therapeutics for this disease. Of these, dupilumab, a fully human monoclonal antibody that inhibits the actions of both IL-4 and IL-13, has shown the greatest promise. Clinical trials of systemic dupilumab in moderate-to-severe atopic dermatitis have demonstrated marked improvement in patient symptoms, including pruritus and clinically visible disease. Importantly, dupilumab treatment has been correlated with changes in the molecular signature of diseased skin, with reduction of both inflammatory and proliferative markers. Dupilumab recently received US FDA breakthrough therapy designation for atopic dermatitis, with ongoing trials in both adult and pediatric populations. Altogether, dupilumab has shed new light on the pathomechanisms driving atopic dermatitis and is making unprecedented advances towards highly effective control of this debilitating disease.

Key Words:
atopic dermatitis, dupilumab, eczema, IL-4Rα, IL-4, IL-13, monoclonal antibody, EASI-50, EASI-75, SCORAD

Introduction

Atopic dermatitis (AD) is the most common chronic in ammatory skin disease, resulting from defects in skin barrier function and innate and adaptive immune responses.1,2 In its acute stages, AD presents with highly pruritic, inflamed lesions. Histologically, the epidermis of acute lesions is characterized by intracellular edema (spongiosis), and a sparse infiltrate consisting primarily of T lymphocytes. Marked perivascular inflammatory cell infiltrates with large numbers of T lymphocytes and macrophages are seen in the dermis. In its chronic stages, lesions are lichenified and plaque-like. Histologically, chronic lesions are distinguished by epidermal hyperplasia with prominent hyperkeratosis and minimal spongiosis.3-7

It is estimated that up to 30% of children and 10% of adults are affected by AD, with approximately 85% of all cases beginning within the first 5 years of life (early-onset AD).3,4,8 Although many children experience remission of their disease by adolescence, a portion will continue to be affected into adulthood.9 As well, a number of patients will have their first episode of AD diagnosed in adult life (late-onset AD), a presentation that often results in a more treatment-refractory form of the disease.4 Of those affected by AD, up to 20% have a moderate-to-severe presentation, which often manifests as a recurrent disease with remitting and relapsing phases.10 Importantly, AD impacts all aspects of patients’ lives, from their physical wellbeing to their psychological and economical quality of life by disrupting sleep, daily functioning, and requiring patients to attend frequent medical appointments.11-14

Genetics play a large role in the development of AD. Affected individuals often have a strong family history of atopy, including AD, asthma and allergic rhinitis: the atopic triad.15 Genome-wide association studies have implicated a number of genetic loci in the development of AD, including the 1q21, 3p26, 3q21, 5q31-33, 16q, 17q25, and 20p regions. These genetic loci are primarily involved in skin barrier and immune function.16-21 Importantly, interventions aimed at repairing these defects in skin barrier function and immune dysregulation hold promise for treatment, prevention and, potentially, a cure for AD.

Recent advances in our understanding of the underlying pathogenesis and risk factors for AD has resulted in two opposing theories that attempt to explain the onset and natural history of the disease: the outside-in and the inside-out hypotheses.22,23 The outside-in hypothesis proposes that genetic variations within the population result in a subpopulation of individuals that harbor defects in skin barrier function. A disrupted barrier permits allergens and microbes to cross the epithelium, which in turn triggers an in ammatory reaction. Alternatively, the inside-out hypothesis proposes that the underlying defects occur at the level of the immune system. A polarized immune response in AD patients results in immunoglobulin E (IgE) sensitization to skin pathogens and contaminants. The resultant immune response induces local inflammation and skin barrier breakdown.22,23 While debate around these theories remains, it is evident that a number of genetic and environmental factors contribute to skin barrier dysfunction and immune dysregulation in AD. The polyfactorial nature of AD accounts for the heterogeneity in severity and natural history of this disease. It is nonetheless apparent that optimal treatment of AD requires a comprehensive approach aimed at repairing defects in skin barrier function and addressing the characteristic immune abnormalities.

No currently available therapy provides complete remission or cure for affected patients. Management of AD includes patient education, optimal skin care practices, antihistamines (preferably first generation – sedating antihistamines), topical corticosteroids or topical calcineurin inhibitors (TCIs), systemic corticosteroids, systemic calcineurin inhibitors, phototherapy, and other oral immune-suppressants.7,24 These treatments work to restore skin barrier function and suppress the in ammatory response.

The availability of safe and effective treatment for moderate-to- severe AD remains a significant unmet need. Research focused on the pathophysiology of AD has identified promising targets for the treatment of this disease. One targeted therapy that has shown promise in early clinical development and is the focus of this review is dupilumab, an interleukin (IL)-4 receptor alpha (IL-4Rα) antagonist.

Immune Dysfunction in AD

Recent research has demonstrated that immune system dysfunction plays a central role in the development and persistence of AD. These cellular and cytokine targets provide potential therapeutic opportunities. AD skin has been shown to harbor increased levels of the TH2 cytokines IL-4, IL-5, IL-10, and IL-13, with a corresponding decrease in the TH1 cytokines interferon-γ and IL-2.25-30 IL-4 and IL-13 have established roles in B-cell differentiation and class switching, thus providing a plausible link to characteristic elevations of serum IgE levels in AD patients.4,31 Importantly, these TH2 cytokines have been shown to contribute to AD pathogenesis, as mice genetically engineered to over-express these cytokines develop skin barrier defects and an AD-like disease.32-35 High levels of the TH2 cytokines IL-4 and IL-13 in AD skin have been shown to act as inhibitors of both epidermal differentiation and production of antimicrobial peptides.36-38 IL-4 and IL-13 signal through a common receptor, IL-4Rα, to activate the Signal Transducer and Activator of Transcription 6 (STAT6)/Janus kinase 1 (JAK1) signalling cascade, and genetic polymorphisms in IL-4, IL-13 and IL-4Rα have all been associated with the development of AD in speci c populations.39-44 Mice that have been genetically engineered to over-express a constitutively active STAT6 display decreased expression of epidermal differentiation complex genes, including laggrin, loricrin, and involucrin, and develop an AD- like disease by allowing for enhanced penetration of allergens and pathogens across the skin barrier.45 Importantly, IL-4 deficiency was shown to be protective against the development of allergic skin inflammation in these mice, as was treatment with immune- modulators targeting either IL-4 or IL-13.45 Additionally, IL-4 and IL-13 have also been demonstrated to regulate expression of genes, such as β-defensins and cathelicidin, involved in susceptibility to skin pathogens including Staphylococcus aureus and herpes simplex virus, potentially accounting for the fact that AD patients have an increased propensity for infection by these pathogens.36-38 Together, this evidence suggests that targeting TH2 polarization in AD, including antagonism of IL-4 and IL-13, could be ef cacious in the treatment of AD.

Dupilumab Clinical Trials in AD

Given the importance of the TH2 in ammatory pathway in AD, it is not surprising that researchers have explored if the inhibition of IL-4 and IL-13 could provide a potential new treatment approach for this chronic, difficult-to-manage disease. Dupilumab is a fully human monoclonal antibody that binds the IL-4α receptor subunit, effectively blocking signalling from both IL-4 and IL-13. First tested for therapeutic value in asthma,46 dupilumab has shown impressive results in trials for AD, and looks to change the management landscape for this debilitating disease. To date, several phase I and II trials have been completed, with other phase II and III trials currently underway in both adult and pediatric populations (Table 1).

Recently, a collection of phase I/II trials were published, which looked at the effects of dupilumab on moderate-to-severe AD refractory to topical glucocorticoids and calcineurin inhibitors.47 Four trials in this publication include two phase I, 4 week monotherapy trials looking at safety as a primary endpoint (NCT01259323/study M4A and NCT01385657/study M4B) and two phase II trials, one 12 week monotherapy trial (NCT01548404/study M12) and one trial of dupilumab plus mid- high potency topical glucocorticoids with 4 weeks active treatment and 8 weeks follow-up period (NCT01639040/study C4). In the program, patients aged 18 years or older with moderate-to-severe AD and an Investigator Global Assessment (IGA) of ≥3 and a Scoring Atopic Dermatitis (SCORAD) score of ≥20 (study C4), or an Eczema Area and Severity Index (EASI) score ≥12 (studies M4A and M4B) or ≥16 (study M12), were included. Remarkably, in these phase I/II trials, patients treated with dupilumab experienced rapid improvement in AD disease activity. In study M12, the 12 week monotherapy trial, significantly more patients in the dupilumab arm experienced a ≥50% reduction in EASI score (EASI-50) as compared to the placebo arm (85% vs. 35%, respectively; p<0.001), near-to-complete clearance of skin lesions with an IGA of 0 or 1 (40% vs. 7%, respectively; p<0.001), and decreased pruritus with improvement on the pruritus Numerical Rating Scale (NRS) (56% vs. 15%, respectively; p<0.05).47 When combined with topical glucocorticoids in the C4 study, all patients treated with dupilumab reached EASI-50, compared with only half of those receiving topical glucocorticoids plus placebo (p=0.002). Importantly, patients receiving dual therapy with dupilumab used less than half the glucocorticoid therapy required by those patients receiving glucocorticoid plus placebo (p=0.16).47

Trial IDPhaseStatusNTitle of StudyPrimary Outcome Measure
NCT01015027ICompleted48A Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Phase 1 Study of the Safety and Tolerability of Intravenously Administered REGN668 in Healthy VolunteersTEAE at 85 days (11 visits)
NCT01259323 (Study M4A)ICompleted30A Randomized, Double-Blind, Placebo-Controlled, Sequential Ascending, Repeated-Dose Study of the Safety and Pharmacokinetics of Subcutaneous REGN668 in Patients With Moderate-to-Severe Extrinsic Atopic DermatitisTEAE at 12 weeks
NCT01385657 (Study M4B)I/IICompleted37A Randomized, Double-Blind, Placebo-Controlled, Sequential Ascending, Repeated-Dose Study of the Safety, Tolerability, and Pharmacokinetics of Subcutaneous REGN668 in Patients With Moderate-to-Severe Atopic DermatitisTEAE at 12 weeks
NCT01859988IICompleted380A Randomized, Double-Blind, Placebo-Controlled, Parallel- Group, Dose-Ranging Study Investigating the Efficacy, Safety, Pharmacokinetic and Biomarker Profiles of REGN668 Administered to Adult Patients With Moderate-to-Severe Atopic DermatitisPercent change in EASI score at 16 weeks
NCT01548404 (Study M12)IICompleted109A Randomized, Double-Blind, Placebo-Controlled, Repeat-Dose Study of the Efficacy, Safety, Tolerability, and Pharmacodynamics of Subcutaneously-Administered REGN668 in Adult Patients With Extrinsic Moderate-to- Severe Atopic DermatitisPercent change in EASI score at 12 weeks
NCT01639040 (Study C4)IICompleted31A Randomized, Double-Blind, Parallel-Group, Placebo- Controlled Study to Assess the Safety of REGN668 Administered Concomitantly With Topical Corticosteroids to Patients With Moderate-to-Severe Atopic DermatitisTEAE at 78 days
NCT01979016IICompleted54A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Investigating the Efficacy, Safety, Serum Concentration and Biomarker Profile of Dupilumab Administered to Adult Patients With Moderate-to-Severe Atopic DermatitisPercent change in EASI score at 16 weeks
NCT02407756IIActive80A Phase 2a Study Investigating the Safety, Pharmacokinetics, Immunogenicity, and Exploratory Efficacy of Dupilumab in Patients Aged ≥6 toPharmacokinetic parameters in pediatric patients at 12 weeks
NCT02277743IIIActive600A Phase 3 Con rmatory Study Investigating the Efficacy and Safety of Dupilumab Monotherapy Administered to Adult Patients With Moderate-to-Severe Atopic Dermatitis (SOLO-1)Proportion of patients with both IGA 0 to 1 and a reduction from baseline of ≥2 points at 16 weeks
NCT02277769IIIActive600A Phase 3 Con rmatory Study Investigating the Efficacy and Safety of Dupilumab Monotherapy Administered to Adult Patients With Moderate-to-Severe Atopic Dermatitis (SOLO-2)Proportion of patients with both IGA 0 to 1 and a reduction from baseline of ≥2 points at 16 weeks
NCT02260986IIIActive700A Randomized, Double-Blind, Placebo-Controlled Study
to Demonstrate the Efficacy and Long-Term Safety of Dupilumab in Adult Patients With Moderate-to-Severe Atopic Dermatitis		Proportion of patients with both IGA 0 to 1 and a reduction from baseline of ≥2 points at 16 weeks (Additional measures assessed up to 52 weeks)
NCT02395133IIIActive440A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Investigating the Efficacy and Safety of Multiple Dupilumab Dose Regimens Administered as Monotherapy for Maintaining Treatment Response in Patients With Atopic DermatitisProportion of patients with IGA scores of 0 or 1 at 36 weeks
NCT01949311IIIActive800An Open-label Study of Dupilumab in Patients With Atopic Dermatitis Who Participated in Previous Dupilumab Clinical TrialsTEAE at 52 and 116 weeks
Table 1: Clinical trials of dupilumab in AD

TEAE = treatment-emergent adverse events; EASI = Eczema Area and Severity Index; IGA = Investigator’s Global Assessment (on a 5-point scale)

The adverse event (AE) profiles were similar between the groups receiving either dupilumab or placebo in all of the studies. Most AEs were considered mild-to-moderate in severity, transient, and more likely to result in study discontinuation in the placebo group. The most common treatment-emergent adverse events (TEAEs) were nasopharyngitis and headache, which were more frequently reported in those subjects receiving dupilumab. Serious AEs were more frequently reported in the placebo groups (9/80) compared with the dupilumab groups (2/127). Interestingly, there were four times as many skin infections reported in the placebo groups (17/80) compared to the dupilumab groups (6/127), suggesting that dupilumab might improve skin barrier function. There were more injection site reactions in the dupilumab group but these were generally mild. There were no opportunistic infections or deaths in any of these studies.47

When evaluating the molecular signature of genes expressed in non-lesional and lesional skin from the patients included in these trials, dupilumab-treated skin showed marked improvements with downregulation of markers of both epidermal proliferation and upregulation of genes involved in skin barrier function.26 Dupilumab treatment also suppressed the expression of genes related to the activation of T cells and related inflammatory pathways, a major driver in AD clinical disease. After only 4 weeks of dupilumab treatment, the transcriptome of skin harvested from AD patients resembled that of non-lesional skin.26

Another phase II international 16 week dose-ranging study (NCT01859988) including 380 patients has been completed and recently published.48 Patients were 18 years or older and had an EASI score of ≥12 at screening (≥16 at baseline) with an inadequate response to topical therapy. This was a dose ranging study and patients were randomized to receive dupilumab 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks or placebo once a week for 16 weeks. When compared to placebo, all dupilumab dosing regimens showed a significant improvement in EASI score from baseline. The least-square means improvement of EASI score was -73.7% (300 mg every week), -68.2% (300 mg every 2 weeks), -65.4% (200 mg every 2 weeks), -63.5% (300 mg every 4 weeks), -44.8% (100 mg every 4 weeks) compared to -18.1% (placebo) (p48 The AE profile was similar to previously published studies with the most commonly reported AEs of nasopharyngitis, exacerbation of AD, headache and upper respiratory tract infection. There were more reports of herpes infections in the dupilumab group (8%) when compared to placebo (2%) as well as conjunctival inflammation (7% vs. 3%, respectively). The rate of injection site reactions was 7% in the dupilumab group vs. 3% in the placebo group.48

A summary of the burden of disease in this patient group has also been published, which showed a significant burden of disease including that on quality of life as based on a number of patient reported measures: Dermatology Life Quality Index (DLQI), EuroQoL (EQ-5D) Health Status Questionnaire, Hospital and Anxiety Depression Scale (HADS), 5-D Pruritus and Patient Oriented Eczema Measure (POEM).49

The pooled results of the 300 mg dupilumab group from this 16 week phase II study and the 300 mg group of the M12 study compared to placebo were presented recently.50 Dupilumab was administered weekly as monotherapy and no additional topical steroids were allowed; the analysis included a total population of patients given placebo (n=115) or dupilumab 300 mg (n=118) with a loading dose at week 1. The improvement in SCORAD from baseline was 37 points for dupilumab (baseline score 66) and 11 for placebo (baseline score 68), respectively (p50 The safety profile was similar to previous studies and between the two groups. The TEAEs occurring in ≥5% of trial participants during the 12 week placebo-controlled period for placebo vs. 300 mg dupilumab included upper respiratory tract infection (33.9% vs. 42.4%), skin infections (29.7% vs. 16.4%), conjunctival inflammation/ infection (3.5% vs. 15.3%), headache (7.8% vs. 14.4%), and dermatitis (14.8% vs. 11.0%), respectively. There were more injection site reactions in the dupilumab group (13.6%) vs. placebo (6.1%). There were no deaths in either study.48,50

Results from these studies have been extremely encouraging and prompted the quick expansion to clinical trials to evaluate the efficacy of dupilumab in pediatric patients, as well as the long- term safety of the drug. Currently, a phase II pharmacokinetic study in pediatric patients ≥6 and

Conclusion

Over the last several years, a number of important scientific and clinical discoveries have been made regarding the pathogenesis of AD. We now understand better than ever that AD results from defects in skin barrier function and innate and adaptive immune responses, both of which have important therapeutic implications. These discoveries not only explain the limitations of currently used treatments for AD, but also provide a map forward in our discovery of novel therapeutics for this difficult-to-treat skin disorder. Dupilumab is helping to shed new light on the pathomechanisms driving atopic dermatitis, and leading the way towards highly effective control of this debilitating disease.

References

  1. Schmitt J, Langan S, Deckert S, et al. Assessment of clinical signs of atopic dermatitis: a systematic review and recommendation. J Allergy Clin Immunol. 2013 Dec;132(6):1337-47.
  2. Shaw TE, Currie GP, Koudelka CW, et al. Eczema prevalence in the United States: data from the 2003 National Survey of Children’s Health. J Invest Dermatol. 2011 Jan;131(1):67-73.
  3. Kay J, Gawkrodger DJ, Mortimer MJ, et al. The prevalence of childhood atopic eczema in a general population. J Am Acad Dermatol. 1994 Jan;30(1):35-9.
  4. Bieber T. Atopic dermatitis. N Engl J Med. 2008 Apr 3;358(14):1483-94.
  5. Guttman-Yassky E, Nograles KE, Krueger JG. Contrasting pathogenesis of atopic dermatitis and psoriasis–part II: immune cell subsets and therapeutic concepts. J Allergy Clin Immunol. 2011 Jun;127(6):1420-32.
  6. Guttman-Yassky E, Nograles KE, Krueger JG. Contrasting pathogenesis of atopic dermatitis and psoriasis–part I: clinical and pathologic concepts. J Allergy Clin Immunol. 2011 May;127(5):1110-8.
  7. Lio PA, Lee M, LeBovidge J, et al. Clinical management of atopic dermatitis: practical highlights and updates from the atopic dermatitis practice parameter 2012. J Allergy Clin Immunol Pract. 2014 Jul-Aug;2(4):361-9; quiz 70.
  8. Williams H, Flohr C. How epidemiology has challenged 3 prevailing concepts about atopic dermatitis. J Allergy Clin Immunol. 2006 Jul;118(1):209-13.
  9. Spergel JM. From atopic dermatitis to asthma: the atopic march. Ann Allergy Asthma Immunol. 2010 Aug;105(2):99-106; quiz 7-9, 17.
  10. DaVeiga SP. Epidemiology of atopic dermatitis: a review. Allergy Asthma Proc. 2012 May-Jun;33(3):227-34.
  11. Beattie PE, Lewis-Jones MS. A comparative study of impairment of quality of life in children with skin disease and children with other chronic childhood diseases. Br J Dermatol. 2006 Jul;155(1):145-51.
  12. Boguniewicz M, Abramovits W, Paller A, et al. A multiple-domain framework of clinical, economic, and patient-reported outcomes for evaluating benefits of intervention in atopic dermatitis. J Drugs Dermatol. 2007 Apr;6(4):416-23.
  13. Mancini AJ, Kaulback K, Chamlin SL. The socioeconomic impact of atopic dermatitis in the United States: a systematic review. Pediatr Dermatol. 2008 Jan-Feb;25(1):1-6.
  14. McKenna SP, Doward LC. Quality of life of children with atopic dermatitis and their families. Curr Opin Allergy Clin Immunol. 2008 Jun;8(3):228-31.
  15. Spergel JM, Paller AS. Atopic dermatitis and the atopic march. J Allergy Clin Immunol. 2003 Dec;112(6 Suppl):S118-27.
  16. Cookson WO. The genetics of atopic dermatitis: strategies, candidate genes, and genome screens. J Am Acad Dermatol. 2001 Jul;45(1 Suppl):S7-9.
  17. Cookson WO, Moffatt MF. The genetics of atopic dermatitis. Curr Opin Allergy Clin Immunol. 2002 Oct;2(5):383-7.
  18. Haagerup A, Bjerke T, Schiotz PO, et al. Atopic dermatitis — a total genome-scan for susceptibility genes. Acta Derm Venereol. 2004 84(5):346-52.
  19. Hoffjan S, Epplen JT. The genetics of atopic dermatitis: recent findings and future options. J Mol Med (Berl). 2005 Sep;83(9):682-92.
  20. Lee YA, Wahn U, Kehrt R, et al. A major susceptibility locus for atopic dermatitis maps to chromosome 3q21. Nat Genet. 2000 Dec;26(4):470-3.
  21. Morar N, Willis-Owen SA, Moffatt MF, et al. The genetics of atopic dermatitis. J Allergy Clin Immunol. 2006 Jul;118(1):24-34; quiz 5-6.
  22. Boguniewicz M, Leung DY. Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev. 2011 Jul;242(1):233-46.
  23. Elias PM, Hatano Y, Williams ML. Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms. J Allergy Clin Immunol. 2008 Jun;121(6):1337-43.
  24. Schneider L, Tilles S, Lio P, et al. Atopic dermatitis: a practice parameter update 2012. J Allergy Clin Immunol. 2013 Feb;131(2):295-9 e1-27.
  25. Esnault S, Benbernou N, Lavaud F, et al. Differential spontaneous expression of mRNA for IL-4, IL-10, IL-13, IL-2 and interferon-gamma (IFN-gamma) in peripheral blood mononuclear cells (PBMC) from atopic patients. Clin Exp Immunol. 1996 Jan;103(1):111-8.
  26. Hamilton JD, Suarez-Farinas M, Dhingra N, et al. Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol. 2014 Dec;134(6):1293-300.
  27. Jujo K,Renz H,Abe J,et al.Decreased interferon gamma and increased interleukin-4 production in atopic dermatitis promotes IgE synthesis. J Allergy Clin Immunol. 1992 Sep;90(3 Pt 1):323-31.
  28. Kaminishi K, Soma Y, Kawa Y, et al. Flow cytometric analysis of IL-4, IL-13 and IFN-gamma expression in peripheral blood mononuclear cells and detection of circulating IL-13 in patients with atopic dermatitis provide evidence for the involvement of type 2 cytokines in the disease. J Dermatol Sci. 2002 May;29(1): 19-25.
  29. Renz H, Jujo K, Bradley KL, et al. Enhanced IL-4 production and IL-4 receptor expression in atopic dermatitis and their modulation by interferon-gamma. J Invest Dermatol. 1992 Oct;99(4):403-8.
  30. Tang M, Kemp A, Varigos G. IL-4 and interferon-gamma production in children with atopic disease. Clin Exp Immunol. 1993 Apr;92(1):120-4.
  31. Lebman DA, Coffman RL. Interleukin 4 causes isotype switching to IgE in T cell- stimulated clonal B cell cultures. J Exp Med. 1988 Sep 1;168(3):853-62.
  32. Chan LS, Robinson N, Xu L. Expression of interleukin-4 in the epidermis of transgenic mice results in a pruritic inflammatory skin disease: an experimental animal model to study atopic dermatitis. J Invest Dermatol. 2001 Oct;117(4): 977-83.
  33. Jin H, He R, Oyoshi M, et al. Animal models of atopic dermatitis. J Invest Dermatol. 2009 Jan;129(1):31-40.
  34. Lee GR, Flavell RA. Transgenic mice which overproduce Th2 cytokines develop spontaneous atopic dermatitis and asthma. Int Immunol. 2004 Aug;16(8):1155-60.
  35. Zheng T, Oh MH, Oh SY, et al. Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J Invest Dermatol. 2009 Mar;129(3):742-51.
  36. Howell MD, Fairchild HR, Kim BE, et al. Th2 cytokines act on S100/A11 to downregulate keratinocyte differentiation. J Invest Dermatol. 2008 Sep;128(9): 2248-58.
  37. Howell MD, Kim BE, Gao P, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2007 Jul;120(1):150-5.
  38. Kim BE, Leung DY, Boguniewicz M, et al. Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin Immunol. 2008 Mar;126(3):332-7.
  39. Bao L, Zhang H, Chan LS. The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis. JAKSTAT. 2013 Jul 1; 2(3): e24137.
  40. Hackstein H, Hecker M, Kruse S, et al. A novel polymorphism in the 5′ promoter region of the human interleukin-4 receptor alpha-chain gene is associated with decreased soluble interleukin-4 receptor protein levels. Immunogenetics. 2001 May-Jun;53(4):264-9.
  41. Hershey GK, Friedrich MF, Esswein LA, et al. The association of atopy with a gain- of-function mutation in the alpha subunit of the interleukin-4 receptor. N Engl J Med. 1997 Dec 11;337(24):1720-5.
  42. Howell MD, Gao P, Kim BE, et al. The signal transducer and activator of transcription 6 gene (STAT6) increases the propensity of patients with atopic dermatitis toward disseminated viral skin infections. J Allergy Clin Immunol. 2011 Nov;128(5):1006-14.
  43. Tamura K, Suzuki M, Arakawa H, et al. Linkage and association studies of STAT6 gene polymorphisms and allergic diseases. Int Arch Allergy Immunol. 2003 May;131(1):33-8.
  44. Tanaka T, Hitomi Y, Kambayashi Y, et al. The differences in the involvements of loci of promoter region and Ile50Val in interleukin-4 receptor alpha chain gene between atopic dermatitis and Japanese cedar pollinosis. Allergol Int. 2012 Mar;61(1):57-63.
  45. Sehra S, Yao Y, Howell MD, et al. IL-4 regulates skin homeostasis and the predisposition toward allergic skin inflammation. J Immunol. 2010 Mar 15; 184(6):3186-90.
  46. Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013 Jun 27;368(26):2455-66.
  47. Beck LA, Thaci D, Hamilton JD, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014 Jul 10;371(2):130-9.
  48. Thaci D, Simpson EL, Beck LA, 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 Jan 2;387(10013):40-52.
  49. Simpson EL, Bieber T, Eckert L, et al. Patient burden of moderate to severe atopic dermatitis (AD): Insights from a phase 2b clinical trial of dupilumab in adults. J Am Acad Dermatol. 2016 Jan 14. [Epub ahead of print]
  50. Papp K, Simpson E, Beck L, et al. Efficacy and safety of dupilumab for moderate- to-severe atopic dermatitis in adults: a pooled analysis of two phase 2 randomized clinical trials. Oral and poster presentations. Presented at the 23rd World Congress of Dermatology; June 8-13, 2015; Vancouver, BC.
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