Development or Exacerbation of Head and Neck Dermatitis in Patients Treated for Atopic Dermatitis With Dupilumab | Allergy and Clinical Immunology | JAMA Dermatology | JAMA Network
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Figure.  Head and Neck Dermatitis Exacerbation 1 Month After Dupilumab Therapy Initiation
Head and Neck Dermatitis Exacerbation 1 Month After Dupilumab Therapy Initiation
Table.  Clinical Characteristics of the Study Population
Clinical Characteristics of the Study Population
1.
Simpson  EL, Bieber  T, Guttman-Yassky  E,  et al; SOLO 1 and SOLO 2 Investigators.  Two phase 3 trials of dupilumab versus placebo in atopic dermatitis.  N Engl J Med. 2016;375(24):2335-2348. doi:10.1056/NEJMoa1610020PubMedGoogle ScholarCrossref
2.
Blauvelt  A, de Bruin-Weller  M, Gooderham  M,  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(10086):2287-2303. doi:10.1016/S0140-6736(17)31191-1PubMedGoogle ScholarCrossref
3.
Zhu  GA, Chen  JK, Chiou  A, Ko  J, Honari  G.  Assessment of the development of new regional dermatoses in patients treated for atopic dermatitis with dupilumab.  JAMA Dermatol. 2019;155(7):850-852. doi:10.1001/jamadermatol.2019.0109PubMedGoogle ScholarCrossref
4.
Blauvelt  A, Rosmarin  D, Bieber  T,  et al.  Improvement of atopic dermatitis with dupilumab occurs equally well across different anatomical regions: data from phase III clinical trials.  Br J Dermatol. 2019;181(1):196-197.PubMedGoogle ScholarCrossref
5.
Darabi  K, Hostetler  SG, Bechtel  MA, Zirwas  M.  The role of Malassezia in atopic dermatitis affecting the head and neck of adults.  J Am Acad Dermatol. 2009;60(1):125-136. doi:10.1016/j.jaad.2008.07.058PubMedGoogle ScholarCrossref
6.
Sparber  F, De Gregorio  C, Steckholzer  S,  et al.  The skin commensal yeast Malassezia triggers a type 17 response that coordinates anti-fungal immunity and exacerbates skin inflammation.  Cell Host Microbe. 2019;25(3):389-403.e6. doi:10.1016/j.chom.2019.02.002PubMedGoogle ScholarCrossref
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    Research Letter
    September 4, 2019

    Development or Exacerbation of Head and Neck Dermatitis in Patients Treated for Atopic Dermatitis With Dupilumab

    Author Affiliations
    • 1Service de Dermatologie et d’Allergologie, Hôpital Tenon, Paris HUEP, APHP, Paris, France
    • 2Sorbonne Universités, Paris, Centre d’Immunologie et des Maladies Infectieuses–Paris (Cimi-Paris), INSERM U1135, Paris, France
    • 3Service de Dermatologie, Centre Hospitalier Universitaire de Montpellier, Montpellier, France
    • 4Service de Dermatologie, Hôpital Saint André, Centre de Référence des Maladies Rares de la Peau, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
    • 5Service de Dermatologie, Hôpital Saint-Louis, Paris, France
    • 6Centre Hospitalier Universitaire de Lille, Service de Dermatologie et Vénérologie, F-59000 Lille, France,
    • 7University of Lille, INSERM U995-LIRIC-Lille Inflammation Research International Center, F-59000 Lille, France
    • 8Centre Hospitalier Universitaire de Nantes, Service de Dermatologie, Nantes, France
    JAMA Dermatol. 2019;155(11):1312-1315. doi:10.1001/jamadermatol.2019.2613

    The efficacy and safety of dupilumab, a humanized monoclonal antibody targeting the α subunit of the interleukin (IL)-4 and IL-13 receptors, has been assessed in adults with moderate-to-severe atopic dermatitis (AD).1,2 Injection site reactions, nasopharyngitis, conjunctivitis, and transient increases in eosinophil counts from baseline were higher in the dupilumab groups than in the placebo groups in pivotal studies.1,2 A recent study by Zhu et al3 reported new regional dermatoses in 17 patients with AD treated with dupilumab, with facial area involvement in 14 cases, whereas Blauvelt et al4 reported an equal improvement of AD with dupilumab on different anatomic regions in a post hoc analysis of data extracted from 4 phase 3 clinical trials.

    Methods

    The objective of this study was to describe development or exacerbation of head and neck dermatitis (HN-D) in patients treated for AD with dupilumab. We conducted a national retrospective study among the GREAT network (Groupe de recherche sur l’eczéma atopique de la Société Française de Dermatologie); in accordance with French legislation, institutional review board approval was waived owing to the retrospective review of patient data for the study; written consent was obtained from each patient. Eligible cases included de novo HN-D (defined as occurrence of HN-D in patients with no particular head and neck involvement at baseline, according to the investigators) (Figure) or exacerbation of HN-D (defined as a more than 50% worsening of the eczema signs from baseline on the head and neck area according to the investigators in patients with preexisting HN-D).

    Results

    Between March 2017 and January 2019, among 1000 adult patients treated for AD with dupilumab, 42 (4.2%) patients with HN-D were included from 29 centers, either HN-D aggravation (n = 32) or de novo occurrences (n = 10).

    The patients’ clinical characteristics are reported in the Table. The average age was 38.6 years (range, 19-67 years); most patients were men (26; 62%) and were diagnosed with AD during infancy or childhood (36; 86%). Among these 42 patients, 18 (43%) had ocular involvement before dupilumab therapy. The HN-D occurred 65.4 days (range, 5-365 days) after initiating dupilumab therapy. Twenty patients (48%) had concomitant ocular adverse effects under dupilumab treatment (mainly conjunctivitis).

    Patients with HN-D were treated with topical therapies, including tacrolimus (19/42), steroids (11/42), tacrolimus and steroids (2/42), or antifungal agents (2/42). Systemic antifungal agents were used in 4 cases, with total regression of HN-D in 2 cases. An improvement of HN-D was reported in 22 cases, an aggravation in 8 cases, and persistence in 5 cases under these concomitant therapies. Dupilumab therapy had to be discontinued for 5 patients owing to HN-D severity in 4 cases, and to concomitant ocular and HN-D involvement in 1 case.

    Discussion

    There are several hypotheses to explain these occurrences of HN-D: (1) a flare of AD owing to topical steroid withdrawal during dupilumab therapy; (2) a modulation of T helper (TH) cell signaling due to IL-4 receptor alpha blockade, unmasking an allergic contact dermatitis; (3) an activation of the TH17 pathway, leading to a proliferation of Malassezia fungus, which is predominantly localized in the sebaceous HN area. Indeed, Malassezia may increase AD severity in patients with HN-D.5 A recent study reported the implication of the TH17 pathway in controlling fungal colonization and driving Malassezia-induced inflammation in atopy-like skin in a mouse model of Malassezia skin colonization.6 Moreover, the authors reported a higher frequency of Malassezia-responsive memory CD4+ T cells among memory T cells from the peripheral blood of patients with AD compared with healthy controls. Interestingly, in the study by Zhu et al,3 of 14 patients with HD treated with dupilumab, 1 patient’s AD improved after topical treatment with the antifungal drug terbinafine. These new facial dermatoses could correspond to the HN-D de novo form, with similarities in terms of epidemiological (sex, onset of AD during childhood) and clinical characteristics (facial lesions, efficacy of antifungal treatment).

    We report herein a novel adverse event in patients treated with dupilumab therapy for moderate-to-severe AD as de novo occurrence or exacerbation of HN-D. A dysregulation in the balance of the TH cell signaling pathway by dupilumab could explain this particular localization.

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    Article Information

    Accepted for Publication: July 18, 2019.

    Corresponding Author: Angèle Soria, MD, PhD, Service de Dermatologie-Allergologie, Hôpital Tenon, APHP, 4 Rue de la Chine, 75020 Paris, France (angele.soria@aphp.fr).

    Published Online: September 4, 2019. doi:10.1001/jamadermatol.2019.2613

    Author Contributions: Dr Soria had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Staumont-Sallé and Barbarot contributed equally to this work.

    Study concept and design: Soria, Staumont-Sallé, Barbarot.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Soria, Staumont-Sallé, Barbarot.

    Critical revision of the manuscript for important intellectual content: All authors.

    Study supervision: Soria, Du-Thanh, Staumont-Sallé, Barbarot.

    Conflict of Interest Disclosures: Dr Soria received personal fees from Sanofi-Genzyme and Novartis. Dr Du-Thanh received personal fees from Sanofi-Genzyme, Novartis, Abbvie, Janssen. Dr Seneschal received personal fees from Sanofi-Genzyme and Lilly. Dr Jachiet received personal fees from Sanofi-Genzyme. Dr Staumont-Sallé received research grants from Pfizer and personal fees from Sanofi-Genzyme, Abbvie, Janssen, Pfizer, and Leo Pharma. Dr Barbarot received personal fees from Bioderma, La Roche Posay, Sanofi-Genzyme, Abbvie, Janssen, and Leo-Pharma and grants from PIERRE FABRE and Fondation pour la dermatite atopique.

    Group Information: The members of the GREAT Research Group are as follows: Juliette Delaunay, MD (Service de Dermatologie, Centre Hospitalier Universitaire de Angers, France), Flavien Huet, MD (Service de Dermatologie, Centre Hospitalier Universitaire de Brest, France), Catherine Droitcourt, MD, PhD (Service de Dermatologie, Hôpital de Pontchaillou, EA 7449 REPERES Pharmacoepidemiology and Health Services Research, Centre Hospitalier Universitaire de Rennes, France), Florence Tétart, MD (Service de Dermatologie, Centre Hospitalier Universitaire de Rouen, France), Claire Bernier, MD (Centre Hospitalier Universitaire de Nantes, Service de Dermatologie, Nantes, France).

    Additional Contributions: We thank the patient pictured in the Figure for granting permission to publish this information.

    References
    1.
    Simpson  EL, Bieber  T, Guttman-Yassky  E,  et al; SOLO 1 and SOLO 2 Investigators.  Two phase 3 trials of dupilumab versus placebo in atopic dermatitis.  N Engl J Med. 2016;375(24):2335-2348. doi:10.1056/NEJMoa1610020PubMedGoogle ScholarCrossref
    2.
    Blauvelt  A, de Bruin-Weller  M, Gooderham  M,  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(10086):2287-2303. doi:10.1016/S0140-6736(17)31191-1PubMedGoogle ScholarCrossref
    3.
    Zhu  GA, Chen  JK, Chiou  A, Ko  J, Honari  G.  Assessment of the development of new regional dermatoses in patients treated for atopic dermatitis with dupilumab.  JAMA Dermatol. 2019;155(7):850-852. doi:10.1001/jamadermatol.2019.0109PubMedGoogle ScholarCrossref
    4.
    Blauvelt  A, Rosmarin  D, Bieber  T,  et al.  Improvement of atopic dermatitis with dupilumab occurs equally well across different anatomical regions: data from phase III clinical trials.  Br J Dermatol. 2019;181(1):196-197.PubMedGoogle ScholarCrossref
    5.
    Darabi  K, Hostetler  SG, Bechtel  MA, Zirwas  M.  The role of Malassezia in atopic dermatitis affecting the head and neck of adults.  J Am Acad Dermatol. 2009;60(1):125-136. doi:10.1016/j.jaad.2008.07.058PubMedGoogle ScholarCrossref
    6.
    Sparber  F, De Gregorio  C, Steckholzer  S,  et al.  The skin commensal yeast Malassezia triggers a type 17 response that coordinates anti-fungal immunity and exacerbates skin inflammation.  Cell Host Microbe. 2019;25(3):389-403.e6. doi:10.1016/j.chom.2019.02.002PubMedGoogle ScholarCrossref
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