Abstract
This cohort study describes the development or exacerbation of head and neck dermatitis in patients treated with dupilumab for atopic dermatitis.
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).
Figure. Head and Neck Dermatitis Exacerbation 1 Month After Dupilumab Therapy Initiation.
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).
Table. Clinical Characteristics of the Study Population.
| Characteristic | Patients, No. | ||
|---|---|---|---|
| Whole Population (n = 42) | Head and Neck Dermatitis | ||
| Exacerbation (n = 32) | De Novo (n = 10) | ||
| Average age, y (median) | 38.6 (38.5) | 39.1 (38.5) | 37.2 (36.5) |
| Range | 19-67 | ||
| Male sex, No. (%) | 26 (62) | 21 (66) | 5 (50) |
| History of AD | |||
| Onset of disease | |||
| Infant | 24 | 19 | 5 |
| Child | 12 | 9 | 3 |
| Teenager | 3 | 1 | 2 |
| Adult | 3 | 3 | 0 |
| Average duration, y (median) | 30.1 (28) | 30.5 (28) | 28.9 (27.5) |
| Severity of AD before/after dupilumab therapy, IGAa | |||
| 0 | 0/4 | 0/3 | 0/1 |
| 1 | 0/21 | 0/17 | 0/4 |
| 2 | 2/9 | 0/6 | 2/3 |
| 3 | 18/2 | 14/2 | 4/0 |
| 4 | 22/4 | 18/3 | 4/1 |
| Delay of occurrence of HN-D, d (median) | 65.4 (47.5) | 72 (44) | 60 (32.5) |
| Ocular involvement before dupilumab therapy (n = 18) | |||
| Conjunctivitis | 8 | 7 | 1 |
| Blepharitis | 0 | 0 | 0 |
| Palpebral eczema | 3 | 3 | 0 |
| Keratitis | 2 | 1 | 1 |
| Others | 5 | 5 | 0 |
| Ocular involvement after dupilumab therapy (n = 25) | |||
| Conjunctivitis | 11 | 10 | 1 |
| Blepharitis | 4 | 2 | 2 |
| Palpebral eczema | 3 | 3 | 0 |
| Keratitis | 2 | 1 | 1 |
| Others | 5 | 4 | 1 |
| Concomitant HN-D and ocular involvement, No. (%) | 20 (48) | 16 (50) | 4 (40) |
| Therapy Used for HN-D Treatment | |||
| Antifungal agents | |||
| Topical | 2 | 2 | 0 |
| Systemic | 4 | 3 | 1 |
| Steroids | |||
| Topical | 11 | 8 | 3 |
| Systemic | 2 | 1 | 1 |
| Topical tacrolimus inhibitors | |||
| Calcineurin | 19 | 16 | 3 |
| Steroids and calcineurin | 2 | 2 | 0 |
| Not known | 2 | 0 | 2 |
| Evolution of HN-D | |||
| Aggravationb | 8 | 6 | 2 |
| Persistencec | 5 | 5 | 0 |
| Improvementd | 22 | 16 | 6 |
| Not known | 7 | 5 | 2 |
| Discontinuation of dupilumab therapy (n = 7) | |||
| HN-D involvement | 4 | 3 | 1 |
| Ocular involvement | 1 | 1 | 0 |
| HN-D and ocular involvement | 1 | 0 | 1 |
| Other involvemente | 1 | 1 | 0 |
Abbreviations: AD, atopic dermatitis; HN-D, head and neck dermatitis; IGA, investigator global assessment.
Severity was evaluated with an IGA scale of 5 points: 0, clear; 1, almost clear; 2, mild; 3, moderate; 4, severe. For 2 patients, IGA after dupilumab was not known.
With topical tacrolimus (n = 4), topical steroids (n = 1), topical steroid and topical tacrolimus (n = 1), and systemic antifungals (n = 2).
With topical tacrolimus (n = 3) and topical antifungals (n = 2).
With topical tacrolimus (n = 12), topical steroids (n = 6), systemic steroids (n = 1), systemic antifungals (n = 2), and unknown (n = 1).
For persistent enlarged lymph node involvement.
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.
References
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