Head and neck atopic dermatitis: still a challenging manifestation in the biologic era

KEYWORDS:

• Atopic dermatitis
• dupilumab
• head and neck
• upadacitinib
• malassezia
• allergens

1. Introduction

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases affecting 5–20% of children and 2–10% of adults worldwide [1]. It is clinically characterized by intense itch and eczematous lesions having a preferential body distribution based on the age of the subject [1].

The involvement of the head-and-neck area, associated or not with lesions occurring in other body regions, likely represents the most typical localization in both childhood and adulthood, as it is observed in up to 38% of both AD children and adults [1]. Notably, the localization of AD at the head-and-neck area, greatly than other areas, has been associated with social embarrassment, stigmatization, and deterioration of patients’ quality of life [2,3]. A US Delphi study reported the AD localization at head-and-neck area in 68% of the study population, and this localization resulted significantly associated with both an increased impact of the disease on anxiety and depression (measured by the EuroQol 5-Dimension tool) and a higher prevalence of bothersome symptoms (Itch, soreness, pain, and stinging) [2]. Moreover, a recently published real-life experience analyzed sectorial Eczema Area and Severity Index (EASI) score of the head-and-neck region, revealing an association between head-and-neck localization and a worse patient’s quality of life (assessed by Dermatology Life Quality Index [DLQI]), whereas a worse patient’s quality of life was not associated with other body areas [3].

In line with these observations, an expert-based consensus considered head-and-neck involvement in AD as one of the criteria, independently from total EASI score, to define AD as moderate-to-severe [4]. The drug-induced achievement of a stable remission of AD in the head-and-neck area might be difficult to obtain because of constant exposition to irritants, allergens, or because of a hypersensitivity to Malassezia yeast [5,6]. Indeed, a selective localization of AD lesions in seborrheic areas is quite common, especially in adulthood, and several studies detected significantly higher levels of Malassezia-specific IgE in patients with head-and-neck involvement in comparison with patients without AD manifestations in that body area [5]. Thereby, an empirical therapy with topical and/or oral antifungals is suggested, though responsiveness to this therapeutic approach is controversial [5,7]. In addition, long-term application of topical steroids on the face is not recommended due to potential side effects (atrophy, dyschromia, and telangiectasias), while application of topical calcineurin inhibitors (tacrolimus and pimecrolimus) is often limited because of the drug-related burning sensation and discomfort [5].

In recent years, dupilumab, the first biologic agent approved for AD that inhibits the signaling of two pathogenic inflammatory type 2 cytokines, interleukin (IL)−4 and IL−13, has revolutionized the therapeutic management of moderate-to-severe AD in both children and adults, enabling a stable, long-term control of disease manifestations in a large percentage of patients and combining a favorable safety profile [8].

Although no warning signal emerged during clinical trials, several case reports and case series reported the occurrence or worsening of dermatitis in the head-and-neck region during dupilumab treatment [9]. Several hypotheses have been proposed to explain the occurrence of this adverse event, including corticosteroid withdrawal, rosacea, allergic contact dermatitis, Malassezia colonization involving face and/or neck, seborrheic dermatitis, photosensitivity, and alcohol-induced facial redness [9].

2. Dupilumab efficacy data in the treatment head-and-neck AD from phase III trials

A post hoc analysis, including data from four phase III studies on adult AD, underlined a comparable therapeutic response of dupilumab, as assessed by EASI, across the four different body regions (head and neck, trunk, upper extremities, lower extremities) [10]. Nevertheless, a more recent post hoc analysis based on data from CHRONOS AD LIBERTY study, analyzing the percentage of improvement in the four clinical signs assessed by EASI (erythema, infiltration/papulation, excoriation, and lichenification), revealed a slightly lower reduction of erythema in the head-and-neck area, than in the other body regions through a 52-week treatment period [11].

3. Dupilumab effectiveness in the treatment of head-and-neck AD: real-world findings

Albeit real-world experiences confirmed the overall efficacy of dupilumab, a slightly lower clinical response of AD in the head-and-neck area, compared to other body regions has been highlighted [12–14].

A real-world study, including 347 adult AD patients treated with dupilumab throughout 2 years of observation, detected an elevated persistence of eczematous lesions localized at the head-and-neck area [12]. In particular, AD involvement of the head-and-neck area was observed in 76% of patients before the start dupilumab and persistence of AD in that area was reported in 68% of patients after 104 weeks of treatment [12]. Similarly, another real-life experience, including 80 adult AD patients, detected head-and-neck AD before starting dupilumab therapy in 49 (61.3%) subjects with a large proportion of patients (35/49, 71.4%) showing persistence of residual facial dermatitis during dupilumab therapy [13].

We also reported a persistence of AD at the head-and-neck region during treatment with dupilumab that was associated with a significantly lower response meant as decrease in mean EASI score and reduced likelihood of achieving an EASI 90 response compared to patients without head-and-neck AD persistence [14]. In addition, our study revealed a significant association between the presence of head-and-neck AD at the baseline and a lower likelihood of achieving an EASI ≤1 that, in turn, correlated with achievement of an absent impact of the disease on patient quality of life (DLQI score of 0–1) [14].

4. Expert opinion

Head-and-neck localization of AD might represent a challenging condition as multiple aggravating factors could potentially contribute to the persistence of the disease notwithstanding the elevated efficacy associated with the use of biological agents, particularly with dupilumab. Indeed, no specific data on the efficacy of tralokinumab, lebrikizumab, or other biological agents developed for the treatment of AD are currently available.

The constant exposure of the head-and-neck area to several types of allergens might be a contributing factor to AD persistence in this body area, and therefore, patch testing in patients with recalcitrant head-and-neck AD may be recommended to rule out concomitant contact allergic dermatitis that might overlap with AD, complicating the therapeutic management [5].

In a recent published real-life experience, a positivity in expanded patch testing was observed in 12 of 13 patients with residual head-and-neck AD during dupilumab treatment, and all patients with positive patch tests experienced a substantial clinical improvement after allergen avoidance [6]. Consistently, in another real-world study performing expanded patch test, positivity for one or more relevant allergens was found in almost all patients (92.9%, 13/14) with dupilumab-resistant head-and-neck AD [13]. Notably, 50% of them obtained a consistent amelioration of facial dermatitis after allergen avoidance [13]. On the contrary, in our experience patch test positivity was observed in 47% (8/17) of patients with residual facial AD during dupilumab therapy, but no meaningful clinical amelioration was obtained by avoiding exposure to allergens wherever possible [7]. In order to evaluate an adequate number of allergens, a comprehensive and expanded patch test series may be advisable, integrating a basic panel (i.e. the standard SIDAPA series) with advanced series chosen according to the patient’s medical history and the identification of potential patient’s commonly used products that can cause sensitization. Patient selection is crucially important because expanded patch testing constitutes an additional cost for the disease management and a time-consuming procedure for patients. The unresponsiveness to current available therapies can be a criterion to identify those patients eligible for patch testing.

The hypersensitivity to Malassezia yeast is another aspect that, for some authors, might be considered in the management of the head-and-neck AD. Because of a potential pathogenic role of Malassezia in AD localized in seborrheic areas, the empirical therapy with topical and/or oral antifungals is suggested [5], including for dupilumab-resistant head-and-neck AD. The efficacy of this therapeutic strategy is still uncertain. In our experience, for instance, a systemic antifungal therapy administered in 5 of 10 patients with Malassezia-specific IgE positivity failed to provide significant benefits [7]. Likely, the favorable response in head-and-neck AD observed with azole antifungals (e.g. itraconazole, fluconazole) might be mainly related to the intrinsic cytostatic and anti-inflammatory properties of these molecules rather than their antimycotic effects.

For the management of dupilumab-resistant head-and-neck AD, we obtained a significant improvement in a large proportion of patients through the combination of topical drugs (corticosteroids and/or calcineurin inhibitor) or traditional systemic immunosuppressants (cyclosporine, methotrexate, or azathioprine) with dupilumab [14]. In case of unsuccessful response to dupilumab in the treatment of head-and-neck AD, we achieved a satisfactory response with upadacitinib, an oral agent selectively inhibiting the Janus kinase (JAK)−1 [15]. A complete remission of head-and-neck AD after dupilumab failure was observed in three of six patients as early as 4 weeks of treatment and was maintained through 52 weeks, while in three patients, a minimal residual AD (EASI ≤1) persisted through the observation period, albeit the residual AD lesions did not affect either symptoms or patients’ quality of life (achievement of DLQI 0/1) [15].

Although the effectiveness of JAK inhibitors has been reported in both trial and real-world settings, in this peculiar localization of AD, data are very limited; thus, further investigation, especially on the long-term period, is needed. The characterization of the transcriptomic profile related to head-and-neck AD would be of great interest, as no data are currently available. In particular, transcriptomic analyses would help to clarify the poor response to dupilumab, and the beneficial effects obtained through JAK inhibition.

Declaration of interest

A Chiricozzi has served as advisory board member and consultant and has received fees and speaker’s honoraria or has participated in clinical trials for AbbVie, Almirall, Boehringer Ingelheim, Bristol Myers Squibb, Leo Pharma, Lilly, Janssen, Novartis, Pfizer, and Sanofi Genzyme. N Gori served as advisory board member and received honoraria for lectures for AbbVie, Sanofi, and Leo Pharma. E Ippoliti has no conflict of interests to declare. K Peris has served on advisory board, received honoraria for lectures and/or research grants for AbbVie, Almirall, Lilly, Galderma, Leo Pharma, Pierre Fabre, Novartis, Sanofi, Sun Pharma, and Janssen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.