Dupilumab‐induced skin‐associated side effects in patients with chronic rhinosinusitis with nasal polyposis

Abstract Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a typical type‐2 inflammation involving T‐helper type‐2 cells and impairing quality of life due to nasal obstruction, discharge and reduced sense of smell. Recently, the anti‐IL4Rα antibody dupilumab was approved for CRSwNP. While dermatologic side effects in patients treated with dupilumab for atopic dermatitis are frequently observed, there is limited knowledge about these effects in patients with CRSwNP. We aimed to investigate frequency and characteristics of dermatologic side effects following initiation of dupilumab treatment in a cohort of Austrian CRSwNP patients. Therefore, CRSwNP patients presenting at the Department of Otorhinolaryngology, Head and Neck Surgery at the Vienna General Hospital were retrospectively evaluated for newly developed skin eruptions while under dupilumab treatment. Incidence was calculated and details on clinical symptoms were collected. One hundred and ninety‐two CRSwNP patients receiving dupilumab treatment were included, comprising a cumulative follow‐up of 89.65 years (median: 5.5, IQR: 5.9). We observed dermatologic side effects in four patients starting at a median time of 15.5 (range 4–23) weeks after dupilumab initiation corresponding to an incidence‐rate of 4.46 (95%‐confidence interval 1.39–11.23) events per 100 patient‐years follow‐up. The majority (75%, 3/4) of affected patients developed psoriasis‐like dermatitis, whereas one individual experienced rosacea‐like folliculitis and alopecia areata. While dupilumab dosing was reduced in 3/4 CRSwNP patients, one patient completely stopped dupilumab therapy. Our study provides the first comprehensive evaluation of both frequency and characteristics of dermatologic side effects caused by dupilumab in CRSwNP patients. All affected patients developed Th1‐inflammatory associated skin disorders – previously observed only in individuals with prior affections of the skin (i.e. atopic dermatitis). Thus, individuals receiving dupilumab for CRSwNP may develop novel symptoms that require interdisciplinary management. Future studies on dupilumab in a real‐world setting will be required to further explore its spectrum of side effects.

for atopic dermatitis are frequently observed, there is limited knowledge about these effects in patients with CRSwNP. We aimed to investigate frequency and characteristics of dermatologic side effects following initiation of dupilumab treatment in a cohort of Austrian CRSwNP patients. Therefore, CRSwNP patients presenting at the Department of Otorhinolaryngology, Head and Neck Surgery at the Vienna General Hospital were retrospectively evaluated for newly developed skin eruptions while under dupilumab treatment. Incidence was calculated and details on clinical symptoms were collected.
One hundred and ninety-two CRSwNP patients receiving dupilumab treatment were included, comprising a cumulative follow-up of 89.65 years (median: 5.5, IQR: 5.9). We observed dermatologic side effects in four patients starting at a median time of 15.5 (range 4-23) weeks after dupilumab initiation corresponding to an incidence-rate of 4.46 (95%-confidence interval 1.39-11.23) events per 100 patient-years follow-up. The majority (75%, 3/4) of affected patients developed psoriasis-like dermatitis, whereas one individual experienced rosacea-like folliculitis and alopecia areata. While dupilumab dosing was reduced in 3/4 CRSwNP patients, one patient completely stopped dupilumab therapy. Our study provides the first comprehensive evaluation of both frequency and characteristics of dermatologic side effects caused by dupilumab in CRSwNP patients.
All affected patients developed Th1-inflammatory associated skin disorders -previously observed only in individuals with prior affections of the skin (i.e. atopic dermatitis). Thus, individuals receiving dupilumab for CRSwNP may develop novel symptoms that require interdisciplinary management. Future studies on dupilumab in a real-world setting will be required to further explore its spectrum of side effects.

K E Y W O R D S
CRSwNP, Dupilumab, nasal polyposis, psoriasiform dermatitis, rosacea-like folliculitis

| INTRODUC TI ON
The estimated prevalence of chronic rhinosinusitis with nasal polyposis (CRSwNP) in Western countries is 1.95%-4%. [1][2][3] CRSwNP is characterized by hyperplasia of the sinonasal mucosa that leads to nasal obstruction, nasal discharge, impaired olfactory performances and poor quality of life. Immunologically, CRSwNP is associated with a type-2 inflammation involving T-helper type-2 cells (Th2), type-2 innate lymphoid cells and interleukin (IL)-4, IL-5, IL-13 signaling and an infiltrate of mast cells, eosinophils and basophils within the polyps. 4 Dupilumab, a monoclonal antibody blocking the IL-4/IL-13 receptor component IL-4Rα, has been recently approved for the treatment of various type-2 inflammatory diseases including moderateto-severe atopic dermatitis (AD), chronic rhinosinusitis and moderate-to-severe asthma. 5,6 While dupilumab is generally well tolerated, typical adverse events in patients with AD comprise ocular complications, dermatologic eruptions (e.g. psoriasiform dermatitis, alopecia areata) and rare cases of other diseases. [6][7][8] A recent report based on the FDA's 'Adverse Event Reporting System' found significantly less dupilumab-related adverse events in patients with CRSwNP as compared to those with AD or asthma. 9 While this study could not further specify adverse skin reactions, series of case reports are describing onset of psoriasiform dermatitis following dupilumab initiation in AD patients. 10,11 Blocking IL4Rα potentially leads to conversion from Th2-to Th1 or Th17-dominated immune pathways resulting in psoriasis-or rosacea-like skin eruptions. 12 Whether this immunologic phenomenon is limited to patients with prior affection of the skin (i.e. AD) remained unanswered. To gain information on dermatologic side effects of dupilumab in CRSwNP patients in a real-world setting, we evaluated an Austrian cohort of CRSwNP patients and described the frequency and nature of newly developed skin eruptions.   (Table S1).

| Ethics
Four skin-related adverse events were recorded during a cumulative follow-up of 89.65 years resulting in an incidence-rate of 4.46 (95%-confidence interval 1.39-11.23) events per 100 patient-years (PY). The median follow-up was 5.5 months (IQR 5.9) and the median time from dupilumab initiation to onset of dermatologic side effects was 15.5 (range 4-23) weeks.

| In-depth analysis of patients with dermatologic side effects
All patients showed a significant improvement of CRSwNP upon dupilumab initiation (Table 1). Patient A presented with multiple

| DISCUSS ION
This study aimed at analyzing dermatologic side effects in 192 patients receiving dupilumab for CRSwNP in a real-world setting.
Dermatologic eruptions occurred at an incidence-rate of 4.46 per 100PY and after a median time of 15.5 weeks after dupilumab TA B L E 1 Characteristics of CRSwNP patients with dermatologic side effects after dupilumab initiation Previous studies reported various adverse events related to dupilumab for CRSwNP occurring in phase-II and phase-III clinical trials. However, skin-related adverse events (non-injection site reactions) were not reported. 5,13 To the best of our knowledge, Swisher A.R. and co-workers performed the only prior investigation providing data on dupilumab-associated dermatologic side effects in CRSwNP patients. While their study included a large number of observations, no details on the nature of dermatologic eruptions were provided. 9 The limited data available in CRSwNP patients is opposed by a multitude of publications reporting either rosacea-like dermatitis or psoriasiform dermatitis in dupilumabtreated patients with AD. 6,10,11,14 In our study, we observed one case of rosacea-like dermatitis and three cases of psoriasiform dermatitis, with one patient additionally developing alopecia areata.
For AD, it was previously hypothesized that blocking IL-4Rα results in inhibition of skin-resident Th2-mediated inflammation thereby stimulating opposing Th1 and Th-17 pathways. This is of particular interest, since CRSwNP like AD is a classical Th2-mediated disease. As psoriasis is a typical Th1/Th17-mediated skin disorder, tipping the immunological scale towards a Th1/Th17 phenotype may result in activation of a psoriasis-specific inflammatory cytokine cascade and eventually in clinical psoriasis-like inflammation. 11 Recently, exacerbation of rosacea caused by demodex infestation was discussed to be caused by Th1 and/or Th17 as well. 8

F I G U R E 2
In patient A, disseminated erythematous plaques with slight, but definite scaling were found on both arms (left arm, (a)) and upper thighs. Punch biopsy revealed a lamellar stratum corneum, parakeratosis and spongiosis with lymphocytic infiltrate, psoriasiform acanthosis with thinning of the granular cell layer and dilated blood vessels and erythrocytic extravasates in the papillary dermis reaching up to dermal-epidermal junction zone in the hematoxylin and eosin staining (b). In patient B, erythematous plaques with distinct white scaling occurred on all extremities, on the scalp and around the face and ears (c). Histologic examination showed clear signs of psoriasiform acanthosis, parakeratosis, neutrophil granulocytes in the stratum corneum and papillomatosis with dilated capillaries (d).