To describe the ocular surface findings in atopic dermatitis patients treated with dupilumab.

This is an observational study including atopic dermatitis patients treated with dupilumab from January 2018 to July 2019. At baseline, patients underwent dermatological and ophthalmological assessments and at least one other joint visit during the 6-month follow-up. Appointments were scheduled at baseline, 1, 3, and 6months for ophthalmologists. Ocular assessment included past ocular history and symptoms, Ocular Surface Disease Index (OSDI) score, slit lamp examination, tear film Break Up Time and Schirmer's test. Atopic dermatitis severity scores were assessed at baseline and 3 and 6months by dermatologists.

Forty-six patients were included. Among them, 31 (67%) had preexisting ocular surface disease at baseline. Mean follow-up was 7.1±1.6months. At the 6-month endpoint, 8 patients (17%) developed newly diagnosed ocular surface disease; 13 patients (28%) experienced exacerbation of ocular surface disease; 8 patients (17%) had stable ocular surface disease, 10 patients (22%) experienced an improvement in their ocular surface disease on dupilumab, and 7 patients (15%) had no ocular surface disease from baseline to the endpoint. The presence of eyelid eczema at baseline was associated with the occurrence of dupilumab induced ocular surface disease. Only 3 patients (7%) had to discontinue treatment due to ocular adverse events.

Atopic dermatitis patients treated with dupilumab may develop polymorphic, potentially severe ocular surface disease. These results highlight the need for careful examination of the eyelids and globe of atopic dermatitis patients and early examination by ophthalmologists if conjunctivitis does not resolve with non-steroid eye drops.

Décrire les atteintes de surface oculaire au cours des dermatites atopiques sous dupilumab.

Il s’agit d’une étude observationnelle réalisée entre janvier 2018 et juillet 2019, chez des patients ayant une dermatite atopique et pour qui du dupilumab a été introduit. Le suivi ophtalmologique a été réalisé à l’inclusion, au 1er, 3e et 6e mois. L’ophtalmologue évaluait les antécédents et les symptômes oculaires, le score OSDI (Ocular Surface Disease Index), le segment antérieur en biomicroscopie, le BUT et réalisait un test de Schirmer. L’examen dermatologique déterminait le score de sévérité de la dermatite atopique à l’inclusion, au 3e et au 6e mois.

Quarante-six patients ont été inclus. Trente et un (67 %) avaient dès l’inclusion une atteinte pré-existante de surface oculaire. Le suivi moyen était de 7,1±1,6 mois. À 6 mois, 8 patients (17 %) ont développé une atteinte de surface oculaire ; 13 patients (28 %) ont eu une exacerbation de celle-ci ; 8 patients (17 %) sont restés stables, 10 patients (22 %) ont eu sous dupilumab une amélioration de leurs manifestations de surface oculaire et 7 patients (15 %) n’ont présenté aucun symptôme. La présence d’un eczéma des paupières à l’inclusion a été associée au développement d’une atteinte de surface induite par le dupilumab. Seuls 3 patients (7 %) ont dû interrompre le traitement en raison d’effets indésirables oculaires.

Au cours des dermatites atopiques sous dupilumab, les patients peuvent développer des atteintes de surface oculaire.

# Introduction

Dupilumab is a monoclonal antibody licensed for atopic dermatitis (AD), moderate to severe asthma, and chronic rhinosinusitis with nasal polyposis. It binds to the alpha-chain of the interleukin (IL)-4 receptor, thus inhibiting signaling of IL-4 and IL-13. This treatment has revolutionized the management of patients with moderate to severe atopic dermatitis refractory to conventional treatments. Dupilumab provides effective control of AD with an IgA score of 0/1 and an EASI-75 at 16weeks which is maintained at 52weeks with good clinical tolerability [1]. Dupilumab-induced ocular surface disease (DIOSD) is one of the most common adverse events in atopic dermatitis, however this complication was not found in asthma and nasal polyposis. In the clinical trials, ocular side effects were more frequent in the dupilumab group than in the placebo group, with an incidence ranging from 5 to 28% [1–3]. In clinical practice, this incidence may be as high as 50% [4,5] leading to non-compliance and even discontinuation of dupilumab despite its effectiveness for AD [6,7].

We previously conducted a pilot study and identified two patterns of DIOSD [8]. The first pattern was a mild non-specific conjunctivitis in 6/10 patients, defined by inferior punctuate keratitis, evaporative dry eye and blepharitis. The second pattern, found in 4/10 patients, defined by follicular conjunctivitis, blepharitis and perilimbal swelling resembling Trantas dots. All of them had undergone slit-lamp examination by a senior ophthalmologist.

The objective of this work was to describe the baseline ocular surface disease (OSD) in AD patients and to determine the incidence of newly diagnosed OSD, exacerbation of preexisting OSD, stabilization and improvement of OSD in patients with AD treated with dupilumab who underwent ophthalmological evaluation and monitoring through the study during at least 6months.

# Materials and methods

## Study design

This is a prospective, observational, longitudinal, single-center study with the acronym OASIS (OculAr Surface after dupIlumab therapy for atopic dermatitiS). Data were collected jointly by the ophthalmology and dermatology teams. The inclusion period was from January 2018 to July 2019. The inclusion criteria were: 1) age ≥15years, 2) moderate to severe atopic dermatitis, 3) unresponsive to systemic therapy requiring initiation of dupilumab, 4) at least one follow-up visit by both dermatologists and ophthalmologists. Exclusion criteria were a discrepancy (interval>1month) between initiation of dupilumab and the initial ophthalmologic assessment, lack of dermatologic or ophthalmologic data during de follow-up. All subjects provided informed consent prior to participation of this study conformance with the principles of the Declaration of Helsinki. Institutional Review Board of Lille Catholic Hospitals approval (OASIS-V2-MR003) was obtained. Patients could also leave the study anytime during the 6-month study.

## Medical evaluations

Dermatological visits were scheduled at baseline, before dupilumab administration, 3 and 6months. At each visit, the patient's skin history, treatment tolerance, description of skin lesions, SCORing Atopic Dermatitis (SCORAD), Eczema Area and Severity Index (EASI), and Dermatology life quality index (DLQI) scores were recorded by the dermatologist. The distribution of AD was determined: “body” as any part of the body affected, “head and body” as head and neck involvement, which is a variant AD characterized by affecting the head, neck, and superior part of the trunk, and any other part of the body. Severity AD score were evaluated at baseline and 6months. Dupilumab response is defined as clear or almost clear skin and a 75% improvement from baseline in EASI.

Ophthalmological visits were scheduled at baseline, at the same day before administration of dupilumab, at 1month, 3months and 6months. They were free to come back earlier in emergency anytime and thereafter if needed. Assessment by the ophthalmologist included ocular history of OSD, ocular symptoms, slit-lamp examination, ocular surface disease index (OSDI) (severe impact >33 to 35) [9], Schirmer's test (aqueous deficient dry eye if <10mm) [10], visual acuity measurement, and slit-lamp examination with fluorescein staining to determine Break Up Time (BUT) (evaporative dry eye if < 7s) [11] and Oxford score (severe dry eye >3). Ocular history taking and diagnosis of allergic conjunctivitis was defined as follows: 1) Seasonal conjunctivitis was defined as bilateral conjunctival injection, chemosis, watery and mild mucous discharge; 2) Vernal keratoconjunctivitis begins in childhood and peaks at about 11-13, with acute exacerbation occurring in the spring and summer, bilateral conjunctival injection with a giant papillary hypertrophy of only the superior tarsal conjunctiva; 3) Atopic keratoconjunctivitis has the onset of symptoms occurring during childhood but peak during young adult, eczematoid blepharitis, papillary hypertrophy of superior or inferior tarsal conjunctival, limbal (Horner-Trantas) dots. Fundoscopy was performed only if visual acuity decreased. Data were reported from the patient's electronic medical record.

To match the analysis in tune with our clinical observations, we decided to name 2 groups: OSD group, including cases with newly diagnosed DIOSD (subgroup A) and cases with worsening of preexisting OSD under dupilumab (subgroup B), and non OSD group, including cases with improvement of preexisting OSD under dupilumab (subgroup C), cases with stabilization of preexisting OSD under dupilumab (subgroup D) and patients without OSD from baseline to endpoint (subgroup E).

Patients with preexisting OSD at baseline were included in subgroup B, C and D. Patients with no existing OSD at baseline were included in subgroup A and E.

## Statistical analytical methods

Parameters were compared between groups using the Chi-square statistical test. Quantitative parameters were compared using non-parametric Wilcoxon tests. The significance threshold was set at 0.05. Analyses were performed using SAS v9.4 software (SAS Institute, Cary NC, USA).

# Results

From the 71 eligible patients, 46 patients who had both visits (by dermatologist and by ophthalmologist) at baseline and at least joint visits during 6months after initiation of dupilumab were included in the OASIS study (Fig. 1
                     ). Twenty-five patients were excluded since interval was>1month between dermatology and ophthalmology visits and/or lack of follow-up (patients who did not have any joint visits during the study, after initiation of dupilumab).

Among 46 patients who had joint visit at baseline before initiation of dupilumab and at least one follow-up visits by both dermatologist and ophthalmologist: 38 patients presented to scheduled ophthalmological appointments at 1month, 29 patients at 3months, 20 patients at 6months and 18 patients after 6months after initiation of dupilumab. Main reason for missed appointments for ocular evaluation was the absence of ocular complaints.

Mean age was 38.6years (ranged from 15–89years); 25 (54.3%) of patients were male (Table 1
                     ). Mean follow-up in dermatology was 7.1±4.6months (0.93–17.8months) and in ophthalmology was 6.9±5.9months (0.93–21months). Eighty-four percent (n
                     =39) of patients had atopic dermatitis since childhood, 87% (n
                     =40) had another form of atopy (asthma, rhinoconjunctivitis, food allergies). A history of allergic conjunctivitis was found in 17.4% (n
                     =8). Atopic dermatitis affected the head and body in 76.1% of cases and among them 40% had eyelid eczema. The median SCORAD was 50.3 (15–83), EASI was 17.3 (1–56) and DLQI was 11 (2–30).

Baseline ophthalmological evaluation revealed posterior blepharitis in 30 patients (65.2%), conjunctivitis in 13 patients (28.2%) and keratitis in 15 patients (32.6%); 17 (37%) patients were diagnosed as having dry eye syndrome. Although these objective ocular findings using slit-lamp examination by ophthalmologists, only 19.6% of patients complained of ocular symptoms (tearing, irritations, itching). The median OSDI was 6.3 (0–85.1), Schirmer test was 18mm (4–30mm) and BUT was 8s (1–12s). After initial evaluation, 13% of patients required eyelid care, 54.3% artificial tears and 13% anti histamine eye drops prescribed by ophthalmologists. Overall, 67% (n
                     =31) of patients had pre-existing OSD before the introduction of dupilumab.

During the study, 17% (n
                     =8) developed newly diagnosed DIOSD (subgroup A), 28% (n
                     =13) had worsening their pre-existing OSD under dupilumab (subgroup B), 22% (n
                     =10) improved their pre-existing OSD under dupilumab (subgroup C), 17% (n
                     =8) had stabilization of OSD (subgroup D) on treatment, and 15% (n
                     =7) did not develop OSD during the study (subgroup E), (Fig. 1).

When we compare the OSD group (subgroups A and B) and the non OSD group (subgroups C, D, and E), the clinical characteristics of these groups were comparable in age, gender, history of atopy, ophthalmologic history, smoking, SCORAD, EASI and OSDI scores, Schirmer test and BUT (Table 1). We found a higher frequency of eyelids eczema at baseline of patients in OSD group compare to non OSD group (52% versus 16%, P
                     =0.012).

Among patients of OSD group, mean time from dupilumab initiation to DIOSD or worsening of preexisting OSD was of 95 days±43 days (28–157 days). During the follow-up, ocular symptoms such as tearing, and irritation occurred in 15 patients (71.2%) and blepharitis in 18 patients (85.7%). Conjunctivitis was observed in 19 (90.5%) patients, which was mainly papillary and rarely follicular, associated with perilimbal lesions (Fig. 2
                     ). Keratitis was found in 30% of patients and an evaporative dry eye syndrome in 76% of patients. The mean OSDI was 26, the median Schirmer test was 25mms and the median BUT was 5.5s. Regarding therapeutic management, all patients received 62% eyelid care, 91% artificial tears, and 38% antihistamine eye drops. Ten patients (48%) required short courses of steroid drops (2 patients from subgroup A and 8 patients from subgroup B). Cyclosporine eye drops (IKERVIS® 0.1%) was necessary for 3 patients (13%) (1 patient from subgroup A and 2 patients from subgroup B). Finally, discontinuation of dupilumab was required in 3 patients (1 in subgroup A and 2 in subgroup B) due to ophthalmologic side effects.

Topical tacrolimus ointment 0.1% was administered in 10 of 46 patients (21.7%) which was applied on the eyelids and not in the conjunctiva. Tacrolimus skin treatment was prescribed by dermatologist, independently of the ocular findings. This treatment is off-label in France whereas cyclosporine eyes drops were fully reimbursed. Of these 10 patients treated with tacrolimus, only three patients showed improvement, and two of them required the discontinuation of dupilumab. Overall, two thirds of the OSD patients were well-controlled by conventional treatments as artificial tears, antihistamine eye drops, eyelid care or short courses of steroid eye drops. One third of patients were dependent to steroid drops, requiring cyclosporine or requiring the discontinuation of dupilumab.

We did not find difference in SCORAD among patients requiring cyclosporine or discontinuation of dupilumab and patients treated with conventional treatment. In OSD patients requiring steroid sparing agent or dupilumab discontinuation, time to onset of OSD was shorter (73±37 days vs 123±47 days), perilimbal lesions were more frequent (42.6% vs 7.1%), and OSDI score was higher (47.9 vs 4 respectively) than group receiving conventional treatment.

At the final assessment, the mean follow-up duration for all patients, OSD group and non OSD group was 207±176 days (45.9–544.8 days) (Table 2
                     ). The follow-up duration was shorter non OSD (141±170 days) than in the OSD group (285±150 days) since this group was composed mainly healthy ocular surface of asymptomatic patients whereas OSD patients needed to be followed until resolution of ocular surface inflammation.

Six patients had to discontinue dupilumab during the study: inefficacy of dupilumab for AD in 2 patients, 3 patients due to the ocular adverse effects, in 1 patient due to inefficacy of the drug, and 1 patient due to discovery of a perianal basal cell carcinoma. Among 3 patients who required discontinuation of dupilumab due to ocular adverse event, all of them gradually returned to normal ocular surface within 3months after stopping dupilumab.

At the final ophthalmologic assessment, there was a significant decrease between the initial and final BUT in OSD group (8s versus 5.5s, p=0.029) after diagnosis and management of OSD by ophthalmologists.

As for the final dermatological evaluation, 87% of patients had significant improvement of AD under dupilumab, as demonstrated objectively by SCORAD score change at 6months from baseline (P
                     <0.001). Response rate to dupilumab for AD between OSD group and non OSD group was similar. We did not find difference in SCORAD, EASI and DLQI changes between both groups.

# Discussion

In the literature, it has been reported that AD patients have a high frequency of OSD, between 25–43% [12,13]. However, these cases were reported by dermatologist investigators, no ophthalmological assessment was performed in clinical trial neither in real life studies.

In this study, we separate newly diagnosed DIOSD, worsening of preexisting OSD, stabilization or improvement of ocular surface findings in patients treated with Dupilumab by an ophthalmologist. Of the 46 patients included in our study, 31 patients (67%) had preexisting OSD before initiation of dupilumab, this higher frequency is probably due to a baseline evaluation of the ocular surface by an ophthalmologist using slit-lamp examination. These ocular lesions were related to AD, and not to dupilumab, since they were observed before dupilumab administration. Indeed, 8 patients with history of allergic conjunctivitis had blepharitis, papillary hypertrophy of tarsal conjunctiva without limbal dots, which correspond to clinical feature of atopic keratoconjunctivitis (AKC). There also might be a time related drug reaction in DA patients who developed a newly diagnosed of OSD or worsening of preexisting OSD.

Overall, twenty-one patients (46%) experienced newly OSD or worsening of their pre-existing OSD. The presence of eyelid eczema on initial assessment was an associated factor for developing DIOSD. Seven of the 21 patients (33%) developed corticosteroid dependence, only three patients (7%) discontinued treatment due to ophthalmological side effects. Shorter interval from dupilumab initiation, history of preexisting OSD, particularly penetrating keratoplasty for keratoconus or herpetic keratitis, and presence of perilimbal inflammation were found in patients requiring steroid sparing agent or dupilumab discontinuation.

Our results also showed improvement (10 patients/subgroup C) of pre-existing OSD under dupilumab, which might be attributed by prescription of artificial tears, eyelid care by ophthalmologists at initial assessment. This has not been reported in the literature previously. These results suggest the usefulness of evaluation and management by ophthalmologists before dupilumab initiation. However, in centers without ophthalmologists, dermatologists can therefore prescribe these eye drops, and referred patients to ophthalmologists in case of persistent conjunctivitis. This preventive treatment was suggested in a recent review conducted by Doan et al. [14].

Nearly half (46%) of AD patients treated with dupilumab develops newly diagnosed or worsening of OSD during the first 6months. In the real-life study, incidence rates of conjunctivitis were between 6.5% and 70% [5,6,8,15–20]. The slightly higher incidence in our study may be related to initial assessment by ophthalmologist [16,21–26]. We acknowledge that missing data from missed appointments in 11 asymptomatic patients results to a bias of incidence of DIOSD, which would be lower if they attended the appointment. The duration of our study is also longer the previous reports (at least 6months in all patients, up to 18months). Only a few studies had longer follow-up, ranging from 24 to 52weeks [6,7,27,28].

The onset or worsening of DIOSD occurred between 1 and 5months of dupilumab treatment in this study, which is consistent with data in the literature [5,6,15]. No patient had infectious conjunctivitis requiring antibiotic eye drops. Two third of them were rapidly relieved by eyelid care, lacrimal substitutes, antihistamine eye drops, short course of steroid eye drops.

Nahum's team showed complete resolution of blepharoconjunctivitis in 4 patients after application of tacrolimus ointment, suggesting that DIOSD is partly related to immune dysregulation [6]. The reason for no improvement with tacrolimus in our study is probably due to cutaneous application and not an off-label conjunctiva use.

The physiopathology of DIOSD can explained by several hypotheses. Blocking the Th2 pathway with dupilumab therapy results in a shift towards Th1, causing the ocular findings associated with dupilumab. In addition, blockage of IL-13 might have implications with regards to mucin production and ocular surface health [17,29]. This action is essential to maintain a healthy epithelial barrier and to avoid a worsening of ocular dryness. IL-13 blockade may play a role in the induction of inflammation of ocular surface [29]. This change in immune profile would be predominant in the mechanisms of atopic keratoconjunctivitis (AKC) [30]. Significant incidence of DIOSD is observed only in AD and not in other Th2-mediated diseases (asthma, rhinoconjunctivitis), showing that AD is probably a role of OSD development [31,32].

One third of OSD patients required steroid sparing agent or dupilumab discontinuation. The characteristics of these disorders were marked by the presence of follicular conjunctivitis, chemosis and limbitis [33–35]. We would recommend management by ophthalmologists in these cases. The use of steroid drops for long duration is harmful without ocular monitoring since steroid drops are known to have ocular side effects such as cataract, glaucoma, and exacerbation of undiagnosed herpetic keratitis in AD patients. Ophthalmologists using various therapeutic arsenal should manage these cases: steroid and sparing steroid agent as cyclosporine eye drops of calcineurin inhibitor.

Recent studies have demonstrated a strong association between the risk of developing OSD and severity AD under dupilumab, or atopy condition, or a history of conjunctivitis reported by dermatologist investigators [4,6,8,15,17]. Our study did not find a significant association between these different elements. Regarding the history of conjunctivitis, the design of the study allows distinction between a newly diagnosed DIOSD entity and a previous history of AKC. In the literature, only the history of conjunctivitis has been noted, often by dermatologist investigators, without distinction of etiology [5,15]. There was a statistical difference between the presence of eyelid eczema on initial evaluation, mainly noticed by ophthalmologists in our study, that had never been reported previously in literature. The presence of eyelid eczema on initial assessment is therefore a potential association factor for developing DIOSD. This observation is supported by the results of a recent multicenter prospective study, demonstrating that head and neck AD localization is strongly associated with DIOSD [26,36].

Our study has the strength of a prospective observational study using a homogenous ocular surface evaluation, with a relative longer duration of 6months. It has the limit of high-rate loss of follow-up, leading to higher incidence bias of DIOSD. It highlights the need of a careful look of the eyelid of DA patients, which is easily evaluated by non-ophthalmologists to identify patients at risk to develop DIOSD, referral for ophthalmologic evaluation in good time and further follow-up for these patients after initiation of dupilumab.

# Conclusion

This study demonstrated the usefulness of collaboration with ophthalmologists at the initiation of dupilumab treatment in patients with AD to discover these findings. Although conjunctivitis is common in AD treated with dupilumab therapy, most newly induced OSD are mild and can be managed by a general practitioner or dermatologist using simple treatment (eyelid care, various artificial tears, preservative-free antihistamine eye drops). dupilumab may develop potentially severe ocular surface disease in patients with eyelids eczema, requiring early examination by ophthalmologists in case of conjunctivitis unresponsive to these drops.