Goblet cell scarcity and conjunctival inflammation during treatment with dupilumab in patients with atopic dermatitis

Bakker, Daphne; Ariëns, Lieneke F.M.; Luijk, Chantal van; Schaft, Jorien van der; Thijs, Judith L.; Schuttelaar, Marielouise; Wijk, Femke van; Knol, Edward F.; Balak, Deepak M W; Dijk, Marijke R. van; Bruin‐Weller, Marjolein S. de

doi:10.1111/bjd.17538

Cited by 119 publications

(141 citation statements)

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“…In addition to mucin deficiency, histological analysis of conjunctival biopsies from patients on dupilumab has shown marked decrease and, in certain patients, complete absence of goblet cells. 8 The median conjunctival intraepithelial goblet cell density was 33 cells/mm 2 in persons on dupilumab versus 323 cells/mm 2 in healthy controls. In addition to a paucity of goblet cells, persons on dupilumab had a multicellular immune cell stromal infiltrate.…”

Section: Discussionmentioning

confidence: 92%

“…In various phase 3 clinical trials, patients with AD treated with dupilumab had a 14% to 19% rate of conjunctivitis, whereas patients with AD treated with a placebo had an 8% rate of conjunctivitis. 5 , 8 – 10 Although the increased rate of conjunctivitis was reported, its underlying etiology was not explored. In the setting of AD, it is not uncommon for patients to have a comorbidity of allergic conjunctivitis.…”

Section: Introductionmentioning

confidence: 99%

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Dupilumab-Associated Mucin Deficiency (DAMD)

Barnett

Afshari

2020

Trans. Vis. Sci. Tech.

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Purpose: Dupilumab, a monoclonal antibody directed against the interleukin-4 receptor subunit α (IL-4Rα) of IL-4 and IL-13, is increasingly being used to control atopic disease. Dupilumab use has been associated with a poorly understood conjunctivitis. In this study, we sought to investigate the hypothesis that dupilumab use and the associated IL-13 blockade causes a relative ocular mucin deficiency. Methods: Tear levels of mucin 5ac (Muc5AC) and total tear protein levels were evaluated from 28 eyes of 14 patients. Bilateral tear samples were acquired from seven patients on dupilumab and seven patients with no exposure to dupilumab. Study subjects were age and gender matched. In addition to tear samples, photographic documentation of ocular surface findings and a questionnaire of ocular surface symptoms were obtained. Between-group mean differences were calculated. Results: Compared with control, ocular Muc5AC levels normalized to total tear protein was statistically significantly lower. The average Muc5AC levels for persons on dupilumab was 1.54 ± 0.58 ng/mg and that of controls was 7.99 ± 1.16 ng/ mg. Persons on dupilumab reported a statistically increased occurrence of ocular fatigue/eye strain, uncomfortable sensation, pain, red eye, and itching. Conclusions: This study demonstrates for the first time, a relative deficiency of Muc5AC in patients on dupilumab. Translational Relevance: The results of this study support the previously reported role of IL-13 in increasing goblet cell density and associated Muc5AC production. Further efforts are underway to better understand the relative contribution of Muc5AC deficiency in the overall presentation of conjunctivitis associated with dupilumab use.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Dupilumab-Associated Mucin Deficiency (DAMD)

Barnett

Afshari

2020

Trans. Vis. Sci. Tech.

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“…Several hypotheses have been proposed for mechanisms driving conjunctivitis in dupilumab‐treated patients with AD, including alterations in cytokine activity leading to (variously) increased Demodex mites, increased OX40 ligand activity, eosinophilia, disruption of an immune‐mediated response of conjunctival‐associated lymphoid tissue, decreased IL‐13‐related mucus production and decreased IL‐13‐related scarcity of conjunctival goblet cells; it is possible that multiple mechanisms may be in effect . In addition, different mechanisms may affect the development of conjunctivitis in dupilumab‐treated patients with AD vs. those with asthma or other type 2 diseases.…”

Section: Discussionmentioning

confidence: 99%

Conjunctivitis in dupilumab clinical trials

et al. 2019

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Summary Background Dupilumab blocks the shared receptor component for interleukin (IL)‐4 and IL‐13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate‐to‐severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate‐to‐severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate‐to‐severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo. Objectives To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials. Methods We evaluated randomized placebo‐controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47). Results In most AD trials, dupilumab‐treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis. Conclusions Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab‐treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD). In most dupilumab AD trials, dupilumab‐treated patients had higher conjunctivitis incidence than those receiving placebo. Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare. Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials. Baseline disease‐related factors, including AD severity, prior conjunctivitis history and certa...

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“…Other hypotheses include a pathogenic role of increased OX40 ligand activity, or IL‐17 driven inflammation following colonization with demodex mites . Notably, a recent histopathology case study showed marked depletion of goblet cells in conjunctivae of patients with dupilumab‐associated conjunctivitis …”

Section: Discussionmentioning

confidence: 99%

Conjunctivitis in atopic dermatitis patients with and without dupilumab therapy – international eczema council survey and opinion

Thyssen

Bruin‐Weller

Paller

et al. 2019

Acad Dermatol Venereol

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Background Conjunctivitis is common in patients with atopic dermatitis ( AD ) in general and a commonly reported adverse event in AD clinical trials with dupilumab. Objective To survey opinions and experience about conjunctivitis occurring in AD , including those during dupilumab treatment in a group of AD experts from the International Eczema Council ( IEC ). Methods Electronic survey and in‐person discussion of management strategies. Results Forty‐six (53.5%) IEC members from 19 countries responded to the survey. Consensus was reached for several statements regarding diagnostic workup, referral and treatment. IEC members suggest that patients with AD should (i) routinely be asked about ocular complaints or symptoms, (ii) obtain information about the potential for conjunctivitis before starting dupilumab therapy and (iii) if indicated, be treated with dupilumab despite previous or current conjunctivitis. In cases of new‐onset conjunctivitis, there was consensus that dupilumab treatment should be continued when possible, with appropriate referral to an ophthalmologist. Limitations The study relies on expert opinion from dermatologists. Responses from few dermatologists without dupilumab access were not excluded from the survey. Conclusion The IEC recommends that dermatologists address conjunctivitis in patients with AD , especially during treatment with dupilumab.

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Goblet cell scarcity and conjunctival inflammation during treatment with dupilumab in patients with atopic dermatitis

Cited by 119 publications

References 8 publications

Dupilumab-Associated Mucin Deficiency (DAMD)

Dupilumab-Associated Mucin Deficiency (DAMD)

Conjunctivitis in dupilumab clinical trials

Conjunctivitis in atopic dermatitis patients with and without dupilumab therapy – international eczema council survey and opinion

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