Conjunctivitis in Dupilumab Clinical Trials

B. Akinlade; E. Guttman-Yassky; M. de Bruin-Weller; E.L. Simpson; A. Blauvelt; M.J. Cork; E. Prens; P. Asbell; E. Akpek; J. Corren; C. Bachert; I. Hirano; J. Weyne; A. Korotzer; Z. Chen; T. Hultsch; X. Zhu; J.D. Davis; L. Mannent; J.D. Hamilton; A. Teper; H. Staudinger; E. Rizova; G. Pirozzi; N.M.H. Graham; B. Shumel; M. Ardeleanu; A. Wollenberg

Disclosures

The British Journal of Dermatology. 2019;181(3):459-473. 

In This Article

Abstract and Introduction

Abstract

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.

Introduction

Ocular surface diseases, such as allergic conjunctivitis, blepharitis and keratitis, are well-known ophthalmic complications in patients with severe atopic dermatitis (AD), with incidence rates of 32·4–55·8%.[1–8] The incidence of ophthalmic complications increases with AD severity.[4,8] Allergic conjunctivitis and other ocular surface disorders are also common comorbidities of other atopic disorders such as asthma and allergic rhinitis.[9–17]

Dupilumab is a fully human VelocImmune-derived[18,19] monoclonal antibody blocking the shared receptor component for interleukin (IL)-4 and IL-13, thus inhibiting signalling of both IL-4 and IL-13.

Dupilumab is approved for subcutaneous administration at 300 mg every 2 weeks (q2w) for patients aged ≥ 12 years in the U.S.A. with moderate-to-severe AD inadequately controlled with topical prescription therapies or when those therapies are not advisable.[20] It is also approved for the treatment of adult patients with AD not adequately controlled with existing therapies in Japan, and for use in adults with inadequately controlled, moderate-to-severe AD who are candidates for systemic therapy in the European Union.[21] Dupilumab is also used as an add-on maintenance treatment in patients aged ≥ 12 years with moderate-to-severe asthma and an eosinophilic phenotype or oral corticosteroid dependence.[20]

In clinical trials, dupilumab demonstrated efficacy and safety in AD,[22–26] asthma,[27–31] chronic rhinosinusitis with nasal polyps (CRSwNP)[32] and eosinophilic oesophagitis (EoE),[33] demonstrating that IL-4 and IL-13 are key drivers of multiple type 2 inflammatory diseases.

Ocular surface disorders, including conjunctivitis, blepharitis, keratitis, eye pruritus and dry eye, are commonly reported adverse events (AEs) in dupilumab-treated patients with AD.[20,21] Conjunctivitis of all aetiologies and phenotypes with or without eyelid or corneal involvement was dominant among all ocular AEs reported in dupilumab clinical trials in AD.[20,21,24–26,34,35] To characterize conjunctivitis in patients treated with dupilumab, we reviewed the results of published clinical trials, and synthesized the available data on incidence rates, disease course and associated baseline characteristics of patients who developed conjunctivitis in randomized, double-blinded, placebo-controlled trials of dupilumab in AD, asthma, CRSwNP and EoE.

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