Dupilumab-Induced Follicular Conjunctivitis

Shen, Edward; Xie, Kate; Jwo, Kevin; Smith, Janellen; Mosaed, Sameh

doi:10.1080/09273948.2018.1533567

Cited by 37 publications

(51 citation statements)

References 11 publications

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“…Case series and case reports have described several therapeutic approaches used successfully in clinical practice for treatment of conjunctivitis associated with dupilumab without discontinuation of dupilumab, including hyaluronic acid eyedrops, topical tacrolimus, TCS (e.g. fluorometholone, dexamethasone, hydrocortisone), artificial tears, compounded oily ciclosporin eyedrops and antibiotic–TCS combination therapies . As long‐term treatment with ophthalmic TCS can lead to more serious eye disorders such as cataracts and glaucoma, products with poor penetration into the anterior chamber of the eye (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Data on specific clinical features of ocular AEs were not collected in these trials, and inconsistencies in how MedDRA PTs were assigned limit the utility of comparison of conjunctivitis PTs between dupilumab and placebo. Case reports have described common features of conjunctivitis in dupilumab‐treated patients from clinical practice, including conjunctival redness, hyperaemia, blepharitis, dryness, irritation, discharge, itch, stinging, burning, tearing, foreign‐body sensation, occasional decrease in bilateral visual acuity and ectropion . Further study into the clinical characteristics of conjunctivitis associated with dupilumab is warranted, and ongoing.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Conjunctivitis in dupilumab clinical trials

et al. 2019

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“…Although IL-4Rα signaling drives allergic disorders, it also protects against multicellular parasites (arthropods and worms), contributes to wound healing, and may protect against immunologic disorders mediated predominantly by non-type 2 T cells. 31 – 41 Consequently, the safety of targeting of IL-4Rα for therapeutic means would be optimal when such therapy is specific to the organ and/or cell types that manifest disease. Because our observations demonstrate that smooth muscle and airway epithelium mediate the great majority, if not all, AHR in experimental allergic asthma and do so through expression of IL-4Rα, future asthma therapeutics might achieve an optimal risk/benefit ratio by targeting IL-4Rα expression on just these two cell types.…”

Section: Discussionmentioning

confidence: 99%

IL-4Rα expression by airway epithelium and smooth muscle accounts for nearly all airway hyperresponsiveness in murine allergic airway disease

McKnight¹,

Potter

Finkelman

2020

Mucosal Immunology

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Airway hyperresponsiveness (AHR) often defines asthma. Murine allergic airway disease (AAD), like human eosinophilic asthma, is characterized by AHR, eosinophilia, goblet cell metaplasia (GCM), smooth muscle hypercontractility and increased production of IL-4 and IL-13—cytokines that induce these characteristics by binding to the IL-4Rα chain. We evaluated the epithelial and smooth muscle IL-4Rα-dependent contributions to AHR of BALB/c mice that possessed 0–2 functional IL-4Rα alleles and had airway disease induced by house dust mite extract (HDM) or exogenous IL-13. Two functional IL-4Rα alleles were required for maximal AHR, while only one functional allele was required for maximal GCM and systemic IL-4/IL-13 levels. Deletion of IL-4Rα from both smooth muscle and epithelial cells inhibited AHR >83% in mice with two functional IL-4Rα alleles. In mice with one functional IL-4Rα allele, selective epithelial cell IL-4Rα deletion maximally inhibited AHR, while selective smooth muscle IL-4Rα deletion decreased IL-13-induced, but not HDM-induced, AHR. Less IL-4Rα signaling is required to maximize the epithelial cell contribution to AHR compared to the smooth muscle contribution to AHR. Additionally, epithelial cell responses to IL-4/IL-13 can increase the IL-4Rα-dependent smooth muscle contribution to AHR. These findings carry increasing relevance as IL-4Rα-targeted therapy is administered to human asthmatics.

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“…the IL‐4Ra subunit, is not confined to just a single‐cell type, like keratinocytes (which themselves secrete numerous cytokines that act as both autocrine and paracrine mediators). Therefore, targeting the IL‐4 receptor pathway with a specific antibody like dupilumab may cause adverse effects – such as the conjunctivitis reported in 14–19% of AD patients treated with dupilumab . Of course, this concern also applies to any other targeted treatment, which is why it is important to evaluate and prioritize both the most relevant disease drivers, pathways, and targets (druggability considerations) as well as to take potential off‐target and on‐target adverse effects into consideration.…”

Section: From Disease Understanding To Biomarkers Endotypes and Tarmentioning

confidence: 99%