Drug-Induced Periocular and Ocular Surface Disorders: An EAACI Position Paper

Abstract

Various systemic and topical medications can induce ocular and periocular cutaneous adverse effects (AEs), ranging from mild to severe. These AEs may lead to ocular surface (OS) damage and, in some cases, life-threatening complications. Drug-induced ocular adverse reactions are generally classified into two primary categories: toxic reactions and/or allergic hypersensitivity reactions, which can be IgE or non-IgE-mediated. Systemic antibiotics, antivirals, and anticonvulsants can trigger adverse reactions that may involve the OS. Drugs like antihistamines, beta-blockers, antipsychotics, antidepressants, and isotretinoin are linked to dry eye disease. Topical treatments-including antibiotics, antiglaucoma medications, preservatives, contact lens solutions, and cosmetics-may elicit allergic or toxic ocular diseases. Recent evidence implicates ocular surface AEs in patients undergoing biological treatments for oncological diseases and atopic dermatitis. Epidermal growth factor receptor inhibitors, used in the treatment of several cancers, have been associated with conjunctivitis, meibomitis, dry eye, periocular skin changes, and trichomegaly. Similarly, dupilumab, the first biologic approved for treating moderate-to-severe atopic dermatitis, has also been linked to OS disease with blepharoconjunctivitis. This position paper provides a comprehensive overview of the clinical presentations, diagnostic approaches, and treatment strategies for drug-induced ocular AEs, integrating the latest literature and clinical guidelines.

Keywords: biological treatments; drug related blepharoconjunctivitis; ocular allergy; ocular drug hypersensitivity reactions; severe cutaneous adverse reactions.

FIGURE 1

Different phenotypes of ocular drug hypersensitivity reactions (ODHR). (A) Lower and (B) upper lid conjunctival follicular reaction do to topical drugs. (C, D) Bilateral chronic ODHR. (E, F) Periocular and facial eczematous reaction as ODHR.

FIGURE 2

Acute a chronic phase of SJS. (A) An acute SJS patient with severe inflammation and a persistent corneal defect. (B) The same patient treated with amniotic membrane graft done using perilimbal purse string sutures. (C) SJS patient in the chronic ocular surface inflammatory phase with dry keratinized surface with minimal haze and low visual function. (D) The same patient with decreased inflammation and visual improvement after a scleral contact lens application. (E) Lid margin keratinization along the upper lid. (F) Keratinized tissue replaced by oral mucous membrane graft. (G) Modified osteodonto keratoprosthesis (MOOKP) in one SJS patient. (H) Boston type 2 keratoprosthesis in one SJS patient.

FIGURE 3

Dupilumab induced ocular surface disease (DIODS). (A) Typical blepharoconjunctivitis in a DIODS patient. (B) Severe conjunctival inflammation in a DIODS patient. (C) Note the severe limbal involvement at a higher magnification in the same patient. (D) A DIODS patient with severe conjunctival, limbal, and peripheral corneal involvement (the lissamine green stain shows the lid margin involvement) successfully treated with topical tacrolimus 0.1% compounded eyedrops (E).

FIGURE 4

(A) Ulcerative blepharitis with crusty secretion at the lid margin, conjunctivitis and trichomegaly (B) induced by EGFR tyrosine kinase inhibitors. (C) PDGFR TK1 (imatinib)‐induced periorbital edema and (D) subconjunctival hemorrhages. (E) Contact eyelid dermatitis induced by cosmetics. (F) Toxic keratopathy with partial hyposensitivity in a glaucoma patient with little complaint despite significant superficial punctate epitheliopathy highlighted by fluorescein staining and yellow filter. (G) Severe blepharokeratoconjunctivits in a patient treated with topical antiglaucoma drugs.

FIGURE 5

Adverse effects of topical ocular medications (TOM) on the ocular surface. (1) Damage to the lid skin and meibomian glands: drug‐induced chronic inflammation stimulates cornified envelope precursors [135], leading to goblet cell entrapment, squamous metaplasia, lid margin keratinization, and further MGD. (2) Tear film disruption: goblet cell dysfunction results in the loss of mucin‐related immunosuppressive feedback to dendritic cells, further enhancing chronic inflammation [137]. Tear film dysfunction triggers biological cascades that perpetuate a vicious cycle of neurogenic ocular surface inflammation and further tear film impairment [136]. (3) Conjunctival and corneal epithelial cell damage: preservatives and drugs induce a concentration‐dependent decrease in cellular viability, increase apoptosis, and oxidative stress resulting in proinflammatory effects, cytokine release, and increased receptor expression of chemokines and cytokines [138, 139]. (4) Conjunctival immune‐mediated inflammation: Th1 and Th2 cytokine profiles are involved, indicating a mixture of allergic and toxic mechanisms [140]. (5) Corneal nerves neurotoxicity: preservatives and drugs may also exhibit neurotoxic effects on trigeminal nerve endings [141, 142].