Dupilumab-associated ocular surface disease

What is dupilumab-associated ocular surface disease?

Dupilumab-associated ocular surface disease (DAOSD) is a spectrum of eye-related adverse effects that typically present within four months of commencing dupilumab therapy.

DAOSD symptoms are generally mild to moderate in severity and can range from nonspecific symptoms to discrete conditions such as conjunctivitis and keratitis.

Approved indications for dupilumab include atopic dermatitis (AD), chronic spontaneous urticaria, bullous pemphigoid, prurigo nodularis, asthma, and chronic rhinosinusitis with nasal polyps.

Dupilumab-induced ocular disease 8 weeks after treatment initiation (OADR-patient1)

Who gets dupilumab-associated ocular surface disease?

Risk factors for dupilumab-associated ocular surface disease include:

• Atopic dermatitis
  • Patients with AD have a higher risk of DAOSD than those treated for other indications eg, asthma, chronic spontaneous urticaria, or prurigo nodularis.
  • A meta-analysis of real-world data reported a 26.1% conjunctivitis incidence among AD patients receiving dupilumab.
  • Higher baseline AD severity is also linked to an elevated DAOSD risk.
• History of ocular surface diseases eg, conjunctivitis, atopic keratoconjunctivitis, dry eye disease with superficial punctate keratitis
• Older age

What causes dupilumab-associated ocular surface disease?

The pathophysiology of dupilumab-associated ocular surface disease is not fully understood. Proposed hypotheses include:

• Reduced conjunctival goblet cells and mucin production due to inhibition of interleukin 13 (IL-13) signalling
• Reduced production of tears due to an increase in free interleukin 4 (IL-4)
• Proliferation of demodex mites due to inhibition of interleukin IL-4 and IL-13 signalling pathways, leading to meibomian gland dysfunction and rosacea-like inflammation
• Activation of inflammation by free IL-4 and IL-13 acting on other receptors or cytokine pathways, such as the type 2 IL-13α and the CD-40-dependent immunoglobulin E pathway
• Unmasking of underlying/subclinical atopic keratoconjunctivitis by dupilumab therapy.

What are the clinical features of dupilumab-associated ocular surface disease?

Patients typically present with mild-to-moderate, nonspecific ocular symptoms. This can include:

• Irritation, pain, or foreign body sensation
• Redness
• Ocular pruritis
• Dryness
• Epiphoria (tearing)
• Discharge
• Photosensitivity
• Blurred vision.

Conjunctivitis and dry eye are the most commonly reported ocular side effects, followed by blepharitis, with cases of keratitis reported infrequently.

What are the complications of dupilumab-associated ocular surface disease?

Although not specific to DAOSD, complications of ocular surface disease can include:

• Madarosis
• Ocular surface keratinisation
• Microbial keratitis
• Corneal abrasion
• Limbitis
• Cicatricial ectropion (eyelid eversion due to scar tissue)
• Symblepharon (adhesion between the eyelid and eyeball)
• Ankyloblepharon (adhesion between the upper and lower eyelids)
• Corneal thinning and perforation in extreme cases.

How is dupilumab-associated ocular surface disease diagnosed?

Dupilumab-associated ocular surface disease is a clinical diagnosis based on the history, ophthalmic examination, and temporal association with dupilumab treatment.

Slit-lamp examination of the ocular surface may demonstrate conjunctival hyperaemia (redness), papillary conjunctivitis, and superficial punctate keratopathy (damage to the cornea’s outer layer) in the early stages of DAOSD.

What is the differential diagnosis for dupilumab-associated ocular surface disease?

• Other causes of conjunctivitis eg, viral, bacterial, and allergic
• Atopic keratoconjunctivitis
• Dry eye syndrome
• Chemical burn
• Episcleritis
• Scleritis
• Ocular cicatricial pemphigoid
• Ocular graft-versus-host disease
• Ocular Stevens-Johnson syndrome / toxic epidermal necrolysis

What is the treatment for dupilumab-associated ocular surface disease?

Dupilumab-associated ocular surface disease responds well to medical treatment, and discontinuation of dupilumab is not usually required.

General measures

• Patient or caregiver education as described under prevention
• Lubricating preservative-free eyedrops and/or antihistamine eyedrops for mild cases
• Seek input from ophthalmology — red flags for urgent referral include:
  • Vision loss, eye pain, purulent discharge, increased ocular pressure, or loss of transparency in the eye
  • New or worsening ocular symptoms in contact lens wearers or those with a history of herpetic keratitis.

Specific measures

There is no consensus on the specific management of DAOSD, but treatment strategies generally aim to halt the inflammatory process:

• Ophthalmic corticosteroids eg, fluorometholone, prednisolone, and dexamethasone
• Calcineurin inhibitors eg, tacrolimus ointment (for eyelids) or ciclosporin drops — may benefit by increasing conjunctival goblet cells and preventing epithelial cell death.

How do you prevent dupilumab-associated ocular surface disease?

Patient or caregiver education is crucial. They should be counselled on:

• Risks and features of ocular adverse effects, including symptoms of conjunctivitis and dry eye (which can also include paradoxical eye watering), keratitis, and ulcerative keratitis.
• Reporting new-onset or worsening eye symptoms to their healthcare professional for timely treatment.

There is limited evidence for lubricating eye drops as prophylaxis, particularly for patients with atopic dermatitis.

What is the outcome for dupilumab-associated ocular surface disease?

Nearly all cases of DAOSD resolve with the initiation of medical treatment. Cases also resolve with discontinuation of dupilumab, though this is not usually required.