Dupilumab and AD: Pediatric Ocular Adverse Effects

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Atopic dermatitis (AD) is characterized by a dysregulated T-helper 2 immune response and an impaired epidermal barrier, leading to pruritic skin lesions.¹ Dupilumab, a monoclonal antibody that inhibits interleukin (IL)-4 and IL-13 signaling, is the first biologic approved for moderate to severe AD treatment in patients aged 6months and older. While dupilumab is clinically effective with a favorable safety profile, dupilumab-associated ocular surface disease (DAOSD) is a notable adverse effect. DAOSD incidence in pediatric patients varies between 5.6% and 17.3% in real-world studies and 8.8%to14.6% in clinical trials, but long-term real-world studies remain limited.²

Incidence and Characteristics of DAOSD

In adult patients with AD, DAOSD incidence reaches up to 39.6%, with nearly half of affected individuals reporting no symptoms.³ The difficulty in recognizing DAOSD symptoms in pediatric patients, particularly young children, poses a challenge, increasing the risk of delayed diagnosis and severe ocular surface disease (OSD). Persistent OSD may lead to long-term complications such as limbitis and irreversible visual impairment. Moreover, young children (<6 years) face an increased risk of keratoconus, which can contribute to amblyopia. Interestingly, DAOSD is less common in patients receiving dupilumab for other type 2 inflammatory disorders, such as asthma or chronic rhinosinusitis, suggesting a unique interplay between AD and DAOSD development.⁴

Although the pathogenesis of DAOSD remains unclear, hypotheses include IL-4 and IL-13 inhibition reducing conjunctival goblet cells and a pre-existing eyelid epithelial barrier dysfunction in patients with AD. Pre-existing ocular pathology and severe AD are established risk factors in adults, but pediatric risk factors remain unknown. A recent study aimed to assess DAOSD incidence and potential risk factors in pediatric patients with AD treated with dupilumab.⁵

Methods

A prospective observational cohort study was conducted, including pediatric patients with AD (ages 3 to 17 years) treated with dupilumab at the Wilhelmina Children's Hospital (Netherlands) from August 2019 to March 2024. Patients were monitored through the BioDay registry, with written informed consent obtained from participants' guardians. Treatment was administered subcutaneously per recommended dosing schedules, with modifications for adverse events.

Clinical assessments included baseline AD severity (EASI, IGA), laboratory markers (IgE, eosinophil counts, TARC), and follow-up visits every 12 weeks. Patients reporting ocular symptoms were evaluated to distinguish DAOSD from allergic conjunctivitis. Severe ocular symptoms warranted referral to an ophthalmologist, with severity graded using the UTOPIA scoring system. Ocular treatment ranged from lubricating eye drops to corticosteroids or immunomodulatory therapies.

Results

Among 104 patients (mean age 11.7 years; 41.3% men), DAOSD incidence was 34.6% (36 out of 104). Most cases (69.4%) were managed with lubricating eye drops and topical treatments, while 30.6% required anti-inflammatory ocular therapy. DAOSD onset occurred at a median of 13 weeks and resolved at a median of 24.5 weeks. Notably, DAOSD incidence was highest in adolescents (39.0%) compared to children (28.6%) and young children (30.0%), though no significant age correlation was found.

Patients with DAOSD exhibited higher baseline IgE levels (≥3000 kU/L) and increased prior ocular medication use, indicating potential pre-existing pathology. Ocular symptoms included pruritus (75.0%), redness (72.2%), and tearing (58.3%), with ophthalmological findings commonly revealing tarsal conjunctivitis, meibomian gland dysfunction, and blepharitis. Severe DAOSD cases (5.8%) exhibited limbitis. Dupilumab discontinuation due to DAOSD occurred in 11.1% of affected patients, with symptom resolution in all cases.

Discussion

This study's 34.6% DAOSD incidence in pediatric AD patients aligns with adult real-world data but exceeds previously reported pediatric rates. Factors contributing to higher rates include increased physician awareness, proactive symptom assessment, and extended follow-up durations. Elevated IgE levels emerged as a significant independent predictor of DAOSD development. Additionally, pre-existing ocular pathology appeared to influence DAOSD severity, as patients with prior ocular medication use were more likely to require intensive treatment.

While most cases were manageable with conservative therapy, the study stated DAOSD remains a burdensome adverse effectnecessitating early recognition and intervention. The findings highlight the importance of routine ophthalmologic screening in pediatric AD patients on dupilumab, particularly those with elevated IgE or prior ocular conditions. Researchers suggested future research should explore preventative strategies and refine DAOSD management protocols to optimize treatment outcomes while minimizing adverse effects.

Conclusion

DAOSD is a prevalent yet manageable adverse effect of dupilumab in pediatric patients with AD, with an incidence of 34.6%. Baseline IgE levels and prior ocular medication use are key risk factors for DAOSD development. Increased clinical awareness and proactive ophthalmologic evaluation can mitigate disease severity, improving patient outcomes. Long-term real-world studies remain necessary to further elucidate risk factors and refine management strategies for DAOSD in pediatric populations.

References

1. Achten R, Van der Rijst L, Piena M, et al. Economic and Humanistic Burden in Paediatric Patients with Atopic Dermatitis. Acta Derm Venereol. 2023;103:adv00881. Published 2023 Mar 8. doi:10.2340/actadv.v103.4842
2. Blauvelt A, Guttman-Yassky E, Paller AS, et al. Long-term efficacy and safety of dupilumab in adolescents with moderate-to-severe atopic dermatitis: Results through week 52 from a phase III open-label extension trial (LIBERTY AD PED-OLE). Am J Clin Dermatol. 2022;23(3):365-383. doi:10.1007/s40257-022-00683-2
3. Achten R, Thijs J, van der Wal M, et al. Dupilumab-associated ocular surface disease in atopic dermatitis patients: Clinical characteristics, ophthalmic treatment response and conjunctival goblet cell analysis. Allergy. 2023; 78: 2266-2276. doi:10.1111/all.15717
4. Liang L, Sheha H, Li J, Tseng SC. Limbal stem cell transplantation: new progresses and challenges. Eye (Lond). 2009 Oct;23(10):1946-53. doi: 10.1038/eye.2008.379. Epub 2008 Dec 19. PMID: 19098704; PMCID: PMC2853891.
5. van der Rijst LP, van LuijkCM, van der Kamp S, et al. Dupilumab-associated ocular surface disease in paediatric atopic dermatitis patients: Resultsfrom the BioDay registry. Clin Exp Allergy. 2025. doi:10.1111/cea.70025