Conjunctivitis in patients with atopic dermatitis treated with dupilumab is associated with higher baseline serum levels of immunoglobulin E and thymus and activation-regulated chemokine but not clinical severity in a real-world setting

Abstract

To the Editor: Conjunctivitis has been observed as an adverse event in patients with atopic dermatitis (AD) receiving dupilumab. Its incidence rate ranges from 8.6% to 21.44% in clinical trials,1Akinlade B. Guttman-Yassky E. de Bruin-Weller M. et al.Conjunctivitis in dupilumab clinical trials.Br J Dermatol. 2019; 181: 459-473Crossref PubMed Scopus (178) Google Scholar whereas real-world data have shown an even higher prevalence.2Uchida H. Kamata M. Mizukawa I. et al.Real-world effectiveness and safety of dupilumab for the treatment of atopic dermatitis in Japanese patients: a single-centre retrospective study.Br J Dermatol. 2019; 181: 1083-1085Crossref PubMed Scopus (25) Google Scholar We analyzed our data to explore practical predictors of later development of conjunctivitis in patients with AD initiating dupilumab in a real-world setting. The study included adult patients with AD who had been treated with dupilumab in our hospital for more than 3 months as of October 1, 2019. Other inclusion criteria were the same as those described in our previous report.2Uchida H. Kamata M. Mizukawa I. et al.Real-world effectiveness and safety of dupilumab for the treatment of atopic dermatitis in Japanese patients: a single-centre retrospective study.Br J Dermatol. 2019; 181: 1083-1085Crossref PubMed Scopus (25) Google Scholar Baseline clinical severity, patents’ history of conjunctivitis, and results from laboratory blood tests were compared between patients who developed conjunctivitis and those who did not. Data on 57 Japanese adult patients (49 men, 8 women) with AD were analyzed. The mean ± standard deviation age at starting dupilumab was 38.1 ± 11.8 years. Conjunctivitis was observed in 22.8% (13 of 57) of patients after starting dupilumab. The mean time to develop conjunctivitis after beginning dupilumab was 5.3 ± 3.9 weeks. Conjunctivitis developed at a higher frequency after starting dupilumab in patients who had a history of conjunctivitis at baseline than in those who did not. Patients in whom conjunctivitis occurred after starting dupilumab had significantly higher serum levels of thymus and activation-regulated chemokine (TARC) and immunoglobulin E (IgE) at baseline than those who did not (Fig 1). The cutoff values at baseline were 3342 pg/mL (sensitivity, 69.23%; specificity, 79.55%) for TARC and 11,200 IU/mL (sensitivity, 76.92%; specificity, 69.77%) for IgE, with moderate accuracy. No significant differences were observed between them in clinical severity, including Investigator's Global Assessment, affected body surface area, the Eczema Area and Severity Index, and results of other laboratory blood tests. Clinical trials have demonstrated that baseline disease-related factors, including AD severity, prior conjunctivitis history, and certain biomarkers (TARC, IgE, eosinophils), are associated with an increased incidence of conjunctivitis.1Akinlade B. Guttman-Yassky E. de Bruin-Weller M. et al.Conjunctivitis in dupilumab clinical trials.Br J Dermatol. 2019; 181: 459-473Crossref PubMed Scopus (178) Google Scholar It is reasonable, because levels of certain biomarkers, such as TARC, IgE, and eosinophils, increase with AD severity.3Beck L.A. Thaci D. Hamilton J.D. et al.Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.N Engl J Med. 2014; 371: 130-139Crossref PubMed Scopus (879) Google Scholar, 4Hamilton J.D. Suarez-Farinas M. Dhingra N. et al.Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis.J Allergy Clin Immunol. 2014; 134: 1293-1300Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar, 5Guttman-Yassky E. Bissonnette R. Ungar B. et al.Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis.J Allergy Clin Immunol. 2019; 143: 155-172Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar However, our real-world data revealed that only baseline serum TARC and IgE levels were significantly higher in patients who developed conjunctivitis and that a history of conjunctivitis and eosinophils showed its tendency, whereas baseline clinical severity did not demonstrate any association with incidence of conjunctivitis. Even in data from clinical trials, the difference in the incidence of conjunctivitis between patients with AD with a baseline score of 3 on the 5-point Investigator's Global Assessment scale and those with a baseline of 4 was quite small in CHRONOS (NCT02260986) (0.06 vs 0.09 per 100 patient-years) and in CAFÉ (NCT02755649) (0.22 vs 0.23).1Akinlade B. Guttman-Yassky E. de Bruin-Weller M. et al.Conjunctivitis in dupilumab clinical trials.Br J Dermatol. 2019; 181: 459-473Crossref PubMed Scopus (178) Google Scholar Distinguishing the subtle differences in disease severity of AD among patients with moderate to severe AD (not including mild AD) is difficult for physicians. Our study underscores that among those parameters, serum levels of TARC and IgE could reflect subtle differences in predisposition for conjunctivitis more accurately than the disease severity of AD evaluated by physicians, especially among patients with moderate to severe AD, indicating that these objective parameters are useful as practical predictors of later development of conjunctivitis.