Management of dupilumab-associated ocular surface diseases in atopic dermatitis patients
Atopic dermatitis is a chronic inflammatory skin disease characterised by eczematous skin lesions and intense pruritus. It is often associated with other atopic diseases such as allergic rhinitis and conjunctivitis, bronchial asthma and eosinophilic oesophagitis. Dupilumab is the first biologic approved for the treatment of moderate-to-severe atopic dermatitis in Switzerland. Dupilumab targets the interleukin (IL)-4/IL-13 receptor and thus inhibits the signalling of IL-4 and IL-13, two key mediators of type 2 inflammation, resulting in an improvement of clinical signs and symptoms of atopic dermatitis. Patients with atopic dermatitis present more often with ocular surface diseases (OSDs), such as allergic conjunctivitis, blepharitis and keratitis as well as infectious conjunctivitis and keratoconus compared with the general population. Upon dupilumab therapy, increased rates of ocular surface diseases have been reported in clinical trials. Interestingly, dupilumab-associated (da) OSD is restricted to atopic dermatitis patients and has not been observed in asthma and chronic rhinosinusitis trials. Fortunately, most cases of dupilumab-associated OSD are mild-to-moderate and transient. Thus, ocular surface disease presents a particular adverse event of treatment with dupilumab in dermatology. This article aims at providing a practical guide for physicians, with a special focus on dermatologists, allergists and ophthalmologists in Switzerland, to the diagnosis and management of dupilumab-associated OSD in atopic dermatitis patients.
For this purpose, an expert group of dermatologists and ophthalmologists from university and cantonal hospitals in Switzerland reviewed data on ocular surface diseases published in clinical trial and real-life reports of dupilumab therapy, published case reports and case series on the management of dupilumab-associated OSD, as well as recent recommendations provided by experts of national and international boards. Based on the observations of dupilumab-associated OSD and practical experiences in identifying and treating OSD, an algorithm has been developed that is specific to the needs in Switzerland. Considering concomitant ocular diseases and differential diagnoses, the clinical presentation of dupilumab-associated OSD and its response to therapeutic measures, a stepwise approach is recommended. Mild dupilumab-associated OSD can be managed by dermatologists and allergists, whereas patients with moderate-to-severe OSD requiring corticosteroid or calcineurin inhibitor therapy should necessarily be referred to an ophthalmologist. The effects of preventive measures, such as artificial tears, are uncertain. The recommendations provided here should guarantee a prompt and effective treatment of OSD for patients under dupilumab therapy in order to prevent that an otherwise potent therapy has to be ceased because of ocular adverse events.
- Simon D, Wollenberg A, Renz H, Simon HU. Atopic Dermatitis: Collegium Internationale Allergologicum (CIA) Update 2019. Int Arch Allergy Immunol. 2019;178(3):207–18. https://doi.org/10.1159/000497383
- Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016 Mar;387(10023):1109–22. https://doi.org/10.1016/S0140-6736(15)00149-X
- Wohlrab J, Wollenberg A, Reimann H, Pleyer U, Werfel T. Interdisziplinäre Handlungsempfehlung bei Dupilumab-assoziierten entzündlichen Augenerkrankungen [Interdisciplinary recommendations for action in dupilumab-related inflammatory eye diseases]. Hautarzt. 2019 Jan;70(1):64–7. https://doi.org/10.1007/s00105-018-4316-1
- Eichenfield LF, Tom WL, Chamlin SL, Feldman SR, Hanifin JM, Simpson EL, et al. Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014 Feb;70(2):338–51. https://doi.org/10.1016/j.jaad.2013.10.010
- Silverberg JI, Nelson DB, Yosipovitch G. Addressing treatment challenges in atopic dermatitis with novel topical therapies. J Dermatolog Treat. 2016 Nov;27(6):568–76. https://doi.org/10.1080/09546634.2016.1174765
- Bieber T. Atopic dermatitis. N Engl J Med. 2008 Apr;358(14):1483–94. https://doi.org/10.1056/NEJMra074081
- Thyssen JP, Toft PB, Halling-Overgaard AS, Gislason GH, Skov L, Egeberg A. Incidence, prevalence, and risk of selected ocular disease in adults with atopic dermatitis. J Am Acad Dermatol. 2017 Aug;77(2):280–286.e1. https://doi.org/10.1016/j.jaad.2017.03.003
- Wohlrab J, Werfel T, Wollenberg A. Pathomechanism of dupilumab-associated inflammatory eye symptoms. J Eur Acad Dermatol Venereol. 2019 Nov;33(11):e435–6. https://doi.org/10.1111/jdv.15755
- Akinlade B, Guttman-Yassky E, de Bruin-Weller M, Simpson EL, Blauvelt A, Cork MJ, et al. Conjunctivitis in dupilumab clinical trials. Br J Dermatol. 2019 Sep;181(3):459–73. https://doi.org/10.1111/bjd.17869
- Bielory L. Allergic and immunologic disorders of the eye. Part II: ocular allergy. J Allergy Clin Immunol. 2000 Dec;106(6):1019–32. https://doi.org/10.1067/mai.2000.111238
- Raffi J, Suresh R, Fishman H, Botto N, Murase JE. Investigating the role of allergic contact dermatitis in residual ocular surface disease on dupilumab (ROSDD). Int J Womens Dermatol. 2019 Nov;5(5):308–13. https://doi.org/10.1016/j.ijwd.2019.10.001
- Cronau H, Kankanala RR, Mauger T. Diagnosis and management of red eye in primary care. Am Fam Physician. 2010 Jan;81(2):137–44.
- Brunner PM, Guttman-Yassky E, Leung DY. The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies. J Allergy Clin Immunol. 2017 Apr;139(4 4S):S65–76. https://doi.org/10.1016/j.jaci.2017.01.011
- Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, et al.; SOLO 1 and SOLO 2 Investigators. SOLO 1 and SOLO 2 Investigators. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016 Dec;375(24):2335–48. https://doi.org/10.1056/NEJMoa1610020
- Blauvelt A, de Bruin-Weller M, Gooderham M, Cather JC, Weisman J, Pariser D, et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet. 2017 Jun;389(10086):2287–303. https://doi.org/10.1016/S0140-6736(17)31191-1
- de Bruin-Weller M, Thaçi D, Smith CH, Reich K, Cork MJ, Radin A, et al. Dupilumab with concomitant topical corticosteroid treatment in adults with atopic dermatitis with an inadequate response or intolerance to ciclosporin A or when this treatment is medically inadvisable: a placebo-controlled, randomized phase III clinical trial (LIBERTY AD CAFÉ). Br J Dermatol. 2018 May;178(5):1083–101. https://doi.org/10.1111/bjd.16156
- Worm M, Simpson EL, Thaçi D, Bissonnette R, Lacour JP, Beissert S, et al. Efficacy and Safety of Multiple Dupilumab Dose Regimens After Initial Successful Treatment in Patients With Atopic Dermatitis: A Randomized Clinical Trial. JAMA Dermatol. 2020 Feb;156(2):131–43. https://doi.org/10.1001/jamadermatol.2019.3617
- Deleuran M, Thaçi D, Beck LA, de Bruin-Weller M, Blauvelt A, Forman S, et al. Dupilumab shows long-term safety and efficacy in patients with moderate to severe atopic dermatitis enrolled in a phase 3 open-label extension study. J Am Acad Dermatol. 2020 Feb;82(2):377–88. https://doi.org/10.1016/j.jaad.2019.07.074
- Beck LA, Thaçi D, Deleuran M, Blauvelt A, Bissonnette R, de Bruin-Weller M, et al. Dupilumab Provides Favorable Safety and Sustained Efficacy for up to 3 Years in an Open-Label Study of Adults with Moderate-to-Severe Atopic Dermatitis. Am J Clin Dermatol. 2020 Aug;21(4):567–77. https://doi.org/10.1007/s40257-020-00527-x
- Thaçi D, L Simpson E, Deleuran M, Kataoka Y, Chen Z, Gadkari A, et al. Efficacy and safety of dupilumab monotherapy in adults with moderate-to-severe atopic dermatitis: a pooled analysis of two phase 3 randomized trials (LIBERTY AD SOLO 1 and LIBERTY AD SOLO 2). J Dermatol Sci. 2019 May;94(2):266–75. https://doi.org/10.1016/j.jdermsci.2019.02.002
- Duxipent® (Dupilumab), product information for healthcare professionals, status of information: September 2020, www.swissmedicinfo.ch, last accessed: 07 January 2021.
- Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med. 2018 Jun;378(26):2486–96. https://doi.org/10.1056/NEJMoa1804092
- Bachert C, Han JK, Desrosiers M, Hellings PW, Amin N, Lee SE, et al. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials. Lancet. 2019 Nov;394(10209):1638–50. https://doi.org/10.1016/S0140-6736(19)31881-1
- Hirano I, Dellon ES, Hamilton JD, Collins MH, Peterson K, Chehade M, et al. Efficacy of Dupilumab in a Phase 2 Randomized Trial of Adults With Active Eosinophilic Esophagitis. Gastroenterology. 2020 Jan;158(1):111–122.e10. https://doi.org/10.1053/j.gastro.2019.09.042
- Ariëns LF, van der Schaft J, Bakker DS, Balak D, Romeijn ML, Kouwenhoven T, et al. Dupilumab is very effective in a large cohort of difficult-to-treat adult atopic dermatitis patients: first clinical and biomarker results from the BioDay registry. Allergy. 2020 Jan;75(1):116–26. https://doi.org/10.1111/all.14080
- Faiz S, Giovannelli J, Podevin C, Jachiet M, Bouaziz JD, Reguiai Z, et al.; Groupe de Recherche sur l’Eczéma aTopique (GREAT), France. Effectiveness and safety of dupilumab for the treatment of atopic dermatitis in a real-life French multicenter adult cohort. J Am Acad Dermatol. 2019 Jul;81(1):143–51. https://doi.org/10.1016/j.jaad.2019.02.053
- Olesen CM, Holm JG, Nørreslet LB, Serup JV, Thomsen SF, Agner T. Treatment of atopic dermatitis with dupilumab: experience from a tertiary referral centre. J Eur Acad Dermatol Venereol. 2019 Aug;33(8):1562–8. https://doi.org/10.1111/jdv.15609
- Bakker DS, Ariens LF, van Luijk C, van der Schaft J, Thijs JL, Schuttelaar ML, et al. Goblet cell scarcity and conjunctival inflammation during treatment with dupilumab in patients with atopic dermatitis. Br J Dermatol. 2019 May;180(5):1248–9. https://doi.org/10.1111/bjd.17538
- Jun I, Kim BR, Park SY, Lee H, Kim J, Kim EK, et al. Interleukin-4 stimulates lipogenesis in meibocytes by activating the STAT6/PPARγ signaling pathway. Ocul Surf. 2020 Oct;18(4):575–82. https://doi.org/10.1016/j.jtos.2020.04.015
- Becmeur PH, Abry F, Bourcier T, Meyer N, Sauer A ; « the French Study Group for Contact Lens-Related Microbial Keratitis ». Facteurs de risque de kératites infectieuses chez les porteurs de lentilles de contact, une étude cas-témoins [Risk factors for contact lens-related microbial keratitis: A multicenter case-control study]. J Fr Ophtalmol. 2017 Mar;40(3):224–31. https://doi.org/10.1016/j.jfo.2016.10.008
- Duxipent® (dupilumab), Federal Office of Public Health (FOPH), Spezialitätenliste. Available at: www.spezialitaetenliste.ch [last accessed: 2021 January 07].