Atopic Keratoconjunctivitis: Pathophysiology, Clinic, and Potential New Therapeutic Concepts

Abstract

Atopic dermatitis (AD) is a chronic recurrent inflammatory skin disease with a bipolar age distribution in childhood, adolescence and middle adulthood. Up to 50% of AD patients show ocular involvement, which can be potentially sight threatening. Clinically, the majority of cases present with atopic blepharo(kerato)conjunctivitis or atopic keratoconjunctivitis (AKC); other clinical variants from this group of inflammatory ocular surface diseases are keratoconjunctivitis vernalis in childhood and adolescence and allergic conjunctivitis. In addition to the aforementioned blepharitis, keratitis and conjunctivitis, AD is also associated with eyelid involvement with subsequent eyelid malposition, limbal insufficiency with the development of pseudopterygia, (chronic) cicatrizing conjunctivitis with symblephara formation and fornix shortening, as well as ocular surface malignancies such as conjunctival intraepithelial neoplasia (CIN) and squamous cell carcinoma. In addition, an association with AD or AKC has been described for keratoconus. Whereas the therapy of AD in dermatology has made revolutionary advances in recent years through the use of biologicals, the primary use of these biologicals in ophthalmological complications is still very hesitant. Treatment here is often provided using topical steroids and calcineurin inhibitors. The following article summarises recent developments in basic and clinical dermatological research and discusses them in the context of current concepts for ophthalmological therapy.

Conclusion

Dermatological Conclusion

• AD is widespread, especially in developed countries, affecting up to 25% of children and 10% of adults.

• Genetically determined skin barrier defects predispose affected individuals to inflammation and consecutive superinfections (in particular with Staphylococcus aureus).

• The localization and symptoms vary depending on age and include severe itching, erythema, and lichenification.

• Standard treatment includes basic therapy and topical immunomodulators.

• A variety of new systemic immunomodulators are now available for diseases stages that do not respond to topical treatment.

Ophthalmological Conclusion

• Involvement of the ocular surface and periocular adnexa in the form of AKC is very common in AD patients, occurring in over 50% of cases.

• If left untreated, AKC can lead to loss of vision.

• Treatment depends on the ophthalmological findings – if topical steroids and topical CsA are insufficient, an appropriate systemic treatment must be evaluated in consultation with the treating dermatologist.

Future developments in pharmacotherapy give cause to hope that the spectrum of available topical drugs will be expanded.

Keywords

atopic dermatitis - atopic keratoconjunctivitis - atopy

Publication History

Received: 29 October 2023

Accepted: 08 January 2024

Article published online:
11 April 2024

• References/Literatur

• 1 Facheris P, Jeffery J, Del Duca E. et al. The translational revolution in atopic dermatitis: the paradigm shift from pathogenesis to treatment. Cell Mol Immunol 2023; 20: 448-474 DOI: 10.1038/s41423-023-00992-4.
• 2 Maier P, Lapp T, Reinhard T. [Ocular involvement in atopic dermatitis: Clinical aspects and therapy]. Ophthalmologe 2017; 114: 514-524 DOI: 10.1007/s00347-017-0473-3.
• 3 Tokura Y, Hayano S. Subtypes of atopic dermatitis: From phenotype to endotype. Allergol Int 2022; 71: 14-24 DOI: 10.1016/j.alit.2021.07.003.
• 4 Guttman-Yassky E, Nograles KE, Krueger JG. Contrasting pathogenesis of atopic dermatitis and psoriasis–part I: clinical and pathologic concepts. J Allergy Clin Immunol 2011; 127: 1110-1118 DOI: 10.1016/j.jaci.2011.01.053.
• 5 Ständer S. Atopic Dermatitis. N Engl J Med 2021; 384: 1136-1143 DOI: 10.1056/NEJMra2023911.
• 6 Langan SM, Irvine AD, Weidinger S. Atopic dermatitis. Lancet 2020; 396: 345-360 DOI: 10.1016/S0140-6736(20)31286-1.
• 7 Eichenfield LF, Stripling S, Fung S. et al. Recent Developments and Advances in Atopic Dermatitis: A Focus on Epidemiology, Pathophysiology, and Treatment in the Pediatric Setting. Paediatr Drugs 2022; 24: 293-305 DOI: 10.1007/s40272-022-00499-x.
• 8 Krilis M, Tsang H, Coroneo M. Treatment of conjunctival and corneal epithelial neoplasia with retinoic acid and topical interferon alfa-2b: long-term follow-up. Ophthalmology 2012; 119: 1969-1973 DOI: 10.1016/j.ophtha.2012.03.045.
• 9 Lapp T, Maier P, Jakob T. et al. [Pathophysiology of atopic blepharokeratoconjunctivitis]. Ophthalmologe 2017; 114: 504-513 DOI: 10.1007/s00347-017-0483-1.
• 10 Hsu JI, Pflugfelder SC, Kim SJ. Ocular complications of atopic dermatitis. Cutis 2019; 104: 189-193
• 11 Ravn NH, Ahmadzay ZF, Christensen TA. et al. Bidirectional association between atopic dermatitis, conjunctivitis, and other ocular surface diseases: A systematic review and meta-analysis. J Am Acad Dermatol 2021; 85: 453-461 DOI: 10.1016/j.jaad.2020.11.037.
• 12 Silverberg JI. Comorbidities and the impact of atopic dermatitis. Ann Allergy Asthma Immunol 2019; 123: 144-151 DOI: 10.1016/j.anai.2019.04.020.
• 13 Hanifin JM, Reed ML. Eczema Prevalence and Impact Working Group. A population-based survey of eczema prevalence in the United States. Dermatitis 2007; 18: 82-91 DOI: 10.2310/6620.2007.06034.
• 14 Lee HH, Patel KR, Singam V. et al. A systematic review and meta-analysis of the prevalence and phenotype of adult-onset atopic dermatitis. J Am Acad Dermatol 2019; 80: 1526-1532.e7 DOI: 10.1016/j.jaad.2018.05.1241.
• 15 Ellis CN, Mancini AJ, Paller AS. et al. Understanding and managing atopic dermatitis in adult patients. Semin Cutan Med Surg 2012; 31: S18-S22 DOI: 10.1016/j.sder.2012.07.006.
• 16 Bylund S, Kobyletzki LB, Svalstedt M. et al. Prevalence and Incidence of Atopic Dermatitis: A Systematic Review. Acta Derm Venereol 2020; 100: adv00160 DOI: 10.2340/00015555-3510.
• 17 Power WJ, Tugal-Tutkun I, Foster CS. Long-term follow-up of patients with atopic keratoconjunctivitis. Ophthalmology 1998; 105: 637-642 DOI: 10.1016/S0161-6420(98)94017-9.
• 18 Singh K, Axelrod S, Bielory L. The epidemiology of ocular and nasal allergy in the United States, 1988–1994. J Allergy Clin Immunol 2010; 126: 778-783.e6 DOI: 10.1016/j.jaci.2010.06.050.
• 19 Fauquert JL. Diagnosing and managing allergic conjunctivitis in childhood: The allergistʼs perspective. Pediatr Allergy Immunol 2019; 30: 405-414 DOI: 10.1111/pai.13035.
• 20 Bremond-Gignac D, Donadieu J, Leonardi A. et al. Prevalence of vernal keratoconjunctivitis: a rare disease?. Br J Ophthalmol 2008; 92: 1097-1102 DOI: 10.1136/bjo.2007.117812.
• 21 Brown SJ, McLean WHI. One remarkable molecule: filaggrin. J Invest Dermatol 2012; 132: 751-762 DOI: 10.1038/jid.2011.393.
• 22 Apfelbacher CJ, Diepgen TL, Schmitt J. Determinants of eczema: population-based cross-sectional study in Germany. Allergy 2011; 66: 206-213 DOI: 10.1111/j.1398-9995.2010.02464.x.
• 23 Thomsen SF, Ulrik CS, Kyvik KO. et al. Importance of genetic factors in the etiology of atopic dermatitis: a twin study. Allergy Asthma Proc 2007; 28: 535-539 DOI: 10.2500/aap2007.28.3041.
• 24 Paternoster L, Standl M, Waage J. et al. Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis. Nat Genet 2015; 47: 1449-1456 DOI: 10.1038/ng.3424.
• 25 Palmer CNA, Irvine AD, Terron-Kwiatkowski A. et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006; 38: 441-446 DOI: 10.1038/ng1767.
• 26 Rodríguez E, Baurecht H, Herberich E. et al. Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease. J Allergy Clin Immunol 2009; 123: 1361-1370.e7 DOI: 10.1016/j.jaci.2009.03.036.
• 27 Irvine AD, McLean WHI, Leung DYM. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med 2011; 365: 1315-1327 DOI: 10.1056/NEJMra1011040.
• 28 Brown SJ, Asai Y, Cordell HJ. et al. Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy. J Allergy Clin Immunol 2011; 127: 661-667 DOI: 10.1016/j.jaci.2011.01.031.
• 29 Lapp T, Auw-Haedrich C, Reinhard T. et al. Analysis of filaggrin mutations and expression in corneal specimens from patients with or without atopic dermatitis. Int Arch Allergy Immunol 2014; 163: 20-24 DOI: 10.1159/000355965.
• 30 Howell MD, Kim BE, Gao P. et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 2009; 124: R7-R12 DOI: 10.1016/j.jaci.2009.07.012.
• 31 Salimi M, Barlow JL, Saunders SP. et al. A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis. J Exp Med 2013; 210: 2939-2950 DOI: 10.1084/jem.20130351.
• 32 Fukuda K, Kishimoto T, Sumi T. et al. Biologics for allergy: therapeutic potential for ocular allergic diseases and adverse effects on the eye. Allergol Int 2023; 72: 234-244 DOI: 10.1016/j.alit.2022.09.005.
• 33 Leyden JJ, Marples RR, Kligman AM. Staphylococcus aureus in the lesions of atopic dermatitis. Br J Dermatol 1974; 90: 525-530 DOI: 10.1111/j.1365-2133.1974.tb06447.x.
• 34 Kong HH, Oh J, Deming C. et al. Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res 2012; 22: 850-859 DOI: 10.1101/gr.131029.111.
• 35 Gandhi NA, Bennett BL, Graham NMH. et al. Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov 2016; 15: 35-50 DOI: 10.1038/nrd4624.
• 36 Yoshida K, Kubo A, Fujita H. et al. Distinct behavior of human Langerhans cells and inflammatory dendritic epidermal cells at tight junctions in patients with atopic dermatitis. J Allergy Clin Immunol 2014; 134: 856-864 DOI: 10.1016/j.jaci.2014.08.001.
• 37 Mittermann I, Wikberg G, Johansson C. et al. IgE Sensitization Profiles Differ between Adult Patients with Severe and Moderate Atopic Dermatitis. PLoS One 2016; 11: e0156077 DOI: 10.1371/journal.pone.0156077.
• 38 Villani E, Rabbiolo G, Nucci P. Ocular allergy as a risk factor for dry eye in adults and children. Curr Opin Allergy Clin Immunol 2018; 18: 398-403 DOI: 10.1097/ACI.0000000000000471.
• 39 González-López JJ, López-Alcalde J, Morcillo Laiz R. et al. Topical cyclosporine for atopic keratoconjunctivitis. Cochrane Database Syst Rev 2012; (09) CD009078 DOI: 10.1002/14651858.CD009078.pub2.
• 40 Hagan S, Martin E, Enríquez-de-Salamanca A. Tear fluid biomarkers in ocular and systemic disease: potential use for predictive, preventive and personalised medicine. EPMA J 2016; 7: 15 DOI: 10.1186/s13167-016-0065-3.
• 41 Roy N, Levanon S, Asbell PA. Potential Biomarkers for Allergic Conjunctival Diseases. Eye Contact Lens 2020; 46: S109 DOI: 10.1097/ICL.0000000000000688.
• 42 Wen J, Hu H, Chen M. et al. Role of Janus Kinase (JAK) Inhibitor in Autoimmune Ocular Inflammation: A Systematic Review. J Immunol Res 2021; 2021: 2324400 DOI: 10.1155/2021/2324400.
• 43 Dainichi T, Kaku Y, Izumi M. et al. Successful treatment of severe blepharitis in a patient with atopic dermatitis by topical delgocitinib. Clin Exp Dermatol 2021; 46: 1119-1120 DOI: 10.1111/ced.14651.
• 44 Nahum Y, Mimouni M, Livny E. et al. Dupilumab-induced ocular surface disease (DIOSD) in patients with atopic dermatitis: clinical presentation, risk factors for development and outcomes of treatment with tacrolimus ointment. Br J Ophthalmol 2020; 104: 776-779 DOI: 10.1136/bjophthalmol-2019-315010.
• 45 Wolf J, Boneva S, Schlecht A. et al. The Human Eye Transcriptome Atlas: A searchable comparative transcriptome database for healthy and diseased human eye tissue. Genomics 2022; 114: 110286 DOI: 10.1016/j.ygeno.2022.110286.
• 46 Wolf J, Lapp T, Reinhard T. et al. Web-based gene expression analysis-paving the way to decode healthy and diseased ocular tissue. Ophthalmologie 2023; 120 (Suppl. 1) S59-S65 DOI: 10.1007/s00347-022-01721-4.
• 47 Wohlrab J, Wollenberg A, Reimann H. et al. [Interdisciplinary recommendations for action in dupilumab-related inflammatory eye diseases]. Hautarzt 2019; 70: 64-67 DOI: 10.1007/s00105-018-4316-1.
• 48 Singh N, Diebold Y, Sahu SK. et al. Epithelial barrier dysfunction in ocular allergy. Allergy 2022; 77: 1360-1372 DOI: 10.1111/all.15174.