Objective: The purpose of this study was to evaluate the efficacy and safety of 0.1% tacrolimus eye drops in the tarsal form of vernal keratoconjunctivitis (VKC) and to survey the changes of dendritic cells at the palpebral conjunctiva in patients with VKC by in vivo confocal microscopy. Methods: A total of 17 patients (34 eyes) with the tarsal form of VKC were enrolled in this prospective, nonrandomized case series. They were treated with 0.1% tacrolimus eye drops twice daily after discontinuation of all other topical medications. Subjective ocular symptoms and objective ocular signs were scored on a 4-point scale by one ophthalmologist and the characteristics of the dendritic cells in each right eye at the palpebral conjunctiva were evaluated by in vivo confocal microscopy before treatment and at the 1st, 2th, 4th, and 8th weeks after treatment. Results: After 1 week of treatment with 0.1% tacrolimus eye drops, the score for each symptom in all patients showed a significant (p < 0.001) improvement, and 13 patients (76%) experienced dramatic relief of symptoms. In addition, there was a significantly (p < 0.001) decreased clinical sign score (except for giant papillae) after 4 weeks, and a significant (p < 0.001) improvement in the score of giant papillae after 8 weeks of treatment. The characteristics of dendritic cells (including cell count, total area, average size, perimeter, and diameter) showed a significant (p < 0.05) decrease after 2 weeks of treatment. During the follow-up, no other topical medications were required and no significant changes in visual acuity were documented. No cataracts or elevation of intraocular pressures were detected. Only 5 patients (29%) had a tingling or burning sensation or discomfort. Conclusions: Tacrolimus 0.1% eye drops are an effective and safe treatment for the tarsal form of VKC, and can rapidly inhibit the activity of dendritic cells, improve symptoms, reduce papillary hyperplasia, and reverse damage at the palpebral conjunctiva. The side effects could affect the compliance of some patients.

Keywords:
Tacrolimus, Palpebral vernal keratoconjunctivitis, Efficacy, Confocal microscopy
1.
Leonardi A: Vernal keratoconjunctivitis: pathogenesis and treatment. Prog Retin Eye Res 2002;21:319-339.
2.
Montan PG, Ekström K, Hedlin G, van Hage-Hamsten M, Hjern A, Herrmann B: Vernal keratoconjunctivitis in a Stockholm ophthalmic centre - epidemiological, functional, and immunologic investigations. Acta Ophthalmol Scand 1999;77:559-563.
3.
Bonini S, Lambiase A, Sgrulletta R, Bonini S: Allergic chronic inflammation of the ocular surface in vernal keratoconjunctivitis. Curr Opin Allergy Clin Immunol 2003;3:381-387.
4.
Manzouri B, Flynn T, Ohbayashi M, Ono SJ: The dendritic cell in allergic conjunctivitis. Ocul Surf 2008;6:70-78.
5.
Manzouri B, Ohbayashi M, Leonardi A, Larkin DFP, Ono SJ: Characterization of dendritic cell phenotype in allergic conjunctiva: increased expression of FcεRI, the high-affinity receptor for immunoglobulin E. Eye 2009;23:2099-2104.
6.
Vichyanond P, Pacharn P, Pleyer U, Leonardi A: Vernal keratoconjunctivitis: a severe allergic eye disease with remodeling changes. Pediatr Allergy Immunol 2014;25:314-322.
7.
Bonini S, Sacchetti M, Mantelli F, Lambiase A: Clinical grading of vernal keratoconjunctivitis. Curr Opin Allergy Clin Immunol 2007;7:436-441.
8.
Al-Amri AM, Mirza AG, Al-Hakami AM: Tacrolimus ointment for treatment of vernal keratoconjunctivitis. Middle East Afr J Ophthalmol 2016;23:135-138.
9.
Vichyanond P, Tantimongkolsuk C, Dumrongkigchaiporn P, Jirapongsananuruk O, Visitsunthorn N, Kosrirukvongs P: Vernal keratoconjunctivitis: result of a novel therapy with 0.1% topical ophthalmic FK-506 ointment. J Allergy Clin Immunol 2004;113:355-358.
10.
Kheirkhah A, Zavareh MK, Farzbod F, Mahbod M, Behrouz MJ: Topical 0.005% tacrolimus eye drops for refractory vernal keratoconjunctivitis. Eye 2011;25:872-880.
11.
Chatterjee S, Agrawal D: Tacrolimus in corticosteroid-refractory vernal keratoconjunctivitis. Cornea 2016;35:1444-1448.
12.
Pucci N, Caputo R, di Grande L, de Libero C, Mori F, Barni S, di Simone L, Calvani A, Rusconi F, Novembre E: Tacrolimus versus cyclosporine eyedrops in severe cyclosporine-resistant vernal keratoconjunctivitis: a randomized, comparative, double-blind, crossover study. Pediatr Allergy Immunol 2015;26:256-261.
13.
Sawada S, Suzuki G, Kawase Y, Takaku F: Novel immunosuppressive agent, FK506. In vitro effects on the cloned T cell activation. J Immunol 1987;139:1797-1803.
14.
Miyazaki D, Fukushima A, Ohashi Y, Ebihara N, Uchio E, Okamoto S, Shoji J, Takamura E, Nakagawa Y, Namba K, Fujishima H: Steroid-sparing effect of 0.1% tacrolimus eye drops for treatment of shield ulcer and corneal epitheliopathy in refractory allergic ocular diseases. Ophthalmology 2017;124:287-294.
15.
Fukushima A, Ohashi Y, Ebihara N, Uchio E, Okamoto S, Kumagai N, Shoji J, Takamura E, Nakagawa Y, Namba K, et al: Therapeutic effects of 0.1% tacrolimus eye drops for refractory allergic ocular diseases with proliferative lesion or corneal involvement. Br J Ophthalmol 2014;98:1023-1027.
16.
Barot RK, Shitole SC, Bhagat N, Patil D, Sawant P, Patil K: Therapeutic effect of 0.1% tacrolimus eye ointment in allergic ocular diseases. J Clin Diagn Res 2016;10:NC5-NC9.
17.
Sengoku T, Sakuma S, Satoh S, Kishi S, Ogawa T, Ohkubo Y, Mutoh S: Effect of FK506 eye drops on late and delayed-type responses in ocular allergy models. Clin Exp Allergy 2003;33:1555-1560.
18.
Müller GG, José NK, de Castro RS: Topical tacrolimus 0.03% as sole therapy in vernal keratoconjunctivitis: a randomized double-masked study. Eye Contact Lens 2014;40: 79-83.
19.
Riau AK, Angunawela RI, Chaurasia SS, Lee WS, Tan DT, Mehta JS: Early corneal wound healing and inflammatory responses after refractive lenticule extraction (ReLEx). Invest Ophthalmol Vis Sci 2011;52:6213-6221.
20.
Angunawela RI, Riau AK, Chaurasia SS, Tan DT, Mehta JS: Refractive lenticule re-implantation after myopic ReLEx: a feasibility study of stromal restoration after refractive surgery in a rabbit model. Invest Ophthalmol Vis Sci 2012;53:4975-4985.
21.
Zhivov A, Stave J, Vollmar B, Guthoff R: In vivo confocal microscopic evaluation of Langerhans cell density and distribution in the normal human corneal epithelium. Graefes Arch Clin Exp Ophthalmol 2005;243:1056-1061.
22.
Rong B, Yan XM: In vivo study of normal human limbal and central corneas using laser confocal microscope. Zhonghua Yan Ke Za Zhi 2006;42:17-21.
23.
Liu M, Gao H, Wang T, Wang S, Li S, Shi W: An essential role for dendritic cells in vernal keratoconjunctivitis: analysis by laser scanning confocal microscopy. Clin Exp Allergy 2014;44:362-370.
24.
Hu Y, Matsumoto Y, Adan ES, Dogru M, Fukagawa K, Tsubota K, Fujishima H: Corneal in vivo confocal scanning laser microscopy in patients with atopic keratoconjunctivitis. Ophthalmol 2008;115:2004-2012.
25.
Dana MR: Corneal antigen-presenting cells: diversity, plasticity, and disguise: the Cogan lecture. Invest Ophthalmol Vis Sci 2004;45:721-727.
26.
Joseph MA, Kaufman HE, Insler M: Topical tacrolimus ointment for treatment of refractory anterior segment inflammatory disorders. Cornea 2005;24:417-420.
27.
Yalçindag FN, Incel O, Ozdemir O: Effectiveness of tacrolimus in high-risk limbal allo-graft transplantation. Ann Ophthalmol 2008;40:152-156.
28.
Labcharoenwongs P, Jirapongsananuruk O, Visitsunthorn N, Kosrirukvongs P, Saengin P, Vichyanond P: A double-masked comparison of 0.1% tacrolimus ointment and 2% cyclosporine eye drops in the treatment of vernal keratoconjunctivitis in children. Asian Pac J Allergy Immunol 2012;30:177-184.
29.
Mayer K, Reinhard T, Reis A, Böhringer D, Sundmacher R: FK 506 ointment 0.1 - a new therapeutic option for atopic blepharitis. Clinical trial with 14 patients.: Klin Monbl Augenheilkd 2001;218:733-736.
30.
Ohashi Y, Ebihara N, Fujishima H, Fukushima A, Kumagai N, Nakagawa Y, Namba K, Okamoto S, Shoji J, Takamura E, Hayashi K: A randomized, placebo-controlled clinical trial of tacrolimus ophthalmic suspension 0.1% in severe allergic conjunctivitis. J Ocul Pharmacol Ther 2010;26:165-174.
31.
Hamrah P, Zhang Q, Liu Y, Dana MR: Novel characterization of MHC class II-negative population of resident corneal Langerhans cell-type dendritic cells. Invest Ophthalmol Vis Sci 2002;43:639-646.
32.
Hamrah P, Liu Y, Zhang Q, Dana MR: The corneal stroma is endowed with a significant number of resident dendritic cells. Invest Ophthalmol Vis Sci 2003;44:581-589.
© 2017 S. Karger AG, Basel
2017
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.