|Year : 2017 | Volume
| Issue : 3 | Page : 145-149
Long-term use of 0.003% tacrolimus suspension for treatment of vernal keratoconjunctivitis
Abdulrahman Mohammed Al-Amri1, Sandra Flavia Fiorentini2, Maan A Albarry3, Ashjan Yousef Bamahfouz4
1 Ophthalmology Department, College of Medicine, King Khalid University, Abha, Saudi Arabia
2 Ophthalmology Department, Moorfields Eye Hospital, Dubai, United Arab Emirates
3 Department of Ophthalmology at Taibah University, KSA
4 Department of Ophthalmology at Umm Al-Qura University, KSA
|Date of Web Publication||5-Oct-2017|
Abdulrahman Mohammed Al-Amri
College of Medicine, King Khalid University, P. O. Box: 641, Abha 61421
Source of Support: None, Conflict of Interest: None
| Abstract|| |
PURPOSE: To evaluate the safety and efficacy of 0.003% tacrolimus suspension for the treatment of refractory vernal keratoconjunctivitis (VKC).
MATERIALS AND METHODS: This prospective study included 40 eyes of 20 patients with severe VKC. After discontinuing all other medications, patients were treated with varying doses of 0.003% tacrolimus suspension. All were followed for at least 24 months. Changes in signs and symptoms after treatment were evaluated; adverse events were assessed. The clinical response to the treatment was the most important measurement to achieve the conclusion.
RESULTS: The mean age of the patients was 15.7 ± 1.4 years. Two patients discontinued treatment due to severe burning sensation and were excluded from the study. Significant improvements in all signs and symptoms, including itching, foreign body sensation, papillae, and Trantas dots, were seen in all patients 6 weeks after starting topical tacrolimus. Itching was the first symptom to improve. Treatment was gradually reduced, and intervals were increasing between applications. Recurrence occurred in all patients who attempted to discontinue treatment. No additional medications were required to provide relief, and no significant changes in visual acuity or refraction were seen.
CONCLUSIONS: The safety and efficacy of 0.003% Tacrolimus suspension treatment for refractory VKC were achieved and it can be considered a useful option instead of steroids, despite the poor compliance in few patients due its adverse effects.
Keywords: 0.003% suspension, allergy, calcineurin inhibitor, tacrolimus, vernal keratoconjunctivitis
|How to cite this article:|
Al-Amri AM, Fiorentini SF, Albarry MA, Bamahfouz AY. Long-term use of 0.003% tacrolimus suspension for treatment of vernal keratoconjunctivitis. Oman J Ophthalmol 2017;10:145-9
|How to cite this URL:|
Al-Amri AM, Fiorentini SF, Albarry MA, Bamahfouz AY. Long-term use of 0.003% tacrolimus suspension for treatment of vernal keratoconjunctivitis. Oman J Ophthalmol [serial online] 2017 [cited 2019 May 20];10:145-9. Available from: http://www.ojoonline.org/text.asp?2017/10/3/145/216005
| Introduction|| |
Vernal keratoconjunctivitis (VKC) is a bilateral, chronic inflammation of the tarsal and/or bulbar conjunctiva that predominantly affects children and adult males. This disease affects children between 3 and 16 years of age though it may appear earlier and continue into adulthood. In most cases, symptoms resolve at puberty. Although the name vernal suggests a seasonal spring time occurrence, frequently, this allergic condition persists throughout the year. Patients with VKC usually get worse of their symptoms during warm seasons.,,
Symptoms of VKC include intense itching, tearing, mucous secretions, and severe photophobia. Common conjunctival signs of VKC are hyperemia, papillary hypertrophy, giant papillae, discharge, and Trantas dots (gelatinous, inflammatory infiltrates around the limbus). Approximately 75% of VKC patients have a history of atopy, and about 66% also have a family history of atopy. The quality of life is much reduced in patients with VKC.
Treatment of VKC has been problematic because its pathogenesis is unclear and anti-allergic therapy is frequently unsuccessful. Because skin tests are often negative in VKC patients, it cannot be regarded as a disease due solely to type-1 hypersensitivity. In fact, numerous biological studies have confirmed that VKC is a T-helper (TH) 2 lymphocyte-mediated disease that involves eosinophils, lymphocytes, and structural cell activation. It has been speculated that interactions between IgE-and TH2-mediated triggers and nonspecific triggers account, in part, for treatment failure.
VKC has been treated with a variety of agents including antihistamines, mast-cell stabilizers, and nonsteroidal anti-inflammatory drugs. Topical steroids have been the treatment of choice for moderate to severe forms of VKC;, but prolonged use of topical steroids may cause complications, such as glaucoma, cataract, and secondary infections. Another important tool in the treatment arsenal for VKC is topical cyclosporine A that has been used with success specially to avoid the side effects of steroids.,,
Tacrolimus is a strong, nonsteroidal, macrolide immunosuppressant isolated from Streptomyces tsukubaensis that is 100 times more potent than cyclosporine., The mechanism of action of tacrolimus has not been fully elucidated as yet. It is known that tacrolimus binds to 12-kDa FK506-binding protein in T-cells and inhibits calcineurin activity. Calcineurin inhibition suppresses dephosphorylation of the nuclear factor of activated T-cells and its transfer into the nucleus, which suppresses the formation of TH1 (interleukin [IL]-2, interferon γ) and TH2 cytokines (IL-4, IL-5). Tacrolimus also inhibits histamine release from mast cells, which is thought to alleviate allergic symptoms.,,,,
Tacrolimus ointment is used widely for the treatment of atopic dermatitis. Topical tacrolimus in doses of 0.02–0.1% have been an effective treatment for a number of refractory inflammatory ocular surface diseases, including VKC and atopic keratoconjunctivitis (AKC).,,,,,,, However, the optimum treatment dose as well as the long-term effects of the treatment at these doses are not known. Topical Tacrolimus 0.003% suspension was used in this study to treat refractory VKC and its clinical outcomes were observed in a long term follow up. This study's purpose was to confirm its efficacy and safety of this new dilution and presentation.
| Materials and Methods|| |
This study included forty eyes from twenty patients with VKC after no response to conventional treatments. It was a prospective and nonrandomized study. The Institutional Review Board of King Khalid University in Abha, Saudi Arabia, approved the study protocol. Patients were recruited from Magrabi Aseer Hospital and written informed consent was obtained. This study adhered to the tenets of the Declaration of Helsinki.
The refractory VKC was defined as VKC that was treated with conventional medications(cyclosporine, antihistamines, mast-cell stabilizers, topical steroid and nonsteroid anti-infl ammatories) with no success. All patients included in the study presented refractory VKC with significant symptoms(chronic, bilateral itching, redness) and (2) signs (Trantas dots, papillae on upper tarsal conjunctiva, corneal erosions).
Complete ophthalmic examinations, including best spectacle-corrected visual acuity (BSCVA), slit-lamp biomicroscopy, fluorescein staining, fundoscopy, and applanation tonometry were conducted.
Exclusion criteria included coexisting conjunctival disorders, chemical injury, Stevens–Johnson syndrome, corneal diseases, uveitis, ocular infections, contact lens use, history of using systemic nonsteroidal anti-inflammatory or immunosuppressive drugs, and ocular surgery within the previous 3 months. One week prior to the treatment beginning, all the patients stopped their current medications. Tacrolimus suspension was prepared by adding carboxymethyl cellulose sodium 1.0% with benzalkonium chloride to tacrolimus powder under sterile condition in the local pharmacy to achieve 0.003% concentration. The dose for VKC was 3 times daily for 1 month followed by monthly tapering (twice daily for 1 month) and once daily afterward. During treatment, patients returned for evaluation after 1, 4, and 6 weeks and every 6 months afterward. Main outcomes were graded by severity of signs and symptoms at baseline (before treatment) and at each visit using a four-grade scale (0 = none; 1 = mild; 2 = moderate; 3 = severe). Graded symptoms included itching, redness, and foreign body sensation, and graded signs included conjunctival hyperemia, papillary hypertrophy of the superior tarsal conjunctiva, Trantas dots, and superficial punctate keratopathy [Table 1].
The software used for statistical analysis of data was SPSS Inc., Chicago, Illinois, USA, ANOVA (analysis of variance) and the Wilcoxon. The last two specifically identified changes in the mean scores of signs and symptoms after tacrolimus 0.003% suspension introduction. P ≤ 0.05% was statistically significant.
| Results|| |
Eighteen men were included in this study and two women. The total of the eyes with bilateral VKC were forty from twenty patients (mean [± standard deviation] duration 72.25 ± 50.20 months). The mean age was 15.7 ± 1.4 years [Table 2]. Itchiness was the most prevalent symptom (19/20) among the other complaints. The common signs were papillary conjunctivitis, moderate to severe conjunctival hyperemia and lid thickening. All of them were symptomatic with active disease presentation and they were followed for a mean duration of 27.4 ± 0.70 months after 0.003% tacrolimus suspension started [Table 2].
|Table 2: Characteristics of adult patients with vernal keratoconjunctivitis|
Click here to view
0.003% Tacrolimus suspension brought improvement of all the symptoms and signs starting after 1 week of treatment. The itchiness was completely disappeared at week 6 [Table 3]. The need to keep the treatment after the patients become asymptomatic was imperative due to the chronic and recurrent characteristics of VKC. No further medications were added.
|Table 3: Mean score of symptoms in patients with vernal keratoconjunctivitis before and after treatment with 0.003% tacrolimus suspension|
Click here to view
Before treatment, conjunctival hyperemia was present in 30 eyes (21 severe, 8 moderate, and 1 mild). Conjunctival hyperemia was completely resolved in 25/40 eyes 6 weeks after starting treatment. There was improvement in conjunctival papillary hypertrophy in 30 eyes 6 weeks after starting treatment. Twenty-nine eyes that had moderate or severe lid thickening at baseline had improved 6 weeks after starting treatment. All patients with moderate or severe corneal punctate epithelial erosions (30/40) had improved 6 weeks after starting treatment. All who had mild corneal punctate epithelial erosions after 6 months achieved almost complete resolution of the corneal punctate epithelial erosions at the last follow-up visit [Table 4]. The VKC recurrence happened in all the patients that stopped the treatment, so, Tacrolimus suspension was kept for a longer period, up to the end of the study. Only 2 patients presented no improvement after the treatment and there was a high suspicious for poor compliance of the posology.
|Table 4: Mean score of objective signs in patients with vernal keratoconjunctivitis before and after treatment with 0.003% tacrolimus suspension|
Click here to view
| Discussion|| |
The effectiveness of topical tacrolimus for the treatment of AKC and VKC has been largely reported in the medical literature as an alternative option for the cases refractory to conventional medication such as steroids and topical cyclosporine.,,,,,,
For example, a randomized placebo-controlled trial that enrolled patients with AKC (n = 21) and VKC (n = 7) achieved a marked improvement in symptoms after 4 weeks of treatment with a 0.1% ophthalmic suspension of tacrolimus twice daily. Five subjective symptoms (itching, discharge, hyperemia, lacrimation, and foreign body sensation) were significantly better in the tacrolimus group than in the placebo group. Tacrolimus significantly improved giant papillae (P = 0.001) and corneal involvement (P = 0.005). In a retrospective study of the effects of 0.02% tacrolimus ointment for refractory ocular surface inflammatory diseases, five patients with AKC and one with VKC achieved marked to moderate improvement of their symptoms within 2–4 weeks of treatment. Moreover, elevated intraocular pressure was reduced in steroid responders after steroid therapy was stopped, and there were no adverse side effects during 2–26 months of continuous treatment.
Our study demonstrated that a 0.003% topical tacrolimus suspension is an effective treatment for the management of severe VKC resistant to cyclosporine. Consistent with previous reports,,,,,, almost all of our patients achieved dramatic improvements in inflammatory signs and symptoms without significant adverse effects. During the follow up, after the first 6 weeks, there was no need of steroid or other medication. The patients kept well controlled only with tacrolimus.
In our study, all patients completed 24 months of follow-up and none required additional medications, such as antihistamines, steroids, or mast cell stabilizers, to control disease activity. Most symptoms were relieved 6 weeks after beginning 0.003% tacrolimus suspension treatment [Table 3]. Allergic symptoms recurred in all patients who attempted to discontinue treatment. Consequently, they were kept on treatment for the entire follow-up period. Although a risk of T-cell lymphoma in patients using topical tacrolimus has been reported, there is insufficient epidemiological evidence to know if topical calcineurin inhibitors can cause malignancy. This effect may be associated with the activation of herpes simplex dendritic keratitis by the immunosuppressive properties of tacrolimus. However, none of our patients developed herpes simplex keratitis during the long-term follow-up period. The possibility for activation of herpes simplex dendritic keratitis by tacrolimus treatment requires further study.
Moreover, there is a scarcity of data regarding the optimal dose and duration of treatment. In fact, the blood concentration profiles of patients using 0.1% tacrolimus suspension were below the limit of quantification (0.5 ng/ml) in the majority of patients. In our study, no malignancies occurred during the 2-year follow-up period, and the risk of developing malignancy after the application of 0.003% topical tacrolimus is extremely unlikely since it is far below that at which adverse effects were reported when administered systemically. Moreover, a retrospective cohort study of more than 950,000 individuals with atopic dermatitis or eczema found that tacrolimus skin ointment was a safe and effective treatment for patients with refractory VKC. There were some limitations in this study such as the size of the sample and the study design itself, not being a case control one.
| Conclusions|| |
The safety and effectiveness were achieved during the period of the VKC treatment only with Tacrolimus 0.003% suspension because the clinical signs and symptoms were well controlled with no important side effects. However, despite to be considered as a good alternative to conventional treatments in VKC, further studies need to be done in order to have a long term follow up aiming the answer for the most appropriate concentration and posology as well as the safety of Tacrolimus in more years.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bielory L. Allergic and immunologic disorders of the eye. Part II: Ocular allergy. J Allergy Clin Immunol 2000;106:1019-32.
Clark AF. Basic sciences in clinical glaucoma: Steroids, ocular hypertension, and glaucoma. J Glaucoma 1995;4:354-69.
Tabbara AK, El-Asrar A. Immunopathogenesis of ocular allergy. Progress in Allergy and Clinical Immunology. Seattle: Hogrefe & Huber; 1997. p. 381-5.
Sacchetti M, Baiardini I, Lambiase A, Aronni S, Fassio O, Gramiccioni C, et al.
Development and testing of the quality of life in children with vernal keratoconjunctivitis questionnaire. Am J Ophthalmol 2007;144:557-63.
Leonardi A. Vernal keratoconjunctivitis: Pathogenesis and treatment. Prog Retin Eye Res 2002;21:319-39.
Stahl JL, Barney NP. Ocular allergic disease. Curr Opin Allergy Clin Immunol 2004;4:455-9.
Bonini S, Bonini S, Lambiase A, Marchi S, Pasqualetti P, Zuccaro O, et al.
Vernal keratoconjunctivitis revisited: A case series of 195 patients with long-term followup. Ophthalmology 2000;107:1157-63.
Keklikci U, Soker SI, Sakalar YB, Unlu K, Ozekinci S, Tunik S Efficacy of topical cyclosporin A 0.05% in conjunctival impression cytology specimens and clinical findings of severe vernal keratoconjunctivitis in children. Jpn J Ophthalmol 2008;52:357-62.
Keklikci U, Dursun B, Cingu AK. Topical cyclosporine a 0.05% eyedrops in the treatment of vernal keratoconjunctivitis - Randomized placebo-controlled trial. Adv Clin Exp Med 2014;23:455-61.
Leonardi A. Management of vernal keratoconjunctivitis. Ophthalmol Ther 2013;2:73-88.
William F. Ganong. Review of medical physiology. 22nd
ed. Lange Medical Books. 2005. p. 530
Murphy CC, Greiner K, Plskova J, Duncan L, Frost NA, Forrester JV, et al.
Cyclosporine vs. tacrolimus therapy for posterior and intermediate uveitis. Arch Ophthalmol 2005;123:634-41.
Peters DH, Fitton A, Plosker GL, Faulds D. Tacrolimus. A review of its pharmacology, and therapeutic potential in hepatic and renal transplantation. Drugs 1993;46:746-94.
Sakuma S, Higashi Y, Sato N, Sasakawa T, Sengoku T, Ohkubo Y, et al.
Tacrolimus suppressed the production of cytokines involved in atopic dermatitis by direct stimulation of human PBMC system. (Comparison with steroids). Int Immunopharmacol 2001;1:1219-26.
Zhai J, Gu J, Yuan J, Chen J. Tacrolimus in the treatment of ocular diseases. BioDrugs 2011;25:89-103.
Al-Amri AM. Long-term follow-up of tacrolimus of ointment for treatment atopic keratoconjunctivitis. Am J Ophthalmol 2014;157:280-6.
Joseph MA, Kaufman HE, Insler M. Topical tacrolimus ointment for treatment of refractory anterior segment inflammatory disorders. Cornea 2005;24:417-20.
Kymionis GD, Goldman D, Ide T, Yoo SH. Tacrolimus ointment 0.03% in the eye for treatment of giant papillary conjunctivitis. Cornea 2008;27:228-9.
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;218:733-6.
Miyazaki D, Tominaga T, Kakimaru-Hasegawa A, Nagata Y, Hasegawa J, Inoue Y. Therapeutic effects of tacrolimus ointment for refractory ocular surface inflammatory diseases. Ophthalmology 2008;115:988-92.e5.
Ohashi Y, Ebihara N, Fujishima H, Fukushima A, Kumagai N, Nakagawa Y, et al.
A randomized, placebo-controlled clinical trial of tacrolimus ophthalmic suspension 0.1% in severe allergic conjunctivitis. J Ocul Pharmacol Ther 2010;26:165-74.
Tam PM, Young AL, Cheng LL, Lam PT. Topical tacrolimus 0.03% monotherapy for vernal keratoconjunctivitis - Case series. Br J Ophthalmol 2010;94:1405-6.
Lee YJ, Kim SW, Seo KY. Application for tacrolimus ointment in treating refractory inflammatory ocular surface diseases. Am J Ophthalmol 2013;155:804-13.
Kheirkhah A, Zavareh MK, Farzbod F, Mahbod M, Behrouz MJ. Topical 0.005% tacrolimus eye drop for refractory vernal keratoconjunctivitis. Eye (Lond) 2011;25:872-80.
Stumpf T, Luqmani N, Sumich P, Cook S, Tole D. Systemic tacrolimus in the treatment of severe atopic keratoconjunctivitis. Cornea 2006;25:1147-9.
Hui RL, Lide W, Chan J, Schottinger J, Yoshinaga M, Millares M. Association between exposure to topical tacrolimus or pimecrolimus and cancers. Ann Pharmacother 2009;43:1956-63.
Tennis P, Gelfand JM, Rothman KJ. Evaluation of cancer risk related to atopic dermatitis and use of topical calcineurin inhibitors. Br J Dermatol 2011;165:465-73.
Ebihara N, Ohashi Y, Fujishima H, Fukushima A, Nakagawa Y, Namba K, et al.
Blood level of tacrolimus in patients with severe allergic conjunctivitis treated by 0.1% tacrolimus ophthalmic suspension. Allergol Int 2012;61:275-82.
[Table 1], [Table 2], [Table 3], [Table 4]