FP1054 : To Evaluate the Efficacy of Topical 0. 03% Tacrolimus Ointment for Treatment of Refractory VKC

Dr. Anurag
Makkar, Dr. Malik K P S, Dr. Charu Jain, Dr. Sanjiv
Kumar, Dr.Virendra Kumar Malik
To Study The Efficacy Of Tacrolimus 0.03% Eye Ointment As A Sole Therapy In Refractory Vernal Keratoconjunctivitis.

Presenting Author – Anurag Makkar¹

Chief Author- VK Malik²

Co Author – Charu Jain³, Sanjiv Gupta ⁴

1.PG student , Department of Ophthalmology , Subharti Medical College , Meerut.

2.Professor, Department of Ophthalmology, Subharti Medical College, Meerut.

3.Associate Professor, Department of Ophthalmology, Subharti Medical College, Meerut.

4.Professor, Department of Ophthalmology, Subharti Medical College, Meerut.

INTRODUCTION

Vernal, derived from the Greek word “Occurring in Spring” is a form of recurrent, bilateral allergic conjunctivitis caused by hypersensitivity reaction to exogenous allergens. Greater prevalence of Vernal Keratoconjunctivitis (VKC) is seen in the regions with hot, humid climate and higher load of air borne allergens. It is a common ocular surface disorder in the Mediterranean region, Central Africa, India and South America. The peak incidence of disease is between April and August but many patients may have symptoms throughout the year. The disease predominantly affects children and young adults and usually resolves around puberty, only rarely persisting beyond the age of 25 years but sometimes seen even beyond this age. It is twice more common in males than in females.

It is more common in patients who have an atopic background. Also VKC has traditionally been considered as a classical IgE mediated disease (Type I Hypersensitivity), recent findings implicate more complex pathogenesis with particular involvement of Th-2 lymphocytes¹Type IV

The chief symptoms of disease include- intense ocular itching, redness ,watering ,thick ropy discharge ,burning or foreign body sensation ,photophobia. The clinical signs of VKC include -conjunctival hyperemia,cobblestone papillae in upper tarsal conjunctiva,limbal conjunctival thickening with gelatinous nodules and trantas dots.

The Clinical Types Of VKC Include:- (a)Palpebral or Tarsal (b)Bulbar (c)Mixed

Moreover, vision threatnening corneal complications in severe and chronic cases coupled with potential iatrogenic side effects made VKC a concerning ocular surface disorder^2,3.

A wide range of therapeutic modalities are currently available for treatment of vernal keratoconjunctivitis. Milder cases can often be treated with cold compresses, tear substitutes, antihistamines, mast cell stabilisers and non-steroidal anti-inflammatory drugs. Nevertheless topical steroids are the mainstay of treatment of moderate-severe forms of VKC⁴.

Some cases, however, remain, still symptomatic despite treatment with topical steroids. Further more, prolonged use of topical steroids may be associated with various complications, such as glaucoma, cataract⁵ and secondary infections⁶. To avoid steroid- related complications, immunomodulatory agents such as topical cyclosporine A and Tacrolimus have recently been used for treatment of VKC^7,8.

TACROLIMUS

Tacrolimus was discovered in 1987; it was among the first macrolide immunosuppressants discovered. It has been isolated from the fermentation  broth of streptomyces tsukubaenis¹¹. The name tacrolimus is derived from Tsukuba macrolide immunosuppressant. Tacrolimus (formerly, FK-506) is an immunomodulatory agent, which is similar to cyclosporine A in mechanism but with much higher potency (up to 100 times)^9.. Its action is initiated by binding to a class of peptidyl-prolyl cis-trans isomerases (PPIases), designated FK506-binding proteins (FKBPs). The predominant FKBP in the T lymphocyte is a cytosolic protein of approximately 12 kDa, and is designated as FKBP-12. It is a lipophilic molecule which blocks the early phase of T-cell activation, thus inhibiting both T-lymphocyte signal transduction and IL-2 transcription. Furthermore, it is also reported that tacrolimus inhibits the release of histamine from mast cells and impairs prostaglandin synthesis in its de novo way.

In Ophthalmology, Tacrolimus has mainly been used to suppress immune reactions in corneal and limbal transplantations ,^12,13 uveitis,¹⁴ and allergic eye disease¹⁵.

The pharmacology of tacrolimus includes reduction of pro-inflammatory cytokines, activated T lymphocytes, and markers of apoptosis; it also exerts neuroprotective effects as well as inhibits the loss of conjunctival epithelium and decrease in the number of goblet cells. Many chronic ocular disorders share similar mechanisms, and the effects of tacrolimus on corneal graft, inflammatory conjunctival and corneal diseases like Atopic Keratoconjunctivitis (AKC),¹⁶ Giant Papillary Conjunctivitis¹⁷, VKC¹⁸, Uveitis, and GVHD have been reported by various studies. Therefore, ophthalmic tacrolimus is a welcome addition to the therapeutic armamentarium for these corneal and ocular surface diseases.

AIMS AND OBJECTIVES

1. To study the efficacy of Tacrolimus 0.03% eye ointment as a sole therapy in
2. To study the time period required to achieve a significant effect in VKC.
3. To study the safety profile of 0.03% Tacrolimus eye ointment.

MATERIALS AND METHODS

This observationl study included 70 eyes of 35 patients of refractory VKC in Subharti Medical College, Meerut. Each patient received 0.03% of Tacrolimus eye ointment along with lubricating eye drops. Patients were followed up for minimum of 12 weeks after the initiation of treatment. Results were compared at the end of study and data was analysed statistically by SPSS version 15.0 software and’ p’ value was calculated using paired and unpaired t test. Patients with active VKC diagnosed on the basis of typical history and slit lamp examination and those with worsening of symptoms during steroid tapering or having steroid induced complications were included. While patients with a history of Herpes(Simplex?Zoster), patients already on immunosuppressants were excluded.

Before starting treatment with Tacrolimus eye ointment and at each visit thereafter, all patients were asked a questionnaire regarding the symptoms of itching, redness, photophobia, foreign body sensation, and mucus discharge. The patients were graded on a grading score of 0 (none), score 1 or mild (occasional symptoms), score 2 or moderate (frequent symptoms), and score 3 or severe (constant symptoms) to report the severity of each individual symptom. In addition they underwent a complete ophthalmic examination including measurement of best spectacle-corrected visual acuity (BCVA), slit lamp biomicroscopy and photography, fluorescein staining and intra ocular pressure. Before starting topical tacrolimus ointment, all patients were asked to discontinue all other medications including steroids for 1 week.

Advantages and disadvantages of the treatment were fully explained to the patients and/or their parents and then informed consent was obtained from each patient or his/her parents. The treatment included 0.03% tacrolimus eye ointment two times a day. The patients were evaluated on 1^st , 3^rd , 6^th , and 12^th weeks after the starting of medication. Efficacy of the tacrolimus was evaluated by assessing the changes in patients symptoms and signs, and by the patients need for additional medications to have more relief. Each patient was examined to evaluate the changes in conjunctival hyperaemia, papillary hypertrophy, giant papillae, limbal hypertrophy and corneal punctate epithelial erosions. Each sign was graded as score 0 (none), score 1 (mild), score 2 (moderate), or score 3 (severe). Improvement of each symptom or sign was defined as atleast 1-score reduction in severity compared with values before the treatment. Paired t-test was used to statistically analyse the changes in mean score of symptoms and signs after treatment with topical 0.03% tacrolimus eye ointment; p values of 0.05 or less was considered as statistically significant.

CLINICAL FEATURES	GRADE 0	GRADE 1	GRADE 2	GRADE 3
ITCHING	ABSENT	MILD	MODERATE	SEVERE
WATERING	ABSENT	MILD	MODERATE	SEVERE
REDNESS	ABSENT	MILD	MODERATE	SEVERE
FB SENSATION	ABSENT	MILD	MODERATE	SEVERE
ROPY DISCHARGE	ABSENT	MILD	MODERATE	SEVERE
PHOTOPHOBIA	ABSENT	MILD	MODERATE	SEVERE
CONJUNCTIVAL HYPERAEMIA	ABSENT	DILATATION OF FEW VESSELS	DILATATION OF MANY VESSELS	IMPOSSIBLE TO DISTINGUISH
TARSAL CONJ CHANGES	ABSENT	PAPILLARY HYPERTROPHY	COBBLESTONE PAPILLAE	GIANT PAPILLAE
LIMBAL CHANGES	ABSENT	LIMBAL THICKENING	1-2 TRANTA DOTS	>2 TRANTA DOTS
KERATOPATHY	ABSENT	1 QUAD INVOLVED	2 QUAD INVOLVED	>2 QUAD INVOLVED

 RESULTS-

• Total number of pateints involved in the study =35, Drop outs= 3
• The maximum cases were in the age group of 6-10 yrs -19 patients (59.37%).
• Mean age of the patients = 9.03 year
• Disease was bilateral in all the cases. Out of 32 patients included in the study, majority were males – 22 (68.75%)

Table 1: CHIEF PRESENTING COMPLAINTS

Chief complaints	No. of Patients	Percentage
Itching	32	100.0
Watering	29	90.6
Redness	20	62.5
Foreign Body Sensation	20	62.5
Ropy Discharge	18	56.3
Photophobia	9	28.1

Itching was found to be most prominent symptom seen in 100% cases followed by watering in 29 patients (90.60%). Photophobia was seen least common in 9 patients (28.12%) cases.

Table 2: CLINICAL SIGNS AT PRESENTATION

Clinical Signs	No. of Patients	Percentage
Conjunctival  Hyperaemia	28	87.25
Tarsal Conjunctival Changes	22	68.75
Limbal Changes	21	65.62
Keratopathy	6	18.75

Most common clinical presentation of disease was  conjunctival  hyperaemia  seen in 28 out of 32 patients (87.25%) followed by tarsal conjunctival changes seen in 22 out of 32 patients (68.75%).  Keratopathy was seen least common in 6 patients (18.75%).

Table 3: MEAN SCORE OF SYMPTOMS BEFORE AND AFTER TREATMENT

SYMPTOMS	DAY 1	1st WEEK	3rd WEEK	6th WEEK	12th WEEK	p-value
Itching	2.90±0.31	0.20±0.42	0	0	0	<0.001
Watering	2.70±0.27	0.40±0.45	0.20±0.32	0	0	<0.001
Redness	2.00±0.82	1.70±0.82	0.70±0.48	0.60±0.50	0.30±0.53	<0.001
FB Sensation	1.80±0.63	1.50±0.53	0.30±0.48	0.20±0.36	0.10±0.32	<0.001
Ropy Discharge	1.80±0.79	1.60±0.52	0.20±0.42	0.20±0.42	0.20±0.42	<0.001
Photophobia	1.50±0.85	0.60±0.85	0.30±0.42	0	0	<0.001

After starting 0.03% tacrolimus eye ointment, the patients were followed up for 12 weeks. The most prominent and the first symptom to show dramatic relief was itching. After  1 week of starting tacrolimus eye ointment majority of the patients were relieved from itching and it was completely relieved by the end of 3^rd week, p value (<0.001).Marked improvement in  watering and photophobia was seen by 3^rd week and they were completely relieved by 6^th week, p value (<0.001).Redness, FB Sensation and Ropy Discharge showed significant improvement by 6^th week, p value (<0.05) and by the end of the 12^th week p value was (<0.001).  However, in some cases mild symptoms persisted even after 12 weeks.

Table 4: MEAN SCORE OF SIGNS BEFORE AND AFTER TREATMENT

SIGNS	DAY 1	1st WEEK	3rd WEEK	6th WEEK	12th WEEK	p-value
Conjunctival hyperaemia	2.60±0.52	0.50±0.52	0.30±0.42	0.10±0.46	0	<0.001
Tarsal conjunctival changes	2.70±0.48	2.0±0.48	1.30±0.67	1.0±0.58	0.60±0.52	<0.001
Limbal changes	1.70±1.29	1.20±1.29	0.80±1.13	0.40±0.50	0.20±0.42	0.005
Keratopathy	0.80±1.23	0.60±1.23	0.50±0.85	0.40±0.66	0.30±0.48	0.036

Conjunctival hyperaemia was the first sign to show improvement, it  improved in all patients by the end of the 1^st week, p value (<0.05) and it completely resolved by the end of 12^th week, p value (<0.001). Tarsal Counjunctival changes, Limbal changes and Keratopathy also showed  improvement after treatment and  significantly improved by the end of 12^th week, p value (<0.001, 0.005 and 0.036) respectively. No ocular complication related to tacrolimus eye ointment was seen in any patient.

DISCUSSION-

The present study has been undertaken to study the efficacy and safety profile of 0.03% tacrolimus eye ointment for treatment of refractory VKC in Indian population. Our study is consistent with Shoughy et al¹⁹.They retrospectively included 62 consecutive patients with VKC refractory to conventional treatment [49 male and 13 female]. Tacrolimus 0.01% ophthalmic solution was administered to patients twice daily from 1 to 29 months. Assessment was carried out before initiation of therapy and on the last visit after treatment.The median age was 12 years (range: 5-47 years). They observed that the mean visual acuity improved from 20/30 to 20/25 following treatment. There was statistically significant improvement in symptoms of itching (P<0.001), redness (P<0.001), foreign body sensation (P<0.001), and discharge (P<0.001). Statistically significant improvement was also observed in clinical signs of conjunctival hyperemia (P<0.001), limbal infiltration (P<0.001), Trantas dots (P<0.001), superficial punctate keratopathy (P<0.001), and conjunctival papillary hypertrophy (P<0.001). The solution form of tacrolimus was well tolerated. They concluded that the low-dose topical tacrolimus 0.01% solution is effective and safe in the management of patients with refractory VKC.

Hazarika et al²⁰ in 2015 evaluated the efficacy of topical 0.03% tacrolimus eye ointment in the management of simple allergic conjunctivitis.They conducted  a prospective observational study consisting of 41 patients with refractory simple allergic conjunctivitis, whose condition responded very poorly to conventional anti-allergic eye drops. Patients were followed up at the end of 1^st week, 4^th week, and at 7^th week (2 weeks washout period). At the end of 4^th week, all cases were fully cured and none of the patient had any recurrences up to 7^th week. Mean score at 1^st day (9.6 ± 3.27) was significantly (P < 0.0001) reduced by 7^th day (1.35 ± 1.19) of treatment. They concluded that topical tacrolimus ointment is an excellent alternative to anti-allergic and steroids eye drops.

Attas-Fox et al²¹ in 2008 evaluated the effectivity  of Tacrolimus 0.03% dermatological ointment (Protopic) in the treatment of intractable allergic conjunctivitis. Twenty patients (mean age 10.8 years, range 6–26) with intractable allergic conjunctivitis were enrolled. Tacrolimus 0.03% ointment was used B.D. for 8 weeks, followed by a 2-week washout period. Conjunctivitis severity was recorded with a composite subjective/objective score (chemosis, tarsal papillary size, corneal staining, tearing, itching, and photophobia) at baseline, week 8, and after washout. Tacrolimus blood levels were measured at 2 weeks. They observed significant improvement in all categories of the conjunctivitis, score was observed between baseline and the week 8 examination (p< 0.001). They concluded that application of tacrolimus 0.03% dermatological ointment into the conjunctival sac appears to be effective, well tolerated, and safe in the treatment of allergic conjunctivitis refractory to traditional treatment.

A Kheirkhah et al²²  in  2011 evaluated the efficacy and safety of topical 0.005% tacrolimus eye drop for treatment of refractory vernal keratoconjunctivitis (VKC). This prospective study included 20 eyes of 10 patients with refractory VKC, who had active symptomatic disease despite conventional medications including topical steroids. After discontinuing all other medications, patients were treated with topical 0.005% tacrolimus eye drop four times a day. Changes in subjective symptoms and objective signs after treatment were evaluated, and development of possible complications was assessed. All symptoms including itching, redness, photosensitivity, foreign body sensation, and mucus discharge improved after the treatment; itching was the first symptom to show dramatic relief. In addition, there was improvement in objective signs including conjunctival hyperaemia, conjunctival papillary hypertrophy, giant papillae, limbal hypertrophy, corneal punctate epithelial erosions, and corneal pannus; conjunctival hyperaemia was the first sign to show improvement. They concluded that topical 0.005% tacrolimus eye drop seemed to be a safe and effective treatment for steroid-resistant refractory VKC; however long term use was needed to control the disease.

CONCLUSION

• Topical tacrolimus 0.03% eye ointment is an effective and safe modality for treatment of patients with refractory VKC.
• But our study has certain limitations. The sample size is relatively small and follow up period is also short. Moreover there was no control group in our study. So, more studies should be conducted to assess the long term efficacy and safety profile of 0.03% tacrolimus eye ointment in VKC.

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