The treatment of severe allergic conjunctivitis (VKC, AKC) is often challenging. These are usually young patients requiring long term treatment. Conventionally, steroids have been used as the mainstay of treatment for severe cases. Considering the young age of the patients and need for long term treatment, the use of steroids raises serious concerns. There is a need for potent steroid sparing therapy for treatment of such patients. Recently, some of the investigators have evaluated the role of tacrolimus in treatment of severe allergic conjunctivitis.[14–17]
We found a significant improvement in the clinical sign score of patients treated with tacrolimus. In Group A, the mean sign score at baseline was 15.48 ± 4.65 which improved to 6.40 ± 0.94 at 3 months. The maximum improvement was noted in first month after initiation of treatment. In Group B, the mean sign score at baseline was 14.58 ± 4.40, which improved to 9.21 ± 2.48 at 3 months. The difference between two treatment groups was clinically significant. These findings are similar to those reported by Fukushima et al[15] and Ohashi et al.[16] In study by Fukushima et al[15] the mean total score of clinical signs was 15.3 ± 5.0 at the start of treatment and decreased to 5.9 ± 4.6 till last observation. Ohashi et al[16] reported that mean change from baseline in total score for objective signs at end of treatment (1 month) was − 5.6 ± 5.1 in the tacrolimus and − 0.1 ± 4.5 in the placebo group.
With improvement in clinical signs, there was a parallel improvement in symptom score and total sign + symptom score of the patients. The mean symptom score in Group A at baseline was 8.71 ± 3.48 which improved to 2.13 ± 1.41 at 3months. The mean symptom score in Group B improved from 8.27 ± 2.32 at baseline to 5.29 ± 1.91 at 3months. The difference between the two groups was statistically significant. The mean sign + symptom score in Group A at baseline was 24.19 ± 7.89 which improved to 8.52 ± 1.94 at 3months and in Group B improved from 22.81 ± 6.63 at baseline to 14.50 ± 4.17 at 3 months. The difference was again statistically significant. Fukushima et al[15] reported that the total clinical symptom score decreased from 8.1 ± 4.5 at baseline to 1.8 ± 2.8 at the last observation (mean change − 6.3). Ohashi et al[16] also reported a significant improvement in symptoms of patients treated with tacrolimus, using VAS (Visual Assessment Scale) for evaluation of symptoms.
Severe allergic conjunctivitis is commonly associated with proliferative changes such as giant papillae. Vision-threatening keratopathy commonly develops in an adjacent location to the giant papillae. In this study, we found that giant papillae responded well to treatment with tacrolimus. In Group A, the proportion of patients with score ≤ 1 at baseline was 37.5% which improved to 91.5% at 3 months follow up. The proportion of patients with score ≥ 2 at baseline was 62.5% which decreased to 8.5% at 3 months follow up. In study by Fukushima et al[15], 87.2% of patients had giant papillae at baseline, with 62.8% having active-stage giant papillae (score ≥ 2). At the time of last observation, only 15.8% patients had active-stage giant papillae, with alleviation of giant papillae (score ≤ 1) in 84.2% of patients. Ohashi et al[16] reported that giant papillae became less inflamed and flattened, with profound decrease in ropy discharge, finally resulting in flat giant papillae in about 60% of patients and disappearance of giant papillae in 20%. Vichyanond et al[17] reported that the mean size of tarsal papilla was significantly reduced with tacrolimus. In study by Kheirkhah et al[14], mean giant papillae score at baseline was 1.10 ± 1.45 which decreased to 0.20 ± 0.42 at 1 month (p value ≥ 0.05). All the other investigators have reported an improvement in giant papillae in their studies. But the proportion of patients who had score ≤ 1 at 3 months was higher in our study as compared to other studies. The probable reason for this is that out of 48 patients in tacrolimus treated group, 36 (75%) had score ≤ 2 at baseline. Only 12(25%) patients had severe giant papillae (score = 3).
Severe allergic conjunctivitis may lead to corneal involvement (keratopathy) which may cause decreased vision. We found that patients with corneal signs responded well to tacrolimus. In Group A, 58.3% patients had corneal involvement at baseline which resolved in all patients at 1 month follow up. In group B, 47.9% patients had keratopathy (score = 1) at baseline. At 1 month, 22.9% patients still had corneal signs which resolved in all the patients at 2 months. Thus, mild corneal involvement responded well in both the groups but the improvement was earlier in group A. Fukushima et al[15] reported that Superficial punctate keratopathy (SPK) was seen in 67.8% of patients at baseline which decreased to 22.3% at last reading. In addition, the percentage of patients with a score ≥ 2 (large impact on VA) decreased from 41.3% at baseline to 6.7% at the final evaluation. Ohashi et al[16] reported that corneal involvement significantly improved in the tacrolimus group compared with the placebo group from week 1 through week 4. No corneal epithelial disturbance was observed in 40.0% (10/25) of patients in the tacrolimus and 7.7% (2/26) in placebo group at end of treatment. In study by Kheirkhah et al[14], mean score of corneal PEE's at baseline was 1.10 ± 1.20 which decreased to 0 at 1 month. They reported that in addition to conjunctival signs, limbal hypertrophy and corneal signs such as corneal PEE's, pannus, and to some degrees corneal stromal opacity showed improvement.
Conjunctival hyperaemia is an indicator of disease activity. In group A, the proportion of patients with palpebral conjunctival hyperaemia score ≤ 1 at baseline was 33.3% which improved to 93.8% at 3 months follow up. In group B, the proportion of patients with score ≤ 1 at baseline was 39.6% which improved to 66.7% at 3 months follow up. In group A, the proportion of patients with bulbar conjunctival hyperaemia score ≤ 1 at baseline was 27.1% which improved to 97.9% at 3 months. In group B, the proportion of patients with score ≤ 1 at baseline was 45.8% which improved to 85.4% at 3 months. There was a significant improvement in conjunctival hyperaemia in both groups. The response was better in group A. The difference between the 2 groups was statistically significant. These findings are similar to those reported by other investigators.
The common symptoms of severe allergic conjunctivitis are itching, watering and foreign body sensation. All these symptoms responded well in group A. In group A, the proportion of patients with minimal or no itching (Score ≤ 1) at baseline was 43.8%, which reached to 100% at 1 month follow-up. Similarly, the proportion of patients with minimal or no watering (Score ≤ 1) at baseline was 4.2%, which improved to 100% at 1 month follow-up. The proportion of patients with minimal or no foreign body sensation (Score ≤ 1) at baseline was 33.3%, which reached to 91.7% at 1 month and 100% at 2 months. The improvement in symptoms paralleled the improvement in clinical signs. These findings are similar to those reported by other researchers.
The side effects reported with the use of tacrolimus include burning sensation, irritation, lacrimation, corneal infections (viral, bacterial), lid infections (hordeolum, herpes, molluscum), conjunctival hyperaemia, foreign body sensation, pruritis, pain. In our study, 6.3% patients in group A complained of burning sensation. No other side effects were noted. No rise in IOP was noted. Fukushima et al[15] reported side effects in 8.15% patients, which included burning sensation (3.2%), irritation (3.27%) and corneal infections (0.28%) patients. Ohashi et al[16] reported ocular irritation in 42.9% (12/28 patients) and herpetic keratitis in 1 patient (3.5%). Kheirkhah et al[14] reported no significant side effects with topical tacrolimus. Vichyanond et al[17] reported transient eye stinging (7 patients) and 1 patient had infectious conjunctivitis, which responded satisfactorily to topical antibiotics. They explained that low concentration of the medication and no additional compound other than balanced salt solution in their preparation may be the reason for this. Corneal infections though uncommon are a serious side effect of topical tacrolimus which must always be considered.
In our study, all the patients enrolled had no response to topical steroids. All patients responded well to tacrolimus plus olopatadine treatment. No serious side effects were noted on treatment with tacrolimus. Thus, tacrolimus can be considered as an option for replacement of steroids in refractory cases or those requiring long term treatment.The strengths of the study are randomized control trial, larger sample size compared to previous studies and it gives insights into outcome of tacrolimus in refractory allergic conjunctivitis in Indian setup. Few of the limitations are modest duration (3 months) of follow up and lack of cases with severe corneal involvement so that outcomes of tacrolimus in patients with severe corneal involvement could not be studied satisfactorily.