Comparison of the effect of tea tree oil eye gel with standard treatment in patients with anterior blepharitis: An open-label clinical trial (2024)

Abstract

Purpose:

Daily cleansing of eyelids is very important to carry out a successful blepharitis treatment. However, there are no therapeutic guidelines for blepharitis. The aim was to compare the symptomatic relief of anterior blepharitis using Blephamed eye gel, a cosmetic product, versus standard treatment.

Methods:

The study was a prospective, interventional open label clinical trial at a university-based hospital. The test population was subjects aged 18–65 years who presented with mild to moderate anterior blepharitis. Eyelid hygiene was applied twice a day. At each visit, a detailed assessment of symptomatology was carried out. A two-way repeated measure mixed model ANOVA was used to compare two groups by time.

Results:

In total, 61 patients with mean age of 60.08 ± 16.69 years were enrolled in the study including 30 patients in standard group and 31 patients in Blephamed group. Two groups did not differ in terms of age (P = 0.31) and eye laterality (P = 0.50). The baseline scores of erythema, edema, debris, and symptoms as well as total score were similar between two groups (all P values >0.50). Two groups became different for all these parameters at day 45 (all P values <0.001). Significant interaction was detected between time and intervention groups for all severity parameters of blepharitis as well as total score (all P values <0.001).

Conclusion:

Eyelid hygiene with Blephamed more significantly decreased symptoms of anterior blepharitis compared to standard treatment.

Keywords: Blephamed, Blepharitis, cleansing gel, eyelid hygiene, tea tree oil

Blepharitis is a frequently encountered chronic inflammatory disorder of the eyelid margin.[1] Blepharitis is divided into anterior and posterior blepharitis.[1] In anterior blepharitis, anterior lid margins and the region of the eyelashes are involved, while posterior blepharitis happens due to meibomian glands dysfunctions.[1] The etiology of anterior blepharitis is not completely determined yet, but three convergent pathways have been proposed: 1) direct bacterial infection, 2) exotoxin hypersensitivity, and 3) delayed cell-mediated immune hypersensitivity response.[1] These processes lead to ocular surface inflammation, itching, redness, burning, dryness, and blurred vision.[2,3] In clinical exam of patients with anterior blepharitis, scaly lashes, collarets around eyelashes as well as eyelash loss, misdirection and depigmentation may be observed. Blepharitis can also result in complications such as marginal ulceration of cornea, conjunctival or corneal phlyctenulosis.[1]

Daily cleansing of eyelids is very important to carry out a successful blepharitis treatment. However, there are no therapeutic guidelines for blepharitis.[3] Various eyelid cleansing products are becoming commercially available to aid in removal of lash debris. Majority of them contain tea tree oil (TTO) which is a natural oil extracted from the leaf of Melaleuca alternifolia. TTO has antibacterial, antifungal, antiviral, and antiprotozoal properties in addition to anti-inflammatory effects.[4] The TTO-impregnated wipes with 2%–4% concentration,[5-7] the TTO foam formulation with 2%,[8] and the TTO eyelid gel with 4%[9] cause an improvement in overall ocular discomfort, in addition to a decrease in the characteristic ocular signs of blepharitis. The Scientific Committee on Consumer Products in European Union considered that at concentrations above 5%, TTO is more likely to induce skin and eye irritation.[10] Therefore, Blephamed is an advanced cleansing gel formulation including 2% TTO which was developed to avoid the irritation and to sensitize the potential of high amounts of TTO. Current study was carried out in order to test the hypothesis that Blephamed can control blepharitis symptoms, damage, and inflammation while providing effective cleansing of eyelashes. The aim of the study was to investigate the efficacy and safety of the advanced gel and to compare its effectiveness with the standard treatment.

Methods

This is a prospective, randomized, controlled parallel-group, open-label clinical study on patients with anterior blepharitis presented to the cornea clinic of the senior author at a university-based hospital from March 2021 to August 2021. The study was registered as a clinical trial at Iranian Registry of Clinical Trial (https://www.irct.ir) (Registration number: IRCT20181102041528N1) and Center for Research and Training in Skin Disease and Leprosy (https://crtsdl.tums.ac.ir) (Registration number:ج/4/23/341) as well as approved by its Ethics Committee (IR.IUMS.FMD.REC.1400.117). The study also adhered to the tenets of the Declaration of Helsinki and conformed to the CONSORT checklist. After explaining the purpose of the study and possible results, all patients provided signed informed consent to participate in this study.

Study population

All patients with complaints of burning, stinging, and heaviness sensations in the eyes were examined by an anterior segment specialist. Patients with hyperemia, edema, and telangiectasia of the anterior lid margin as well as scaling, collarets, cylindrical dandruff, and oily secretion in the eyelashes who aged between 18 and 65 years were enrolled in the study. Patients with concomitant corneal ulcer, acute ocular infection (bacterial, viral, or fungal), any clinically significant lash or lid abnormality other than blepharitis, previous eyelid surgery within 12 months before study, eyelid cellulitis, eyelid hordeolum, moderate-to-severe dry eye, ocular surgery within the last 3 months were not included. Moreover, subjects who use systemic anti-inflammatory drugs, are pregnant, are nursing, are using contact lenses, and received topical treatment other than artificial tear preparations within the last 2 weeks were excluded from the study.

Study protocol

The patients were randomly assigned in 1:1 ratio to one of two groups (standard-treatment group and Blephamed group) by an independent clinical research coordinator according to a computer-generated randomization list. Randomization sequence was stratified with a 1:1 allocation. Duration of treatment was two weeks. In Blephamed group, participants were instructed to apply the gel to the eyelid and roots of the eyelashes for 3–5 min, twice a day. Blephamed eye gel (Saya Teb Mana Co., Tehran, Iran) contains TTO 2%, hyaluronic acid 0.2%, deionized water, glycerin, sodium pyrrolidone carboxylic acid, vitamin B5, aloe vera extract, and ORONAL LCG (a mild anionic surfactant). The eye gel was given for the patients free of charge. Patients of standard-treatment group were prescribed topical erythromycin ointment (Sina Daru Co., Tehran, Iran) per night and fluorometholone 0.01% (Sina Daru Co., Tehran, Iran) eye drops three times a day. They are also instructed to apply the heated compress to the eyelid for 3–5 min with a slight pressure and then cleansing the eyelid margins with baby shampoo, twice daily.

Clinical measurement

To evaluate degree of anterior blepharitis, both upper and lower eyelids were observed with slit-lamp biomicroscopy and clinical measurements were conducted at baseline and days 14 and 45 of the treatment period. Clinical signs, including erythema, edema, debris, and symptoms were evaluated by an anterior segment specialist (HA). All of these items scored on a 0–3 scale.[11] Erythema is graded as 0 for redness at eyelash bases without eczema, 1 for pink appearance, 2 for light red appearance or presence of eczema and, 3 for dark red appearance.[11] Eyelash debris is scored 0 if no debris, 1 if scattered, 2 if half, and 3 if most of the eyelashes have debris.[11] Lid edema more than 1 mm is considered score 3, 0.5 to 1 mm score 2, just noticeable score 1, and none score 0.[11] If patient is asymptomatic, the symptom score is 0. Occasional, frequent, and persistent symptoms are considered score 1, 2, and 3, respectively.[11] Total score was calculated by summing up scores assigned to each item. Participants were asked to contact the clinic in case of any side effects.

Statistical analyses

SPSS software version 22 (SPSS, Inc., Chicago, IL, USA) was used to perform analysis. A P < 0.05 was considered statistically significant. Baseline characteristics of the two groups were compared using a Chi-square test (categorical variables) and independent t-test (continuous variables). A two-way repeated measure mixed model ANOVA was used to simultaneously test the null hypotheses of the study: There is no interaction between time and intervention (the two groups do not differ in their degree of change in the blepharitis over time). Therefore, we evaluated whether the two intervention affect the blepharitis differently over time by considering intervention × time interactions as our primary outcome measure. The changes of blepharitis at the baseline and follow-up examinations in each group of the study (intragroup) were analyzed by one-way repeated measure ANOVA and post hoc tests. The sample size was calculated based on the one-way ANOVA formula using G*Power software. By assuming ɑ =0.05, power = 80%, the standardized Cohen effect size (f = 0.40), and a 10% dropout rate, the final sample size of each group was estimated at 30 patients.

Results

In total, 61 patients with mean age of 60.08 ± 16.69 years were enrolled in the study including 30 patients in standard group and 31 patients in Blephamed group. More than 60% (63.9%, 39/61) were females. The two groups did not differ in terms of age (P = 0.31) and eye laterality (P = 0.50) [Table 1]. However, the percentage of females was higher in the standard group (P = 0.003).

Table 1.

Baseline characteristics of 61 patients with anterior blepharitis received standard-treatment (30 patients) or Blephamed eye gel (31 patients)

Variables	Standard-treatment	Blephamed	P
Age (years)	57.78±17.76	62.23±15.57	0.31*
Sex (Female %)	83.3% (25/30)	45.2% (14/31)	0.003^†
Laterality (OD%)	63.3% (19/30)	54.8% (17/31)	0.50^†

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*: independent sample t-test; ^†: Chi-square test

The baseline scores of erythema (P = 0.40), edema (P = 0.16), debris (P = 0.62), and symptoms (P = 0.60) as well as total score (P = 0.29) were similar between two groups [Table 2]. At day 14, eyelid erythema (P = 0.07) and edema (P = 0.26) of two groups were also similar while Blephamed group had less debris (P < 0.001), symptoms (P = 0.04) and total score (P < 0.001) [Table 2]. Two groups became different for all these parameters at day 45 [Table 2]. In two groups, all severity parameters of blepharitis as well as total score decreased significantly by time [Table 2].

Table 2.

Severity of anterior blepharitis among 61 patients received standard-treatment (30 patients) or Blephamed eye gel (31 patients) at baseline and days 14 and 45.

Variables	Time- point	Standard-treatment n=30			Blephamed n=31			P^‡ for difference between two groups at each time point	P^§ for difference between total pattern of two groups

		Mean±SD	P *	P^†	Mean±SD	P *	P^†
Erythema	Baseline	1.80±0.81	-	0.03	1.97±0.75	-	<0.001	0.40	<0.001
	Day 14	1.67±0.71	0.21		1.35±0.61	0.001		0.07
	Day 45	1.50±0.63	0.02		0.74±0.58	<0.001		<0.001
Edema	Baseline	1.60±0.62	-	0.003	1.87±0.85	-	<0.001	0.16	<0.001
	Day 14	1.43±0.63	0.02		1.26±0.58	<0.001		0.26
	Day 45	1.33±0.55	0.003		0.77±0.50	<0.001		<0.001
Debris	Baseline	2.77±0.43	-	<0.001	2.71±0.46	-	<0.001	0.62	<0.001
	Day 14	2.33±0.76	0.001		1.58±0.81	<0.001		<0.001
	Day 45	1.67±0.71	<0.001		0.90±0.70	<0.001		<0.001
Symptoms	Baseline	1.83±0.91	-	0.003	1.94±0.57	-	<0.001	0.60	0.001
	Day 14	1.50±0.63	0.01		1.16±0.64	<0.001		0.04
	Day 45	1.40±0.62	0.003		0.90±0.47	<0.001		0.001
Total	Baseline	8.00±1.82	-	<0.001	8.48±1.75	-	<0.001	0.29	<0.001
	Day 14	6.93±1.74	<0.001		5.32±1.42	<0.001		<0.001
	Day 45	5.87±1.68	<0.001		3.32±1.08	<0.001		<0.001

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*One-way ANOVA repeated measure post hoc tests for comparing with baseline; ^†: One-way ANOVA repeated measure Greenhouse–Geisser correction, ^‡Independent student t-test, ^§One-way ANOVA repeated measure Greenhouse–Geisser correction to evaluate the interaction between time and intervention

Discussion

Current study tried to compare the effect of Blephamed with standard treatment in patients with anterior blepharitis. Although the severity of blepharitis has been reduced in two groups, the improvement was more pronounced in Blephamed.

Blepharitis is a multifactorial disease. The bacteria overload and the inflammation due to a load of bacteria, especially staphylococcal or seborrheic contamination, have a significant role in developing the disease.[1-3] Chronic forms of anterior blepharitis tend to reveal increased numbers of nonpathologic flora.[1] Increased cell-mediated immunity to S. aureus was reported in nearly 40% of anterior blepharitis patients, necessitating topical corticosteroid therapy.[12] In addition to the bacterial etiology, the potential association between Demodex infestation and blepharitis has also been recognized.[13] Lashes with cylindrical dandruff are a pathognomonic sign of ocular Demodex. Demodex has been found to localize in 50% of patients even after cleaning the roots of the eyelashes with baby shampoo for 1 year.[14]

Daily cleansing of eyelids is very important to carry out a successful blepharitis treatment. Routine application of eyelid hygiene removes debris, softens thickened secretions, removes ciliary dandruff and cleans the eyelid margin.[2,3] However, there are no therapeutic guidelines for blepharitis.[3] In the standard treatment, patients are instructed to perform hyperthermic lid compress, clean the eyelids with wet, warm gauze applied to closed eyelids for several minutes to remove pathogens and secretion along the eyelid margin.[15] Topical and systemic antibiotics, topical corticosteroids, and tear-replacement therapy are common adjunctive therapies for standard treatment.[15]

Various eyelid cleansing products are becoming commercially available to aid in removal of lash debris although, baby shampoo continues to be frequently used.[16-18] The comparative studies of soap, shampoo versus eyelid cleansing products have revealed that both cleansing regimens improve some symptoms.[19] It is in agreement with current study. Nevertheless, eyelid cleansing products are preferred by patients against baby shampoo and soap.[17,19,20] It could be explained by increased ocular inflammation with baby shampoo.[21] Furthermore, the preparation and storage of the diluted baby shampoo solution is unlikely to be done by patients accurately and in sterile conditions at home.[19]

The TTO is one of the main components of the eyelid cleansing products. The most active component of TTO is terpinen-4-ol, accounting for 40% of its composition, which is the primary agent responsible for the Demodex killing effect.[5] In in-vitro studies, it has been shown that Demodex is resistant to many antiseptic solutions, but is sensitive to TTO.[22] TTO-containing eyelid scrub has shown to be a useful tool for encouraging patients to persist with eyelid hygiene regimens.[23] TTO inhibits iNOS expression, NO production and NF-κB activation in human macrophages.[24] It also reduces proinflammatory mediators including IL-1b, IL-1b, IL-8, L-17, and TNFa levels in blepharitis patients.[25,26]

Various forms of TTO have been made to treat patients with blepharitis. The TTO-impregnated wipes with 2%–4% concentration have comparable effect to 50% TTO.[5-7] The TTO cleansing wipes administered daily, cause an improvement in overall ocular discomfort, in addition to a decrease in the characteristic ocular signs of Demodex infestation.[6] Patients found wipe form easy to use and convenient despite they felt stinging upon application.[27] De Luca et al.[28] showed that wet wipes imbibed with a solution of TTO and hyaluronic acid as well as aloe, natural anti-inflammatories and antiseptics were effective than standard treatment in patients with posterior blepharitis. The composition of this product is similar to Blephamed eye gel. A foam formulation with 2% TTO also confirmed its ability to exert a broad-spectrum antimicrobial effect without causing ocular or skin irritation.[8] Eyelid gel with 4% improves ocular symptoms of blepharitis in 90% of Demodex positive patients after one-month treatment.[9] In line with previous studies, current study showed that Blephamed eye gel with TTO concentration of 2% was also effective in treatment of patients with anterior blepharitis.

Some side effects of high ratio of TTO as a bioactive component in the eyelid cleansing formulations include contact dermatitis, allergic reactions, and ocular irritation.[29] Some organic compounds of TTO such as terpinolene, α-terpinene, ascaridol, and 1,2,4-trihydroxymethane induce these reactions.[5] The Scientific Committee on Consumer Products in European Union considered that at concentrations above 5%, TTO is more likely to induce skin and eye irritation.[10] It necessitates prudent clinical judgment surrounding therapeutic benefits of TTO-containing formulations and highlights the need for elimination of the unwanted chemical ingredients and concentration adjustment to promote overall safety and develop appropriate cosmeceutical/pharmaceutical preparations. Majority of possible side effects of TTO can be reduced by appropriate formulations.

Beside acute reactions, theoretically, chronic subtle cutaneous irritation can also lead to transient or permanent cutaneous changes such as hyperpigmentation. However, there is no data about the chronic (>12 months) dermatologic side effects of TTO in the literature.[10] Similarly, no study assessed the adverse events of chronic TTO use in subjects with blepharitis, and all studies applied the treatment for 1–8 weeks. Therefore, the absence of long-term follow-up also prevents us to generalize our finding for long-term users although we did not detect any adverse effect of TTO in short-term.

Some agents such as hyaluronic acid, vitamin B5, and aloe might synergistically interact with TTO in the eyelid cleansing products. These agents are used in Blephamed eye gel, as well. Hyaluronic acid is a well-known natural polysaccharide with unique viscoelastic, moisturizing, soothing, regenerative, and antibacterial properties that, in combination with TTO, could help alleviate ocular discomfort in patients with anterior blepharitis.[30,31] In addition, hyaluronic acid has potential anti-inflammatory properties in various inflammatory conditions.[30] Vitamin E and B5 have moisturizing properties. Aloe has antibacterial and anti-inflammatory activities and have been shown to reduce the presence of Demodex mites in the eyelid margin and improve the signs and symptoms of chronic blepharitis.[32] Patients who used a phospholipid–liposome solution specially designed for lid scrub demonstrated a significantly greater clinical improvement than those who used a mild baby shampoo.[20] The ORONAL LCG is another main component of Blephamed eye gel. It is a mild anionic surfactant with its exceptional skin and ocular tolerance. This material is specially adapted for fragile skin and mucous membranes. It’s excellent for lifting and suspending particulate soils, crusts, and oil. At the concentrations used, ORONAL LCG was completely non-irritant.

Encouraging long-term use of eyelid hygiene presents a challenge for the ophthalmologist.[33] Similar to long-term treatment adherence for other chronic asymptomatic conditions, the compliance with everyday lid hygiene could be a demanding task.[34] Approximately half of the patients had good compliance with lid hygiene.[35] The reasons for incompliance for lid hygiene are divided into patient-centered and procedure-related factors.[35] Regarding patient centered factors, a lack of time, uncomprehending the disease, concerns about other systemic conditions, and forgetting are the most common reasons.[35] As for procedure-related factors, complexity of the regimen and difficulty in remembering the steps of the regimen were the primary reasons.[35] Theoretically, a straightforward technique should provide better lid hygiene compliance.[33] Therefore, the compliance rate would be improved if the lid hygiene protocol is modified to obtain the simplest effective regimen. Blephamed seems to be simpler and easier technique comparing to standard treatment.

Current study has some limitations. First, it was not known if patients were positive for Demodex mites. Second, compliance of the patients was not evaluated by a valid tool.

Conclusion

In conclusion, current study has shown that the combination of 2% TTO with vitamins and essential plant oils effectively reduced anterior blepharitis severity. In addition, none of the adverse effects reported for the existing cosmeceutical/pharmaceutical formulations containing higher concentration of TTO were observed in this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

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