Comparative efficacy of the ophthalmic gel containing metronidazole, hyaluronic acid, Aloe vera extract, and sulfur preparations in the treatment of patients with chronic blepharitis on the background of meibomian gland dysfunction

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Abstract

BACKGROUND: Meibomian gland dysfunction (MGD) and chronic blepharitis remain significant challenges in ophthalmology. Standard therapy comprises phytoblepharohygiene and eyelid massage, with anti-inflammatory and tear substitutes. However, the efficacy of the sequential use of phytoblepharohygiene and the ophthalmic gel containing metronidazole, hyaluronic acid, Aloe vera extract and sulfur preparations (Blepharogel Forte®; Geltek-Medica, Russia) for chronic blepharitis and MGD, remains underexplored.

AIM: To evaluate the therapeutic effect of a sequential regimen comprising a line of phytoblepharohygiene products, including the ophthalmic gel containing metronidazole, hyaluronic acid, Aloe vera extract and sulfur preparations (in patients with prolonged chronic blepharitis and MGD).

MATERIALS AND METHODS: The study involved 42 patients (84 eyes) aged 16–73 years, including 30 men (60 eyes, 71.4%) and 12 women (24 eyes, 28.6%), diagnosed with chronic blepharitis, MGD, and dry eye syndrome. Depending on the treatment method, two groups were formed. Patients of control group I (20 subjects, 40 eyes, 47.6%) received eyelid massage and phytoblepharohygiene with the ophthalmic gel containing hyaluronic acid and Aloe vera extract (agent 1) or the ophthalmic gel containing hyaluronic acid, Aloe vera extract, and sulphur preparations (agent 2) (in case of confirmed demodicosis). The comparison group II (22 subjects, 44 eyes, 52.4%) underwent eyelid massage and phytoblepharohygiene, which was completed by applying the ophthalmic gel containing metronidazole, hyaluronic acid, Aloe vera extract, and sulfur preparations (agent 3) (irrespective of a positive or negative test for demodicosis).

RESULTS: From the first week onwards, the indices characterizing hyposecretion of meibomian glands in groups I and II were already 1.9±0.2 and 1.1±0.3 points lower than the initial values of 2.6±0.2 and 2.4±0.3 points, respectively (p <0.05). Furthermore, the dynamics of hypersecretion indices exhibited a comparable trend, with values of 1.6±0.2 and 1.5±0.2 points recorded after a week in comparison with the initial values of 2.3±0.3 and 2.2±0.2 points, respectively (p <0.05). The index characterizing eyelid edema at this stage of the study exhibited a statistically significant decrease only in group II of patients who received the ophthalmic gel containing metronidazole, hyaluronic acid, Aloe vera extract and sulfur preparations (1.4±0.2 points after a week in comparison with the initial 2.3±0.2 points) (p <0.05). In group I, only the initial results were maintained, whereas in group II, a stable increase was observed.

CONCLUSION: The ophthalmic gel containing metronidazole, hyaluronic acid, Aloe vera extract and sulfur preparations can be effective in the treatment of patients with blepharitis and MGD due to its superior therapeutic effectiveness compared with the standard blepharohygiene and phytoblepharohygiene regimens.

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Background

Meibomian gland dysfunction (MGD) is one of pressing issues today's ophthalmology [1–3]. Mild MGD is typical for 70.0% patients with primary dry eye disease (DED), 47.0% of patients with chronic blepharitis, and 46.7% of patients with DED accompanied by gland hypersecretion [4]. Severe MGD, mainly hyposecretory, leads to secondary DED in 80% cases and associated with plugs of dried discharge or thick meibum in ducts [5].

Moderate MGD is more often associated with hypersecretion leading to maceration the eyelid skin, itching, and keratoconjunctivitis sicca (50% of cases). It also occurs in 10% patients with DED not caused by blepharitis [5]. Blepharitis often complicated by concomitant conditions, such as gastroenterological disorders (biliary dyskinesia, constipation), rosacea, and allergies. Patients with rosacea complicated by demodicosis have an increased recurrence rate and greater affected skin area compared to uncomplicated disease [6].

Demodex mites (Demodex folliculorum, Demodex brevis) live in sebaceous and meibomian glands creating favorable conditions for inflammation. The prevalence demodicosis reaches from 2% to 5%, and it is 7th among skin diseases [7–9]. Optimal growth temperature for the mites is 30–40 °C, and they survive off the host for up 9 days at room temperature and up to 25 days in water [10]. Lipid meibum supports Demodex life cycle, which worsens inflammation [11].

Skin-surface biopsy is considered gold standard for the diagnosis demodicosis [12–14]. Skin scrapings and adhesive tape impressions have low specificity and are of little value [5]. Background therapy includes lid hygiene using first-line products such as blefarogels containing hyaluronic acid, aloe, and sulfur. This improves MGD symptoms and prepares the eyelid skin for anti-inflammatory and antiseptic agents [15–18].

Doxycycline has an anti-inflammatory effect by inhibiting phospholipase A2 and matrix metalloproteinases, which benefits tissues and reduces inflammation [19–21]. In studies, long-term doxycycline administration (16 weeks) led to clinical remission in 75.9% patients; however, the recurrence rate at 3 months was 5.6% [22]. The drug well tolerated, but can cause dyspepsia.

Retinoids (isotretinoin in particular) have proven their efficacy in treatment severe rosacea associated with demodicosis. They reduce the proliferation gland duct epithelium, reduce keratinization, and have an anti-inflammatory effect [23]. However, their use is limited due side effects, such as dry skin and mucous membranes, and they are also contraindicated in children under 12 years age.

Metronidazole is intended for systemic and topical treatment of blepharitis and demodicosis. Long-term metronidazole therapy improves clinical and microbiological parameters [24]. Topical metronidazole (from 0.75 to 1.0% gel) is less toxic and well tolerated by patients.

Combination treatment, including herbal products for eyelid care and medicinal products, effectively improves the MGD and demodex blepharitis symptoms. The study confirms the need to inverstigate the effect of the ophthalmic gel containing metronidazole, hyaluronic acid, Aloe vera extract, and sulfur preparations, especially in chronic inflammation.

The aim evaluate therapeutic effect consecutive herbal lid hygiene products, including the ophthalmic gel containing metronidazole, hyaluronic acid, Aloe vera extract, and sulfur preparations, in patients with long-lasting chronic blepharitis associated with MGD.

Materials and methods

Study design

It a prospective, parallel, non-randomized, single-center study.

The study examined 42 patients (84 eyes) with chronic blepharitis associated with low-to-moderate MGD. The study included 30 (71.4%) men and 12 (28.6%) women, aged 16 to 73 years, with DED, hypersecretory (42.9%) and hyposecretory (57.1%) MGD. Medical record review was confidential, the samples were examined anonymously; patients or their legally authorized representatives voluntarily signed an informed consent form. The study was conducted according to the ethical principles stated in the Helsinki Declaration (2013) and the principles of bioethics; the results may be published in scientific journals.

In this study, an objective sign of hyposecretory MGD was plugging of excretory duct orifices with dried meibum or thick toothpaste-like meibum when pressing on the lid. For patients with hypersecretory MGD, the inclusion criteria and objective sign hypersecretion were skin irritation caused by meibomian gland secretion or irritation marginal conjunctiva where the secretion accumulated, generally in outer and/or inner canthus.

The MGD severity was assessed using the previously proposed point scale [2, 5] based cumulative estimate secretory function meibomian glands (total meibomian index, TMI). The index is sum deformation index (DI) of the lid margin and occlusion index (OI). Mild, moderate, severe, and extremely severe grades of MGD correspond to 1, 2, 3–6, and 7–12 points, respectively.

Eligibility criteria

The study inclusion criteria were the following:

  • no deformation of the lid margin (DI=0) or the presence of single/multiple scars on the lid margin or palpebral conjunctiva when the lids are completely closed (ID=1–2);
  • single or multiple obstructed meibomian gland ducts or ductules, accounting for not more than 50% of the total ducts and ductules on the lid margin (OI=1–2);
  • diagnosed moderate or severe MGD according to the previously proposed point scale (TMI ≥2) [2, 5];
  • signs of hyposecretory MGD (plugs of dried meibum in the ducts) or hypersecretory MGD (skin irritation caused by meibum);
  • DED in combination with chronic blepharitis;
  • six or more Demodex mites in the sample of 16 eyelashes (during the diagnosis of demodicosis).

Exclusion criteria:

  • severe deformation of the lid margin preventing the lid closure;
  • over 50% of obstructed meibomian gland ducts or ductules;
  • progressive or acute inflammation in the anterior segment;
  • intolerance to the components of the drugs used;
  • co-morbidities which can affect the results (e.g., diabetes mellitus, severe allergic reactions).

Study setting

The study was performed in ophthalmology department Children's Clinical Hospital at Saint-Petersburg State Pediatric Medical University.

Study duration

The study was conducted from September 2023 to December 2023.

Intervention description

All patients had lid massage twice a week (the course consisted of 10 sessions), low viscosity artificial tears 4 times a day, and an artificial tear gel at night. In addition, all patients used herbal lid hygiene products at home twice a day for 8 weeks.

The study subjects were divided into 2 groups by the treatment method. Control patients in Group I (20 subjects, 40 eyes, 47.6%) had eyelid massage using the above lid care procedure, followed by the ophthalmic gel containing hyaluronic acid, Aloe vera extract, and sulphur preparations (agent 2), twice a day if demodicosis was confirmed or the ophthalmic gel containing hyaluronic acid and Aloe vera extract (agent 1) in case negative results for demodicosis.

In addition to lid massage, all patients in comparison Group II (22 subjects, 44 eyes, 52.4%) used herbal lid hygiene products daily, followed by application of the ophthalmic gel containing metronidazole, hyaluronic acid, Aloe vera extract, and sulfur preparations (agent 3 — Blepharogel Forte®; Geltek-Medica, Russia), on the lids twice a day (regardless of the test result for demodicosis).

Objective (hyperemia of the lid margins, edema of the lid margins, plugs of dried meibum or toothpaste-like meibum in the meibomian gland ducts or ductules (hyposecretory MGD), areas of skin irritation in the outer and/or inner canthus caused by meibum (hypersecretory MGD)) and subjective (eyelid heaviness, tenderness of the lid margins, eyelid itching and burning sensation, subjective discomfort) signs were assessed using a 4-point scale where:

  • 0: no signs;
  • 1: subtle signs;
  • 2: clear signs;
  • 3: significant signs.

This method helped standardize the strategy for treatment and assessment of the patients' condition and provided objective comparison of the efficacy of different treatment methods.

Patients were followed up for 8 weeks (at Weeks 1, 2, 4, and 8); the first examination was performed to obtain baseline data, and each subsequent examination included control of objective clinical signs of MGD.

Acaricidal effect was evaluated twice, to obtain baseline data and at Week 8.

Statistical analysis

The sample size was not pre-calculated. Statistical processing of results was carried out using Statistica 12.0 (StatSoft, USA). The normal distribution was assessed with the Kolmogorov–Smirnov test. Mean and mean error were calculated (М±m). Two-tailed Student's t-test (parametric method) was used to assess the significance of differences. Critical level of significance in testing statistical hypotheses was set at 0.05, 0.01, or 0.001.

Results

All patients with chronic blepharitis associated with MGD had a similar reduction of objective and subjective signs over time, regardless of the severity and nature of secretions. Clinical signs of MGD improved as early as Week 1 and included decreased hyposecretion (plugs in the meibomian gland ducts or ductules) and hypersecretion (skin irritation). However, there was no statistically significant change in hyperemia of the lid margins after the first week. Eyelid edema was significantly reduced only in Group II, where agent 3 was used (Table 1).

 

Table 1. Dynamics of expression of objective clinical signs of meibomian gland dysfunction in patients treated with different therapies (n=42, 84 eyes) (points, M±m)

Symptom

Group

Number of eyes

Initial data

Stages of observation (wk)

1

2

4

8

Hyperemia of the eyelid margins

I

40

2.1±0.2

2.1±0.3

1.6±0.2*

0.6±0.3* #

0.4±0.3*

II

44

2.6±0.2

2.3±0.2

1.6±0.2* #

0.4±0.2* #

0.3±0.2*

Edema of the costal margin of the eyelids

I

40

2.4±0.2

2.5±0.2

2.0±0.3*

1.3±0.1* #

1.4±0.1*

II

44

2.3±0.2

1.4±0.2*

0.7±0.2* # †

0.1±0.1* # †

0.3±0.2* †

Presence of plugs of dried secretion or pasty secretion in the ducts of the meibomian glands (dysfunction of the meibomian glands with hyposecretion)

I

16

2.6±0.2

1.9±0.2*

1.3±0.1* #

0.4±0.3* #

1.1±0.3*

II

32

2.4±0.3

1.1±0.3*

0.4±0.1* # †

0.5±0.3*

0.4±0.1* †

Presence of areas of skin irritation in the area of the external and|or internal adhesion with caustic secretion (dysfunction of the meibomian glands with hyposecretion)

I

24

2.3±0.3

1.6±0.2*

1.5±0.2*

0.8±0.2* #

1.3±0.3*

II

12

2.2±0.2

1.5±0.2*

0.8±0.1* # †

0.2±0.1* # †

0.5±0.2* †

* differences are statistically significant compared to baseline data; # compared to the corresponding data of the previous observation stage; † compared to the data of the control group; in all cases p <0.05–0.001.

 

A statistically significant reduction in all signs of blepharitis, including hyperemia, was observed from Week 2. These changes were maintained throughout the follow-up period (up to Week 8). A significant increase in the treatment effect was observed in Group II from Week 2 to Week 4 for hyperemia, eyelid edema, and signs of secretion, especially with agent 3 (Fig. 1, 2). The results in Group II were stable.

 

Fig. 1. Presence of thick, pasty meibomian gland secretion in patient D. with hyposecretory meibomian gland dysfunction before treatment.

 

Fig. 2. Picture of the eyelid rib margin with almost complete absence of thick secretion in patient D. at the 4th week of follow-up.

 

The inter-group comparison showed that the clinical effect on most signs was higher in patients using agent 3. The exception was hyperemia of the lid margins, where no significant difference was noted between the groups. Subjective symptoms, such as itching, burning, and eyelid heaviness, reduced as soon as by Week 2 in both groups, with a more significant effect in Group II. By Week 8, symptoms in patients using agent 3 were statistically significantly better than in Group I (Table 2).

 

Table 2. Dynamics of severity of clinical symptoms (subjective signs) of meibomian gland dysfunction in patients receiving different therapy (n=42, 84 eyes) (points, M±m)

Symptom

Group

Number of eyes

Initial data

Stages of observation (wk)

1

2

4

8

Feeling of heaviness of the eyelids

I

40

2.4±0.3

2.2±0.3

1.5±0.3*

0.7±0.1* #

0.7±0.1*

II

44

2.6±0.2

2.1±0.3

1.1±0.2*

0.3±0.1* †

0.2±0.1* †

Feeling of pain in the edges of the eyelids

I

40

1.8±0.3

1.0±0.3*

0.6±0.4*

0.6±0.2*

0.2±0.1*

II

44

1.6±0.1

1.1±0.1*

0.5±0.1* #

0.3±0.1*

0.4±0.2*

Feeling of itching and burning of the eyelids

I

40

2.8±0.2

2.3±0.4

1.6±0.2*

0.7±0.1* #

0.6±0.1*

II

44

2.7±0.3

2.7±0.1

1.7±0.2*

0.2±0.1* # †

0.2±0.1* †

Subjective discomfort

I

40

2.5±0.4

1.6±0.1*

1.1±0.1* #

1.1±0.2*

0.6±0.1* #

II

44

2.6±0.3

1.9±0.1*

1.0±0.1* #

0.4±0.1* †

0.2±0.1* †

* differences are statistically significant compared to baseline data; # compared to the corresponding data of the previous observation stage; † compared to the data of the control group; in all cases p <0.05–0.001.

 

By Week 8, an acaricidal effect was achieved in both groups, with a more significant effect in Group II (Table 3). The results were confirmed by evaluation of acaricidal activity, showing the significantly decreased number of mites. The difference between the groups is shown in Fig. 3.

 

Fig. 3. Comparative characterization of acaricidal effect in subjects receiving different therapies depending on the nature of meibomian gland secretion (n=28, 56 eyes).

 

Table 3. Comparative evaluation of acarograms in patients of study groups with chronic blepharitis and meibomian gland dysfunction on the background of different therapy regimens (n=28, 56 eyes) (points, M±m)

Acarogram dynamics

Group I (13 patients, 26 eyes) Phytoblepharocleaning + eyelid massage + artificial tears

Group II (15 patients, 30 eyes) Phytoblepharocleaning + eyelid massage + artificial tears + agent 3

Hyposecretion of meibomian glands, 10 eyes

Hypersecretion of meibomian glands, 16 eyes

Hyposecretion of meibomian glands, 22 eyes

Hypersecretion of meibomian glands, 8 eyes

Stages of observation

Initial data

Week 8

Initial data

Week 8

Initial data

Week 8

Initial data

Week 8

The number of Demodex mites in a preparation from 16 eyelashes

10.3±0.2

3.4±0.2*

8.7±0.3

4.4±0.3*

8.9±0.2

2.3±0.4* †

9.6±0.3

2.5±0.5* †

* differences are statistically significant compared with baseline data; † compared with control group data; in all cases p <0.05–0.001.

 

Discussion

The study evaluated the therapeutic effect of agent 3 in patients with long-lasting chronic blepharitis associated with MGD. The dosage form selection remains an important therapeutic challenge in these patients. Given the side effects and risks of concomitant use of agent 3 with other drugs during systemic therapy with metronidazole, including long-term use for 16 weeks with tapering, as well as certain disadvantages of metronidazole ointments (a favorite medium for D. folliculorum), metronidazole topical gels offer some benefits in ophthalmology. In addition, it has a clear benefit of no age restrictions for therapy compared to gel products used in dermatology.

Treatment regimens used in ophthalmology, based on herbal lid hygiene products in combination with therapeutic lid massage, provide a positive therapeutic effect in patients. However, the most rapid and beneficial clinical effect, its prolongation, and acaricidal effect of the therapy remain important issues, since diagnosed demodicosis in patients with chronic blepharitis associated with MGD requires therapy adjustments.

Therefore, this study of the the ophthalmic gel containing metronidazole, hyaluronic acid, Aloe vera extract, and sulfur preparations efficacy (a topical gel for herbal lid hygiene) demonstrated that it was more beneficial compared to other dosage forms of metronidazole and also provided the most significant clinical effect compared to the baseline herbal lid hygiene products.

Study limitations

Not found.

Conclusion

Addition of metronidazole to the topical gel products for the lid margins (the ophthalmic gel containing metronidazole, hyaluronic acid, Aloe vera extract, and sulfur preparations) resulted in a statistically significant difference in the clinical effect compared to the baseline therapy at Week 4 and also helped maintain a stable therapy effect during the following 4 weeks. Thus, topical gels for lid hygiene containing metronidazole as part of combination therapy can be recommended for patients with blepharitis and MGD due to a more significant therapeutic effect compared to the baseline herbal lid hygiene products. In our opinion, when choosing combined therapy for patients with blepharitis associated with MGD, it is important to focus on preliminary diagnosis in order to confirm or rule out demodicosis.

Additional information

Funding source. The research was carried out under the grant of the Russian Science Foundation No. 22-15-00135 "Scientific substantiation, development and implementation of new technologies for the diagnosis of comorbid iodine deficiency and autoimmune diseases of the thyroid gland, including the use of artificial intelligence."

Competing interests. The authors declare that they have no competing interests.

Authors’ contribution. All authors confirm compliance of their authorship with the international ICMJE criteria. The largest contribution is distributed as follows: L.P. Prozornaya — curation, treatment of patients, literature review, collection, and analysis of literary sources, writing and editing of the article; A.A. Prozorny — literature review, collection and analysis of literary sources, preparation and writing of the text of the article; T.A. Mashenkova — literature review, collection, and analysis of literary sources, writing and editing of the article.

Ethics approval. The present study protocol was approved by the local Ethics Committee of the Saint-Petersburg State Pediatric Medical University (No. 39/07 by 30.05.2024).

Consent for publication. Written consent was obtained from the representatives of the patients for publication of relevant medical information and all accompanying images. Date of signing 30.09.2024.

×

About the authors

Lyudmila P. Prozornaya

Saint-Petersburg State Pediatric Medical University

Email: prozornaya@mail.com
ORCID iD: 0000-0001-7436-1915
SPIN-code: 3762-0548

MD, Cand. Sci. (Medicine)

Russian Federation, Saint Petersburg

Alexander A. Prozorny

Saint-Petersburg State Pediatric Medical University

Author for correspondence.
Email: alexprozornyy@gmail.com
ORCID iD: 0009-0005-5263-8852
SPIN-code: 6356-1791
Russian Federation, Saint Petersburg

Tatyana A. Mashenkova

Saint-Petersburg State Pediatric Medical University

Email: m.t.mashenkova@gmail.com
ORCID iD: 0009-0004-0860-2708
SPIN-code: 2438-7679
Russian Federation, Saint Petersburg

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2. Fig. 1. Presence of thick, pasty meibomian gland secretion in patient D. with hyposecretory meibomian gland dysfunction before treatment.

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3. Fig. 2. Picture of the eyelid rib margin with almost complete absence of thick secretion in patient D. at the 4th week of follow-up.

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4. Fig. 3. Comparative characterization of acaricidal effect in subjects receiving different therapies depending on the nature of meibomian gland secretion (n=28, 56 eyes).

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