Abstract
OBJECTIVE
To observe the clinical efficacy on improving the quality of meibum in patients suffer from dry eye disease (DED) due to meibomian gland dysfunction (MGD) with hyperactivity of Yang due to Yin deficiency pattern after being treated with Pinggan Yuyin Qingre formula (平肝育阴清热方, PGYYQR).
METHODS
Totally 120 patients who met the inclusion criteria were included and stratified into three levels according to the level of MGD (1-3), and patients in each level was randomly allocated into the treatment group and control group according to a 1∶1 ratio. Both groups were treated with sodium hyaluronate eye drops, and the treatment group was also given PGYYQR granules. Both groups were treated continuously for eight weeks. The score of the properties of meibomian gland (MG) secretion, the score of the palpebral margins, the average noninvasive tear breakup time (NITBUTav), lipid layer thickness (LLT), and Traditional Chinese Medicine (TCM) syndrome efficacy were compared between the two groups after treatment.
RESULTS
A total of 116 cases were included in the statistical analysis. The differences were statistically significant in the score of the properties of MG secretion, the score of the palpebral margins, and NITBUTav between the two groups after treatment, the treatment group was superior to the control group; there was no evidence of a difference in LLT. In terms of TCM syndrome efficacy, the total effective rate was 84.7% in the treatment group and 50.9% in the control group, with the statistically significant difference. None of the included cases had adverse reactions.
CONCLUSIONS
PGYYQR is effective in improving the quality of meibum, and the tear film stability which thereby relieving the ocular symptoms in MGD-related DED patients with hyperactivity of Yang due to Yin deficiency pattern.
Keywords: Meibomian gland dysfunction, dry eye syndromes, Yin deficiency Yang hyperactivity, Pinggan Yuyin Qingre formula
1. INTRODUCTION
Dry eye disease (DED) is a chronic multifactorial ocular surface disease caused by abnormal quality, quantity and dynamics of tears, leading to tear film instability or imbalance of the ocular surface microenvironment, associated with inflammation of the ocular surface, tissue damage and neurological abnormalities, resulting in ocular discomfort and/or visual dysfunction.1 The moderate to severe DED can be accompanied by significant pain, leading to a decrease in quality of life and even depression and other psychological disorders. DED can be grouped into aqueous deficiency, evaporative, and mixed types according to the different causes, with the highest incidence of evaporative DED, about 35.8% to 58%.2
Meibomian gland dysfunction (MGD), a chronic, diffuse abnormality of the meibomian gland (MG), commonly characterized by terminal duct obstruction and/or qualitative/quantitative changes in the glandular secretion, is a major cause of evaporative DED.3 Global epidemiological surveys have shown that more than 65% of DED patients suffer from MGD, and the prevalence of MGD in people over 40 years old ranges from 38% to 68%, with a linear increase with age.4,5 Currently, Western Medicine focuses on treating MGD through infection control, inhibition of inflammatory response, and local physiotherapy to improve the secretory function of the MG and relieve obstruction of the MG orifice. However, these traditional methods are not very effective due to the prolonged treatment period, complicated operations, and poor adherence. Although there are now advanced treatment options such as LipiFlow and intense pulsed light available, it is still challenging to completely relieve symptoms and signs associated with MGD.6
MGD is often classified as “white astringent pattern” or “red ulcerated eyelid” in Traditional Chinese Medicine (TCM) due to its various symptoms, such as dryness, foreign body sensation and thickening of the palpebral margins. In recent years, the combination of oral Chinese medicine with external therapies, such as fumigation and nebulization, can significantly relieve the symptoms and enhance the tear film stability.7 However, in the TCM studies retrieved so far, most of the patients included in the trials were accompanied by insufficient tear secretion, i.e., they were mixed DED, and the outcome indicators were mostly DED-related, such as tear film break-up time (TBUT) and tear secretion, leaving fewer studies on the improvement of MG function.
The liver and kidney are the root of Yin and blood, and contains the ministerial fire. Nowadays, the change of lifestyles, such as fast-paced social life and high mental stress, are prone to lead to reckless stirring of ministerial fire and diseases due to Yin deficiency which will result in Yang hyperactivity. Therefore, most of the modern people have the constitution of Yin deficiency and Yang hyperactivity. Professor KONG Sibo, the famous TCM doctor, applied this theory to the treatment of eye diseases. There is a saying that “the Yin Qi of the body will be halved after 40 years old”, so with the increased life expectancy, it is more common for middle-aged and elderly people to suffer from liver and kidney Yin deficiency, also, the incidence of DED is higher in that population. What’s more, the liver governs the free flow of Qi, as a Yin organ with Yang functions, so insufficient Yin blood in the liver and kidney will affect the free flow of Qi, resulting in the stagnation of liver Qi. And if liver Qi is stagnated for a long time, it will turn into fire and produce liver heat, which will further injure Yin. “The combination of heat and fire will inflame the eyes”, so the symptoms of DED are appeared.8
Based on this feature, Professor Kong developed Pinggan Yuyin Qingre formula (平肝育阴清热方, PGYYQR), for the treatment of DED. We applied this formula in the stratified randomized controlled study of 120 patients with normal tear secretion, whose DED caused only by MGD, and with TCM syndrome of hyperactivity of Yang due to Yin deficiency pattern. The results showed that this formula significantly increased the first TBUT, resulting in the alleviation of ocular symptoms and an improvement in the ocular surface disease index (OSDI) score, while no significant improvement in MG function indicators such as MG exclusion and MG atrophy.9 As these two are mainly related to the quantity of meibum, we speculate that the improvement of TBUT and related indicators may be associated with the improvement of the quality of meibum by this formula. To explore this possibility, further analysis was carried out.
2. MATERIALS AND METHODS
2.1. Study design
This was a stratified randomized controlled study with 120 consecutive patients with MGD-related DED enrolled in the outpatient clinic of the Department of Traditional Chinese Medicine, Beijing Tongren Hospital from January 2018 to October 2018.
The trial protocol was reviewed and approved by the China Clinical Trials Registry in October 2017 (registration number: ChiCTR-INR-17012994).
The protocol was accordance with ethical standards and approved by the clinical research ethics committee of Beijing Tongren Hospital, Capital Medical University (No. TRECKY2016-049).
2.2. Diagnostic criteria
2.2.1 Diagnostic criteria for evaporative DED.1
(a) reduced TBUT (< 10 s); (b) normal tear secretion; (c) MGD.
2.2.2 Diagnostic criteria for MGD3
(a) symptoms: burning sensation, eye itching, foreign body sensation, scratching sensation, blurred vision, fluctuating vision, etc.; (b) abnormal palpebral margins and MG orifice; (c) abnormal secretion of meibum; (d) MG atrophy; (e) abnormal lipid layer thickness (LLT). MGD can be diagnosed by any of the eye symptoms + (b) or (c), and (d) and (e) are enhanced diagnostic indicators.
2.2.3 MGD grading criteria:3,10 grading after scoring according to the indicators related to the MG function
(a) Palpebral margins: 0 point: normal; 1 point: mild congestion, capping in the MG orifices; 2 points: blunt rounding and thickening of the palpebral margins, obstruction and bulging in the MG orifices; 3 points: hypertrophy of the palpebral margin with significant neovascularization, epithelial plugging in the MG orifices.
(b) The ability of MG secreting meibum: squeeze the MG of the lower eyelid and evaluate the difficulty of secretion discharge from the glands in three areas: nasal, medial, and temporal, and finally add up the three scores.
0 point: secretion discharge in all glands; 1 point: secretion discharge in 3-4 glands; 2 points: secretion discharge in 1-2 glands; 3 points: no secretion discharge in all glands.
(c) The properties of MG secretion: the scores were summed after scoring the upper and lower eyelids separately.
0 point: clear, transparent meibum; 1 point: dirty meibum; 2 points: dirty granular meibum; 3 points: thick meibum like toothpaste.
A total score of (a) + (b) + (c) was the grading of MGD: Level 1: 1-3 points, Level 2: 4-6 points, Level 3: 7-12 points, Level 4: more than 12 points.
2.2.4 TCM pattern identification criteria of hyperactivity of Yang due to Yin deficiency pattern (according to the Criteria of Diagnosis and Therapeutic Effect of Diseases and Syndromes in Traditional Chinese Medicine11 and Ophthalmology of Traditional Chinese Medicine12
(a) Main symptoms: dryness, burning sensation, itch, and grinding pain in the eyes; (b) secondary symptoms: dizziness, vexation and irritability, insomnia and excessive dreaming, dry mouth, sore waist, yellow urine, and dry stool; (c) tongue and pulse: red or purple dark tongue with little coating, and thin-string pulse.
The pattern can be diagnosed with at least three of the following main symptoms, at least four of the secondary symptoms and at least one of the tongue and pulse characteristics.
2.3. Inclusion criteria
(a) Accordance with the diagnostic criteria of evaporative DED; (b) level 1-3 of MGD; (c) accordance with the diagnostic criteria of TCM for hyperactivity of Yang due to Yin deficiency pattern; (d) suffer from the disease at least 6 months, with the age of 18-60 years old; (e) sign the informed consent form voluntarily.
2.4. Exclusion criteria
(a) Eye diseases other than DED; (b) history of ophthalmic surgery or laser treatment; (c) history of medication other than sodium hyaluronate eye drops in the last two weeks; (d) serious primary diseases such as cardiovascular, cerebrovascular, pulmonary, hepatic, renal and hematopoietic system diseases; (e) dry syndrome; (f) serious psychiatric and neurological diseases; (g) women who are pregnant, lactating or planning pregnancy; (h) allergic history of sodium hyaluronate eye drops or Chinese herbal medicine.
2.5. Elimination criteria
(a) Patients who do not follow the required time for follow-up; (b) patients who develop the conditions listed in the exclusion criteria after inclusion; (c) patients who do not follow the trial protocol for more than 5 times in total; (d) patients who have serious adverse reactions or safety problems, and the trial should be immediately suspended and reported to the Ethics Committee.
2.6. Sample size estimation
According to previous studies, the effective rate of PGYYQR plus sodium hyaluronate eye drops for the treatment of DED with hyperactivity of Yang due to Yin deficiency pattern was 76%.13 Sodium hyaluronate eye drops are less frequently used alone for the treatment of MGD, with a 50% effective rate based on relevant literature search and clinical experience. The required sample size of 60 patients each group was estimated, based on the comparison of independent sample rates of the two groups, with a randomization ratio of 1:1 and a 20% dropout rate taken into account.
2.7. Randomization and blinding
Stratified random assignment was generated by an independent statistician who was not involved in the inclusion based on SAS (vers 9.1.3, SAS Institute, Chicago, IL, USA) software. Patients were stratified into Level 1, 2, 3 of MGD (40 cases per level), and were assigned to the treatment and control groups at a 1:1 ratio on each level.
An independent staff who was not involved in the inclusion was responsible for maintaining the original random number sequence and assignment form, after the patient was enrolled, the researcher was informed the inclusion group by contacting this staff.
The study could not be blinded to the patients and researchers for the medication regimen, instead the protocol was concealed from the researchers who collected and analyzed the trial results.
2.8. Treatments
Control group: Sodium hyaluronate eye drops (Qilu Pharmaceutical Co., Ltd., Jinan, China; national drug approval number: H20133263; batch number: 8D0432M05) were given, 1 drop per time, 3 times a day.
Treatment group: in addition to the control group treatment, the PGYYQR granules (Beijing Temages Pharmaceutical Co., Ltd., Beijing, China) was added, which consists Shigao (Gypsum Fibrosum) 15 g, Shijueming (Concha Haliotidis) 30 g, Baijili (Fructus Tribuli) 10 g, Pugongying (Herba Taraxaci Mongolici) 10 g, Juhua (Flos Chrysanthemi) 10 g, Sangye (Folium Mori) 10 g, Huangqin (Radix Scutellariae Baicalensis) 10 g, Mudanpi (Cortex Moutan Radicis) 10 g, Mimenghua (Flos Buddlejae) 10 g, Muzei (Herba Equiseti Hiemalis) 5 g, Shihu (Herba Dendrobii Nobilis) 20 g, Gouqizi (Fructus Lycii) 12 g, Shayuanzi (Semen Astragali Complanati) 10 g, Gegen (Radix Puerariae Lobatae) 6 g, Lingyangjiao (Cornu Saigae Tataricae) 0.6 g, Shenqu (Massa Medicata Fermentata) 10 g, 1 pack per time, taking it half an hour after breakfast and dinner. Both groups were treated continuously for 8 weeks.
2.9. Outcome assessment
The main outcome measurement are related to the quality of meibum and the secondary outcome measurement are TBUT, LLT, and TCM syndrome efficacy score. All indicators were measured once before and after treatment, and TCM syndrome score was measured once more at the fourth week of treatment.
2.9.1. Quality of meibum
(a) The score of the properties of MG secretion; (b) The score of the palpebral margins.
The measurement method and scoring criteria were the same as before.
2.9.2. Average noninvasive tear breakup time (NITBUTav) measurement
Adjust the focal length of the Oculus Keratograph. The patients were asked to blink gently three times and then look at the red visual marker directly in front of them and open their eyes naturally until the next blink. During this period, the instrument automatically calculated the NITBUTav of the patients.
2.9.3. LLT measurement
Use an ocular surface interferometer. The patients were asked to look straight ahead and blink naturally with both eyes. The camera of the instrument was adjusted so that the pupil was visible on the the center of the image, and the reflected tear film image appeared in the area that is 1 mm above the lower tear meniscus to the lower pupil margin. The clear tear film image appeared after automatic focus of the camera, and a dynamic tear film interference image of 20 s duration was taken. The machine automatically derived the LLT value according to the tear film interference image.
2.9.4. TCM syndrome efficacy
(a) The following quantitative scoring scale for TCM syndromes was developed with reference to the Criteria of Diagnosis and Therapeutic Effect of Diseases and Syndromes,11 and Guiding principles for clinical research of new Chinese Medicines14 (Tables 1, 2).
Table 1.
Scoring criteria of the main symptoms
| Item | 0 point | 2 points | 4 points | 6 points |
|---|---|---|---|---|
| Dry eyes | None | Occasionally, not obvious | Frequent dryness and discomfort, relieved on its own | Persistent, severe, unbearable dryness |
| Burning sensation in the eyes | None | Occasionally | Persistent, tolerable | Very obvious, intolerable, affecting daily life |
| Itchy eyes | None | Occasionally | Usually | All the time |
| Painful eyes | None | Mild pain in the eyes, occasionally | Persistent pain, tolerable, eye available | Obvious pain, eyes unavailable |
Table 2.
Scoring criteria of the secondary symptoms
| Item | 0 point | 1 point | 2 points | 3 points |
|---|---|---|---|---|
| Dizziness | None | Sometimes, occasionally tinnitus | Persistent, frequent tinnitus | Dizziness, persistent tinnitus |
| Vexation and irritability | None | Vexation, occasional irritability | Upset, impatient, irritable | Uncontrollable vexation and irritability |
| Insomnia and excessive dreaming | None | Occasionally insomnia and forgetfulness | Wake up during sleeping sometimes, excessive dreaming, often forget things | Sleepless all night, forget things quickly |
| Dry mouth | None | Mild dry mouth and throat | Dry mouth and throat | Dry mouth and throat with the desire to drink |
| Sore waist | None | Mild soreness, stop by beating | Persistent, weak knees, cannot carry heavy things | Unbearable sore waist and weak knees, cannot walk |
| Yellow urine | None | Have | ||
| Dry stool | None | Have |
(b) TCM syndrome efficacy index = (score before treatment — score after treatment) / score before treatment × 100%
The efficacy was evaluated as follows: recovery: TCM syndrome efficacy index ≥ 95%; excellent: TCM syndrome efficacy index ≥ 70%; effective: TCM syndrome efficacy index ≥ 30%; invalid: TCM syndrome efficacy index < 30%.
2.9.5. Safety indicators: liver and kidney function, electrocardiogram.
2.10. Statistical analysis
The eyes included in the analysis were screened based on the minimum value of NITBUTav of the patients measured by the Oculus Keratograph before treatment. All data were analyzed using SAS (vers 9.4, SAS Institute, Chicago, IL, USA) software. The Shapiro-Wilk test was used to test the normality of the measurement data, and the normal data were expressed as mean (standard deviation) and were analyzed with the independent sample t test for comparison between groups; the non-normal data were expressed as median (interquartile range, IQR) and were analyzed with the Wilcoxon test for comparison between groups. Count data were expressed as frequencies or percentages, and were compared using the χ2 test or Fisher's exact probability method. The rank data were analyzed with the Wilcoxon test. Subgroup analysis was performed for the main outcome measurement, and the subgroup variables were gender, age, duration of disease, and the level of MGD. P < 0.05 was considered statistically significant differences.
3. RESULTS
3.1. Summary of patient flow diagram
One hundred and twenty patients were initially included, and one case (treatment group, MGD 1) was lost to follow-up, one case (control group, MGD 2) was discontinued due to the ocular trauma after enrollment, and two cases (control group, MGD 1) were eliminated due to more than five violations of the medication protocol, and no follow-up information was available for the above four patients. Therefore, a total of 116 patients were finally included in the analysis (Figure 1).
Figure 1. Flow diagram of the study.
MGD: meibomian gland dysfunction.
3.2. Baseline data of the two groups
A total of 116 cases of 120 included patients were finally analyzed, including 57 in the control group and 59 in the treatment group. There were no statistically significant differences (P > 0.05) between the two groups in terms of baseline indicators, such as age, gender, duration of disease, MGD grading, the score of the properties of MG secretion, the score of palpebral margins, NITBUTav, LLT, and TCM syndrome score (Table 3).
Table 3.
Baseline characteristics
| Item | Control group (n = 57) | Treatment group (n = 59) |
|---|---|---|
| Age (years) | 42.00 (32.00-49.50) | 41.00 (31.00-49.00) |
| Gender [n (%)] | ||
| Male | 22 (39) | 18 (31) |
| Female | 35 (61) | 41 (69) |
| Duration of DED (years) | 8.00 (5.00-12.00) | 10.00 (6.00-12.00) |
| MGD level [n (%)] | ||
| MGD 1 | 18 (32) | 19 (32) |
| MGD 2 | 19 (33) | 20 (34) |
| MGD 3 | 20 (35) | 20 (34) |
| Score of the properties of MG secretion (scores) | 2.00 (2.00-2.00) | 2.00 (2.00-2.00) |
| Score of palpebral margins (scores) | 2.00 (1.00-2.00) | 2.00 (2.00-2.00) |
| NITBUTav (seconds) | 8.69 (5.62-10.50) | 8.23 (6.18-11.31) |
| LLT (nm) | 65.00 (50.00-92.00) | 60.00 (42.00-80.00) |
| TCM syndrome score (scores) | 13.00 (11.00-15.00) | 13.00 (11.00-17.00) |
Notes: control group: treated only with sodium hyaluronate eye drops (n = 57); treatment group: treated with PGYYQR granules and sodium hyaluronate eye drops (n = 59). DED: dry eye disease; MGD: meibomian gland dysfunction; MG: meibomian gland; NITBUTav: the average noninvasive tear breakup time; LLT: lipid layer thickness; TCM: traditional Chinese medicine; PGYYQR: Pinggan Yuyin Qingre formula. Data were expressed as Median (IQR) or n (%). IQR: interquartile range.
3.3. Main outcome measurement
3.3.1. Comparison of the score of the properties of MG secretion
After treatment, the differences were statistically significant in the treatment group compared with the control group overall (P < 0.01, Wilcoxon test); subgroup analysis of the MG secretion revealed that the differences between the two groups were still statistically significant in the subgroup with gender, age and duration of disease as the grouping variables, and the differences were statistically significant in the subgroup of MGD 3 (P < 0.05, Wilcoxon test) (Figure 2).
Figure 2. Comparison of the score of the properties of MG secretion.
A: total comparison; B-E: subgroup comparison. B: the subgroup variable was gender; C: the subgroup variable was age; D: the subgroup variable was duration; E: the subgroup variable was MGD level. Control group: treated only with sodium hyaluronate eye drops (n = 57); treatment group: treated with PGYYQR granules and sodium hyaluronate eye drops (n = 59). MG: meibomian gland; MGD: meibomian gland dysfunction; PGYYQR: Pinggan Yuyin Qingre formula. Compared with the control group, aP < 0.01, bP < 0.05 (Wilcoxon test).
3.3.2. Comparison of the score of palpebral margins
After treatment, the overall differences were statistically significant in the treatment group compared with the control group (P < 0.01, Wilcoxon test); subgroup analysis of the palpebral margins score revealed that the differences between the two groups were still statistically significant in the subgroup with gender, age, and duration of disease as subgroup variables, and the differences were statistically significant in the subgroup of MGD 3 (P < 0.05, Wilcoxon test) (Figure 3).
Figure 3. Comparison of the score of palpebral margins.
A: total comparison; B-E: subgroup comparison. B: the subgroup variable was gender; C: the subgroup variable was age; D: the subgroup variable was duration; E: the subgroup variable was MGD level. Control group: treated only with sodium hyaluronate eye drops (n = 57); treatment group: treated with PGYYQR granules and sodium hyaluronate eye drops (n = 59). MGD: meibomian gland dysfunction; PGYYQR: Pinggan Yuyin Qingre formula. Compared with the control group, aP < 0.01, bP < 0.05 (Wilcoxon test).
3.4. Secondary outcome measurement
3.4.1. Comparison of NITBUTav
After treatment, there were statistically significant differences between the treatment group compared and the control group (P < 0.05, t-test) (Figure 4A).
Figure 4. Comparison of the secondary outcome.
A: comparison of NITBUTav, compared with the control group, aP < 0.05 (t-test); B: comparison of LLT; C: comparison of TCM syndrome score at 4 and 8 weeks, compared with the control group, aP < 0.01 (Wilcoxon test). Control group: treated only with sodium hyaluronate eye drops (n = 57); treatment group: treated with PGYYQR granules and sodium hyaluronate eye drops (n = 59). NITBUTav: the average noninvasive tear breakup time; LLT: lipid layer thickness; TCM: traditional Chinese medicine; PGYYQR: Pinggan Yuyin Qingre formula.
3.4.2. Comparison of LLT
After treatment, there was no statistically significant difference between the treatment group and the control group (P > 0.05, Wilcoxon test) (Figure 4B).
3.4.3. Comparison of the TCM syndrome score
After 4 weeks of treatment, there was no statistically significant difference between two groups (P > 0.05, Wilcoxon test); after 8 weeks of treatment, there were statistically significant differences between two groups (P < 0.01, Wilcoxon test) (Figure 4C).
3.4.4. TCM clinical efficacy
After treatment, the total effective rate was 50.9% in the control group and 84.7% in the treatment group, with statistically significant differences (P < 0.01, Wilcoxon test) (Table 4).
Table 4.
Comparison of the clinical efficacy of the two groups
| Group | n | Recovery (n) |
Excellent (n) |
Effective (n) |
Invalid (n) |
Total effective rate (%) |
|---|---|---|---|---|---|---|
| Control | 57 | 0 | 3 | 26 | 28 | 50.9 |
| Treatment | 59 | 1 | 10 | 39 | 9 | 84.7 a |
Notes: control group: treated only with sodium hyaluronate eye drops (n = 57); treatment group: treated with PGYYQR granules and sodium hyaluronate eye drops (n = 59). PGYYQR: Pinggan Yuyin Qingre formula. Compared with the control group, aP < 0.01 (Wilcoxon test).
3.5. Evaluation of safety
No abnormalities were found in liver and kidney function and electrocardiogram examination before and after 8 weeks of treatment in both groups, and there were no other adverse reaction.
4. DISCUSSION
The meibum secreted by MGs are rich in lipids, which are the main component of the superficial lipid layer of the tear film that protects it against evaporation of the aqueous phase and is believed also to stabilize the tear film by lowering surface tension. MGD is caused by a dysfunctional secretion (qualitative/quantitative change) of meibum, resulting in alteration of the tear film, symptoms of eye irritation, clinically apparent inflammation, eventually leading to an evaporative DED.3 Currently, Western Medicine treatment is unable to fundamentally improve the MG function by improving the microenvironment of MG and meibum metabolism. Although TCM has shown efficacy in the treatment of MGD-related DED, most of the studies involved patients with mixed DED, and further research is needed on the mechanism of TCM in improving the MG function.
In the study, 120 MGD-related DED patients with hyperactivity of Yang due to Yin deficiency pattern and normal tear secretion function were enrolled in the stratified blocked randomized controlled study according to the level of MGD. The control group received treatment with sodium hyaluronate eye drops, which is a commonly treatment for DED, while the treatment group received the same eye drops and PGYYQR granules for 8 weeks. Previous studies have shown that there is no significant improvement in the quantity of meibum indicators, therefore, this study mainly focused on the quality of meibum. The score of the properties of MG secretion was used as one of the main outcome measurement. Additionally, the palpebral margin score was measured, which included palpebral margin morphology and MG orifice morphology scores. These two are positively correlated, with the latter also positively correlated with the properties of MG secretion.15 Therefore, the score of palpebral margin was used as another main outcome measurement. The results showed that PGYYQR can significantly improve the score of the properties of MG secretion and palpebral margin, with more significant improvement in patients with MGD3.
MGD starts with the occlusion of terminal ducts, which caused by the hyperkeratinization of the ductal epithelium, resulting in the accumulation of meibum within collecting ducts, causing a build-up of pressure and ultimately leading to the disuse atrophy of MG. As the quantity of meibum decreases, the clear and transparent meibum turns into the milky-yellow, granular, and toothpaste-like secretions, which is a compensatory response to the abnormal MG secretion, making it more difficult to discharge, and eventually causing the MG to change from atrophy to loss;16,17 Moreover, the altered composition of meibum causes “dysbiosis” of the ocular surface microenvironment,18,⇓-20 promoting the growth of opportunistic pathogens on the ocular surface and alter the composition of meibum, causing an increase in viscosity, irritation of the epithelia, and inducing keratinization.21,22 This leads to a “vicious cycle” of MGD.23 This study confirms that, PGYYQR can improve the quality of meibum, allowing its easy discharge from the duct and enhancing the lipid layer function. Additionally, the “vicious cycle” can be interrupted by improving the ocular surface microenvironment, and the hyperkeratinization of the ductal epithelium and the ductal occlusion can be gradually reduced, which confirmed by the significant improvement in palpebral margin score. With prolonged treatment time, the quantity of meibum is expected to increase due to the continuous improvement of the hyperkeratinization of the ductal epithelium.
In the study, the indicators such as NITBUTav, LLT, and TCM syndrome were also analyzed, and the results showed that NITBUTav and TCM syndrome score significantly improved in the treatment group after the treatment, while LLT did not show significant changes. TBUT is a direct and reliable indicator of tear film stability,24 The same subgroup analysis was conducted on the NITBUTav, the result also showed that MGD3 level had significant difference between two groups (The specific results are not listed in the article), further confirming that the formula can enhance tear film stability by improving the quality of meibum. The decrease in TCM syndrome score suggested that the formula is effective in relieving the symptoms associated with hyperactivity of Yang due to Yin deficiency pattern, while relieving ocular symptoms. LLT is an essential component of tear film and is related to the onset of DED. In the study, since the TBUT increased without an increase in LLT, we consider that the improvement in meibum quality mainly affects the composition or structure of tear film lipids, but has no effect on its amount. Previous studies have also suggested that the thicker LLT in MGD patients are due to the poor quality of lipid layer which caused by the increased viscosity and the increased keratinized epithelial debris in MG secretion,25 and there is no significant correlation between LLT and TBUT.26,⇓-28
PGYYQR takes nourishing liver and kidney, soothing liver Yang and relieving liver heat as the main principle, and the specific formula has been discussed in detail in the previous article.9 Modern research has proved that Shigao (Gypsum Fibrosum) can strengthen the anti-inflammatory effect by improving cellular immune function and activating phagocytes;29 Calming liver wind herbs such as Shijueming (Concha Haliotidis) and Lingyangjiao (Cornu Saigae Tataricae) have anti-inflammatory and sedative effects;30,31 Quercetin, the principal chemical constituent of Juhua (Flos Chrysanthemi), Muzei (Herba Equiseti Hiemalis), Mudanpi (Cortex Moutan Radicis) and Gouqizi (Fructus Lycii), can reduce the phosphorylation of p38 and JNK in p38 mitogen-activated protein kinases (MAPK) and JNK signaling pathway, which leading to downstream effects such as reduced production of pro-inflammatory cytokines and suppression of stress-induced cellular damage.32 Huangqin (Radix Scutellariae Baicalensis) can protect cells from oxidative stress induced by H2O2 via inhibiting autophagy and apoptosis,33 and baicalin can inhibit the secretion of inflammatory factors by inhibiting the TLR4-MyD88-NF-κB/NLRP3 pathway and the MAPK signaling pathway.34 It has been shown that oxidative stress can regulate long-chain saturated fatty acid (SFA) metabolism in meibum and initiates the apoptotic program by activating MAPK/JNK and MAPK/ERK signaling pathways, resulting in glandular atrophy and an inflammatory response, which leading to MGD.35 Through the pharmacological analysis, we hypothesized that PGYYQR could reduce the inflammatory response by decreasing oxidative stress and regulating SFA metabolism, which laid the foundation for our in-depth study of the action mechanism of this formula in the treatment of MGD.
This study confirmed that PGYYQR can effectively improve the stability of the tear film and alleviate symptoms of DED by improving the quality of meibum in MGD patients with a good safety profile. However, the study is limited by the fact that it relies on subjective evaluations by the researchers rather than objective experimental data to support the specific mechanism by which TCM improves MG function. Additionally, further studies are needed to examine the effects of the different active ingredients in PGYYQR. The next step is to determine the primary targets and pathways acted by the active ingredients through animal experiments and other methods on the basis of this study, in order to better reveal the scientific nature of the formula, and to improve the recognition of TCM in both domestic and international settings.
5. ACKNOWLEDGMENTS
We thank all participants for their trust and persistence. We also thank all ophthalmologists, medical staff, and other contributors to this trial.
Contributor Information
Haihong LIAN, Email: lianhh@163.com.
Shijing DENG, Email: dengsj26@163.com.
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