Therapeutic Evaluation of Recurrent Aphthous Ulcer with Integrated Traditional Chinese Medicine and Western Medicine

Objective: To observe the curative effects of Yiqing granule and Zhibai Dihuang pill combined with Oralpolin gel on recurrent aphthous ulcer. Methods: 150 patients with mild recurrent aphthous ulcer were classified as excessive internal heat type and deficiency internal heat type by traditional Chinese medicine theory. Then, they were randomly divided into the positive control group (thalidomide group), the trial group (Yiqing granule group/Zhibai Dihuang pill group), and the negative control group (topical medication group). All the patients in every group used Oralpolin gel. Additionally, the patients in the positive control group took thalidomide tablets orally and those in the trial group orally took proprietary Chinese medicine (Yiqing granule/Zhibai Dihuang pill). The treatment lasted for 4 weeks. The curative effects were all evaluated according to the “RAU Efficacy Evaluation Trial Standard” which was formulated by the Professional Committee of Mucosal Diseases of Chinese Stomatological Association. Results: Of all the 150 patients involved in this medical experiment, 146 cases finished it, including 66 ones in the trial group, 36 ones in the positive control group, and 44 ones in the negative control group. The total drop-out rate was 2.7%. For the excessive internal heat type, the effective rates in the thalidomide group, the Yiqing granule group and the local medication group were 91.7%, 52.6% and


Introduction
Recurrent aphthous ulcer (RAU), also known as recurrent oral ulcer (ROU) or recurrent aphthous stomatitis (RAS), generally shows a round or oval shape, a sunken center, a surface covered with yellow-white pseudomembrane, and a flushed edge, and causes clearly-felt pains [1]. It is the most common oral mucosal ulcer disease, and its incidence among the population can reach 10% -25%. The cause of the disease stays unclear, so there is still no specific therapy for it up to now. The commonly used systemic drugs for the disease [2] include glucocorticoids and immunosuppressants, among which thalidomide, as an immunosuppressant, has a good effect on inhibiting ulcers, but its long-term use will cause many adverse reactions. Zhibai Dihuang pill and Yiqing granule are proprietary Chinese medicine preparations. This study observed the efficacy of Zhibai Dihuang pill and Yiqing granule combined with Oralpolin gel in the treatment for recurrent aphthous ulcer of different TCM types, in order to provide a basis for the treatment for recurrent aphthous ulcer with the combination of traditional Chinese medicine and western medicine.

Clinical Data
1) Diagnostic criteria [3]: patients diagnosed with mild recurrent aphthous ulcer in terms of their past or current medical history and clinical manifestations according to Oral Mucosal Diseases (Fifth Edition, People's Health Publishing House). TCM syndrome: according to the 2002 edition of Guidelines for Clinical Research of New Drugs of Traditional Chinese Medicine (Trial), aphtha is divided into the following two types: solid fire type: acute onset, short course of disease, severe local pain, a large area and a large number of ulcers, red, swollen and protuberant surrounding mucous membrane, even fused into patches, likely accompanied by fever, thirst, irritability, constipation, halitosis, red corpora lingua, yellow tongue coating, rapid pulse and so on; deficiency fire type: slow onset, long course of disease, mild local pain, small area, small number and dispersion, light and non-red surrounding mucous membrane, often with a history of repeated attacks, long-term healing, likely accompanied by soreness and weakness of waist and knees, fatigue, red zygomatic region, dry mouth but no thirst, hot palms and soles, red tongue, little or dry tongue coating, thready rapid pulse and so on.
2) Inclusion criteria: patients are willing to participate in this study and sign the informed consent form (if a patient is under the legal age, the form must be signed by his legal guardian); ulcers occur at least once a month with a medical history of more than 1 year; birth control is performed during medication.   Table 1 and Table 2.

General Information
This study has been reviewed and approved by the Hospital Medical Ethics Committee and has received the informed consent of the patients.

Treatment Scheme
Positive control group: Thalidomide tablets, 50 mg each time, taken orally once before bedtime; Oralpolin gel, smeared in a proper amount on the ulcer surface 3 times a day.  Treat all the three groups with 2 weeks as a course of treatment and a total of 2 courses of treatment.
Perform blood cell analysis before and after medication.

Indexes of Curative Effect Observation
Patients were instructed to pay subsequent visits or accept telephone follow-ups by telephone within 1 -4 weeks, 5 -8 weeks, 9 -12 weeks, 13 -16 weeks, 17 -20 weeks and 21 -24 weeks after medication. The number of ulcer occurrence and the interval time of ulcer attacks in each observation period were recorded.

Criteria of Curative Effect Evaluation
Refer to the RAU evaluation criteria adopted by the Professional Committee of Significantly effective: I 1 N 1 , that is, the total interval time is prolonged and the total number of ulcers is reduced.
Effective: I 1 N 0 or I 0 N 1 , that is, the total interval time is prolonged and the total number of ulcers does not change, or the total interval time does not change and the total number of ulcers decreases.
Ineffective: I 0 N 0 , that is, neither the total interval time nor the total number of ulcers changes.

Statistical Method
SPSS 18.0 professional statistical software is used to process the data, and the measurement data are expressed as ( x s ± ). Paired sample t-test is used to compare the data before and after treatment, and χ 2 -test is used to compare the counting data. The difference of P < 0.05 is statistically significant.

Analysis of the Curative Effect of Excessive Internal Heat Type
The total effective rate of the three groups was more than 50%. By pairwise comparison, there was statistically significant difference in the total effective rate between Yiqing granule group and thalidomide group χ 2 = 5.898, P = 0.018 (P < 0.05). There was no statistically significant difference in the total effective rate between Yiqing granule group and local medication group χ 2 = 2.212, P = 0.191 (P > 0.05). However, by comparing marked effectiveness with effectiveness, after χ 2 -tests of Yiqing granule group and local medication group χ 2 = 30.780, P = 0.000 (P < 0.05), we found that the markedly effective rate of Yiqing granule group was higher than that of local medication group (Table 3).

Analysis of the Curative Effect of Deficiency Internal Heat Type
By pairwise comparison, there was no statistically significant difference in the between Zhibai Dihuang pill group and local medication group χ 2 = 4.741, P = 0.040 (P < 0.05). The curative effect of Zhibai Dihuang pill group was better than that of local medication group but similar to that of thalidomide group (Table 4).

Adverse Reactions of Patients after Taking Drugs
Among the patients given thalidomide, the indexes of blood cell analysis of one case decreased significantly in part after taking thalidomide, and returned to normal one month after stopping taking thalidomide; the constipation of two cases was relieved after symptomatic treatment; the lethargy of 2 cases and the dizziness of 1 case were improved without special treatment after stopping taking thalidomide. There was no obvious abnormality in the test group and the negative control group.

Discussion
Recurrent oral ulcer is a kind of oral mucosal disease characterized by "red, yellow, concave and pain" [4]. Although it does not endanger the patients' life, it seriously affects the patients' quality of life [5] [6], and since its etiology and pathogenesis are not clearly known, there is still no specific treatment for the disease at present, and the general treatment for it is local and systemic medication. The main function of local medication is to relieve inflammation and pain and shorten the ulcer period. Systemic therapy can reduce the number of ulcers and prolong the interictal period, and it is often used when the ulcer attack is severe and there is no obvious effect of local treatment [7] [8]. The drugs routinely selected for systematic therapy are glucocorticoids, immune enhancers and immunosuppressants. Although these drugs have a positive curative effect, but their long-term application will cause many adverse reactions. Traditional Chinese medicine has been used in the treatment for recurrent aphthous ulcer for over a thousand years, showing outstanding characteristics and efficacy in long-term clinical practice [9]. Recurrent aphthous ulcer belongs to the category of "aphthous ulcer" and "mouth chancre" in traditional Chinese medicine. In ancient and modern times, aphthous ulcers are divided by "deficiency" and "excess" [10]. It is generally believed that the three factors of wind, heat and dryness out of the six climatic exogenous pathogens are more closely related to aphthous ulcer, among which heat has the closest relation with the disease. Both  [13]. Cooked rehmannia sweet and warm, nourishing marrow and kidney; Chinese yam has the effect of nourishing spleen and kidney; Dogwood converges and nourishes the kidney; Moutan peel can cool blood and retreat deficiency fever [14]. The recipe has the effect of nourishing yin and reducing fire [15] [16]. In this study, 28 patients with recurrent aphthous ulcer caused by deficiency fire were treated with Zhibai Dihuang pill for four weeks on the basis of topical application of Oralpolin gel. Six months after treatment, the total effective rate of Zhibai Dihuang pill group was higher than that of local medication group (P < 0.05), and the curative effect was similar to that of thalidomide group (P > 0.05). But after comprehensive consideration of the facts [17] that thalidomide with severe teratogenicity should be used by people at gestational age only when they take contraception measures and that thalidomide may result in many adverse reactions, such as peripheral neuritis, leukopenia, lethargy, headache, dizziness, constipation, fatigue, dry mouth and so on, the author thinks that Zhibai Dihuang pill plus Oralpolin gel is more applicable, safer and easy to be accepted by patients.
Traditional Chinese medicine is the crystallization of the wisdom of ancestral doctors, and it has been proved to be good medication in thousands of years of medical practice and has achieved good results in the treatment for recurrent aphthous ulcer [18], but most of the treatment schemes are based on the clinical experience of doctors with lack of a more systematic theoretical basis, which indicates that the concept of traditional Chinese medicine needs to be changed from empirical medicine to evidence-based medicine. At present, the decrease of cellular immune function and the imbalance of T-lymphocyte subsets are considered to be one of the important pathogenic factors of recurrent aphthous ulcer [19] [20]. Previous studies have shown that Cornus officinalis and Cortex Phellodendri in Zhibai Dihuang pill can regulate immunity [13] [21]. This can be taken as a cut-in point to provide a new objective index for TCM "syndrome" and syndrome differentiation from the mechanism of Zhibai Dihuang pill in the treatment for recurrent aphthous ulcer.

Conclusion
Treatment of RAU based on syndrome differentiation, especially for patients with hypofire RAU, has a good effect in both reducing the number of ulcers and prolonging interictal periods.

Funding
This work was supported by S&T Program of Chengde (Grant No. 201804A019).