This study provides a comprehensive review of the characteristics of CHM treatments for UC in the past 30 years, which have identified a remarkable increase in the number of publications after 2007. In this review, we have identified that the most common studied condition(s), intervention(s) and comparison(s) of included articles were active UC, CHM fixed formula in decoction, and active control. Most included studies are RCT with design of parallel two arms, single centre, and open label. It is important to note that only 697 (30.2%) trials mentioned the safety assessment of CHM interventions, of which 230 (33.0%) articles reported the specific adverse effects (e.g., symptoms of the gastrointestinal tract, etc.). The reasons of there are less emphasized in safety consideration of clinical studies might be the mistakenly assumption of Chinese medicinal substances originating from natural sources are harmless . However, adverse effects derive from unpredictable adverse events, improper use, contamination, misidentification, and herb-drug interactions . Inadequate or absent reporting of safety evaluation on CHM interventions greatly degrades the scientific evidence of clinical trials. Therefore, we recommend that the future clinical studies should pay more attention to the high standard of study design, especially for the randomized, multicentre, double blind, placebo control (or double-dummy), and large sample size.
Moreover, although the CM pattern differentiation is critical in the determination of CHM interventions, there are only 895 (38.7%) studies that adopted the CM pattern diagnosis for the inclusion of UC participants and 524 (22.7%) articles that included CM-related outcomes, such as pattern scale questionnaire. In a CHM interventional trial, if the CM pattern is included, the concept of pattern differentiation should be carried out throughout the entire process with regard to the rationale of the study design, selection of inclusion and exclusion criteria, CHM formula prescription, selection of outcome measures and data interpretation, etc. In clinical practice, the CHM treatment is guided with CM principles and determined by pattern differentiation. If the pattern of a condition is misdiagnosed, the treatment principles will be incorrect, and its derivative CHM formula will be ineffective. Therefore, we recommend that the reporting of such studies should follow the guideline of “CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration", especially for the reporting of details and rationale regarding the definite diagnostic criteria of studied CM pattern, correspondence between pattern identification and CHM formula (e.g., Fang-Zheng-Dui-Ying), and CM-related outcome(s) [29, 30].
In this review, we systematically examined the use of single herbs, CHM fixed formulas, individualized formulas and patent proprietary formulas, and the combination of CHM and Western medicine in the clinical practice of UC. We identified a total of 245 types of CHM formulas and further summarized the top five frequently used formulas and top ten commonly herbs. Specifically, the classic CHM formula included Bai-Tou-Weng-Tang, Shen-Ling-Bai-Zhu-San, Shao-Yao-Tang, Bu-Zhong-Yi-Qi-Tang, and Tong-Xie-Yao-Fang. Sulfasalazine and Mesalazine are the most common concomitant western medicines for CHM formulas. The patent proprietary CHM formulas are Xi-Lei-San (enema), Yun-Nan-Bai-Yao, Fu-Fang-Ku-Shen-Jie-Chang-Rong-Jiao-Nang, Bu-Pi-Yi-Chang-Wan, and Shen-Ling-Bai-Zhu-San. It is indicated that the administration route of CHM interventions for UC not only include oral delivery, but also have the external use with directly effect, such as enema. The most common herbs in practice mainly focused on the types of heat-clearing, dampness-draining, toxin-removing, spleen-invigorating, qi-moving, and blood-stopping, such as Huang Lian, Huang Bai, Bai Tou Weng, Bai Zhu, Gan Cao, Bai Shao, Huang Qi, Dang Shen, Mu Xiang, and Bai Ji. More than half of these identified CHM therapies are consistent with the recommendations of “Experts-based consensus of integrative Chinese and western medicine treatment for ulcerative colitis (2017 version)” . Moreover, the results also provide the basis and reference for the future update of clinical practice guideline for UC in terms of CM diagnosis and treatment.
According to CM theory, zheng (pattern) is a pathological cluster or summary of signs and symptoms at a certain stage of a disease, which reflect the relationship between the pathogens and the body’s resistance . Practically, pattern identification refers to the analysis and summarization of the clinical symptoms obtained through the four diagnostic methods of CM (inspection, auscultation and smell, inquiry, and pulse taking and palpation), after which CM practitioners can accordingly determine the therapeutic principles and select the appropriate CHM treatments based on the patient’s current essential pattern [33, 34]. In this study, we found that the most common CM zheng of UC patients were the patterns of Large intestine dampness-heat, Spleen-kidney yang deficiency, Liver depression and spleen deficiency, Spleen-stomach weakness, and Spleen deficiency with dampness accumulation, which reflected the progress of UC with different phases. Through the association analysis on herbal applications and their relationships, we formulated one core herb with fifteen commonly combined herbs for each CM pattern. Specifically, in the CM pattern of Large intestine dampness-heat, Huang Lian, a typical heat-clearing and dampness-drying medicinal, was more frequently combined with the following three categories of herbs: (i) dispelling and heat-clearing medicinal, including Bai Tou Weng, Huang Bai, and Huang Qin; (ii) harmonizing qi and blood medicinal, including Bai Shao, Mu Xiang, Dang Gui, and Bai Ji; and iii) tonifying qi and invigorating spleen medicinal, including Bai Zhu and Gan Cao. Among these, the compatibility of blood-activating and qi-moving medicinals was very important due to the identification of strong correlations between Mu Xiang and Bai Shao/Gan Cao. Besides, herbs of invigorating spleen and draining dampness (e.g., Dang Shen, Huang Qi, Fu Ling, Yi Yi Ren) and astringent hemostatic (e.g., Di Yu) could be supplemented in the CHM formula for the treatment of UC with Large intestine dampness-heat pattern (Fig. 4a).
For the remaining four CM patterns, Bai Zhu, as their common core herb, was usually combined with Dang Shen, Fu Ling, and Gan Cao to treat the pattern of spleen deficiency which is the basic type included in the four patterns. In addition, Huang Lian and Mu Xiang were commonly added in the prescriptions to treat the four patterns, due to their role of heat-clearing, dampness-drying, and qi-moving. However, there are some differences among each specific pattern. In terms of Spleen-kidney yang deficiency, herbs of warming and tonifying yang qi, astringing intestines and checking diarrhea were emphasized, including Bu Gu Zhi, Rou Dou Kou, Wu Zhu Yu, and Huang Qi (Fig. 4b). For the pattern of Liver depression and spleen deficiency, Bai Shao is another vital herb, similar to the core herb of Bai Zhu, which was associated with Chai Hu, Fang Feng and Chen Pi to achieve soothing liver, emolliating liver, regulating qi and relieving depression (Fig. 4c). Compared the two patterns of Spleen-stomach weakness and Spleen deficiency with dampness accumulation, the former presented more correlations between the core herb and tonifying qi and invigorating spleen medicinal, such as Shan Yao and Huang Qi (Fig. 4d); the latter focused on the draining or drying dampness medicinal, such as Yi Yi Ren, and added more herbs for clearing heat, removing toxin, cooling blood, and stopping bleeding, such as Di Yu, Bai Ji, Bai Jiang Cao, and Bai Tou Weng (Fig. 4e). Based on the results of herbal correlation analysis, the CM treatment principles for UC could be summarized as clear heat and dampness, tonify and strength spleen, and harmony qi and blood.
This study has some limitations. First, this review identified articles published up to 25 November 2020 in the targeted seven databases. Any records which had not been included in these databases by that cut-off period have not been included. In addition, we included only articles in English and Chinese because of language limitations. As such, we may not have captured otherwise eligible trials published in other languages. Second, the data were extracted from clinical studies that used seven different types of design, including both interventional and observational studies (e.g., RCTs, cohort study, case–control study, etc.). The quality of these studies varied and therefore it is difficult to compare them quantitatively. Thus, we only provided the descriptive analysis for the general characteristics of included studies, not included the methodology and reporting quality assessments.