An evidence mapping of systematic reviews and meta-analysis on traditional Chinese medicine for ulcerative colitis

Background Traditional Chinese Medicine (TCM) has been a proposed treatment option for ulcerative colitis (UC), however it has been difficult to understand the breadth and depth of evidence as various Chinese medicine therapies may produce effects differently. The aim of this evidence mapping is to visually understand the available evidence in the use of TCM in the treatment of UC, and to identify gaps in evidence to inform priorities of future research. Methods A systematic electronic literature search of six databases were performed to identify systematic reviews (SRs) on different Chinese medicine therapies in the treatment in UC. Methodological quality of the included SRs was assessed using AMSTAR 2. Results The mapping was based on 73 SRs, which included nine interventions that met eligibility criteria. The quality of the included SRs was very low. The diseases stages of patients with UC varied greatly, from active to remission, to non-acute outbreak, to not reported. The results mostly favored the method of intervention. Oral administration combined with enema was the most widely used route of administration in secondary research. Conclusion Based on the current evidence, the treatment of UC with TCM can only be recommended cautiously. A majority of included SRs did not report the location of the disease, the disease classification, and the route of administration of the intervention. Further research is needed on the effectiveness of Chinese medicine alone in the treatment of UC. The effectiveness of combined Chinese and conventional medicine combined with different routes of administration cannot be confirmed. Attention should be paid to the methodological quality of the systematic review. Unifies the outcome indicators used in the evaluation of effectiveness. Supplementary Information The online version contains supplementary material available at 10.1186/s12906-021-03387-y.


Background
Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) caused by a variety of factors. UC has a tendency of recurrence throughout life [1,2]. Crohn's disease (CD) and UC are the main disease types [3]. In 1875, Wilks and Moxon established the term UC into the medical vernacular [4,5]. The main clinical manifestations of this condition are recurrent diarrhea, mucus bloody stool, and abdominal pain [6]. The primary purpose of UC treatment is to control the acute onset of the disease, heal the mucosa, maintain remission, reduce recurrence, and prevent complications [7].
Several studies have reported that UC appeared initially in urban areas, where its incidence rose rapidly before decreasing slowly [8]. The crude annual overall incidence for IBD per 100,000 individuals in 2011-2012 was 1.37 in Asia. China have high disease incidence according to an inception cohort study [9]. The incidence of IBD in China has risen by threefold in the past decade. UC is the predominant IBD in Asia [10].
This evidence mapping is largely driven by the execution of SRs and meta-analysis. In recent years, evidence-based studies of TCM in the treatment of UC are continuing to increase. At present, there are two overviews of SRs [11,12] about the treatment of UC with TCM. One focuses on treatment with retention-enema of Chinese herbal medicine, and the other uses an overview method to summarize the evidence. Our study is not limited to the route of administration in treatment; rather our focus is on the distribution of evidence. There is value in evaluating research conducted in terms of quality and interventions used to help evaluate progress made to date as well as determine future directions in research. We used evidence mapping to visualize the results, where the systematic review mapping can map out and categorize existing literature on a particular topic in order to identify gaps in research literature from which to commission further reviews and/or primary research [13].
Mapping review is used to present evidence in a field using a visual graph or chart after systematic researched. These maps provide assessments of knowledge gaps, knowledge gluts, and patterns across the research literature that promote best practice and direct research resources towards the highest quality research [14]. It can provide a broad and often comprehensive summation of a topic area and, as such, have value for those coming to a subject for the first time. However, as it is difficult to obtain a complete overview of a research topic for a single original study or a systematic review, we chose to conduct a mapping review of SRs. To provide the depth and width of current evidence on various interventions, we conducted an overview of relevant systematic reviews that have been published to date. Therefore, the objective of this study was to identify, describe and organize the current available evidence about TCM on the treatment of UC.

Criteria for considering reviews for inclusion
A comprehensive search of databases PubMed, Cochrane Library, CNKI, WanFang, VIP, and SinoMed, was conducted for systematic reviews published from database inception up to and including March 16, 2021. Search terms included "ulcerative colitis", "Chinese herbal medicine", "plant", "systematic review" and "meta".

Type of study
We included systematic reviews with or without metaanalysis.

Participants
Patients with a confirmed diagnosis of UC, regardless of disease duration and severity, were included.

Interventions
We included SRs where TCM interventions were used, including Chinese herbal medicine, extracts from herb mixtures, individual herbs, Chinese patent medicine, or herb compounds prescribed by Chinese medicine practitioners, regardless of the potential mechanisms of action. Eligible treatments allowed the intervention to be combined with conventional medicine or placebo. No limitation on drug dosage form and route of administration.

Outcome measures
Systematic reviews were considered where outcome measures included clinical effectiveness, TCM syndromes, inflammatory levels, immunological indicators, blood indicators, electronic endoscopy results, intestinal flora, clinical symptom and incidence of adverse reactions.

Exclusion criteria
Studies that involved comorbidity, in particular intestinal diseases, such as CD, schistosomiasis, bacillary dysentery, and intestinal tuberculosis, were excluded. Interventions involving herbal medicines not prescribed according to TCM theory or by Chinese medicine practitioners, were also excluded.

Data extraction and methodological quality
Microsoft Excel was used for data extraction and bubble plot creation. Two researchers independently screened the studies, extracted the data, and evaluated the report. A third author was consulted if there were discrepancies. Relevant data extracted included author(s), year of publication, country of origin (based on primary author's affiliation), total number of patients, diagnostic criteria, severity of illness, medication in intervention group and control group, outcomes, safety evaluation, quality assessment tools, and funding support. We used AMSTAR 2 [15] (a measurement tool to assess systematic reviews 2) as a quality assessment tool, and two experts assessed each study. If there were any discrepancies between the two reviewers, a third reviewer was consulted. AMSTAR 2 was used to critically appraise the methodological quality of the SRs. AMSTAR 2 contains 16 items that appraise critical flow and bias using ratings of "yes", "partial yes" or "no". Using this rating system, the overall confidence for the SRs were assessed as "high" (no or non-critical weakness in all items), "moderate" (more than one non-critical weakness among all the items), "low" (one critical flaw with or without non-critical weakness), or "critically low" (more than one critical flaw with or without non-critical weakness) [15].

Graphical visualization of results
Findings for included SRs were summarized in: (a) tables describing the characteristics and outcomes of the included SRs; (b) graphical display of the results of literature quality evaluation, with mapping based on bubble plots. Display information includes: (1) effectiveness trend as 'no difference', 'potentially effective', and 'effective' in x-axis. (2) estimated size of the literature y-axis; and (3) the bubble size as per AMSTAR 2 assessment, representing Chinese herbal therapy intervention type.

Overall assessment of included systematic reviews
Our search identified 1892 potential systematic reviews ( Fig. 1). After removing duplicate publications, the titles and abstracts of 1731 reviews were screened for relevancy. Of these, the full-text articles of 102 reviews were reviewed for eligibility. Finally, 73 SRs were included in our final review ( Fig. 1) . The basic characteristics of the included SRs are shown in Table 2 in Appendix 1. Among the included studies, one systematic review reported participants in the active phase of UC [16], one reported participants in remission [17], whilst another reported participants that were in a non-acute occurrence of UC [18]. 10 SRs did not limit the severity of the disease [19][20][21][22][23][24][25][26][27][28], whilst other reviews did not report severity of UC. In most studies, the control group included the first-line medication of conventional medicine, such as mesalamines, amino preparations, hormone preparations, and probiotics, whilst some studies used other herbal medicines and placebo. The administration routes of the intervention groups included oral administration, enema, embolization, injection, ultrasound induction and acupoint application. Quality of included systematic reviews AMSTAR 2 was used to critically appraise the reporting quality of each included systematic review and all reviews were found to be of critically low quality (Fig. 3). Whilst majority of reviews assessed the risk of bias in interpreting results and reported any conflicts of interest, we found that no reviews mentioned study lists and reported exclusion criteria in the review methods.

Discussion
There is a constant demand for health care when it comes to chronic disease. Patients with UC tend to have long term effects with increased risk of cancer, which may develop into UC-related colorectal cancer (UC-CRC). UC-CRC is one of the most serious complications in patients with long-term UC [89]. Among all cancers, colorectal cancer is a high-cost, high-burden malignancy that takes a heavy toll on health care systems and patients [90][91][92]. Evidence mapping of SRs in TCM is therefore critical to understand where further research should be focused to ensure the financial and health toll on patients with UC.

Main findings
In accessing the clinical effectiveness of treatment options for UC in the published SRs, we found that a majority of clinical trials used TCM as intervention through a variety of routes of administrations.
Our evidence mapping showed that oral administration and enema with both Chinese and conventional medicine was most widely studied (n = 18). Oral combined enema was the most widely used route of administration in the trials. TCM only was the most common intervention (n = 34), followed by the combination of TCM and conventional medicine (n = 23). The overall confidence level for each review was limited. So whilst TCM treatments may be effective in UC, more research is needed to determine whether it can be recommended to patients. The conclusion of this evidence mapping review however cannot provide recommendations for clinical practice due to insufficient strength of evidence and limitation of research type. AMSTAR2 was only used to evaluate the quality of methodological reports and not the efficacy of medicine. A mapping review can help in describing the research field and provide a basis for an informed decision about whether to undertake an in-depth review and synthesis of all or a subset of studies. However, its analysis only characterizes quantity and quality of literature rather than offering recommendations for practice and future research though the quantitative synthesis. The SR can only answer one specific PICOS clinical question at a time. We chose to include SRs as the study type in our evidence mapping as it can provide a broad and often comprehensive summation of a topic area, providing value for those coming to a subject for the first time. There are some shortcomings attributed to mapping reviews, specifically characterizing at a broad descriptive level. This can oversimplify the picture or mask considerable variation (heterogeneity) between studies and their findings, depending on the degree of specificity of the coding process [13]. The purpose of the statistics of outcomes is to sort out the outcomes and degree of concern in the past clinical trials of TCM in the treatment of UC: the greater the percentage, the more attention it is likely to receive. It provides evidence for the establishment of 'core outcome set (COS)', that is a set of minimum and consensus standardized indicators that should be measured and reported by all clinical trials in a specific health or healthcare field. However, we should consider that the choice of outcomes in clinical trials depends on the stage of UC, active or in remission, and the selection of primary and secondary outcomes.
It is noteworthy that the number of SRs on TCM in the treatment of UC has increased since 2012. Prior to this, the number of trials in 2006-2011 was 0-1. Previously UC had a higher incidence in Western countries, but there has been a dramatic increase in the incident rate of UC in Asia in recent years. Because the disease is difficult to cure, easy to relapse, and the risk of cancer lesions is high, it often takes lifelong medication. There are major concerns in diagnosis and treatment of UC worldwide, with research currently being a hot topic in the field of gastroenterology.
Various guidelines for the diagnosis and treatment of UC are constantly being revised. In 2004, the American Gastroenterology Association (AGA) revised "Ulcerative colitis practice guidelines in adults" [93], British Society of Gastroenterology (BSG) reviewed "Guidelines for the management of inflammatory bowel disease in adults" [94], and 2010 World Gastroenterology Organization Practice Guidelines for the Diagnosis and Management of IBD [95]. In 2007, Chinese Society of Gastroenterology (CSGE) "the Consensus Opinions on the Diagnostic and Treatment Specifications for Inflammatory Bowel Disease in China" [96]. In 2010, after repeated discussions and practice, the "Consensus on the Diagnosis and Treatment of Integrated and conventional Medicine for Ulcerative Colitis" [97] was formed. This is the first formal consensus opinion on the treatment of UC in Chinese medicine. This may be one of the reasons why the Chinese medicine field began to pay

Strength and limitations Strength
The systematic evaluation of relevant topics was searched. We used the PICOS format to organize the available information and describe the results applied to more specific scenarios according to current clinical practice. Our study included 73 SRs, and it is difficult to describe the information involved by general methods. In fields where there are enormous amounts of available information, the bubble plots are a good option. Mapping methodologies describe the quality of included SRs, and we could combine the results of all conducted studies in the field. We assessed the quality of included reviews with AMSTAR 2. This approach allowed results to be displayed on a bubble plot for each systematic review with respect to the other ones with the same comparison, providing a quick view of the existing evidence and their quality.

Limitations
There were several limitations to this research. Firstly, the results of our review need to be interpreted carefully because of the many characteristics in the SRs. Current evidence for interventions used in UC therefore cannot be considered conclusive and show a clear need for further research. Second, our study has some methodologic limitations. When drawing the evidence map, we included domains of estimated overall clinical effectiveness (x-axis), literature size (y-axis), and the confidence of the evidence (size of the bubble). When determining clinical effectiveness, we relied on the results of 58 SRs that potentially included biased information. The clinical effectiveness depends on these outcome indicators, including clinical effectiveness, total effectiveness, cure rate, significant effectiveness, inefficiency rate. Moreover, the AMSTAR 2, used to determine the confidence level, was originally developed to assess the appropriateness of reporting SRs and not to evaluate the confidence level of SRs. We acknowledge that there may be more efficient ways of drawing an evidence map.
Since only a few SRs in the included studies showed the stage of the disease, we did not evaluate characteristics on subgroups in acute and non-acute phase of UC. The main reason may be that many RCTs did not clearly define the disease stages of participants, which is a methodological demerit in this field. We hope that more RCTs with definite inclusion and exclusion criteria can be carried out to evaluate the effects on subgroups in the future.

Conclusion
In conclusion, oral administration, in combination with enema in both Chinese and conventional medicine, has been the most frequently tested intervention in TCM for UC. But on the basis of current evidence, this therapy can only be recommended cautiously. The low grade methodology quality of the included SRs in our mapping research cannot provide a high level of evidence to recommend in clinical practice. The major issue was that SRs failed to report the location of the disease, the type of the disease, and the route of administration of the intervention. Outcome indicators were also not uniformly reported, and the exact effect of Chinese medicine on UC cannot be derived from available evidence. Further evaluation of the effects of TCM is needed, either alone or in combination with conventional medicine, or via multiple administration routes. Low quality RCTs of TCM in the treatment of UC is of concern. As no valid conclusion can be drawn, it is a waste of energy of authors. Clinicians should carefully execute the trial and report details of the research process. They should also be aware that negative published data do not change the reputation of these authors, whilst do not annoying editors and readers. Before the systematic evaluation, the researchers should register the protocol and list the excluded literatures. In the future, we believe when high quality clinical studies are conducted of various Chinese herbal interventions, superior evidence will be available to confirm the results of these trials. In the meanwhile, evidence mapping is a useful and reliable methodology to identify and present the current evidence about therapeutic interventions. The results can help us accurately locate the focal point and insufficiency of current research in the field.