Curative effect of anti-fibrosis Chinese patent medicines combined with ursodeoxycholic acid for primary biliary cholangitis: A systematic review and meta-analysis

Objective: To delineate the curative effect and safety of anti-fibrosis Chinese patent medicines (CPMs) combined with ursodeoxycholic acid (UDCA) for primary biliary cholangitis (PBC). Methods: A literature search was conducted using PubMed, Web of Science, Embase, Cochrane Library, Wanfang database, VIP database, China Biology Medicine Database, and Chinese National Knowledge Infrastructure from their inception until August 2022. Randomized controlled trials (RCTs) of the treatment of PBC with anti-fibrotic CPMs were collected. The eligibility of the publications was assessed using the Cochrane risk-of-bias tool. The evaluation indicators were the clinical efficacy rate, liver fibrosis, liver function, immune function, and symptom score. Meta-analysis and subgroup analysis were conducted to evaluate the effectiveness of anti-fibrosis CPMs. Risk ratio (RR) was used to assess dichotomous variables, and continuous variables with a 95% confidence interval were calculated using mean difference. Results: Twenty-two RCTs including 1,725 patients were selected. The findings demonstrated that anti-fibrotic CPMs combined with UDCA improved the efficacy rate, liver function, liver fibrosis, immunological indicators, and clinical symptoms compared with UDCA alone (all p < 0.05). Conclusion: This study demonstrates that the combination of anti-fibrotic CPMs and UDCA can improve both clinical symptoms and outcomes. Nevertheless, more high-quality RCTs are needed to assess the effectiveness of anti-fibrosis CPMs for PBC.


Introduction
Primary biliary cholangitis (PBC), also called primary biliary cirrhosis, is a chronic autoimmune cholestatic liver disease whose pathogenesis has not been fully elucidated (European Association for the Study of the Liver, 2017). PBC frequently occurs in middle-aged women, and its clinical serological characteristics include positive anti-mitochondrial antibodies and elevated levels of alkaline phosphatase (ALP) or gamma-glutamyl transpeptidase (GGT) (You et al., 2022). The main pathological features of the liver include progressive, non-suppurative, and destructive intrahepatic cholangitis, leading to fibrosis and eventually cirrhosis You et al., 2022; European Association for the Study of the Liver, 2017). PBC is mainly caused by genetic and environmental factors, with unknown pathogenesis and hidden clinical manifestations (You et al., 2022). Some patients with PBC have cirrhosis at the time of diagnosis , making anti-fibrotic therapy particularly important.
Ursodeoxycholic acid (UDCA) is an effective treatment for PBC (You et al., 2022), and its mechanism of action includes cholelithiasis, cytoprotection, anti-inflammatory effects, and immune regulation . UDCA has greatly improved longevity in patients with PBC. However, 40% of patients with PBC still respond poorly to it (Cheung et al., 2016), and non-responders have a lower survival rate than the general population. Owing to rapid disease progression and poor long-term prognosis, patients who respond poorly to UDCA may require alternative treatment methods urgently; however, currently, no unified therapies exist.
Traditional Chinese medicine (TCM) has advantages in treating liver fibrosis, owing to its combination of ingredients and multiple pathways and targets. Previous studies have shown that Fuzheng Huayu capsules (FZHY) (Liu et al., 2019), Fufang Biejia Ruangan tablets (FFBJRG) (Ji et al., 2022), and Anluo Huaxian pills (ALHX) (Lu et al., 2017) are commonly used clinically as Chinese patent medicines (CPMs) for the anti-fibrosis treatment of liver these have been approved by the State Food and Drug Administration of China, with national medicine permission numbers of Z20020074 (FZHY), Z19991011 (FFBJRG), and Z20010098 (ALHX). The fibrosis stage is important in the progression of PBC. If anti-fibrosis treatment is administered in time at this stage, the occurrence of liver cancer or even liver failure will be reversed (Prince et al., 2002). Additionally, a recent study demonstrated that the treatment of PBC with TCM exerts anti-fibrotic effects and helps improve patients' pruritus, fatigue, and the response rate to UDCA (Chen et al., 2018). Meanwhile, several studies have revealed that FZHY, FFBJRG, and ALHX have unique advantages in improving biochemical indices, anti-fibrosis, and quality of life in patients with PBC (Chen et al., 2019;Jiang et al., 2019;Wang et al., 2020). Furthermore, a previous real-world cohort study (Chen et al., 2018) conducted by our research group found that TCM combined with UDCA increased the 1-year biochemical response rate of patients with PBC by 15.1% compared with that of UDCA alone (43.0% vs. 27.9%, p < 0.05). Therefore, it is of great significance to explore the clinical curative effects of CPMs combined with UDCA on PBC. Therefore, a meta-analysis of randomized controlled trials (RCTs) was conducted to measure the efficacy of CPMs plus UDCA for treating PBC.

Standards for inclusion and exclusion of literature
The inclusion criteria were: 1) the studies reported RCTs; 2) the participants were diagnosed with PBC based on the consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL); 3) the treatment involved anti-fibrotic CPMs plus UDCA; and 4) at least one of the following outcome indices was used: clinical efficacy rate, ALP, GGT, alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), laminin (LN), collagen type IV (IV-C), type III procollagen (PC-III), immunoglobulin M (IgM), immunoglobulin G (IgG), and clinical symptoms. The primary outcome was the clinical efficacy rate, whereas the secondary outcomes were liver function, hepatic fibrosis, immunological indicators, and clinical symptoms.
The exclusion criteria were: 1) the experimental group used none of the three aforementioned anti-fibrotic CPMs or other TCMs; 2) duplicate studies; 3) studies with incomplete research data; and 4) animal experiments, conferencing articles, reviews, non-RCTs, and other unrelated studies.

Data acquisition and quality evaluation
The literature was independently screened by two researchers (BI and SHI) in terms of the inclusion and exclusion standards. Data Frontiers in Pharmacology frontiersin.org acquisition consisted of 1) general information: title, first author, and publication year; 2) sex, age, sample size, intervention measures, and treatment course; and 3) observed outcome indicators. Literature eligibility was estimated using the Cochrane collaboration tool, including incomplete outcome data, selective reporting, allocation concealment, random-sequence generation, blinding of outcome assessment, blinding of participants and personnel, and other biases. Based on these standards, the literature eligibility was categorized as three levels of risk of bias: high, unclear, and low.

Statistical methods
The statistical analysis was performed using RevMan 5.4 software. According to the type of outcome, continuous data

FIGURE 1
Flow diagram of the literature screening and selection process.

FIGURE 2
Risk of bias graph.
Frontiers in Pharmacology frontiersin.org 04 are depicted as mean difference (MD) or standardized mean difference (SMD), while categorical data are presented as risk ratios (RRs); all are expressed with a 95% confidence interval (CI). Furthermore, the χ 2 and I 2 tests were used for heterogeneity analysis.
The fixed-effects model was used for analysis if p ≥ 0.1 and I 2 ≤ 50% in the subgroup or overall. Conversely, the random-effects model was employed if p < 0.1 and I 2 > 50%. Additionally, we searched for sources of heterogeneity in the results and employed a sensitivity analysis to affirm whether the results were stable. Moreover, subgroup analyses were performed based on the use of three different CPMs. A p-value less than 0.05 was considered statistically significant. Publication bias was analyzed using funnel plots.

Study characteristics
All 22 included studies were RCTs conducted in China and involved 1,725 patients with PBC. All studies were classified into an experimental group and a control group to compare the efficacies of CMPs combined with UDCA and UDCA monotherapy. The basic traits of each study are summarized in Table 2.

CPMs drug composition
These studies used three anti-fibrosis CPMs, including FZHY, FFBJRG, and ALHX, and listed the TCMs used. Dongchongxiacao (Cordyceps sinensis (Berk.) Sacc) is an ingredient in FZHY and

Outcome index 3.5.1 Clinical efficacy rate
A total of 13 clinical trials described the clinical efficacy rate as the main outcome, which was classified as markedly effective, effective, and ineffective grades. A random-effects model was implemented for analysis regarding heterogeneity testing (p = 0.0009, I 2 = 64%), and anti-fibrosis CPMs plus UDCA improved the clinical efficacy rate compared with UDCA alone (RR = 0.11, 95% CI: 0.06, 0.16; p < 0.00001) ( Figure 4A). Subgroup analysis showed that the clinical efficacy rate of FFBJRG was better than that of the other two CPMs and had no heterogeneity (p = 0.96, I 2 = 0%) ( Figure 4B).

Alkaline phosphatase
We found 10 trials that reported the effects of anti-fibrotic CPMs plus UDCA on ALP levels. A random-effects model was implemented based on the p-value and I 2 value. The subgroup analyses showed that anti-fibrotic CPMs plus UDCA were superior to UDCA alone in terms of serum ALP levels (RR = −28.83, 95% CI: −36.57, −21.10; p < 0.00001) ( Figure 5A).

Immunoglobulin M and immunoglobulin G
The IgG data were processed using a fixed-effects model based on the heterogeneity test (p = 0.96, I 2 = 0%), and a random-effects model was used for the IgM data with high heterogeneity (p = 0.03, I 2 = 63%). The MD (95% CI) of IgG and IgM were −2.86 (−3.63, −2.08) and −1.28 (−1.62, −0.94), respectively. Compared with UDCA alone, the additional use of anti-fibrosis CPMs was more effective in reducing IgG and IgM levels ( Figures 7A, B).

Symptom score
Three trials reported Symptom Score Change as the main outcome. The fixed-effects model was adopted because of the

Adverse events
Adverse events were described in seven studies. Three articles reported a total of nine patients who developed mild diarrhea and  Frontiers in Pharmacology frontiersin.org 11 nausea after taking CPM; however, these symptoms were not severe and did not require treatment. Four studies reported no adverse reactions.

Publication bias
An inverted funnel plot analysis of the clinical efficacy rate revealed that there may be publication bias in the asymmetric distribution of these publications (Figure 9).

Discussion
PBC is the most common autoimmune cirrhotic hepatic disease, occurring in all ethnic groups worldwide (Lv et al., 2020). The prognosis of patients with PBC mostly depends on the degree of liver fibrosis and its complications (Lammers et al., 2015). Patients with PBC tend to seek additional pharmacological treatments because UDCA is not uniformly effective (Lammers et al., 2015). In recent years, TCM has been widely studied and discussed as a complementary therapy. Many studies have shown that TCM plus UDCA has diverse advantages in relieving the clinical symptoms and improving the prognosis of PBC.
This meta-analysis validated the advantages of FZHY, FFBJRG, and ALHX combined with UDCA in the treatment of PBC. Compared with UDCA treatment alone, anti-fibrotic CPMs plus UDCA improved efficacy rates. Furthermore, liver function tests are widely used in clinical practice as indicators of the degree of liver damage. ALP, ALT, AST, and GGT levels decreased after combined treatment with anti-fibrotic CPMs and UDCA. LN, IV-C, PC-III, and HA are indicators for the detection of liver fibrosis, and the addition of anti-fibrosis CPMs to UDCA resulted in decreased levels of these compared with UDCA treatment alone. Moreover, immunological indicators (IgM and IgG) and clinical symptoms also notably improved with the combined treatment of anti-fibrotic CPMs and UDCA. In conclusion, anti-fibrotic CPMs combined with UDCA in the treatment of PBC effectively relieved various clinical indicators. These results provide hope for the treatment and prevention of liver fibrosis and cirrhosis in the future.
The pathobiology of PBC is characterized by inflammation, bile duct damage, and fibrosis (You et al., 2022), of which fibrosis appears in stage Ⅱ. It is believed that TCM is hepatoprotective and anti-inflammatory and suppresses the activation of hepatic stellate cells, which is advantageous in the treatment of liver fibrosis. Additionally, TCM may have multilevel, multi-pathway, and multi-target pharmacological actions on the comprehensive pathogenesis of PBC. For example, P. notoginseng is an ingredient in FFBJRG and ALHX, and P. notoginseng saponins are its main active constituent, which play an immunomodulatory role by reducing the levels of pro-inflammatory cytokines (Jiang et al., 2013). Furthermore, Ophiacordyceps sinensis, as a duplicate herb in FZHY and FFBJRG, can attenuate liver inflammation and fibrosis by regulating the expression of the TGF-β/MAPK pathway (Fu et al., 2021). Moreover, a mechanistic study has revealed that FZHY can decrease the expression levels of α-SMA, CTGF, TIMP-1, TGF-β1, and Smads, thereby reducing hepatic apoptosis, acute liver injury, and liver fibrosis (Cheng et al., 2013;Xie et al., 2013). An animal experiment reported that FFBJRG ameliorates hepatic disease by reducing the serum collagen levels of LN, HA, and IV-C and downregulating TGF-β-Smad pathway fibroblast signal transduction (Yang et al., 2013). The possible mechanism of ALHX for the inhibition of hepatic fibrosis is related to enhancing MMP2 activity in liver tissue and promoting extracellular matrix degradation by hepatoprotective enzymes (Tan et al., 2010). In brief, certain evidence support the anti-inflammatory and anti-fibrosis effects of FZHY, FFBJRG, and ALHX as the appropriate CPMs for treating PBC.

FIGURE 8
Forest plot of meta-analysis of syndrome score.

FIGURE 9
The funnel plot of total effective rate.
Frontiers in Pharmacology frontiersin.org However, this meta-analysis had some limitations. First, the 22 studies included had a small sample size, all were Chinese, and only a small number of studies reported several outcome indicators. Second, most publications only mentioned random assignment, and only one-third of the studies described a specific randomization method, such as a random number table. Therefore, the findings need to be further evaluated using high-quality trials. Third, different studies had different experimental periods, ranging between 12 and 48 weeks, which may be a source of heterogeneity. Fourth, although anti-fibrosis CPMs were always used in the experimental group, there were three different types-FZHY, FFBJRG, and ALHX, which could also be a source of heterogeneity. Finally, because half of the studies did not mention adverse events, the safety of CPMs as an anti-fibrosis therapy for PBC should be further evaluated, and caution is needed when drawing conclusions.

Conclusion
Our research shows that the combination of anti-fibrosis CPMs and UDCA is more effective than UDCA alone in treating PBC in improving clinical efficacy rate, liver fibrosis, liver function, immune function, and symptom score. This systematic review and metaanalysis provides reliable clinical evidence for PBC treatment. Antifibrotic CPMs are a promising therapeutic approach to supplement the conventional treatment of PBC. However, further evidence from high-quality and multi-center studies with larger samples is warranted to confirm the curative effect of anti-fibrosis CPMs during follow-up periods.

Data availability statement
The original contributions presented in the study are included in the article/Supplementary Materials, further inquiries can be directed to the corresponding author.