Efficacy and safety of Xileisan combined with mesalazine for ulcerative colitis: A meta-analysis and trial sequential analysis

Abstract

BACKGROUND

The benefits and risks of Xileisan (XLS) in the treatment of ulcerative colitis (UC) remain unclear.

AIM

The present study aimed to evaluate the efficacy and safety of the combination of XLS and mesalazine when treating UC.

METHODS

We searched eight databases for clinical trials evaluating the combination of XLS and mesalazine in the treatment of UC, up to January 2024. Meta-analysis and trial sequential analysis (TSA) were performed using Revman 5.3 and TSA 0.9.5.10 beta, respectively.

RESULTS

The present study included 13 clinical studies involving 990 patients, of which 501 patients received XLS combined with mesalazine while 489 patients received mesalazine alone. The meta-analysis showed that, in terms of efficacy, the combination of XLS and mesalazine significantly improved the clinical efficacy rate by 22% [risk ratio (RR) = 1.22; 95%CI: 1.15–1.28; P < 0.00001] and mucosal improvement rate by 25% (RR = 1.25; 95%CI: 1.12–1.39; P = 0.0001), while significantly reducing the duration of abdominal pain by 2.25 days [mean difference (MD) = -2.25; 95%CI: -3.35 to -1.14; P < 0.0001], diarrhea by 2.06 days (MD = -2.06; 95%CI: -3.92 to -0.20; P = 0.03), hematochezia by 2.32 days (MD = -2.32; 95%CI: -4.02 to -0.62; P = 0.008), tumor necrosis factor alpha by 16.25 ng/mL (MD = -16.25; 95%CI: -20.48 to -12.01; P < 0.00001), and interleukin-6 by 14.14 ng/mL (MD = -14.14; 95%CI: -24.89 to -3.39; P = 0.01). The TSA indicated conclusiveness in the meta-analysis of the efficacy endpoints. In terms of safety, the meta-analysis revealed that the combination of XLS and mesalazine did not increase the occurrence of total and gastrointestinal adverse events, abdominal distension, and erythema (P > 0.05). The TSA showed non conclusive findings in the meta-analysis of the safety endpoints. Harbord’s test showed no publication bias (P = 0.734).

CONCLUSION

Treatment with XLS alleviated the clinical symptoms, intestinal mucosal injury, and inflammatory response in patients with UC, while demonstrating good safety.

Key Words: Xileisan; Mesalazine; Ulcerative colitis; Meta-analysis; Trial sequential analysis

Core Tip: The benefits and potential risks of Xileisan (XLS) in the treatment of ulcerative colitis (UC) remain unclear. The present study aimed to evaluate the efficacy and safety of XLS combined with mesalazine in the treatment of UC through meta-analysis and trial sequential analysis. The meta-analysis showed that XLS alleviated the clinical symptoms, intestinal mucosal injury, and inflammatory response in patients with UC, while demonstrating good safety. XLS, therefore, represents a safe and effective treatment strategy for UC.

INTRODUCTION

Ulcerative colitis (UC) is the chronic idiopathic inflammation of the colonic mucosa caused by immune system dysfunction[1]. In recent years, the incidence of UC has increased globally, particularly in developing regions[2,3]. The main symptoms of UC are abdominal pain, diarrhea, rectal bleeding, and fatigue; however, in some severe cases, serious complications, such as systemic infections, thromboses, and malignant tumors can occur[4,5]. Due to its recurrent nature and difficult healing, UC has a severe impact on patients’ quality of life and mental health[6]. Currently, there are no specific drugs to treat UC, and 5-aminosalicylic acid, corticosteroids, immunosuppressants, and biologics are still the primary treatments for the symptoms of UC[7]. Mesalazine, a traditional 5-aminosalicylic acid, is a first-line drug for the treatment of mild-to-moderate UC, and is important for maintenance UC treatment. Although mesalazine relieves the clinical symptoms and inflammatory response in patients with UC, its efficacy remains limited[8]. Therefore, exploring novel auxiliary treatments for UC is import.

Xileisan (XLS) is a classical Chinese patent medicine. According to traditional Chinese medicine theory, XLS has the following effects: Heat-clearance and detoxification, blood activation, pain relief, promotion of pus discharge and tissue regeneration, and putrefaction elimination[9]. In clinical practice in China, XLS was originally used to treat oral ulcers, but later became widely used for the treatment of mucosal inflammatory diseases[10]. XLS has been reported to reduce inflammation in the intestinal mucosa, and its efficacy in treating mild UC is comparable to that of mesalazine, suggesting its potential as a complementary treatment for UC[11]. Due to a lack of high-quality evidence, however, the specific benefits and potential risks of XLS in the treatment of UC remain unclear. The present study, therefore, aimed to evaluate the efficacy and safety of the combination of XLS and mesalazine in treating UC through a meta-analysis and trial sequential analysis (TSA), and to provide evidence for the clinical applications of XLS.

MATERIALS AND METHODS

Search strategy and study selection

The protocol for the present meta-analysis and TSA was registered in PROSPERO (No. CRD42024501208). We conducted a literature search on UC with XLS, using a strategy that integrated subject terms and expanded keywords. The subject terms used were “Xileisan” and “ulcerative colitis,” and expanded keywords were obtained from Medical Subject Headings and Sinomed. We searched the following public databases from the inception of each database until January 2024: The China National Knowledge Internet; Wanfang Data; China Science and Technology Journal Database; Sinomed; EMBASE; PubMed; the Cochrane Library; and Web of Science. The search was conducted without any language or other specified restrictions.

Inclusion and exclusion criteria

The inclusion criteria were as follows, based on the Population, Intervention, Comparison, Outcomes and Study structure: (1) Participants, those who met the diagnostic criteria for UC[12]; (2) Intervention, patients in the experimental group received treatment with XLS (National Medicine Permission Nos: Z32020770, Z32020726, Z33020847, DZD036016G) in combination with the widely-used drug mesalazine, with the steps of XLS administration outlined as follows–prior to administering the preparatory enema it is crucial that the patient empties their bowels, 2.0 g of XLS was dissolved into 100 mL of warm water (35–40 °C) to prepare the enema solution, with the patient on their left side the enema tip was inserted 10–15 cm into the anus and the solution was slowly administered, after which the patient was guided through the knee-chest, right lateral, and supine positions to spread the solution evenly throughout the intestines, and instructed to retain the enema for 2–4 h, ideally before bedtime; (3) Control, the control group received mesalazine treatment alone; (4) outcomes, efficacy endpoints–clinical efficacy rate, mucosal improvement rate, duration of abdominal pain, duration of diarrhea, duration of hematochezia, tumor necrosis factor alpha (TNF-α), and interleukin (IL)-6, where the clinical efficacy rate refers to the proportion of individuals with relief of clinical symptoms and a reduction in intestinal mucosal inflammation, which is an indicator of the overall effectiveness of treatment, clinical symptom relief refers to the near disappearance of various symptoms, such as bloody diarrhea, abdominal pain, bloody stools, urgency and heaviness, and a normal stool routine, while reduction in intestinal mucosal inflammation refers to a state in which the intestinal mucosa is generally normal under colonoscopy or there is still mild congestion and edema without obvious ulcers or bleeding–and safety endpoints, which included total and gastrointestinal adverse events, abdominal distension, erythema, and relapse; and (5) study design, randomized controlled trial.

The exclusion criteria were as follows: (1) Reviews, animal experiments, or case reports, etc.; (2) duplicate publications; and (3) studies with incomplete data.

Literature screening

After importing all the search results into Endnote X9, the irrelevant articles were eliminated based on the inclusion and exclusion criteria to determine the included literature.

Data analysis

The included literature was categorized and organized, and basic information, such as author(s), publication year, sample size, mean age, sex ratio, intervention measures, and duration of treatment was extracted.

Risk of bias assessment

The risk of bias for each study was assessed according to the methods specified in the Cochrane guidelines. These tasks were conducted independently by the two researchers, and any disagreements were resolved by consensus with a third researcher.

Data synthesis and analysis

Meta-analysis: Revman 5.3 was used for the meta-analysis. The I² test was used to analyze the heterogeneity among the included studies, with I² < 50% indicating low heterogeneity, for which a fixed-effects model was used for the analysis, while I² ≥ 50% indicated high heterogeneity, for which a random-effects model was used for the analysis. Risk ratio (RR) and 95%CI were used as the effect size for dichotomous variables, while mean difference (MD) and 95%CI were used as the effect size for continuous variables. The threshold for statistical significance was set at P < 0.05.

Sensitivity analysis: A leave-one-out sensitivity analysis was used to assess the robustness of the meta-analysis results as follows: One study at a time was excluded while the remaining studies were combined in each analysis. The results were considered robust if there was no significant change in the combined effect size due to the absence of one study.

TSA: TSA 0.9.5.10 was used for the TSA, a cumulative meta-analysis method that prevents erroneous conclusions due to an insufficient sample size by controlling for random errors in a study. The TSA assessed whether the results of the current meta-analysis were conclusive based on the variability and sample size of the data, with type I and II errors set at 5% and 20%, respectively. When the Z-value curve crossed the boundary, the results of the meta-analysis were considered conclusive.

Publication bias assessment: Stata 15.0 was used for the publication bias assessment. Harbord’s test is a method for assessing publication bias in meta-analyses, and is particularly suitable for dealing with data involving dichotomous variables. It detects publication bias on the basis of the relationship between the effect size of an outcome and its standard error. A P value > 0.1 for Harbord regression suggests that there is no significant publication bias.

RESULTS

Literature screening results

A total of 1571 articles were initially obtained through the literature search, of which 792 articles were excluded as duplicates and 766 because they did not meet the selection criteria. In total, 13 articles[13-25] were included in the present analysis, as shown in Figure 1.

Figure 1 Literature screening flowchart.

Basic characteristics of included studies

The 13 included articles[13-25] referenced a total of 990 patients, among which 501 were treated with acombination of XLS and mesalazine, and 489 mesalazine alone. The publication dates of the included studies ranged from 2009 to 2022, and all study centers were located in China, as shown in Table 1.

Table 1 Basic characteristics of the included studies.

Ref.	Sample size	Age (years)	Male	Disease duration (years)	Intervention	Treatment duration (weeks)
Cai et al[13], 2022	38	30.2	44.7	3.0	XLS 1.0 g/d, mesalazine 3.0 g/d	8
	38	30.2	50.0	3.0	Mesalazine 3.0 g/d	8
Ding et al[14], 2019	27		62.3		XLS 1.0 g/d, mesalazine 4.0 g/d	4
	26		62.3		Mesalazine 4.0 g/d	4
Ge et al[15], 2011	30				XLS 1.0 g/d, mesalazine 4.0 g/d	4
	30				Mesalazine 4.0 g/d	4
Li et al[16], 2017	50	72.8	56.0		XLS 1.0 g/d, mesalazine 3.0 g/d	8
	50	60.8	58.0		Mesalazine 3.0 g/d	8
Liu et al[17], 2015	30	38.9	46.7		XLS 2.0 g/d, mesalazine 1.0 g/d	8
	26	37.4	42.3		Mesalazine 1.0 g/d	8
Ni et al[18], 2011	30	53.6	80.0		XLS 1.0 g/d, mesalazine 1.25-1.75 g/d	4
	30	50.8	73.3		Mesalazine 1.25-1.75 g/d	4
Wang et al[19], 2016	58	25.6	55.1	3.6	XLS 1.0 g/d, mesalazine 4.0 g/d	3
	58	26.5	60.3	3.2	Mesalazine 4.0 g/d	3
Xu et al[20], 2010	42	38.4	69.0	5.1	XLS 2.0 g/d, mesalazine 4.0 g/d	4
	42		59.5	6.5	Mesalazine 4.0 g/d	4
Yao et al[21], 2022	30	50.2	50.0		XLS 1.0 g/d, mesalazine 3.0 g/d	4
	30	49.7	53.3		Mesalazine 3.0 g/d	4
Zhang et al[22], 2013	35	35.3	62.9		XLS 1.0 g/d, mesalazine 4.0 g/d	2
	35	35.8	60.0		Mesalazine 4.0 g/d	2
Zhang et al[23], 2016	45	37.3	51.1		XLS 1.0 g/d, mesalazine 3.0 g/d	3
	45	36.2	55.6		Mesalazine 3.0 g/d	3
Zhu et al[24], 2013	58		45.5		XLS 1.0 g/d, mesalazine 3.0 g/d	4
	52		45.5		Mesalazine 3.0 g/d	4
Zhu et al[25], 2009	28				XLS 1.0 g/d, mesalazine 4.0 g/d	4
	27				Mesalazine 4.0 g/d	4

XLS: Xileisan.

Risk of bias assessment

Among the 13 included clinical studies, 9 did not clearly specify the randomization method, 11 did not clearly specify the allocation concealment, and 13 did not clearly specify the blinding of interventions to participants and selective reporting. The remaining domains had low risks of bias, as shown in Figure 2.

Figure 2 Risk of bias summary.

Efficacy endpoints

Clinical efficacy rate: The results of the present meta-analysis showed that the combination of XLS and mesalazine significantly improved the clinical efficacy rate–by 22% compared to mesalazine alone (RR = 1.22; 95%CI: 1.15–1.28; P < 0.00001). The results of the present TSA indicated conclusiveness in the meta-analysis results regarding the clinical efficacy rate, as shown in Figure 3.

Figure 3 The results of meta-analysis and trial sequential analysis for clinical efficacy rate. The Z-value curve crossed the boundary value in the second study, indicating that the meta-analysis results of clinical efficacy rate are conclusive. M-H: Mantel-Haenszel; RIS: Required information size.

Mucosal improvement rate: The results of the present meta-analysis revealed that the combination of XLS and mesalazine significantly increased the mucosal improvement rate–by 25% compared to mesalazine alone (RR = 1.25; 95%CI: 1.12–1.39; P = 0.0001). The results of the present TSA indicated conclusiveness in the meta-analysis results for the mucosal improvement rate, as shown in Figure 4.

Figure 4 The results of meta-analysis and trial sequential analysis for mucosal improvement rate. The Z-value curve crossed the boundary value in the second study, indicating that the meta-analysis results of mucosal improvement rate are conclusive. M-H: Mantel-Haenszel; RIS: Required information size.

Duration of symptoms: The results of the present meta-analysis demonstrated that the combination of XLS and mesalazine significantly shortened the duration of abdominal pain, by 2.25 days (MD = -2.25; 95%CI: -3.35 to -1.14; P < 0.0001), diarrhea by 2.06 days (MD = -2.06; 95%CI: -3.92 to -0.20; P = 0.03), and hematochezia by 2.32 days (MD = -2.32; 95%CI: -4.02 to -0.62; P =0.008) compared to mesalazine alone. The results of the present TSA indicated conclusiveness in the meta-analysis results for the duration of abdominal pain, diarrhea, and hematochezia, as shown in Figure 5.

Figure 5 The results of meta-analysis and trial sequential analysis for duration of syndromes. A: Duration of abdominal pain; B: Duration of diarrhea; C: Duration of hematochezia. The three Z-value curves all crossed the boundary value in the first study, indicating that the meta-analysis results of duration of abdominal pain, duration of diarrhea, and duration of hematochezia are conclusive. IV: Inverse variance; SD: Standard deviation; RIS: Required information size.

Inflammatory factors: The results of the present meta-analysis showed that the combination of XLS combined and significantly decreased TNF-α levels, by 16.25 ng/mL (MD = -16.25; 95%CI: -20.48 to -12.01; P < 0.00001) and IL-6 levels by 14.14 ng/mL (MD = -14.14; 95%CI: -24.89 to -3.39; P = 0.01) compared to mesalazine alone. The results of the present TSA indicated conclusiveness in the meta-analysis results for TNF-α and IL-6, as shown in Figure 6.

Figure 6 The results of meta-analysis and trial sequential analysis for inflammatory factors. The two Z-value curves all crossed the boundary value in the second study, indicating that the meta-analysis results of tumor necrosis factor alpha (TNF-α), and interleukin (IL)-6 are conclusive. A: TNF-α; B: IL-6. IV: Inverse variance; SD: Standard deviation; RIS: Required information size.

Safety endpoints

The results of the present meta-analysis showed that the combination of XLS and mesalazine significantly reduced relapse, by 59% (RR = 0.41; 95%CI: 0.22–0.76; P = 0.005) compared to mesalazine alone, while total adverse events (RR = 1.10; 95%CI: 0.61–1.97; P =0.75), gastrointestinal adverse events (RR = 1.08; 95%CI: 0.50–2.36; P = 0.84), abdominal distension (RR =0.99; 95%CI: 0.23–4.22; P = 0.99), and erythema (RR = 0.98; 95%CI: 0.27–3.57; P= 0.98) were comparable. The results of the present TSA indicated conclusiveness in the meta-analysis results of relapse, as shown in Table 2.

Table 2 The results of meta-analysis and trial sequential analysis for safety endpoints.

Outcome	Experimental	Control	I2	RR (95%CI)	P value	TSA
Total adverse events	21/226	19/224	0	1.10 (0.61-1.97)	0.75	No
Gastrointestinal adverse events	11/168	10/166	0	1.08 (0.50-2.36)	0.84	No
Abdominal distension	3/73	3/72	0	0.99 (0.23-4.22)	0.99	No
Erythra	3/130	3/128	0	0.98 (0.27-3.57)	0.98	No
Relapse	12/116	29/115	50	0.41 (0.22-0.76)	0.005	Yes

TSA: Trial sequential analysis; RR: Risk ratio.

Sensitivity analysis

The results of the leave-one-out sensitivity analysis indicated that the meta-analysis results for clinical efficacy and mucosal improvement rates, duration of abdominal pain, diarrhea, and hematochezia, TNF-α and IL-6 Levels, total and gastrointestinal adverse events, abdominal distension, and erythema were robust. The results for relapse, however, were not found to be robust, due to the study by Wang et al[19]. Once the aforementioned study by Wang et al[19] was removed, the combined result for relapse no longer held significance (RR = 0.36; 95%CI: 0.12–1.05; P = 0.06).

Subgroup analysis

The results of the subgroup analysis showed that in terms of XLS dosage, doses of 1.0 g/d (RR = 1.23; 95%CI: 1.15–1.30; P < 0.00001) and 2.0 g/d (RR = 1.16; 95%CI: 1.03–1.31; P = 0.01) both significantly improved the clinical efficacy rate. When evaluating mesalazine dosage, the combination of XLS with 1.0–2.0 g/d (RR = 1.15; 95%CI: 1.01–1.32; P = 0.04), 3.0 g/d (RR = 1.20; 95%CI: 1.11–1.30; P < 0.00001), and 4.0 g/d (RR = 1.26; 95%CI: 1.15–1.37; P < 0.00001) of mesalazine all significantly improve the clinical efficacy rate. When evaluating treatment duration, XLS treatment for 3 (RR = 1.26; 95%CI: 1.12–1.42; P = 0.0002), 4 (RR 1.23; 95%CI: 1.14–1.34; P < 0.00001), and 8 (RR = 1.16; 95%CI: 1.05–1.29; P = 0.003) weeks all significantly improved the clinical efficacy rate. There was no significant benefit observed, however, with 2 weeks of XLS treatment (RR = 1.17; 95%CI: 1.00–1.38; P = 0.05). The subgroup analysis, therefore, did not find a dose-related difference in the clinical efficacy rate, but did find a treatment duration-related difference, suggesting that a treatment duration ≥ 3 weeks was more effective than 2 weeks, as shown in Table 3.

Table 3 The results of subgroup analysis for Xileisan dosage, mesalazine dosage, and treatment duration.

Subject	Subgroup	I2	RR (95%CI)	P value
XLS dosage	1.0 g/d	0	1.23 (1.15-1.30)	< 0.00001
	2.0 g/d	0	1.16 (1.03-1.31)	0.01
Mesalazine dosage	1.0-2.0 g/d	0	1.15 (1.01-1.32)	0.04
	3.0 g/d	3	1.20 (1.11-1.30)	< 0.00001
	4.0 g/d	0	1.26 (1.15-1.37)	< 0.00001
Treatment duration	2 weeks	0	1.17 (1.00-1.38)	0.05
	3 weeks	0	1.26 (1.12-1.42)	0.0002
	4 weeks	0	1.23 (1.14-1.34)	< 0.00001
	8 weeks	33	1.16 (1.05-1.29)	0.003

XLS: Xileisan; RR: Risk ratio.

Publication bias

The results of Harbord’s test for the clinical efficacy rate showed P = 0.734, indicating no significant publication bias, as shown in Figure 7.

Figure 7 Publication bias assessment.

DISCUSSION

UC is a recurrent and difficult-to-cure disease that severely affects patients’ quality of life, while also imposing medical and social security costs[26,27]. Unfortunately, the etiology of UC remains unclear; therefore, current clinical management focuses on relieving acute symptoms, reducing complications, and maintaining remission[28,29]. The current mainstream approach involves using 5-aminosalicylic acid for mild-to-moderate UC, adding corticosteroids for patients with uncontrolled inflammation, and immunosuppressants and TNF-α monoclonal antibodies for moderate-to-severe cases[30,31]. As a commonly used medication for treating mild-to-moderate UC and maintaining remission, mesalazine partially alleviates patients’ clinical symptoms and intestinal mucosal inflammation[32]. Almost half of the patients treated mesalazine, however, do not achieve the expected therapeutic effects, and one-third are at risk of relapse[33,34]. XLS, a traditional Chinese medicine with heat-clearing, detoxifying, and ulcer-healing properties, has garnered increasing attention in recent years[9]. XLS consists of multiple ingredients, and was initially used to treat oral ulcers and acute pharyngitis[35]. XLS was first reported in the treatment of UC in 1964[36], and in 1988, it was reported that XLS was more effective in an enema form than as an oral administration for the treatment of UC[37]. Further research has indicated that XLS enemas are an effective treatment for UC[38]; however, the specific benefits of XLS in patients with UC are not yet clear, due to the current lack of high-quality evidence. The present study included 13 clinical trials and 990 participants in a meta-analysis and TSA to assess the efficacy and safety of XLS in the treatment of UC.

Compared to mesalazine alone, the combination of XLS and mesalazine improved the clinical efficacy and mucosal improvement rates by 22% and 25%, respectively, and shortened the duration of abdominal pain by 2.25 days, diarrhea by 2.06 days, hematochezia by 2.32 days. The clinical efficacy rate is a comprehensive indicator for evaluating the relief of clinical symptoms and intestinal mucosal inflammation in patients with UC, while the mucosal improvement rate is an objective indicator for evaluating the condition of the intestinal mucosa[39]. Abdominal pain, diarrhea, and hematochezia are the most common clinical symptoms in patients with UC, and are significant factors affecting patients’ quality of life. The benefits of XLS on the clinical efficacy rate, mucosal improvement rate, and duration of symptoms indicate that it promotes the restoration of the normal structure and function of the intestinal mucosa, thereby alleviating clinical symptoms. Relevant studies showed that XLS significantly increased the levels of occludin, claudin-1, and secretory immunoglobulin A, while it decreased β-defensin levels, which may be the mechanism by which it inhibits intestinal inflammation[40]. XLS has also been reported to inhibit endothelial nitric oxide synthase and vascular endothelial growth factor, which may be the mechanism by which it reduces intestinal mucosal bleeding[41]. Additionally, the results of the present meta-analysis showed that XLS significantly reduced TNF-α by 16.25 ng/mL and IL-6 by 14.14 ng/mL. Considering that TNF-α and IL-6 are classic pro-inflammatory factors, the role of XLS in reducing TNF-α and IL-6 further confirms its function in inhibiting intestinal inflammation.

The results of the present subgroup analysis revealed that XLS doses of both 1.0 g/d and 2.0 g/d, when used in combination with mesalazine, significantly improved the clinical efficacy. This results indicates that a dosage range of 1.0–2.0 g/d presents an effective option for clinicians to consider. Additionally, XLS combined with 1.0–2.0 g/d, 3.0 g/d, and 4.0 g/d mesalazine all significantly improved clinical efficacy. This result suggests, therefore, that the additional benefit provided by XLS was not limited by mesalazine dosage. Furthermore, the results of the present analysis showed that treatment with XLS for 3, 4, and 8 weeks significantly improved the clinical efficacy; however, treatment for 2 weeks did not provide significant benefits, indicating that adequate treatment duration may be an important factor in achieving the benefits of XLS. Therefore, we recommend that clinicians ensure an XLS treatment duration of ≥ 3 weeks to ensure that patients achieve optimal benefits.

The combination of XLS and mesalazine, when compared to mesalazine alone, did not increase the total number of adverse events, gastrointestinal adverse events, abdominal distension, or erythema, indicating that the combination of XLS and mesalazine did not increase the risk of adverse events. Additionally, the results of the present study showed a significant, 59%, reduction in relapse with the combination of XLS and mesalazine compared to mesalazine alone, indicating that XLS plays a role in stabilizing conditions and reducing the relapse rate. However, sensitivity analysis revealed that the significance of relapse disappeared after excluding the study by Wang et al[19] suggesting that the benefit of this outcome may be driven that study. Among the three studies included in the analysis of relapse, Wang et al[19] found a benefit in relapse in 116 patients, whereas Ge et al[15] and Zhu et al[25] did not find this benefit in 60 and 55 patients, respectively. The authors speculate, however, that the negative results may be due to an insufficient sample size. The results of the present TSA, therefore, confirmed the aforementioned viewpoint, indicating that the meta-analysis results for relapse, after appropriate adjustments, provide conclusive evidence for the role of XLS in reducing the rate of relapse in patients with UC. This is a positive finding for these patients, as they can maintain relatively good safety while achieving better disease control. However, considering that the results of the present TSA indicated that safety endpoints other than relapse did not reach the desired information value, large-scale, multicenter, randomized controlled trials are needed to validate the safety of XLS. Furthermore, because of individual variations among patients, it is essential for doctors to conduct further personalized assessments and exercise clinical judgment to determine the most appropriate treatment for each patient.

The present study does have some limitations that need to be noted. First, since XLS is mainly used in the Chinese market, the study samples included are all from China, and research results from other regions and ethnicities are lacking. The authors, therefore recommend establishing research centers in diverse continents and countries in the future to explore the role of XLS in patients with UC of different races. However, as XLS has not yet been listed in other countries, this issue can only be resolved after its approval by the food and drug regulatory authorities in other countries and the studies can be repeated. Second, the overall quality of the included studies was low, and the implementation details of the intervention blinding method were not described, which may increase the risk of implementation bias in the research results. Researchers should develop and execute large-sample, double-blind, randomized controlled trials across multiple centers to provide high-quality evidence for XLS analyses. Third, only two studies reported values for TNF-α and IL-6, which may lead to a decreased accuracy of the research results. The authors recommend, therefore, that future studies focus on the study of blood biochemical indicators to further elucidate the impact of XLS on classical inflammatory factors, such as TNF-α, IL-1β, IL-6, and IL-10. Fourth, The safety endpoints were derived from only 6 studies, with a total sample size of 450, potentially constraining the comprehension of safety in the present study. Therefore, an accurate assessment of drug safety requires observation and analysis across a more substantial patient cohort. The authors recommend that future studies should focus on the evaluation of the safety of XLS and enrich the evaluation indicators of adverse events while conducting large-sample clinical trials.

CONCLUSION

The addition of XLS alleviated the clinical symptoms, intestinal mucosal injury, and inflammatory response in patients with UC, while demonstrating good safety.