Published online Dec 6, 2018. doi: 10.12998/wjcc.v6.i15.961
Peer-review started: August 28, 2018
First decision: October 5, 2018
Revised: October 16, 2018
Accepted: November 14, 2018
Article in press: November 15, 2018
Published online: December 6, 2018
Processing time: 100 Days and 16.9 Hours
Ulcerative colitis (UC), an inflammatory bowel disease (IBD) of the colonic gastrointestinal tract, is steadily increasing across the globe, particularly in Asian countries such as China, where rapid industrialization and urbanization are contributing factors to the growing onset. Mild-to-moderate UC is the most prevalent amongst diagnosed cases, and although targeted pharmacological therapies, such as aminosalicylates, have been at the forefront of UC therapy, growing evidence suggests the integral role of intestinal microflora in UC pathogenesis. Subsequently, researchers are interested in the use and development of alternative therapies, such as probiotics, for the management and treatment of this colonic disease. This systematic review and meta-analysis addresses the use of a probiotic product, Medilac-S®, as adjunctive therapy for the induction of clinical UC remission and improvement of UC symptoms in a defined Chinese population, through the evaluation of 53 randomized, controlled trials (RCTs). Past reviews of probiotics for the induction of UC remission have described the positive effects of probiotic combination therapy in patients, however, many of these reviews demonstrated significant variability in study populations and probiotic treatments, making it difficult to interpret results accurately. This study therefore aims to provide a more focused analysis through the evaluation of one disease state, one probiotic and one population.
The incidence of UC has increased rapidly around the globe and although current pharmacological therapies elicit high response rates, they also present high-risk side effects or adverse events (AEs), growing rates of non-adherence and high costs to patients. Growing evidence also illustrates the important role of gut microflora in UC pathogenesis and the influence of the intestinal microbiome on drug pharmacokinetics. Therefore, it is important to identify treatments, such as probiotics, which can mediate the gut microflora to improve symptoms of UC and also improve responses to currently available therapies, whilst mitigating potential side effects.
Our primary objective was to conduct an up-to-date systematic review and meta-analysis to assess the efficacy of Medilac-S® as an adjunctive to conventional oral drugs for the induction of UC clinical remission within a Chinese population. One prior systematic review and meta-analysis, published by Hu et al, had, to date, discussed the efficacy of the probiotic Medilac-S® on the induction and maintenance of remission in UC patients. However, since its publication, a large number of new studies had been published and remained to be evaluated in a meta-analytic setting. In this review, we assessed 53 RCTs which highlighted the efficacy of the probiotic Medilac-S®, in combination with conventional aminosalicylates, to induce UC clinical remission within a Chinese population, improve UC symptoms and decrease AEs. This supports suggestions of the important role of the gut microbiome in the modulation of IBDs and presents a new potential treatment to mitigate the effects of the microflora on worsening UC symptoms.
The review protocol was registered in PROSPERO and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed for the review to ensure up-to-date methodology and study reasoning. Nine databases, both English and Chinese, were searched from 2000 to 2017, unrestricted by language or trial size to identify RCTs evaluating the therapeutic effects of Medilac-S® combination therapy with conventional aminosalicylate drugs in the treatment of UC within a Chinese population. If the study met the inclusion criteria, then outcome data extraction and assessment of both study quality and risk of bias was independently performed by two authors. Any disagreement was resolved by discussion and if consensus could not be reached, a third author was addressed. The included studies were evaluated on clinical remission, changes in patient-reported clinical symptoms, maintenance of remission and relapse rate, Sutherland index, endoscopic score, histological score and AEs. Meta-analysis was conducted on each outcome of interest using a fixed effect or a random effect model, depending on the significance of the heterogeneity. For dichotomous outcomes (e.g., clinical efficacy), risk ratios (RR) were calculated while the mean difference was used for continuous variables (e.g., histology scores). CIs were calculated at 95% and, when possible, the type of the conventional drug was applied as a moderator in the model of analysis. The overall quality of evidence supporting the outcome was assessed through the use of the Cochrane Collaboration tool and a risk of bias analysis was conducted on each study. The risk of bias parameters included the type of randomization method, allocation concealment, blinding of participants, personnel and outcome assessments, incomplete outcome data, selective reporting and other sources of bias. Additionally, selective reporting (reporting bias) and other types of bias were also considered. The potential for publication bias across studies was analyzed using the rank correlation test Kendall’s Tau, which tested for asymmetry in a funnel plot showing the relationship of the effect size [log (RR)] and its standard error (SE) among studies.
Fifty-three studies involving 3984 patients were identified and included in the systematic review. Forty-five studies were analyzed for the primary outcome of clinical remission and results demonstrated that combination Medilac-S® therapy is significantly more effective than conventional drug therapy alone (RR = 1.21, CI: 1.18-1.24, P < 0.0001). Moreover, sulfasalazine (SASP) outperformed mesalazine as a concomitant drug. Further meta-analysis also provided evidence that the combination of Medilac-S® significantly improved the Sutherland index score (P < 0.05), endoscopic score (P = 0.0001), histological score (P < 0.0001) and the number of patient reported symptoms (P < 0.0001), which include, abdominal pain, tenesmus, blood and mucous in stool, and diarrhea. The proportions of individuals who received combination therapy and complained of the aforementioned symptoms were 44%, 53%, 40% and 47% respectively of the proportion of individuals in the control group reporting the symptoms. The test for difference in the RR with different drugs also revealed that SASP in combination with Medilac-S® is more effective than mesalazine as a concomitant drug. The meta-analysis comparing the number of AE’s found that addition of Medilac-S® to conventional drug plays a role in significantly reducing (P = 0.0175) AE incidence, with the proportion of individuals in the treatment arm reporting an AE estimated to be 72% of the proportion of individuals reporting an AE in the control arm. Due to the insufficient data to evaluate relapse rate as a function of follow-up time, a descriptive analysis was conducted on the maintenance of remission. It was found that 80% (8/10) of the studies presenting the outcome showed that the recurrence rate of UC was significantly lower in the Medilac-S® combination group. The quality and risk of bias amongst included studies found the majority of the studies presented a low risk of attrition bias, reporting bias and other potential sources of bias. However, failure to report the methods for randomization or implementation of blinding resulted in unclear risk of bias evaluations. Thus, evidence from studies is considered of moderate-quality. Since no restrictions on the severity of UC were made, this confounding factor was not considered in the analysis because of the very limited number of studies with severe UC patients. Additionally, due to the limited number of studies which included the aminosalicylate drugs olsalazine and balsalazide, sub-analysis could not be conducted to compare their efficacy as concomitant medications.
This systematic review and meta-analysis is the most up-to date, comprehensive review evaluating the effectiveness of probiotic Medilac-S® adjunctive therapy in treatment of UC. It critically examined currently available data and found evidence that Medilac-S® as adjunctive therapy to conventional oral aminosalicylate medications significantly increases UC clinical remission and leads to improvements in the Sutherland index, endoscopy and histology scores, patient-reported clinical symptoms, and AEs. Although review has provided further insight to the global community on the application of this probiotic therapy for inducing symptom remission, further analytical evidence is also required to determine the benefit of Medilac-S® combination therapy for the maintenance of UC remission. The uniformity in study design of the included studies, such as per os administration of Medilac-S® and concomitant therapies, minimizes the heterogeneity of medication delivery method across studies and facilitates a more applicable future global clinical application due to ease of practical use. The most effective combination: Medilac-S® with SASP, was also identified through sub-analysis presented in this review. In addition, it was concluded that Medilac-S® has significant effect in reducing the incidence of AEs in UC treatment and thus, indicates another option for patients with low tolerance of conventional drug treatments. This new finding is of importance because the side effects and tolerance of the anti-inflammatory drugs in UC treatment is a big concern of both physicians and patients and the previous studies have shown conflicting results in the function of probiotics in reducing the occurrence of AEs. This meta-analysis has great value for clinicians as evidence from this study implies that Medilac-S® in conjunction with conventional oral therapy, predominantly, SASP, should be considered as standard care for UC in the Chinese population.
Through the use of a focused meta-analysis and sub-analyses, evaluating Medilac-S® for UC remission within the Chinese population, heterogeneity across studies was limited, which allowed for greater accuracy when defining results. Although evidence from the study suggests the incorporation of Medilac-S® into standard UC therapy for Chinese populations, future studies should aim to conduct additional work with the probiotic in non-Chinese populations to substantiate its use. Additional research can also be conducted to evaluate variables of Medilac-S® treatment such as optimal treatment dosage and treatment duration in participants with varying levels of UC severity. In addition, future Chinese clinical trials evaluating probiotics are recommended to use large sample sizes and incorporate rigorous study design methodology, which includes reporting of blinding, the techniques for randomization and allocation concealment, as it limits risk of bias, and will aid researchers in drawing firmer conclusions on the benefits of probiotics, like Medilac-S® for IBD.