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Abstract

Background:

Inflammatory bowel disease (IBD) occurs in up to 70%–80% of patients with primary sclerosing cholangitis (PSC). Oral vancomycin therapy (OVT) has been reported to be effective in the treatment of IBD associated with PSC (IBD-PSC).

Objectives:

To examine the effectiveness and safety of OVT in the treatment of IBD-PSC by performing a systematic review and pooled analysis of the literature.

Design:

We performed a systematic review and pooled analysis of studies reporting IBD clinical response to OVT in IBD-PSC.

Data sources and methods:

A systematic search was conducted in Cochrane Library, Embase, Google Scholar, Medline, PubMed, Scopus, and Web of Science from database inception to June 3, 2024. We included adult and pediatric studies that reported on clinical response (defined as any improvement in IBD-related clinical symptoms) of IBD-PSC patients treated with OVT (including pre- and post-liver transplantation cohorts). Pooled analyses of OVT response and safety were performed.

Results:

A total of 21 (open-label, non-controlled) studies including 290 patients with IBD-PSC treated with OVT were included. The median duration of OVT to treat IBD-PSC was 32.5 weeks (interquartile range (IQR): 19–83 weeks). The total daily dose of OVT ranged from 250 to 1500 mg. Concomitant treatment included the following: mesalamine in 14.5% (n = 42), advanced therapies in 10.7% (n = 31), and immunosuppressive agents in 14.1% (n = 41). Clinical response was noted in 47.6% (138/290) and clinical remission in 43.5% (100/230). The biochemical remission rate post-OVT was 68.8% (55/80) and endoscopic remission was 39.4% (80/203). Three studies (n = 11) reported no episodes of acute cholangitis while on OVT. Five studies (n = 69) reported an incidence rate of 8.7% of vancomycin-resistant enterococci post-OVT to treat IBD-PSC.

Conclusion:

OVT was associated with clinical response/remission in almost half of patients with IBD-PSC with a favorable side effect profile. Further prospective randomized trials are needed to confirm the dosing, efficacy, treatment duration, and long-term safety of OVT for the treatment of IBD-PSC.

Trial registration:

The study protocol was registered with PROSPERO a priori (no. CRD42023438341).

Keywords

IBD PSC ulcerative colitis vancomycin

Introduction

Primary sclerosing cholangitis (PSC) is a chronic progressive disease that is characterized by inflammation, fibrosis, and stricture formation in the biliary tree.¹ PSC is associated with significant morbidity including increased risk of cholangiocarcinoma, hepatocellular carcinoma, gallbladder carcinoma, and colorectal carcinoma.² Currently, the only effective treatment for PSC is liver transplantation.³ About 70% of patients with PSC have underlying inflammatory bowel disease (IBD).⁴

Ulcerative colitis (UC) has been classically thought to be more common in PSC compared to Crohn’s disease (CD). However, IBD associated with PSC (IBD-PSC) seems to represent a distinctive phenotype in comparison to UC and CD without PSC.^5,6 IBD-PSC is more likely to be associated with rectal sparing, pancolitis with greater severity of inflammation in the right compared to the left colon and backwash ileitis.⁷ In addition, IBD-PSC is associated with a significantly higher rate of colorectal cancer compared with UC without PSC.⁸ The current treatment paradigm of IBD-PSC mirrors that of IBD without PSC starting with mesalamine for mild–moderate colonic disease and immunosuppressants/advanced therapies in moderate-to-severe or steroid-dependent disease which can be required in up to a one-third of IBD-PSC patients.⁹ Up to 50% of patients with IBD-PSC do not achieve endoscopic remission despite treatment with advanced therapies.⁹

The pathogenesis of PSC-IBD is multifactorial and involves genetic susceptibility, impaired bile acid hemostasis, immune dysregulation, and alterations in the microbiome.^10
–12 In terms of gut microbiome alterations, IBD-PSC seems to be associated with a different gut microbial composition compared to healthy controls and UC without PSC.^13,14 For example, in IBD-PSC, there is marked increase in Veillonella species and an over-representation of Enterococcus in comparison to UC without IBD.^13,14 Therefore, targeting gut microbial dysbiosis is emerging as a potential treatment strategy for IBD-PSC.

Oral vancomycin is a poorly absorbed oral antibiotic that is thought to have immunomodulating properties separate from its antibiotic properties.¹⁵ Vancomycin has been shown to affect tumor necrosis factor-alpha, transforming growth factor beta, and increase regulatory T cells along with influencing gut microbiota.¹⁵ Hence, it is suspected that oral vancomycin would be effective in the treatment of IBD-PSC. Multiple studies have investigated the use of oral vancomycin for the treatment of PSC with conflicting results.^16
–23 However, studies assessing the efficacy and safety of oral vancomycin therapy (OVT) to treat the IBD associated with PSC are scarce. In a case series of three adult patients with IBD-PSC, 500 mg of oral vancomycin showed significant clinical improvement of IBD and was well tolerated.²⁴

While oral vancomycin has been a promising agent worthy of further study, only a few small cohorts have evaluated its use for IBD-PSC patients. Therefore, a thorough review and analysis of the available literature is warranted. We aim to perform a comprehensive systematic review and pooled analysis of the literature of all studies evaluating the use of oral vancomycin for the treatment of IBD-PSC patients to ascertain the OVT effect on IBD-PSC.

Methods

The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement for reporting was used in this study (Supplemental Table 1).^25,26 The study protocol was registered with PROSPERO a priori (no. CRD42023438341). The search strategy, study inclusion and exclusion criteria, primary and secondary outcomes, and statistical analyses were defined a priori and described below.

Literature search

Systematic searches of bibliographic databases (Cochrane Library, Ovid Embase, Google Scholar, Ovid Medline All, PubMed, Scopus, and Web of Science Core Collection) from inception until June 3, 2024. Databases were searched using a combination of controlled vocabulary and free-text terms for IBD, PSC, and vancomycin. The search was not limited by language, publication type, or year (full search strategies available in Supplemental Table 2). The search was peer-reviewed by a second medical librarian using the Peer Review of Electronic Search Strategies (PRESS).²⁷ Forward and backward citation chasing was performed using Citation Chaser using selected included studies.²⁸

Selection of articles

We included randomized controlled trials, observational studies, case–control studies, and case series/reports that met the following inclusion criteria: (1) Patients: all patients with PSC and IBD (adult and pediatric); (2) Intervention: treatment with oral vancomycin; and (3) studies reported on IBD clinical response (defined as any improvement in IBD-related clinical symptoms) to OVT. We excluded studies with the following: (1) cohorts that did not have PSC-IBD patients or were not treated with oral vancomycin; (2) Studies that investigated the use of oral vancomycin for PSC only and (3) Studies that did not report on IBD clinical response to oral vancomycin. Search results from all databases were imported into an Endnote 21 library (Clarivate Analytics Company, Berkley, CA). Duplicates were removed using the Yale Reference Deduplicator.²⁹ The deduplicated results were then imported into Covidence, a systematic review software for screening and data extraction (Covidence, Melbourne, Australia). Two reviewers (W.S. and M.A.) independently screened article titles and abstracts for selection. Disagreement regarding study selection was resolved by a third member (senior author B.A). Each eligible article was reviewed in full once unrelated articles were excluded.

Outcomes

The primary IBD outcome was clinical response (defined as any improvement in IBD-related clinical symptoms). Secondary outcomes included the following: clinical remission (resolution of all IBD-related clinical symptoms), biochemical remission (defined as either C-reactive protein (CRP) <5 mg/dL or fecal calprotectin (FCP) <250 μg/g), endoscopic remission (defined as the absence of erosions or ulcers on endoscopy; Mayo score 0–1, SES-CD < 4). Safety outcomes included the following: risk of infection, acute cholangitis, development of cirrhosis, liver decompensation (ascites, encephalopathy, variceal bleeding), need for liver transplantation, cholangiocarcinoma, and development of vancomycin-resistant enterococci (VRE).

Data extraction and analysis

Data were abstracted by two investigators (W.S. and M.A.) into an Excel spreadsheet (Microsoft Corp, Redmond, Washington). The following information was abstracted from each study: (1) Study characteristics: primary author, period of study including the period of recruitment and follow-up evaluation, year of publication, country of origin, study design; (2) Patient characteristics: age, sex, smoking status, IBD disease characteristics (phenotype, duration, disease localization, and history of intestinal surgery), concomitant medications (corticosteroids, mesalamine, immunomodulators, advanced therapies), previous advanced therapies, PSC phenotype (small duct, large duct); transplant status (pre or post); (3) Exposure characteristics to vancomycin: vancomycin daily dosage, vancomycin duration of therapy, and indefinite maintenance on vancomycin. Differences between the two abstracting investigators were settled by reviewing the article together and seeking independent input from a third investigator (B.A.). Data were pooled from individual case reports and series. Outcomes were reported as frequencies and percentages.

Risk of bias in individual studies

The risk of bias for case–control studies was assessed by the two abstracting investigators independently, using the tool for evaluating the methodological quality of case reports and case series described by Murad et al. for series that included ⩽10 patients.³⁰ The tool considers four domains (selection, ascertainment, causality, and reporting). If all of the domains were satisfied, the study would be classified as “low bias risk”; if three of the domains were satisfied, the study would be classified as “intermediate bias risk”; and if only 2 or 1 of the domains were satisfied, the study would be classified as “high bias risk.” The risk of bias for cohort studies (>10 patients) was assessed using the Newcastle–Ottawa Scale (NOS).³¹ The NOS assigns up to a maximum of 9 points for the least risk of bias in three domains: selection of study groups (4 points), comparability of study groups (2 points), and ascertainment of outcomes (3 points). The quality of studies was determined by adding points in each domain.³² Scores of 7–9, 4–6, and <4 were classified as having a low, intermediate, or high risk of bias, respectively. Discrepancies in scoring were adjudicated by a third investigator (B.A.).

Results

Literature search results

A total of 21 studies (open-label, non-controlled) involving a total of 290 patients with IBD-PSC treated with oral vancomycin were included in the analysis.^{17,20,24,33
–50} Figure 1 summarizes the results of the literature search, including the reasons for the exclusion of studies (Supplemental Table 3). Table 1 summarizes the characteristics of the 21 studies that were included in the analysis.

Figure 1.

Flow chart of the methods used for identification of studies reporting clinical response/remission to oral vancomycin in inflammatory bowel disease associated with primary sclerosing cholangitis. The flow chart is designed in accordance with the PRISMA.

Table 1.

Characteristics of included studies reporting clinical response/remission to oral vancomycin in inflammatory bowel disease associated with primary sclerosing cholangitis.

Study	Study design	IBD-PSC patients (n)	Mean/median age (years)	Study population	Male (n)	Disease location	Post-liver transplant (n)	Mean/median follow-up time (months)	Mean/median vancomycin duration (weeks)
Ahmed et al. (2023)³³	Case report	1	30	Adult	0	Colon	1	3	12
Ali et al. (2020)²⁰	Case report	1	51	Adult	1	Colon	1	3	12
Almomen et al. (2023)³⁴	Case report	1	34	Adult	1	Colon	1	6	24
Balouch et al. (2023)³⁵	Retrospective Case series	29	11	Pediatric	18	Colon	NR	24	24
Buness et al. (2021)³⁶	Case report	1	15	Pediatric	0	Colon	0	96	384
Cox et al. (1998)³⁷	Retrospective Case series	3	14.3	Pediatric	2	Colon Ileocolonic	0	16.7	14
Damman et al. (2018)³⁸	Retrospective Case series	59	13.5	Adult and Pediatric	38	NR	NR	180	139
Dao et al. (2019)³⁹	Retrospective Case series	8	38	Adult	1	Colon	6	21	8
de Chambrun et al. (2018)²⁴	Retrospective Case series	3	37.7	Adult	2	Colon	0	28.5	114
Gomez et al. (2022)⁴⁰	Case report	1	28	Adult	1	Colon	NR	6	24
Kaya et al. (2023)⁵¹	Retrospective case series	4	32.3	Adult	1	Colon Ilecolonic J-Pouch	1	8	28
Higley et al. (2020)⁴¹	Retrospective Case series	9	39	Adult	NR	NR	NR	NR	40
Lev-Tzion et al. (2015)⁴²	Case report	2	1.5	Pediatric	1	Colon	NR	7	NR
Martin et al. (2023)⁴⁸	Case report	1	13	Pediatric	NR	NR	0	91	52
Quraishi et al. (2023)⁵⁰	Prospective Cohort	15	33	Adult	11	Colon	NR	NR	4
Rahman et al. (2021)⁴³	Case report	1	51	Adult	1	Colon	1	10	40
Ricciuto et al. (2024)⁵²	Multicenter Retrospective Cohort	113	12.7	Pediatric	71	Colon	12	12	125
Shah et al. (2022)⁴⁴	Retrospective Case series	7	42.9	Adult	5	Colon	4	6	128
Shen et al. (2021)⁴⁵	Case report	1	48	Adult	1	J-Pouch	NR	48	52
Tan et al. (2019)⁴⁶	Retrospective Case series	17	11.2	Pediatric	11	Colon	2	NR	32.5
Tsay et al. (2019)	Retrospective Case series	13	13.9	Pediatric	3	Colon	NR	22	NR

IBD, inflammatory bowel disease; NR, not reported; PSC, primary sclerosing cholangitis.

Baseline characteristics of study participants

The median age of the 290 patients was 30 years (interquartile range (IQR) 13.5–38 years), and 169 (58.3%) were male. Pediatric patients made up 77.2% (n = 224) of the study population while 22.8% (n = 66) were adults. The majority of patients had PSC-UC (46.2%, n = 143), followed by PSC-Crohn’s in 13.1% (n = 38), IBD-U in 4.0% (n = 13), and PSC-pouchitis in 0.7% (n = 2). PSC-IBD phenotype was not identified in 36.0% (n = 103). The median duration of IBD disease was 15.0 years (interquartile range (IQR): 2.5–15 years). A total of 29 patients (10.0%) were post-liver transplantation at the time of initiating OVT. Five studies explicitly reported negative Clostridioides difficile (C. diff) testing before starting oral vancomycin.^{20,24,34,37,51} The rest of the included studies did not report on C. diff testing. The total daily dose of oral vancomycin used ranged from 250 to 1500 mg. Three studies reported dosages per kilogram ranging from 35 to 50 mg/kg involving 89 participants.^35,36,38 The median duration of follow-up post-initiating vancomycin therapy was 14.4 months (IQR: 6.3–27.4 months).

Previous and concurrent medical therapy to treat IBD-PSC

A total of 74 patients (25.5%) had been previously exposed to advanced therapy to treat IBD-PSC prior to starting OVT. A total of 113 patients (38.9%) were reported to be on concomitant treatment with oral vancomycin. Concomitant treatment included the following: oral mesalamine in 14.5% (n = 42), steroids in 6.9% (n = 20), advanced therapies in 10.4% (n = 30), and immunosuppressive agents in 14.1% (n = 41). The median duration of OVT to treat IBD-PSC was 32.5 weeks (IQR: 19–83 weeks). While OVT was maintained indefinitely in 5.9% of the patients (n = 17).

Primary IBD clinical and objective effectiveness outcomes

Clinical response was noted in 47.6% (138/290) of IBD-PSC patients treated with OVT. Clinical remission was reported in 43.5% (100/230) and steroid-free clinical remission was reported in 58.3% (28/48). Data regarding biochemical remission was available for 80 patients. The rate of biochemical remission post-OVT was 68.8% (55/80). Data regarding endoscopic remission were available on 203 patients. The rate of endoscopic remission post-OVT was 39.4% (80/203) in IBD-PSC patients.

IBD effectiveness outcomes in pediatric versus adult populations

Outcomes restricted to pediatric IBD-PSC patients were reported by eight studies (n = 179) while one study combined both adult and pediatric outcomes.^{35
–38,42,46
–49,52} Restricting the analysis to the eight studies that reported on pediatric outcomes post-OVT, the rate of clinical response was 51.9% (93/179) and clinical remission was 64.2% (76/148). Biochemical remission in the pediatric population was only reported in five studies (n = 50) with a rate of 64.0% (n = 32).^{35,36,42,46,48} A total of four studies (n = 160) reported the rates of endoscopic remission.^35,36,46,49 The pooled rate of endoscopic remission of IBD-PSC in pediatric patients post-OVT was 24.4% (39/160).

A total of 12 studies (n = 52) reported on IBD-PSC outcomes in adult patients.^{20,24,33,34,39
–41,43
–45,50}. IBD-PSC clinical response rate post-OVT in adults was 84.6% (44/52). Clinical remission rate data was available in 16 patients all of whom were reported to be in clinical remission post-OVT.^{20,24,33,34,39,45}

Safety outcomes

Data regarding the improvement/normalization of liver enzymes was available on 83 patients, of which 39.8% (n = 33) had improvement/normalization of alkaline phosphatase. In terms of safety, four studies (20 patients in total) reported no episodes of acute cholangitis while on OVT.^36,37,41,44 Five studies (n = 69) reported an incidence rate of VRE post-OVT in 8.7% (n = 6) of IBD-PSC.^{35,43,44,46,50} Data regarding the need for liver transplant were available in 5 studies (n = 197) and only 13 patients (6.6%) needed liver transplantation after starting OVT.^{38,40,44,46,49}

Risk of bias assessment

Overall, the majority of studies had a low or intermediate risk of bias. Of the 15 studies assessed using the Murad methodologic bias assessment tool, 13 had a low risk of bias, 1 had an intermediate risk, and 1 had a high risk of bias (Supplemental Table 4). Of the six studies assessed using the Newcastle–Ottawa scale for cohort studies, one had a low risk of bias and five had an intermediate risk of bias (Supplemental Table 5).

Discussion

IBD-PSC is a distinct phenotype as compared to UC and CD without PSC posing unique management challenges. In this systematic review and pooled analysis, we have found that OVT resulted in clinical response in 47.6% of patients and improvement in objective parameters such as CRP in up to two-thirds of patients. In terms of safety, no increase in acute cholangitis was reported in the reviewed studies and VRE was reported in 8%. Therefore, OVT seems to be a viable consideration for IBD-PSC patients who particularly fail to respond to conventional or advanced therapies.

Oral vancomycin is a bactericidal, poorly absorbed oral antibiotic that has activity against gram-positive bacteria. It is still unclear how oral vancomycin exerts its beneficial effects on IBD-associated PSC. It is hypothesized that it might be partly mediated by microbiome changes and or alterations in bile acid metabolism. IBD-PSC is associated with microbiome dysbiosis associated with decreased diversity and is distinct from IBD without PSC.^13,14 In a pilot study of IBD-PSC patients, oral vancomycin resulted in potent inhibition of secondary bile acid production such as deoxycholic acid and was associated with alterations in the microbiome with a decrease in the abundance of Bacteroides.⁵³ It is also suspected that OVT exerts its effects through its immunomodulatory effects as it has been shown to affect tumor necrosis factor-alpha, transforming growth factor beta (TGF-β), and increase regulatory T cells along with influencing gut microbiota.¹⁵ In a pilot study of 14 patients with IBD-PSC, oral vancomycin was associated with a decrease in white blood cell count (driven mainly by a decrease in neutrophils), elevation in TGF-β (which plays a role in the function of regulatory T cells), and a twofold increase in regulatory T-cell frequencies.

The first case series investigating oral vancomycin in IBD-PSC was reported by Cox et al. in 1998 in three pediatric patients.³⁷ Those patients had improvement in biochemical liver function tests as well as IBD clinical response. Our review has shown that both clinical and objective measures of inflammation improved after starting OVT to treat IBD-PSC. In those patients who had CRP or FCP performed after vancomycin, up to two-thirds of patients had improvement. In addition, endoscopic remission was achieved in up to 40% of patients. It is also important to note that up to 25% of the patients included in the pooled analysis had been exposed to advanced therapies which typically reflects a difficult-to-treat phenotype. Despite this, clinical remission was still achieved in about 43.5%.

In terms of safety, our review did not reveal any increased incidence of acute cholangitis or progression of liver disease. Improvement in liver enzymes was noted across studies that reported the status of liver enzymes pre- and post-vancomycin therapy. This is in line with previously published studies examining the utility of vancomycin for the treatment of PSC. The data on the efficacy and safety of vancomycin to treat PSC remain limited. In two small pilot trials, vancomycin showed promising results in improving alkaline phosphatase and Mayo Risk Scores without demonstrating any safety signals.^16,19 However, the impact of depleting vancomycin-sensitive microbiota with OVT in PSC is unclear. Awoniyi et al. identified resident microbiome associated with protective and detrimental effects on PSC progression via antibiotic-induced dysbiosis in a murine model.⁵⁴ It was demonstrated that vancomycin led to exacerbation of hepatic fibrogenesis and mortality. This is thought to be secondary to the depletion of potentially protective Lachnospiraceae species with augmenting intestinal pathobionts like Enterobacteriaceae and Enterococcus species. A concern for the development of VRE with long-term use of OVT exists particularly due to the risk of acute cholangitis in these patients. There was limited data regarding the incidence of VRE post-OVT in our review as only five studies (n = 69) reported the development of VRE in six patients. Due to the limitations of the current published data and the potential for antibiotic resistance, the American Association for the Study of Liver Diseases (AASLD) guidelines for PSC have made a statement highlighting that there is insufficient evidence to recommend the use of oral vancomycin for PSC itself.⁵⁵

Strengths and limitations

The strength of our study is the inclusion of a diverse body of cases including adult and pediatric populations. We specifically looked at the effect of OVT on IBD in patients with PSC. Most prior reviews looked at the effect of OVT mainly on PSC and not IBD. There are multiple limitations to our review. For one, many of the included studies lacked long-term follow-up which limits the assessment of safety. Furthermore, the limited reporting of C. diff status in the included studies highlights the need for future research to explicitly account for and report C. diff testing to better understand the specific efficacy of oral vancomycin in PSC-IBD independent of C. diff-related effects. In addition, all the studies included were limited by small sample size as they were either small cohorts or case series/reports as no randomized prospective data have been published on the utility of OVT for the treatment of IBD associated with PSC. Another limitation is that favorable outcomes are more likely to be published in case series/reports which could lead to a publication bias. It is important to emphasize that the studies included in the review were non-controlled and lacked a comparator group except for the study by Ricciuto et al. which matched the oral vancomycin treated with an untreated IBD-PSC group. This highlights the need for an adequately powered randomized control trial to investigate the utility and safety of OVT for the treatment of IBD-PSC. OVT appropriate dose, duration of therapy, and long-term safety for the treatment of IBD-PSC need to be further investigated.

Conclusion

Our study shows the potential benefit of OVT in treating IBD associated with PSC. Due to the poor quality of published evidence, the use of OVT for the treatment of IBD-PSC cannot be universally recommended. However, in IBD-PSC cases refractory to conventional and advanced therapies, consideration can be made to utilize OVT after informed consent of off-label use. Further study of OVT and its relation to the microbiome profile, IBD response, and PSC safety in patients with IBD-PSC should be investigated. There are currently multiple clinical trials being conducted to investigate OVT for the treatment of PSC and associated IBD and the results are highly anticipated (NCT03710122, NCT05376228).

Supplemental Material

sj-docx-1-tag-10.1177_17562848241312766 – Supplemental material for Effectiveness and safety of oral vancomycin for the treatment of inflammatory bowel disease associated with primary sclerosing cholangitis: a systematic review and pooled analysis

Supplemental material, sj-docx-1-tag-10.1177_17562848241312766 for Effectiveness and safety of oral vancomycin for the treatment of inflammatory bowel disease associated with primary sclerosing cholangitis: a systematic review and pooled analysis by Wassel Sannaa, Mazen Almasry, Mustafa Peedikayil, Alyssa A. Grimshaw, Mashary Attamimi, Abdulelah AlMutairdi and Badr Al-Bawardy in Therapeutic Advances in Gastroenterology

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Wassel Sannaa

Supplemental material

Supplemental material for this article is available online.

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