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Abstract

Background:

Vedolizumab (VDZ), a humanized monoclonal antibody that selectively inhibits the binding of the α4β7 integrin, has been approved for treating inflammatory bowel disease (IBD). Long-term safety studies of VDZ in clinical trials identified Clostridium difficile infection (CDI) as the major opportunistic infection.

Objectives:

We aimed to address the incidence and risk factors of C. difficile colonization (CDC) and CDI in a real-world setting among IBD patients treated with VDZ.

Design:

Retrospective multicenter study.

Methods:

We retrospectively included IBD patients who tested negative for C. difficile before initiating standard VDZ therapy at four tertiary hospitals from November 1, 2021, to November 31, 2023. The primary outcome was the occurrence of CDC after VDZ initiation, and the secondary outcome was the occurrence of CDI and severe CDI.

Results:

A total of 454 patients were included in the final analysis. The median follow-up time was 12.9 (8.2–16.3) months, and the study was followed for 2488.6 person-months. The CDC occurred in 28 patients (6.2%), including 23 (11.4%) patients with ulcerative colitis (UC; 18 asymptomatic carriers and 5 with symptomatic CDI) and 5 (2.0%) patients with Crohn’s disease (asymptomatic carriers). Multivariate analysis showed that age >40 years old and UC were independent risk factors for the occurrence of the CDC after VDZ initiation. The incidence of CDI was 1.1%, and all patients were able to continue VDZ therapy after receiving antibiotic treatment. No risk factors were found to be significantly associated with CDI. There were no cases of severe CDI or deaths within 30 days.

Conclusion:

The incidence of CDC after VDZ treatment was 6.2% and the majority of patients identified as asymptomatic carriers and were able to continue VDZ treatment. Age (>40 years old) and UC were the risk factors for CDC.

Plain language summary

Risk factors and clinical characteristics of Clostridium difficile colonization and infection in patients with inflammatory bowel disease exposed to Vedolizumab: a multi-center, retrospective study

In this real-world study, the incidence of Clostridium Difficile colonization during the follow-up period is 6.2%. Most of the patients with positive C. difficile were asymptomatic and were able to continue VDZ treatment. UC and age (> 40 years) were risk factors of Clostridium Difficile colonization after initiating VDZ. The incidence of CDI in patients with IBD treated with VDZ was be 1.1%. Our results provided valuable insights into the frequency of Clostridium Difficile colonization and infection in patients receiving VDZ, particularly in UC patients over 40 years old. This data may assist clinicians in making treatment decisions in real-world clinical practice.

Keywords

Crohn’s disease ulcerative colitis Vedolizumab

Introduction

Inflammatory bowel disease (IBD) is a chronic, progressive inflammatory disorder that includes Crohn’s disease (CD) and ulcerative colitis (UC).¹ Although the pathogenesis and treatment of IBD have long been explored, in the last 20 years only, biologics have significantly changed the treatment strategy. Effective biologics currently approved for treating CD and UC include anti-tumor necrosis factor (anti-TNF), interleukin-12 and interleukin-23 inhibitors, and anti-integrin antibodies.^2,3 However, an increased risk of opportunistic infection is a potential concern with biologic therapy.³

Clostridium difficile infection (CDI) is the leading cause of healthcare-associated infection.⁴ Patients with IBD are at increased risk of developing CDI, which can have detrimental clinical effects.^5,6 A study conducted in the United States on CDI prevalence in patients with IBD revealed a fold of CDI rates among hospitalized IBD patients compared to the outpatient setting, particularly in those with UC.⁷ CDI infection has been associated with increased surgical rates, clinical relapses, treatment failure, and hospitalization in patients with IBD.⁸ The use of biologics appears to be a risk factor associated with CDI among IBD patients.⁹

Vedolizumab (VDZ) is a humanized monoclonal antibody that selectively inhibits the binding of the α4β7 integrin with the mucosal addressin cell adhesion molecule-1. This action prevents memory T cells from migrating through the endothelium into inflamed gastrointestinal tissue.^10,11 Due to its gut-selective nature, VDZ is expected to have a lower risk of infections compared to other biologic medications.¹² However, clinical trials have shown that the rate of CDI was higher after initiating VDZ compared to the placebo, at approximately 0.3/100 patient year (95%CI 0.2–0.5).¹³ Real-world safety data from the VICTORY Consortium reported CDI rates of 4.4% in the CD cohort and 1.6% in the UC cohort.¹⁴ Long-term safety studies of VDZ in clinical trials identified CDI as the major opportunistic infection.¹⁵ Current infection control recommendations proposed treatment for patients with CDI.^16,17 A practical guide recommends temporarily discontinuing VDZ during C. difficile treatment and resuming therapy after C. difficile resolution.¹⁸ However, asymptomatic carriers may also contribute to the spread of pathogens.¹⁹ C. difficile colonization (CDC), which includes both symptomatic CDI and asymptomatic carriers, may impact the management of IBD.

So far, real-world data focusing on the characteristics and clinical risk of CDC and CDI with VDZ therapy has been scarcely reported. In this study, we aim to address this by reporting the incidence of CDC and CDI in IBD patients treated with VDZ using multi-center clinical data in China. Meanwhile, we also assess the characteristics and risk factors associated with CDC and CDI.

Materials and methods

Study design and population

This retrospective study was conducted synchronously at four tertiary hospitals (The Sixth Affiliated Hospital of Sun Yet Sen University, Chongqing General Hospital, The First People’s Hospital of Foshan, and The First Affiliated Hospital of Guangxi Medical University) between November 1, 2021, and November 31, 2023. The diagnosis of IBD was made according to the current guidelines, which are based on a combination of clinical, endoscopic, radiologic, and histological investigations.^20,21 The inclusion criteria for the study were IBD patients who tested negative for C. difficile before initiating VDZ therapy. The exclusion criteria included patients with incomplete data, discontinuation of VDZ therapy within 14 weeks due to insufficient efficacy, and discontinuation of VDZ therapy within 14 weeks for reasons other than CDI.

All patients received standardized VDZ therapy. VDZ was administered intravenously 300 mg at weeks 0, 2, and 6 for induction, and then every 8 weeks for maintenance. C. difficile was routinely detected within 2 weeks before and at 14–26 and 48–54 weeks after initiating VDZ therapy or suspected CDI with concomitant symptoms of colitis, such as diarrhea, increased stool frequency, rectal bleeding, etc. All tests were performed with appropriate patient consent. The use of concomitant drugs such as steroids and mesalazine was at the discretion of the physician. Follow-up data were collected until January 2024. This study followed STROBE reporting guidelines.²²

Data collection

Demographic and clinical variables were collected for all patients. Demographic variables included age according to the Montreal Classification, gender, disease duration, and follow-up time, among others. Clinical factors included previous anti-TNF therapy, steroid use, disease activity, symptoms, etc. The study also recorded the incidence of CDI, time-to-CDI, symptoms related to CDI, endoscopic findings of CDI, antibiotic use, and anti-infection outcomes. For UC, clinical remission was defined as a Mayo score of 2 or lower with no subscore >1; mild UC was defined as a Mayo score of 3–5; moderate UC was defined as a Mayo score of 6–10; and severe UC was defined as a Mayo score of 11 and 12.²³ For CD, disease severity was classified based on the Harvey-Bradshaw index (HBI) score as at remission (HBI ⩽4), mild (HBI 5–7), mild (HBI 8–16), or severe (HBI ⩾16).²⁴ Endoscopic activity was assessed using the Mayo endoscopic score for UC and the simple endoscopic score for CD (SES-CD).^23,25 Time-to-CDI was defined as the time interval between the first VDZ therapy and the first positive infection. The selection of antibiotics, antibiotic dosing, and duration of therapy were based on the clinical discretion of the managing physician.

Outcome measures

The primary outcome was the occurrence of CDC after VDZ initiation. The C. difficile positivity rate represented both those with CDI and those with colonization which were asymptomatic C. difficile carriage.²⁶ The secondary outcome was the occurrence of CDI and severe CDI. CDI is characterized by symptoms, typically diarrhea, along with one of the following: a positive stool test for C. difficile toxin, detection of toxigenic C. difficile, or colonoscopic or histopathological evidence of pseudomembranous colitis.²⁷ A severe CDI was identified with white blood cells >15,000 or serum creatinine >1.5 mg/dL, drug withdrawal for any reason, colectomy, and death within 30 days after CDI diagnosis.²⁸ The clinical characteristics of patients with CDI were collected at the time of CDI diagnosis and during follow-up.

Statistical methods

Continuous parameters were presented as mean ± standard error (S.D.E) or median with interquartile range (IQR) depending on normality, while categorical parameters were presented as percentages. Univariate logistic regression analysis was carried out first, followed by multivariate logistic regression model analysis, and variables with p < 0.05 single-factor analysis were included. All analyses were conducted using SPSS 27.0 (SPSS, Chicago, IL, USA). The significance level was set to a p value <0.05.

Results

Clinical characteristics of the patients

A total of 454 patients who met the inclusion criteria were included in the final analyses. Among them, 202 (44.5%) were UC patients, and 252 (55.5%) were CD patients. The median age of the patients was 35 years (IQR: 26–46), and 59.9% of the patients were male. The median disease duration at the time of initiating VDZ treatment was 48 months (IQR: 23–96). The characteristics of the study population are presented in Table 1.

Table 1.

Baseline characteristics of the patients.

Characteristics	UC (n = 202)	CD (n = 252)	Total (n = 454)
Gender, male, n (%)	119 (58.9)	153 (60.7)	272 (59.9)
Age, years (IQR)	39 (27–51)	33 (25–41)	35 (26–46)
Disease duration, month (IQR)	39 (18–84)	59 (24–102)	48 (23–96)
Disease activity, n (%)
Remission	14 (6.9)	130 (51.6)	144 (31.7)
Mild	32 (15.8)	41 (16.3)	73 (16.1)
Moderate	104 (51.5)	65 (25.8)	169 (37.2)
Severe	52 (25.7)	16 (6.3)	68 (15.0)
Previous medication, n (%)
Corticosteroid	79 (39.1)	110 (43.7)	189 (41.6)
Anti-TNF	47 (23.3)	129 (51.2)	176 (38.8)
Follow-up time, month (IQR)	11.0 (4.8–15.2)	14.6 (10.2–16.7)	12.9 (8.2–16.3)

Anti-TNF, anti-tumor necrosis factor; CD, Crohn’s disease; UC, ulcerative colitis.

The incidence of CDC and infection

The median follow-up time was 12.9 months (8.2–16.3). The study was conducted over a period of 2488.6 person-months. Twenty-eight patients (6.2%) were positive for C. difficile, including 23 (11.4%) UC patients (18 asymptomatic carriers and 5 with CDI) and 5 (2.0%) CD patients (asymptomatic carriers). The incidence of CDC during the follow-up period is presented in Table 2. The incidence of CDI in IBD patients treated with VDZ was 1.1% (5/454). All five patients who developed CDI were UC patients with an active status (3 male and 2 female; median age: 42). The median time-to-CDI was 7 months (IQR: 5.5–9). Diarrhea and bloody stool symptoms were observed in CDI patients. The C. difficile turned negative in all five patients who were treated with antibiotics (metronidazole and vancomycin) for 14 days. These patients continue to receive VDZ therapy. No recurrence of CDI-related symptoms was recorded during the follow-up.

Table 2.

The incidence rate of positive C. difficile results after the start of VDZ treatment.

Characteristics	UC (n = 202)	CD (n = 252)	Total (n = 454)
Incidence rate, n (%)	23 (11.4)	5 (2.0)	28 (6.2)
Time-to-positive C. difficile, month (IQR)	13.5 (6.9–16.1)	10.4 (8.4–12.5)	12.9 (8.2–16.3)
Incidence rate of different ages, n (%)
⩽16	0 (0)	0 (0)	0(0)
17–40	10 (5.0)	1 (0.4)	11 (2.4)
>40	13 (6.4)	4 (1.6)	17 (3.7)
Incidence rate of different disease activities, n (%)
Remission	0 (0)	4 (1.6)	4 (0.9)
Mild	7 (3.5)	0 (0)	7 (1.5)
Moderate	9 (4.5)	0 (0)	9 (2.0)
Severe	7 (3.5)	1 (0.4)	8 (1.9)
Symptoms, n (%)
Abdominal pain	0 (0)	0 (0)	0 (0)
Diarrhea	3 (13.0)	0 (0)	3 (10.7)
Bloody stool	2 (8.7)	0 (0)	2 (7.1)
Fever	0 (0)	0 (0)	0 (0)
Asymptomatic	18 (78.3)	5 (100)	23 (82.1)
Endoscopic findings (Mayo score), n (%)
0	3 (23.1)	N/A	3 (23.1)
1	2 (15.4)	N/A	2 (15.4)
2	5 (38.5)	N/A	5 (38.5)
3	3 (23.1)	N/A	3 (23.1)
Endoscopic findings (SES-CD score), n (%)
0	N/A	1 (33.3)	1 (33.3)
3	N/A	2 (66.6)	2 (66.6)
VDZ status, n (%)
Yes	20 (87.0)	4 (80.0)	24 (85.7)
Withdrawal due to positive results	0 (0)	0 (0)	0 (0)
Withdrawal due to poor efficacy	3 (13.0)	1 (20.0)	4 (14.3)
Anti-infection treatment, n (%)	8 (34.8)	3 (60.0)	11 (39.3)
Anti-infection medications, n (%)
Metronidazole	2 (25.0)	1 (33.3)	3 (27.3)
Vancomycin	6 (75.0)	2 (66.7)	8 (72.7)
Anti-infection outcomes, negative conversion rate, n (%)
Negative	7 (87.5)	3 (100)	10 (90.1)
Positive	1 (12.5)	0 (0)	1 (9.1)

CD, Crohn’s disease; UC, ulcerative colitis; VDZ, Vedolizumab.

Clinical characteristics of C. difficile carriers

When patients were divided into different groups, those who were older than 40 years at the start of VDZ treatment had the highest incidence of CDC (17/454, 3.7%). This trend was consistent across subgroups, with rates of 6.4% (13/202) in UC patients and 1.4% (4/252) in CD patients. The rate was 2.4% (11/454, 10 with UC, 1 with CD) in patients aged 17–40 years old. None IBD patients under 16 years old developed CDC.

We also divided patients into remission groups and active groups. Out of the 130 CD patients with a remission status, only 4 (3.1%) experienced CDC after starting treatment. None of the 14 UC patients with a remission status acquired CDC. The proportion of IBD patients with an active status who acquired CDC was 7.7% (24 of 310 patients). The majority of these patients were UC (12.2%, 23 out of 188). Only one CD patient (0.8%, 1 out of 122) with an active status acquired CDC.

In patients with UC, a majority of patients (78.3%, 18/23) with C. difficile were asymptomatic. All five CD patients with positive C. difficile were asymptomatic. Among the 16 patients who underwent a follow-up colonoscopy, 6 patients (37.5%) achieved mucosal healing despite testing positive for C. difficile. Among these patients, the majority (85.1%, 24/28) continue to receive VDZ therapy, without experiencing relapse during the follow-up. Two out of 23 UC patients and one out of five CD patients had to discontinue VDZ therapy due to poor efficacy. There were no cases of VDZ treatment discontinuation due to infection. A total of 11 patients (6 asymptomatic carriers and 5 with CDI) who tested positive for C. difficile were treated with antibiotics (metronidazole and vancomycin) after a shared decision-making between the doctors and patients for 14 days. The C. difficile turned negative in 10 patients (90.1%, 10/11), including 7 UC patients (87.5%, 7/8) and 3 CD patients. The patient with positive C. difficile continued to receive VDZ therapy and no adverse events were observed in this patient. The remaining 17 patients received only medical follow-up and did not receive treatment due to the absence of CDI-related symptoms. Baseline characteristics of C. difficile carriers and C. difficile noncarriers are presented in Supplemental Table 1.

Risk factors of CDC in patients with IBD

The results of the univariate and multivariate analyses are presented in Table 3. The univariate analysis revealed that age (A3) (OR = 3.368 (1.535–7.387); p = 0.002), CD (OR = 0.121 (0.032–0.449); p = 0.002), and concomitant steroid use (OR = 5.588 (1.535–20.339); p = 0.009) were associated with CDC. The multivariate analysis demonstrated that the age (A3) and UC type of IBD were independent risk factors for the occurrence of CDC after VDZ initiation.

Table 3.

Risk factors for positive C. difficile results among IBD patients who received Vedolizumab treatment.

Variables	Univariate analysis	p Value	Multivariate analysis	p Value
Variables	Odds ratio (95%CI)	p Value	HR (95%CI)	p Value
Gender (female)	1.180 (0.396–3.517)	0.767
Age (A3)	3.368 (1.535–7.387)	0.002	10.253 (2.022–52.003)	0.005
IBD types (CD)	0.121 (0.032–0.449)	0.002	0.081(0.021–0.315)	<0.001
Disease activity
Remission	Reference
Mild	3.029 (0.610–15.043)	0.175
Moderate	3.807 (0.950–15.261)	0.059
Severe	3.025 (0.314–29.108)	0.338
Prior medication use
Steroids (yes)	1.785 (0.584–5.459)	0.310
Anti-TNF use (yes)	0.430 (0.132–1.397)	0.160
Concomitant corticosteroid	5.588 (1.535–20.339)	0.009	1.281 (0.331–4.962)	0.720

CD, Crohn’s disease; CI, confidence interval; IBD, inflammatory bowel disease.

Clinical characteristics and risk factors of CDI

No risk factors were found to be significantly associated with CDI. The results of the univariate and multivariate analysis are presented in Supplemental Table 2. There were no cases of severe CDI or deaths within 30 days among the patients.

Discussion

In this retrospective multicenter study conducted in the Chinese population, we investigated the incidence of CDC and CDI following VDZ therapy in a real-world setting. Our finding revealed that after VDZ therapy, the incidence of CDC during the follow-up period is 6.2%. The incidence of CDI in IBD patients was 1.1%. It is worth mentioning that in this study most patients who acquired the CDC were asymptomatic and were able to continue VDZ treatment. We also identified UC and age (A3) as risk factors for CDC following the initiation of VDZ.

The influence of CDC and CDI on the prognosis of patients with IBD is significant, and whether to discontinue VDZ in such cases is a major concern in clinical practice. Based on clinical trial and post-marketing surveillance data, CDI was the most commonly reported infection, with an incidence rate of 0.7 per 100 patient-years (GEMINI 1 and 2 clinical trials) and 1.0 (long-term safety study) per 100 patient-years.¹² In the VICTORY Consortium, CDI occurred in 3.3% of treated patients (5 cases per 100 patient years). A systematic review of safety data from post-marketing open-label studies found a CDI rate of 1.2% (13/1049).¹⁴ The incidence of CDI was 3.1 per 1000 patient-years (95%CI 2.1–4.5) derived from the Health Core Integrated Research Database data.²⁹ In this cohort, the incidence of CDI was 1.1% (5/454) in UC and CD patients. Although patients in our cohort had a younger age (median: 35 years vs 39 years) and a lower use of steroids (39.1% vs 53%) compared to the phase III safety population, the CDI incidence rate was similar to the incidence rates reported in the published studies.^12,14,29,30 These patients were not difficult to treat and received anti-infective treatment with Metronidazole/vancomycin. Therefore, it should be noted that clinicians should evaluate whether CDC or CDI affects the efficacy of VDZ instead of blindly discontinuing its use.

Interestingly, in the current study, CD patients, who received the same therapy with VDZ, did not develop CDI. This may be attributed, in part, to the presence of colonic disease among CD patients, which has been previously established as a reliable indicator of CDI in the IBD population according to Issa et al.³¹ Our multivariate analysis demonstrated that CD was an independent protective factor against the occurrence of CDI following VDZ initiation, further supporting the findings of the previous study. Previous data also indicate that children with IBD are less likely to develop CDI during VDZ treatment.⁷ In addition, clinical research conducted among pediatric IBD patients has shown that they do not have an increased risk of CDI during VDZ treatment.¹² In our study, patients younger than 16 years old did not experience CDI after initiating VDZ. It is worth noting that advanced age is a known risk factor for infections. However, previous studies have indicated that, when considering comorbidity and disease activity in IBD, the risk of infection during VDZ treatment is similar between younger and older patients.¹³ Age-stratified analyses had limited statistical power due to the rarity of CDI events.

Our study investigated the incidence of CDC and CDI after VDZ treatment and provided insights into the clinical characteristics of patients with CDC and CDI, contributing valuable data for clinical practice. However, it is important to acknowledge the limitations of this study. Due to the retrospective nature, information bias and selection bias may exist. Information bias could stem from incomplete or inaccurate records, while selection bias may arise if the sample does not fully represent the broader population, impacting the generalizability of the findings. Therefore, the findings should be validated in a larger sample size. In addition, the follow-up period was relatively short, limiting the availability of long-term data on the risk of CDI.

Conclusion

In this real-world study, the incidence of CDC after VDZ treatment was 6.2% and the majority of patients identified as asymptomatic carriers and were able to continue VDZ treatment. Age (>40 years old) and UC were the risk factors for CDC. The incidence of CDI in patients with IBD treated with VDZ was found to be 1.1%. No risk factors were found to be significantly associated with CDI. Our results provided valuable insights into the frequency of CDC and CDI in patients receiving VDZ, particularly in UC patients over 40 years old. The data may assist clinicians in making informed treatment decisions in real-world clinical practice.

Supplemental Material

sj-docx-1-tag-10.1177_17562848251321707 – Supplemental material for Risk factors and clinical characteristics of Clostridium difficile colonization and infection in patients with inflammatory bowel disease exposed to Vedolizumab: a multicenter retrospective study

Supplemental material, sj-docx-1-tag-10.1177_17562848251321707 for Risk factors and clinical characteristics of Clostridium difficile colonization and infection in patients with inflammatory bowel disease exposed to Vedolizumab: a multicenter retrospective study by Qing Li, Xiaomei Song, Peizhu Su, Xiaoping Lv, Xinyu Liu, Xuemin Chen, Jian Tang, Xiang Gao and Kang Chao in Therapeutic Advances in Gastroenterology

Footnotes

Acknowledgements

We appreciate the help during data acquisition of Hong Guo from Chongqing General Hospital, Qinyan Wu from the First People’s Hospital of Foshan and Shiquan Li from the First Affiliated Hospital of Guangxi Medical University.

Declarations

ORCID iDs

Xiang Gao

Kang Chao

Supplemental material

Supplemental material for this article is available online.

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Supplementary Material

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