Few studies have thoroughly assessed the efficacy and safety of vedolizumab (VDZ) in the treatment of inflammatory bowel disease (IBD). Therefore, this systematic review and meta-analysis was performed to further evaluate this association. PubMed, Embase, and the Cochrane databases were searched until April 2022. Randomized controlled trials (RCTs) evaluating the efficacy and safety of VDZ in the treatment of IBD were included. The risk ratio (RR) and 95% confidence intervals (CI) were estimated for each outcome using a random effects model. A total of 12 RCTs, including 4,865 patients, met the inclusion criteria. In the induction phase, VDZ was more effective than placebo for patients with ulcerative colitis and Crohn's disease (CD) in clinical remission (RR=2.09; 95% CI=1.66-2.62) and clinical response (RR=1.54; 95% CI=1.34-1.78). In the maintenance therapy group, VDZ reached higher clinical remission (RR=1.98; 95% CI=1.58-2.49) and clinical response (RR=1.78; 95% CI=1.40-2.26) rates compared with the placebo group. VDZ particularly improved clinical remission (RR=2.07; 95% CI=1.48-2.89) and clinical response (RR=1.84; 95% CI=1.54-2.21) in patients with TNF antagonist failure. In terms of corticosteroid-free remission, VDZ was also more effective than placebo in patients with IBD (RR=1.98; 95% CI=1.51-2.59). In Crohn's patients, VDZ was more effective than placebo in terms of mucosal healing (RR=1.78; 95% CI=1.27-2.51). With respect to adverse events, VDZ significantly reduced the risk of IBD exacerbation compared with the placebo (RR=0.60; 95% CI=0.39-0.93; P=0.023). However, when compared with the placebo, VDZ increased the risk of nasopharyngitis in patients with CD (RR=1.77; 95% CI=1.01-3.10; P=0.045). No significant differences in other adverse events were observed. Although there might be underlying risk, such as selection bias, in the present study it can be safely concluded that VDZ is a safe and effective biological agent for IBD, particularly for patients with TNF antagonist failure.
Inflammatory bowel disease (IBD) results from the interaction between genetic and environmental factors, which may influence immune responses. Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of IBD (
Conventional treatments for IBD include 5-aminosalicylates, corticosteroids, azathioprine, or 6-mercaptopurine. Novel anti-TNF-α biologics, such as infliximab and adalimumab, have been used as the basis for moderate-to-severe IBD treatment (
In recent years, VDZ has been approved for the treatment of moderate-to-severe active UC and CD patients with at least one conventional treatment failure. There are multiple randomized controlled trials (RCTs) on the use of VDZ for the treatment of IBD, whose findings on efficacy and adverse reactions differ. Therefore, this systematic review and meta-analysis was conducted to thoroughly evaluate the therapeutic value of VDZ for the treatment of IBD by selecting high-quality RCTs and providing an objective basis for its clinical application.
The present systematic review and meta-analysis was registered in PROSPERO (
PubMed (
The inclusion criteria were as follows: i) Adults (age, >18 years) with moderate-to-severe UC or CD (confirmed endoscopically and/or histopathologically, with a partial Mayo score of 1-12 at screening) who were either treatment-naive, previously exposed to anti-TNF agents, or had failed TNF antagonist therapy; ii) randomized, double-blinded, placebo-controlled studies to evaluate the efficacy and safety of VDZ in the treatment of IBD; iii) available studies reporting the risk estimates with their corresponding 95% confidence interval (CI) or original data allowing us to compute them; and iv) if the published studies reported data for specific subgroups, results for the whole population were considered.
The exclusion criteria were as follows: i) Not RCTs; ii) animal studies; iii) studies on children and pregnant women; iv) non-original papers; v) duplicate reports and abstracts; vi) comparison of VDZ with other biological agents; and vii) full-text or complete data were not available.
The data extracted from each study included the name of the first author, publication year, location, sample size (number of cases and total number of participants), type of IBD, categories of efficacy indicators, and types of adverse reactions. Three investigators (LLZG, LXZ, and HJT) independently extracted the data, and discrepancies were resolved by consensus.
The clinical response of CD patients was defined as CD Activity Index (CDAI)-100 response. Mucosal healing was determined using a sub-score of 0 or 1 on the Mayo endoscopic component. Adverse events included serious adverse events, such as infusion reaction and delayed hypersensitivity that led to discontinuation of the drug, headaches, nasopharyngitis, upper respiratory tract infection, arthralgia, abdominal pain, and vomiting.
The methodological quality of the included RCTs was evaluated based on the Cochrane Collaboration's risk of bias tool (
All statistical analysis was performed using STATA version 12.0 (StataCorp LLC). The results are presented as the risk ratio (RR) and 95% CI for the comparison of VDZ and placebo treatment in IBD. A random effects model was used to calculate the pooled estimates. Statistical heterogeneity between studies was examined using the I² value, and I²>50% was considered to indicate statistically significant heterogeneity (
As shown in
A total of 9 studies (
A total of 10 studies (
A total of 7 studies (
A total of 7 (
Three studies (
A total of 3 studies (
A total of 7 studies (
A total of 2 studies (
A total of 7 studies (
The safety results of VDZ compared with those of the placebo in IBD are shown in
Sensitivity analysis was conducted to evaluate the influence of a single study on the overall risk estimate by omitting one study at a time (
In the present meta-analysis, 12 high-quality published RCTs assessing IBD patients were identified by searching several English databases to review relevant articles. The results showed that VDZ was superior to placebo for the treatment of IBD during both induction and maintenance therapy, especially for patients with TNF antagonist failure. VDZ also showed significant efficacy in IBD patients with regard to corticosteroid-free remission compared with the placebo. In terms of mucosal healing, VDZ had significant effects on UC patients during both induction and maintenance therapy. It was also found that VDZ significantly reduced the risk of IBD exacerbation when compared with the placebo groups. In subgroup analysis, evidence in favor of the association was weaker among induction therapy when compared with maintenance therapy. Placebo increased the risk of exacerbation in patients treated with CD compared with those treated with VDZ. These results fully demonstrate the effectiveness of VDZ in the induction and maintenance of IBD treatment.
Adverse reactions are very common in the treatment of biological agents. The most common adverse reactions in the VDZ treatment group were headache, nasopharyngitis, upper respiratory tract infection, and arthralgia. VDZ increased the risk of nasopharyngitis in patients with CD when compared with the placebo, but these symptoms quickly improved with symptomatic treatment. Concerning the incidence of serious adverse events and the other assessed adverse reactions, there were no significant differences between VDZ and placebo. Therefore, VDZ was shown to be a relatively safe biological agent in the treatment of IBD.
IBD is a chronic inflammatory disease of the gastrointestinal tract, which consists of two major subtypes, CD and UC (
Anti-TNF-α is the first-line treatment for the management of moderate-to-severe IBD at present (
The present study had some limitations. First, although all included studies were assessed as having a low or moderate risk of bias, there was a slight heterogeneity among individual outcome indicators, which may have biased the results to a certain extent. Secondly, due to the limitation of existing studies, further subgroup analysis was not performed. For example, all included RCTs were published abroad. Although the research data from Asia (Japan) were updated and included, there was no domestic data. Furthermore, there were no RCTs evaluating the mucosal healing of UC patients following VDZ treatment. With regard to different types of VDZ administration, there were only 2 RCTs evaluating the efficacy and safety of the subcutaneous injection of VDZ in IBD patients. Dose-response analysis of VDZ treatment was also limited since a few studies reported the comparison among different dosages. In addition, research on the efficacy and safety of VDZ in the treatment of pediatric IBD remains incomplete. All included studies were conducted in adults, even though the incidence of pediatric IBD in industrialized or Western countries is increasing annually (
The present meta-analysis is an updated and expanded version of a previous meta-analysis (
This meta-analysis study also had several strengths. First, the heterogeneity between studies was low in most of the analyses. Secondly, the largest RCT studies so far were included, containing new data from Asian countries and other countries, which may provide a more comprehensive analysis of the efficacy of VDZ in the treatment of IBD patients. Thirdly, sensitivity analysis was performed to investigate the stability of the results. Finally, most of the present meta-analyses did not analyze the common adverse reactions of IBD patients treated with VDZ in specific subgroups. The data on common adverse effects were summarized, and subgroup analysis showed that placebo increased the risk of exacerbation in patients with CD when compared with VDZ.
Although the present study clarified the effective role of VDZ in the treatment of IBD patients, several questions still need to be addressed in future studies. Large domestic RCTs with long-term follow-ups are required to further compare different types of administration and different dosages of VDZ in both adult and pediatric patients.
In conclusion, this meta-analysis comprehensively evaluated the efficacy and safety of VDZ in IBD patients. It was found that VDZ is a safe and effective biological agent for IBD, particularly for patients with TNF antagonist failure.
Not applicable.
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
HT, LG, and CB designed the study. ST performed the literature search and screened the articles for relevancy. LG, LZ and HT abstracted the data. LZ and CB assessed the methodological quality of the studies. LG and HT performed the statistical analysis and drafted the manuscript. ST was responsible for revising the manuscript. HT, CB and LG confirm the authenticity of the data. All authors have read and approved the final manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing interests.
Flow diagram of the assessment of studies identified by the literature search for inclusion.
Randomized effects meta-analysis of the efficacy of vedolizumab treatment in the induction phase. (A) Clinical remission and (B) clinical response. UC, ulcerative colitis; CD, Crohn's disease; RR, risk ratio; CI, confidence interval.
Randomized effects meta-analysis of the efficacy of vedolizumab treatment in the maintenance phase. (A) Clinical remission and (B) clinical response. UC, ulcerative colitis; CD, Crohn's disease; RR, risk ratio; CI, confidence interval.
Random-effect meta-analysis of VDZ in IBD patients with a history of TNF antagonist failure. (A) Clinical remission and (B) clinical response. VDZ, vedolizumab; IBD, irritable bowel disease; RR, risk ratio; CI, confidence interval.
Detailed information on the included studies.
First author, year | Country | Diagnosis | Intervention measures and administration methods of VDZ group | No. of patients | Female (%) | Outcomes | Follow-up | (Refs.) |
---|---|---|---|---|---|---|---|---|
Feagan |
Canada | UC | Induction Phase: | Induction Phase: | 8 weeks | ( |
||
VDZ(0.5 mg/2.0 mg/kg, iv) | 118 | - | Clinical response, clinical remission | |||||
Placebo | 63 | - | Adverse events | |||||
Parikh |
USA | UC | Induction Phase: | Clinical response; clinical remission | 253 days | ( |
||
VDZ (2 mg/kg, 6 mg/kg, 10 mg/kg, iv) | 37 | 57 | ||||||
Placebo | 9 | 67 | ||||||
Feagan |
Canada | UC | Induction Phase: | Induction Phase: | 6 weeks | ( |
||
VDZ (300 mg, iv) | 225 | 41.3 | Clinical response, clinical remission | |||||
Placebo | 149 | 38.3 | ||||||
Maintenance Phase: | Maintenance Phase: | 52 weeks | ||||||
VDZ (300 mg iv, Q4/Q8W) | 247 | - | Clinical response, clinical remission | |||||
Placebo | 126 | - | ||||||
Feagan |
Canada | UC | Induction Phase: | Induction Phase: | 6 weeks | ( |
||
TNF-naïve: VDZ (300 mg, iv) | 130 | 47.0 | Clinical response, clinical remission | |||||
Placebo | 76 | 38.2 | TNF-failure: clinical response, | 6 weeks | ||||
TNF-failure: VDZ (300 mg, iv) | 82 | 39.0 | clinical remission | |||||
Placebo | 63 | 44.4 | ||||||
Motoya |
Japan | UC | Induction Phase: | Induction Phase: | 10 weeks | ( |
||
VDZ: 300 mg iv | 164 | 39.6 | Clinical response, clinical remission | |||||
Placebo | 82 | 32.9 | Maintenance Phase: | 60 weeks | ||||
MaintenancePhase: | Clinical response, clinical remission | |||||||
VDZ300 mg iv (Q8W) | 41 | - | Adverse events | |||||
Placebo | 42 | - | ||||||
Sandborn |
USA | UC | Maintenance Phase: | Maintenance Phase: | 52 weeks | ( |
||
VDZ (108 mg, SC, Q2W) | 106 | 38.7 | Clinical response, clinical remission | |||||
VDZ (300 mg, iv, Q8W) | 54 | 42.6 | Adverse events | 52 weeks | ||||
Placebo | 56 | 39.3 | ||||||
Feagan |
Canada | CD | Induction Phase: | Induction Phase: | 57 days | ( |
||
VDZ (0.5 mg/2.0 mg/kg, iv) | 127 | 56.0 | Clinical response, clinical remission | |||||
Placebo | 58 | 48.3 | Adverse events | |||||
Sandborn |
USA | CD | Induction Phase: | Induction Phase: | 6 weeks | ( |
||
VDZ (300 mg, iv) | 220 | 52.3 | Clinical response, clinical | |||||
Placebo | 148 | 53.4 | remission | |||||
Maintenance Phase: | Maintenance Phase: | 52 weeks | ||||||
VDZ (300 mg, iv, Q4/8W) | 308 | - | Clinical response, clinical remission | |||||
Placebo | 153 | - | ||||||
Sands |
USA | CD | Induction Phase: | Induction Phase: | 10 weeks | ( |
||
TNF-naïve: | 51 | 55.0 | Clinical response, clinical remission | |||||
VDZ (300 mg, iv) | 50 | 46.0 | TNF-failure: clinical response, | 6 weeks | ||||
Placebo | clinical remission. Adverse reactions | |||||||
TNF-failure: | ||||||||
VDZ (300 mg, iv) | 158 | 57.0 | ||||||
Placebo | 157 | 61.0 | ||||||
Sands |
USA | CD | Induction Phase: | Induction Phase: | 6 weeks | ( |
||
VDZ (300 mg, iv) | 154 | 48.7 | Clinical response, clinical remission | |||||
Placebo | 123 | 47.2 | ||||||
Maintenance Phase: | Maintenance Phase: | 52 weeks | ||||||
VDZ (300 mg, iv, Q4/8W) | 137 | - | Clinical response, clinical remission | |||||
Placebo | 71 | - | TNF-failure: clinical response, | 6 weeks | ||||
TNF-failure: | clinical remission | |||||||
VDZ (300 mg, iv) | 263 | 56.7 | ||||||
Placebo | 227 | 60.0 | ||||||
Watanabe |
Japan | CD | Induction Phase: | Induction Phase: | 10 weeks | ( |
||
VDZ (300 mg, iv) | 79 | 35.4 | Clinical response, clinical remission | |||||
Placebo | 78 | 33.3 | 60 weeks | |||||
Maintenance Phase: | Maintenance Phase: | |||||||
VDZ (300 mg, iv, Q8W) | 12 | 50.0 | Clinical response, clinical remission | |||||
Placebo | 12 | 25.0 | Adverse events | |||||
Vermeire |
Belgium | CD | Maintenance Phase: | Maintenance Phase: | 52 weeks | ( |
||
VDZ (108 mg, SC, Q2W) | 275 | 42.9 | Clinical response, clinical remission | |||||
Placebo | 134 | 50.7 | Adverse events. |
SC, subcutaneous injection; IV, intravenous injection; VDZ, vedolizumab.
Summary of results.
Heterogeneity | |||||||
---|---|---|---|---|---|---|---|
Treatment | Outcome | Subgroups | No. of studies | Pooled RR (95% CI) | P-value | I2 (%) | Ph |
Induction therapy | Clinical remission | IBD | 9 | 2.09 (1.66-2.62) | <0.001 | 0.0 | 0.810 |
UC | 4 | 2.33 (1.61-3.38) | <0.001 | 5.20 | 0.367 | ||
CD | 5 | 1.95 (1.45-2.61) | <0.001 | 0.0 | 0.944 | ||
Clinical response | IBD | 10 | 1.54 (1.34-1.78) | <0.001 | 20.5 | 0.254 | |
UC | 5 | 1.68 (1.39-2.03) | <0.001 | 10.9 | 0.344 | ||
CD | 5 | 1.41 (1.16-1.73) | 0.001 | 16.5 | 0.309 | ||
Maintenance therapy | Clinical remission | IBD | 8 | 1.98 (1.58-2.49) | <0.001 | 43.9 | 0.086 |
UC | 4 | 2.55 (1.93-3.35) | <0.001 | 0.0 | 0.482 | ||
CD | 4 | 1.59 (1.32-1.91) | <0.001 | 0.0 | 0.566 | ||
Clinical response | IBD | 8 | 1.78 (1.40-2.26) | <0.001 | 68.7 | 0.002 | |
UC | 4 | 2.23 (1.82-2.73) | <0.001 | 0.0 | 0.807 | ||
CD | 4 | 1.38 (1.10-1.74) | 0.006 | 45.3 | 0.140 | ||
Failure of TNF antagonists | Clinical remission | All studies | 5 | 2.07 (1.48-2.89) | <0.001 | 10.2 | 0.348 |
Induction therapy | 3 | 1.85 (1.30-2.65) | 0.001 | 0.0 | 0.601 | ||
Maintenance therapy | 2 | 3.29 (1.06-10.15) | 0.039 | 58.2 | 0.122 | ||
Clinical response | All studies | 5 | 1.84 (1.54-2.21) | <0.001 | 0.0 | 0.820 | |
Induction therapy | 3 | 1.83 (1.50-2.23) | <0.001 | 0.0 | 0.951 | ||
Maintenance therapy | 2 | 1.97 (1.17-3.31) | 0.010 | 29.6 | 0.233 | ||
Corticosteroid-free | IBD | 8 | 1.98 (1.51-2.59) | <0.001 | 17.4 | 0.293 | |
remission/glucocorticoid | UC | 4 | 2.79 (1.84-4.21) | <0.001 | 0.0 | 0.876 | |
free remission | CD | 4 | 1.58 (1.21-2.07) | 0.001 | 0.0 | 0.461 | |
Mucosal healing | UC | All studies | 4 | 1.78 (1.27-2.51) | 0.001 | 68.4 | 0.023 |
Induction therapy | 2 | 1.43 (1.05-1.95) | 0.022 | 35.1 | 0.215 | ||
Maintenance therapy | 2 | 2.35 (1.66-3.34) | <0.001 | 26.5 | 0.243 | ||
Adverse event | |||||||
Headache | IBD | 9 | 1.09 (0.81-1.47) | 0.567 | 0.0 | 0.561 | |
UC | 4 | 0.98 (0.60-1.58) | 0.921 | 0.0 | 0.837 | ||
CD | 5 | 1.08 (0.63-1.86) | 0.769 | 35.7 | 0.198 | ||
Induction therapy | 5 | 1.05 (0.71-1.55) | 0.805 | 17.0 | 0.307 | ||
Maintenance therapy | 4 | 1.13 (0.58-2.21) | 0.720 | 0.0 | 0.603 | ||
Nasopharyngitis | IBD | 7 | 1.43 (0.98-2.08) | 0.062 | 31.0 | 0.191 | |
UC | 4 | 1.28 (0.76-2.16) | 0.350 | 49.2 | 0.116 | ||
CD | 3 | 1.77 (1.01-3.10) | 0.045 | 0.0 | 0.421 | ||
Induction therapy | 4 | 1.49 (0.95-2.34) | 0.084 | 0.0 | 0.600 | ||
Maintenance therapy | 3 | 1.38 (0.64-2.97) | 0.416 | 70.0 | 0.036 | ||
Upper respiratory tract | IBD | 7 | 1.30 (0.85-2.00) | 0.223 | 0.0 | 0.643 | |
infection | |||||||
UC | 3 | 1.60 (0.43-5.99) | 0.488 | 38.9 | 0.195 | ||
CD | 4 | 1.30 (0.81-2.09) | 0.281 | 0.0 | 0.793 | ||
Induction therapy | 3 | 1.11 (0.64-1.94) | 0.706 | 0.0 | 0.468 | ||
Maintenance therapy | 4 | 1.63 (0.84-3.16) | 0.149 | 0.0 | 0.569 | ||
Arthralgia | IBD | 5 | 1.15 (0.71-1.86) | 0.561 | 0.0 | 0.841 | |
UC | 3 | 1.46 (0.63-3.39) | 0.373 | 0.0 | 0.630 | ||
CD | 2 | 1.03 (0.57-1.84) | 0.927 | 0.0 | 0.839 | ||
Induction therapy | 3 | 1.16 (0.61-2.19) | 0.652 | 0.0 | 0.968 | ||
Maintenance therapy | 2 | 1.31 (0.45-3.84) | 0.625 | 27.7 | 0.239 | ||
Abdominal pain | IBD | 4 | 0.90 (0.61-1.33) | 0.590 | 0.0 | 0.726 | |
UC | 1 | 0.73 (0.31-1.73) | 0.480 | NA | NA | ||
CD | 3 | 0.95 (0.61-1.47) | 0.807 | 0.0 | 0.592 | ||
Induction therapy | 3 | 0.88 (0.55-1.41) | 0.608 | 0.0 | 0.521 | ||
Maintenance therapy | 1 | 0.93 (0.46-1.87) | 0.839 | NA | NA | ||
Vomiting | IBD | 5 | 0.87 (0.42-1.83) | 0.720 | 31.2 | 0.213 | |
UC | 3 | 0.89 (0.32-2.48) | 0.821 | 12.8 | 0.318 | ||
CD | 2 | 0.86 (0.21-3.58) | 0.838 | 71.6 | 0.061 | ||
Induction therapy | 3 | 1.03 (0.45-2.37) | 0.948 | 18.7 | 0.292 | ||
Maintenance therapy | 2 | 0.89 (0.13-6.00) | 0.903 | 60.8 | 0.110 | ||
Serious adverse events | IBD | 9 | 0.90 (0.67-1.20) | 0.473 | 0.0 | 0.891 | |
UC | 4 | 1.27 (0.77-2.11) | 0.352 | 0.0 | 0.899 | ||
CD | 5 | 0.76 (0.54-1.08) | 0.130 | 0.0 | 0.985 | ||
Induction therapy | 5 | 0.93 (0.64-1.34) | 0.694 | 0.0 | 0.647 | ||
Maintenance therapy | 4 | 0.86 (0.54-1.36) | 0.513 | 0.0 | 0.788 |