The duration of prior anti-tumor necrosis factor agents is associated with the effectiveness of vedolizumab in patients with ulcerative colitis: a real-world multicenter retrospective study

Taku Kobayashi; Tadakazu Hisamatsu; Satoshi Motoya; Minoru Matsuura; Toshimitsu Fujii; Reiko Kunisaki; Tomoyoshi Shibuya; Ken Takeuchi; Sakiko Hiraoka; Hiroshi Yasuda; Kaoru Yokoyama; Noritaka Takatsu; Atsuo Maemoto; Toshiyuki Tahara; Keiichi Tominaga; Masaaki Shimada; Nobuaki Kuno; Mary Cavaliere; Kaori Ishiguro; Jovelle L Fernandez; Toshifumi Hibi

doi:10.5217/ir.2024.00126

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Original Article The duration of prior anti-tumor necrosis factor agents is associated with the effectiveness of vedolizumab in patients with ulcerative colitis: a real-world multicenter retrospective study: Taku Kobayashi¹, Tadakazu Hisamatsu², Satoshi Motoya³, Minoru Matsuura², Toshimitsu Fujii⁴, Reiko Kunisaki⁵, Tomoyoshi Shibuya⁶, Ken Takeuchi⁷, Sakiko Hiraoka⁸, Hiroshi Yasuda⁹, Kaoru Yokoyama¹⁰, Noritaka Takatsu¹¹, Atsuo Maemoto¹², Toshiyuki Tahara¹³, Keiichi Tominaga¹⁴, Masaaki Shimada¹⁵, Nobuaki Kuno¹⁶, Mary Cavaliere¹⁷, Kaori Ishiguro¹⁷, Jovelle L Fernandez¹⁷, Toshifumi Hibi^1,; DOI: https://doi.org/10.5217/ir.2024.00126
Published online: June 4, 2025

¹Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan

²Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Tokyo, Japan

³Inflammatory Bowel Disease Center, Sapporo-Kosei General Hospital, Sapporo, Japan

⁴Department of Gastroenterology and Hepatology, Institute of Science Tokyo, Tokyo, Japan

⁵Inflammatory Bowel Disease Center, Yokohama City University Medical Center, Yokohama, Japan

⁶Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan

⁷Department of Gastroenterology and Hepatology, IBD Center, Tsujinaka Hospital Kashiwanoha, Kashiwa, Japan

⁸Department of Gastroenterology and Hepatology, Okayama University Hospital, Okayama, Japan

⁹Department of Gastroenterology, St. Marianna University School of Medicine, Kawasaki, Japan

¹⁰Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan

¹¹Inflammatory Bowel Disease Center, Fukuoka University Chikushi Hospital, Chikushino, Japan

¹²Inflammatory Bowel Disease Center, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan

¹³Department of Gastroenterology, Saiseikai Utsunomiya Hospital, Utsunomiya, Japan

¹⁴Department of Gastroenterology, Dokkyo Medical University, Mibu, Japan

¹⁵Department of Gastroenterology, NHO Nagoya Medical Center, Nagoya, Japan

¹⁶Department of Gastroenterology and Medicine, Fukuoka University Hospital, Fukuoka, Japan

¹⁷Japan Medical Office, Takeda Pharmaceutical Company Limited, Tokyo, Japan

Correspondence to Toshifumi Hibi, Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, 5 Chome-9-1 Shirokane, Minato City, Tokyo 108-8642, Japan. E-mail: thibi@insti.kitasato-u.ac.jp

• Received: August 9, 2024 • Revised: March 20, 2025 • Accepted: March 20, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract
INTRODUCTION
METHODS
RESULTS
DISCUSSION
NOTES
Supplementary Material
REFERENCES

Abstract

Background/Aims
Previous literature suggests that the response of patients with ulcerative colitis to vedolizumab may be affected by previous biologic therapy exposure. This real-world study evaluated vedolizumab treatment effectiveness in biologicnon-naïve patients.
Methods
This was a multicenter, retrospective, observational chart review of records from 16 hospitals in Japan (December 1, 2018, to February 29, 2020). Included patients who had ulcerative colitis, were aged ≥ 20 years, and received at least 1 dose of vedolizumab. Outcomes included clinical remission rates from weeks 2 to 54 according to prior biologic exposure status and factors associated with clinical remission up to week 54.
Results
A total of 370 eligible patients were included. Clinical remission rates were significantly higher in biologic-naïve (n=197) than in biologic-non-naïve (n=173) patients for weeks 2 to 54 of vedolizumab treatment. Higher clinical remission rates up to week 54 were significantly associated with lower disease severity (partial Mayo score ≤ 4, P= 0.001; albumin ≥ 3.0, P= 0.019) and the duration of prior anti-tumor necrosis factor α (anti-TNFα) therapy (P= 0.026). Patients with anti-TNFα therapy durations of < 3 months, 3 to < 12 months, and ≥ 12 months had clinical remission rates of 28.1%, 32.7%, and 60.0%, respectively (P= 0.001 across groups).
Conclusions
The effectiveness of vedolizumab in biologic-non-naïve patients was significantly influenced by duration of prior anti-TNFα therapy. (Japanese Registry of Clinical Trials: jRCT-1080225363)
Keywords: Tumor necrosis factor-alpha; Real-world evidence; Colitis, ulcerative; Vedolizumab; Sequencing

INTRODUCTION

Ulcerative colitis (UC) is a chronic disease of the colon that is characterized by intermittent periods of active inflammation and high levels of disease burden [1]. Standard pharmacological treatment starts with conventional therapies (i.e., 5-aminosalicylates, corticosteroids, and immunomodulators) before moving on to more targeted biologic therapies and/or other novel small molecules (e.g., Janus kinase inhibitors) [2]. Tumor necrosis factor α inhibitors (anti-TNFα) are suggested as the first-line treatment for patients with moderately to severely active UC who have an inadequate response or intolerance to conventional therapy [2]. However, primary nonresponse to anti-TNFα therapy occurs in up to one-third of patients, and many lose their response over time [3].

Vedolizumab (VDZ), another treatment for patients with moderately to severely active UC, is a human monoclonal antibody that inhibits lymphocyte infiltration into gut tissues without inducing systemic immunosuppression by selectively binding to α4β7 integrin [4]. In the global phase 3 GEMINI 1 UC study, VDZ was more effective than placebo as both induction and maintenance therapy [5]. However, patients’ responses to VDZ may be affected by prior exposure to other biologic therapies [6]. In particular, there are reports that patients with UC with prior anti-TNFα exposure (biologic-non-naïve) have lower remission rates with VDZ than those without prior anti-TNFα exposure (biologic-naïve) [7,8], and therefore other classes of treatment may be used [9]. However, the reasons for patients needing to switch from anti-TNFα therapy may vary, including primary nonresponse, loss of response, or intolerance, yet most previous studies have grouped patients together without differentiation into a single cohort of patients with prior failure of anti-TNFα therapy.

With the increase in therapies for UC, there is a need to identify clinical factors predictive of treatment response. There is also a need for real-world data to investigate in further detail the effect of prior therapies on treatment response to improve treatment continuity for patients with UC. In this multicenter, retrospective chart review of factors that contribute to responsiveness to treatment with VDZ, we evaluated the effectiveness of VDZ treatment in biologic-naïve and biologic-non-naïve patients. For biologic-non-naïve patients, especially those with prior exposure to anti-TNFα therapy, we evaluated the clinical course leading to the initiation of VDZ and its impact on VDZ effectiveness and discontinuation rates.

METHODS

1. Study Design

This was a multicenter, retrospective, observational chart review of hospital medical records, including case notes, prescribing records, and laboratory and investigation reports, from 16 tertiary hospitals in Japan (Japanese Registry of Clinical Trials: jRCT-1080225363). The chart review included patients with UC who received at least 1 dose of intravenous VDZ from December 1, 2018, to February 29, 2020. The observation period comprised 54 weeks, and the index date was defined as the date at which a patient received their first dose of VDZ.

The study was conducted in accordance with the Declaration of Helsinki, the Ethical Guideline for Clinical Research (the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare, December 22, 2014), and all applicable laws and regulations, including, without limitation, data privacy laws and conflict of interest guidelines. Relevant Independent Ethics Committees (IECs) and/or Institutional Review Boards (IRBs) reviewed the study protocol and the participant information sheet/opt-out form in accordance with local requirements. Personal identifiable data were not collected for this study, so informed consent was not required. However, all study sites were required to grant patients the right to refuse collection of their data, and informed consent was obtained if requested by an IEC/IRB. At any time between study site approval to the end of data collection at that site, a patient could also use an IEC-approved form to opt out; data from any patient who opted out were removed from the study.

2. Study Population

1) Inclusion Criteria

VDZ is approved in Japan for treatment of moderately to severely active inflammatory bowel disease (IBD; comprising both UC and Crohn’s disease). Patients were included in this chart review if they: (1) had a confirmed diagnosis of UC; (2) were aged ≥ 20 years at the first dose of VDZ; (3) initiated VDZ in Japan during the eligibility period; and (4) had medical information available from the date of their UC diagnosis. Disease severity was determined by the attending physician. It was assumed that VDZ was used in accordance with the package insert for VDZ in Japan.

2) Exclusion Criteria

Patients were excluded from the study if they: (1) were enrolled in another clinical trial or interventional clinical study for IBD when they started VDZ treatment, or received VDZ as part of a clinical trial or interventional clinical study at another institution; (2) initiated VDZ in combination with another biologic; (3) had a missing partial Mayo score at baseline; or (4) requested to opt out of the study.

3. Outcome Measures

Clinical remission was defined as a partial Mayo score ≤2 points, with no individual subscore >1, or a complete Mayo score ≤2 points, with no individual subscore >1. Primary nonresponse was defined as discontinuation because of lack of efficacy within the first 3 months of treatment (12 weeks). Loss of response was defined as patients who achieved clinical remission at least once within the first 3 months of treatment (12 weeks) and had a sustained nonresponse, disease worsening, or need for rescue medication while being treated with VDZ.

The primary endpoint was clinical remission rates among biologic-naïve patients during induction (weeks 2, 6, 14, 30) and maintenance phases (week 54). Secondary endpoints were clinical remission rates in biologic-non-naïve patients during induction and maintenance phases, and the characteristics of prior biologics in biologic-non-naïve patients. Exploratory endpoints were predictors of clinical remission up to week 54; reasons for VDZ treatment discontinuation in the group of patients who discontinued VDZ and anti-TNFα within 3 months; and the impact of anti-TNFα duration on clinical remission up to week 54 and VDZ discontinuation.

4. Statistical Analysis

The planned sample size was approximately 400 patients, which was anticipated to comprise 35% to 50% biologic-naïve patients and 50% to 65% biologic-non-naïve patients; the sample size was not based on statistical considerations but instead on feasibility. All analyses were conducted on the full analysis set, comprising all patients who received at least 1 dose of VDZ during the eligibility period and met all eligibility criteria. For the primary and secondary endpoints, clinical remission rates at each evaluation time point (weeks 2, 6, 14, 30, and 54) were compared between biologic-naïve and biologic-non-naïve patients using a logistic regression model. Covariates were sex, age, body mass index, concomitant steroid use, extraintestinal complications, anti-TNFα exposure, disease duration, disease extent, partial Mayo score, endoscopic findings, hospitalization, and serum levels of hemoglobin, albumin, and C-reactive protein (CRP).

For the first exploratory endpoint, predictors of clinical remission up to week 54 of VDZ treatment were investigated using univariate and multivariate logistic regression models. Predictors were reported using odds ratio (OR) and 95% confidence interval (CI). Variables in the univariate analysis included the following: sex; median age at first administration of VDZ; median disease duration; duration of anti-TNFα therapy; concomitant use of tacrolimus, corticosteroids, or immunomodulators; partial Mayo score; endoscopic findings (Mayo Endoscopic Score 3 or 2); and serum levels of hemoglobin, albumin, and CRP. Multivariate analysis was used to further explore factors that were statistically significant in the univariate analysis. Missing values were handled by multiple imputation for baseline variables used in the multivariate analyses.

For the other exploratory endpoints, the proportions of patients in clinical remission at week 54 and the rate of discontinuation of VDZ were tabulated and compared as follows: duration of treatment with anti-TNFα monoclonal antibody before VDZ administration ( <3 months/ ≥3 to <12 months/≥12 months, compared using the Kruskal-Wallis test).

Descriptive statistics included the number of observations (n), mean and standard deviation (SD) for continuous variables, and frequency (n and percentage) for categorical variables. Quantitative values were evaluated using the t test, and qualitative values were evaluated by the Fisher exact test. The significance level was set at 5% (2-tailed). Statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC, USA).

RESULTS

1. Demographic and Baseline Clinical Characteristics

A total of 374 patients with UC were included in the study (Fig. 1). The eligibility criteria were met by 370 patients, comprising 197 in the biologic-naïve group and 173 in the biologic-nonnaïve group. Patients were excluded for the following reasons: received VDZ outside the study period (n=2), uncertain diagnosis of UC (n=1), or had a missing partial Mayo score at the first dose of VDZ treatment (n=1).

Patient demographics and clinical characteristics were generally similar between the biologic-naïve and biologic-non-naïve groups (Table 1). Patients in the biologic-naïve group were significantly older than patients in the biologic-non-naïve group both at diagnosis (mean±SD age: 40.0 ± 16.7 years vs. 34.7±15.5 years, P<0.01) and at first dose of VDZ (48.7±17.0 years vs. 44.5 ± 15.7 years, P<0.05). Most patients in both the biologic-naïve and biologic-non-naïve groups had pancolitis (73.1% and 71.1%, respectively, P>0.05). Significantly more patients in the biologic-naïve group than in the biologic-nonnaïve group had the symptom of bloody stool (72.1% vs. 57.8%, respectively, P<0.01). Baseline disease severity based on mean partial and complete Mayo scores was not significantly different between the biologic-naïve and biologic-nonnaïve groups (4.5 vs. 4.5 and 6.7 vs. 6.8, respectively, P>0.05 for both). Significantly fewer patients in the biologic-non-naïve group received concomitant oral corticosteroid therapy compared with the biologic-naïve group (43.4% vs. 56.3%, respectively, P<0.05). There was no significant difference in the concomitant use of other treatments (immunomodulators, 5-aminosalicylates).

2. Characteristics of Prior Advanced Therapies

Among the 173 patients in the biologic-non-naïve group, 171 (98.8%) had been previously treated with an anti-TNFα (Table 2). In this group, 56.1% of patients had received infliximab, 50.9% had received adalimumab, and 34.1% had received golimumab. The mean (±SD) duration of anti-TNFα therapy was 21.49±25.95 months. The most common reasons for discontinuation of prior biologic therapy were primary nonresponse and loss of response. Primary nonresponse was the reason for discontinuation in 32.0%, 33.0%, and 37.3% of patients receiving infliximab, adalimumab, and golimumab, respectively. Discontinuation due to loss of response was reported for 33.0% of infliximab-treated, 50.0% of adalimumab-treated, and 47.5% of golimumab-treated patients.

Prior tofacitinib (a Janus kinase inhibitor) therapy was received by 8.7% of patients in the biologic-non-naïve group, and the mean duration of tofacitinib therapy was 3.56±3.65 months. Discontinuation of tofacitinib was most commonly due to primary nonresponse (53.3%) or loss of response (26.7%) in tofacitinib-treated patients (Table 2). Other Janus kinase inhibitors and other biologic agents such as ustekinumab were not included in this study because they were not approved when the study was conducted.

3. Clinical Remission Rates and Predictors of Clinical Remission

The clinical remission rates for biologic-naïve and biologicnon-naïve patients are shown in Fig. 2. The clinical remission rate was significantly higher in the biologic-naïve group than in the biologic-non-naïve group from week 2 (40.6% vs. 30.6%, respectively, P<0.01) to week 54 (49.2% vs. 43.4%, respectively, P<0.05) of VDZ treatment (Fig. 2). ORs for biologic-naïve versus biologic-non-naïve from the logistic regression model, after adjusting for confounding factors, ranged from 1.37 to 1.64. Among patients receiving concomitant steroids, steroid-free remission ranged from 2.7% (biologic-non-naïve patients at week 6) to 31.1% (biologic-non-naïve patients at week 54) (Supplementary Fig. 1). There was no difference in steroid-free remission rates between the biologic-naïve and biologicnon-naïve patients receiving concomitant steroids from week 6 to week 54 of VDZ treatment (week 6, P=0.1313; week 14, P=0.9730; week 54, P=0.5253).

Duration of anti-TNFα therapy was significantly associated with a higher proportion of patients in clinical remission up to week 54 (OR for ≥3 months vs. <3 months: 2.714, OR for 0 months vs. <3 months: 3.245, grouped P=0.007) (Table 3). Indicators of higher disease severity, including a partial Mayo score ≥5 (OR vs. ≤4: 0.363, P<0.001), serum albumin <3.0 g/dL (OR vs. ≥ 3.0 g/dL: 0.213, P< 0.001), hemoglobin < 10 g/dL (OR vs. ≥ 10 g/dL: 0.340, P=0.001), and CRP ≥ 0.26 mg/dL (OR vs. <0.26 mg/dL: 0.526, P=0.008), were significantly associated with a lower proportion of patients in clinical remission up to week 54. In the multivariate logistic regression analysis, a higher proportion of patients in clinical remission up to week 54 remained significantly associated with duration of anti-TNFα therapy (OR for ≥3 months vs. <3 months: 2.209, OR for 0 months vs. <3 months: 3.087, grouped P=0.026) (Table 3), and a lower proportion of patients in clinical remission remained significantly associated with a partial Mayo score ≥5 (OR vs. ≤4: 0.412, P=0.001) and albumin <3.0 g/dL (OR vs. ≥3.0 g/dL, 0.362, P=0.019). Hemoglobin and CRP were not significantly associated with clinical remission in the multivariate analysis.

4. Impact of Prior Anti-TNFα Therapy

The duration of anti-TNFα therapy significantly influenced the clinical remission rate at 54 weeks of VDZ treatment (Fig. 3). The percentage of patients achieving clinical remission at week 54 was 28.1%, 32.7%, and 60.0% for patients with anti-TNFα therapy durations of <3 months, ≥3 to <12 months, and ≥12 months, respectively (significant difference across groups [P=0.001], Kruskal-Wallis test) (Fig. 3A). The duration of anti-TNFα therapy also significantly affected the percentage of patients who discontinued VDZ within 3 months. The percentage of patients who discontinued VDZ within 3 months was 34.4%, 20.0%, and 13.3% for patients with anti-TNFα therapy durations of <3 months, ≥3 to <12 months, and ≥12 months, respectively (significant difference across groups [P=0.044], Kruskal-Wallis test) (Fig. 3B).

The reasons for discontinuing anti-TNFα therapy and VDZ are summarized in Supplementary Table 1. Among patients who discontinued anti-TNFα therapy within 3 months and then discontinued VDZ within 3 months, the most common reasons for discontinuing VDZ were primary nonresponse (7 patients) and adverse events (3 patients).

DISCUSSION

In this retrospective chart review of patients with UC treated with VDZ, we found the rate of clinical remission was higher in biologic-naïve patients than in biologic-non-naïve patients. Among biologic-non-naïve patients, anti-TNFα duration <3 months was associated with lower effectiveness of VDZ treatment. These results provide real-world evidence that treatment decisions for biologic-non-naïve patients need to be based on the duration of anti-TNFα therapy.

Over the 54 weeks of this chart review, patients in the biologic-naïve group had a higher remission rate than those in the biologic-non-naïve group. This result is consistent with the findings from a systematic review and meta-analysis comprising 4,520 biologic-naïve and 8,105 biologic-exposed patients with UC, which found that patients who were naïve to anti-TNFα therapy had a higher probability of clinical remission with VDZ than patients exposed to anti-TNFα therapy [6]. In the meta-analysis, patients naïve to anti-TNFα therapy were significantly more likely to achieve clinical remission at weeks 26 and 52 than those who had received prior therapy, with risk ratios of 1.29 and 1.32, respectively [6].

In the present study, higher rates of clinical remission up to 54 weeks of VDZ treatment were associated with lower baseline disease severity, as previously reported [10]. The current study is the first to report that duration of anti-TNFα therapy was also positively associated with clinical remission. We examined the remission rate at week 54 and the early discontinuation rate of VDZ within 3 months in 3 categories: within 3 months, ≥3 to <12 months, and more than 12 months. Notably, the remission rate at week 54 (60.0%) of VDZ treatment in patients receiving anti-TNFα therapy for more than 12 months was favorable. On the other hand, the clinical remission rate at week 54 with VDZ in patients who discontinued anti-TNFα therapy within 3 months (28.1%) was about half that of patients who continued anti-TNFα therapy for more than 12 months (60.0%), and the early discontinuation rate of VDZ in patients who discontinued anti-TNFα therapy within 3 months (34.4%) was more than twice that of patients who continued anti-TNFα therapy for more than 12 months (13.3%). Thus, the benefit of VDZ in this patient population was dependent on the duration of anti-TNFα therapy. There are several possible explanations as to why the longer duration of prior anti-TNFα is associated with a higher likelihood of remission. Longer treatment duration may indicate that those patients required VDZ for secondary loss of response. It has been reported that loss of response to anti-TNFα develops most frequently due to pharmacological reasons—namely, immunogenicity—but not due to the refractory nature of the disease. Therefore, patients with loss of response to anti-TNFα are expected to respond to VDZ better than primary nonresponders to anti-TNF, who have had a shorter duration of treatment. It is also possible that TNFα-related inflammation may remain inhibited by long-term anti-TNFα treatment, and thus the different mechanism of action of VDZ works more efficiently in patients who have had a longer treatment duration. However, further studies are needed to confirm these hypotheses.

Next, we examined the relationship between duration of treatment and reasons for discontinuation. We hypothesized that patients who discontinued or changed therapy after a short treatment period would be more likely to have a primary failure. As we expected, 23 of 34 cases who discontinued anti-TNFα therapy within 3 months discontinued anti-TNFα due to a primary nonresponse (Supplementary Table 1). Recently, it has been suggested that the reason for discontinuation (e.g., primary nonresponse, loss of response, or intolerance) of one biologic may guide selection of a subsequent biologic in patients with IBD [11]. However, evidence for this association is conflicting for patients with UC who receive VDZ after an anti-TNFα. Systematic reviews and meta-analyses suggest that patients with a history of primary nonresponse to anti-TNFα agents may be less likely to achieve remission with other non-anti-TNFα biologic agents compared with those with loss of response [12]. However, the reports on VDZ as a second-line therapy are limited and inconclusive [12].

As a strength of this study, we were able to investigate the effect of prior exposure to anti-TNFα agents by matching patient background in the biologic-naïve and biologic-non-naïve groups. Our patient cohort had approximately equal numbers of biologic-naïve and biologic-non-naïve patients enrolled in the study, and there were no differences in concomitant medications (steroids, immunomodulators) or complications between the 2 groups. Moreover, the greatest strength of our study is that we were able to analyze information on the duration of the anti-TNFα therapy.

A limitation of the design of this retrospective study is that it was completely dependent on the schedule of follow-up clinical assessments, which may vary due to patient, provider, and institutional factors, and therefore the timing of outcomes may not be accurate. In this study, clinical remission was defined as a complete Mayo score of ≤ 2 with no subscore >1. Due to the retrospective nature of the study, endoscopy findings were limited, and alternative definitions of remission based on complete Mayo score could not be evaluated. While almost all (98.8%) of the biologic-non-naïve patients had prior anti-TNFα exposure, 39.9% had failed multiple prior biologics; future analyses should address whether the number of prior anti-TNFα failures affects the therapeutic effect of VDZ. Although there were some cases with inconsistent treatment duration records and inconsistent reasons for discontinuation among anti-TNFα products, these were excluded from our analysis.

In this retrospective chart review of patients with UC, the duration of anti-TNFα therapy prior to VDZ treatment was demonstrated to significantly influence the effectiveness of VDZ. This suggests that VDZ can be expected to be highly effective after a long period of prior therapy, even in biologicnon-naïve patients.

NOTES

Funding Source

This work was supported by Takeda Pharmaceutical Company Limited, manufacturer/licensee of vedolizumab. Takeda Pharmaceutical Company Limited was involved in the study design, data collection, data analysis, and preparation of the manuscript.

Conflict of Interest

Kobayashi T reports grants/contracts from AbbVie GK, Activaid, Alfresa Pharma Corporation, Bristol Myers Squibb, EA Pharma Co., Ltd., Eli Lilly Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Inc., Google Asia Pacific Pte. Ltd., Janssen Pharmaceutical K.K., JIMRO Co., Ltd., JMDC Inc., Kyorin Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Otsuka Holdings, Pfizer Japan Inc., Takeda Pharmaceutical Company Limited, and Zeria Pharmaceutical Co., Ltd.; payments/honoraria from AbbVie GK, Activaid, Alfresa Pharma Corporation, EA Pharma Co., Ltd., Janssen Pharmaceutical K.K., JIMRO Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Nippon Kayaku Co., Ltd., Pfizer Japan Inc., Thermo Fisher Diagnostics K.K., Takeda Pharmaceutical Company Limited, and Zeria Pharmaceutical Co., Ltd.; and payment for expert testimony from AbbVie GK, Activaid, Alfresa Pharma Corporation, EA Pharma Co., Ltd., Galapagos, Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Japan Inc., and Takeda Pharmaceutical Company Limited.

Hisamatsu T reports grants/contracts from AbbVie GK, Daiichi Sankyo Company, Limited, EA Pharma Co., Ltd., JIMRO Co., Ltd., Kissei Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc., Takeda Pharmaceutical Company Limited, and Zeria Pharmaceutical Co., Ltd.; advisory fees from AbbVie GK, Bristol Myers Squibb, EA Pharma Co., Ltd., Eli Lilly and Company, Gilead Sciences, Inc., Mitsubishi Tanabe Pharma Corporation, Nichi-Iko Pharmaceutical Co., Ltd., Pfizer Inc., and Takeda Pharmaceutical Company Limited; and payments/honoraria from AbbVie GK, Daiichi Sankyo Company, Limited, EA Pharma Co., Ltd., Janssen Pharmaceutical K.K., JIMRO Co., Ltd., Kissei Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc., Takeda Pharmaceutical Company Limited, and Zeria Pharmaceutical Co., Ltd.

Motoya S reports grants/contracts from Janssen Pharmaceutical K.K.; and payments/honoraria from AbbVie GK, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, and Mochida Pharmaceutical Co., Ltd.

Matsuura M reports consulting fees from AbbVie GK, Pfizer Japan Inc., and Takeda Pharmaceutical Company Limited; and payments/honoraria from AbbVie GK, EA Pharma Co., Ltd., Janssen Pharmaceutical K.K., JIMRO Co., Ltd., Kissei Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Company Limited, Viatris Inc., and Zeria Pharmaceutical Co., Ltd.

Fujii T reports grants/contracts from AbbVie GK, Alfresa Pharma Corporation, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Celltrion Healthcare, EA Pharma Co., Ltd., Eli Lilly and Company, Gilead Sciences, Inc., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Mebix, Inc., Sanofi, and Takeda Pharmaceutical Company Limited; payment for lectures/presentations and speaker bureaus from AbbVie GK, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo Company, Limited, EA Pharma Co., Ltd., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Kyowa Hakko Kirin, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nichi-Iko Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc., Takeda Pharmaceutical Company Limited, Taiho Pharmaceutical Co., Ltd., and Zeria Pharmaceutical Co., Ltd.; and is a councillor for the Japanese Society of Gastroenterology.

Kunisaki R reports support from Takeda Pharmaceutical Company Limited for the present manuscript; grants/contracts from AbbVie GK and Janssen Pharmaceutical K.K.; consulting fees from Nippon Kayaku Co., Ltd.; payments/honoraria from AbbVie GK, Kyorin Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., and Takeda Pharmaceutical Company Limited; and participation on a data safety monitoring board/advisory board for Nippon Kayaku Co., Ltd.

Shibuya T reports support from Takeda Pharmaceutical Company Limited for the present manuscript.

Takeuchi K reports grants/contracts from AbbVie GK, Amgen K.K., AstraZeneca K.K., Bristol Myers Squibb K.K., EA Pharma Co., Ltd., Eli Lilly Japan K.K., Ferring Pharmaceuticals, Iqvia Inc., Nippon Shinyaku Co., Ltd., and Takeda Pharmaceutical Company Limited; consulting fees from Thermo Fisher Diagnostics K.K.; payments/honoraria from AbbVie GK, Ayumi Pharmaceutical Corporation, Celltrion Healthcare, EA Pharma Co., Ltd., Gilead Sciences, Inc., Janssen Pharmaceutical K.K., JIMRO Co., Ltd., Kissei Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Otsuka Holdings, Pfizer Japan Inc., Takeda Pharmaceutical Company Limited, Viatris Inc., and Zeria Pharmaceutical Co., Ltd.

Hiraoka S reports payments/honoraria (lecture fees) from AbbVie GK, EA Pharma Co., Ltd., Janssen Pharmaceutical K.K., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Company Limited.

Yasuda H reports grants/contracts from Nippon Kayaku Co., Ltd., and support from Takeda Pharmaceutical Company Limited for the present manuscript.

Yokoyama K reports payments/honoraria from AbbVie GK, EA Pharma Co., Ltd., Gilead Sciences, Inc., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Company Limited.

Maemoto A reports support from Takeda Pharmaceutical Company Limited for the present manuscript; grants/contracts from AbbVie GK, EA Pharma Co., Ltd., Eli Lilly Japan K.K., Gilead Sciences, Inc., Janssen Pharmaceutical K.K., Kaken Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Pfizer R&D Japan K.K., and Takeda Pharmaceutical Company Limited; and payments/honoraria from AbbVie GK, EA Pharma Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., JIMRO Co., Ltd., Nippon Kayaku Co., Ltd., and Takeda Pharmaceutical Company Limited.

Cavaliere M was an employee of Takeda Pharmaceutical Company Limited at the time of the study.

Ishiguro K was an employee of Takeda Pharmaceutical Company Limited at the time of the study.

Fernandez JL was an employee of Takeda Pharmaceutical Company Limited at the time of the study and reports stock or share ownership in Cococell Nanotech, Inc., GlaxoSmithKline, Immunorock Co., Ltd., Mirai Biotech Inc., and Takeda Pharmaceutical Company Limited; and other financial interests in Jovelle Fernandez LLC.

Hibi T reports grants/contracts from AbbVie GK, Activaid, Alfresa Pharma Corporation, Celltrion Healthcare, EA Pharma Co., Ltd., Eli Lilly Japan K.K., Gilead Sciences, Inc., Janssen Pharmaceutical K.K., JMDC Inc., Mitsubishi Tanabe Pharma Corporation, Nichi-Iko Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Takeda Pharmaceutical Company Limited, and Zeria Pharmaceutical Co., Ltd.; payments/honoraria from AbbVie GK, EA Pharma Co., Ltd., JIMRO Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Pfizer Inc., Sandoz K.K., Takeda Pharmaceutical Company Limited, and Zeria Pharmaceutical Co., Ltd.; and payment for expert testimony from AbbVie GK, Celltrion Healthcare, EA Pharma Co., Ltd., Eli Lilly Japan K.K., Gilead Sciences, Inc., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Company Limited. Hibi T is on the Editorial Board of Intestinal Research and recused himself from all editorial decisions pertaining to this manuscript.

Takatsu N, Tahara T, Tominaga K, Shimada M, and Kuno N have no conflicts of interest to declare.

Data Availability Statement

The datasets, including the redacted study protocol, redacted statistical analysis plan, and individual participants data supporting the results reported in this article, will be made available within 3 months from initial request, to researchers who provide a methodologically sound proposal. The data will be provided after their de-identification, in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization.

Author Contributions

Conception: Ishiguro K, Fernandez JL, and Cavaliere M. Investigation: Kobayashi T, Hisamatsu T, Motoya S, Matsuura M, Fujii T, Kunisaki R, Shibuya T, Takeuchi K, Hiraoka S, Yasuda H, Yokoyama K, Takatsu N, Maemoto A, Tahara T, Tominaga K, Shimada M, and Kuno N. Formal analysis: Kobayashi T, Hisamatsu T, Motoya S, Ishiguro K, Fernandez JL, and Hibi T. Writing – original draft: Kobayashi T. Writing – review & editing: all authors. Approval of final manuscript: all authors.

Additional Contributions

The authors would like to thank all study participants. The authors also thank Hisato Deguchi, PhD, of Japan Medical Office, Takeda Pharmaceutical Company Limited, for his significant intellectual input into the original design and methodology of the research procedures, analyses, and selection of statistical tests. Medical writing assistance was provided by Koa Webster, PhD, CMPP, and Serina Stretton, PhD, CMPP, of ProScribe – Envision Pharma Group, and was funded by Takeda Pharmaceutical Company Limited. ProScribe’s services complied with international guidelines for Good Publication Practice.

Supplementary Material

Supplementary materials are available at the Intestinal Research website (https://www.irjournal.org).

Supplementary Table 1.

Reasons for Anti-TNFα and VDZ Discontinuation in Patients with Ulcerative Colitis

ir-2024-00126-Supplementary-Table-1.pdf

Supplementary Fig. 1.

Rates of steroid-free remission at weeks 6, 14, and 54 among biologic-naïve patients (n=112) and biologic-non-naïve patients (n=74) receiving VDZ therapy with concomitant steroids for ulcerative colitis. ORs were calculated for “steroid-free remission=yes”, with P-values from a chi-square test. VDZ, vedolizumab; OR, odds ratio; CI, confidence interval.

ir-2024-00126-Supplementary-Fig-1.pdf

Fig. 1.

Patient flow diagram. VDZ, vedolizumab; UC, ulcerative colitis.

Fig. 2.

Rates of clinical remission at weeks 2, 6, 14, 30, and 54 among biologic-naïve patients (n=197) and biologic-non-naïve patients (n=173) receiving VDZ therapy for ulcerative colitis. ^aORs of the VDZ-treated group after adjusting for covariates (ORs of biologic-naïve vs. biologic-non-naïve), from the logistic regression model with time to clinical remission (proportion) as the objective variable and the VDZ-treated group and covariates (confounding factors) as explanatory variables. VDZ, vedolizumab; OR, odds ratio; CI, confidence interval.

Fig. 3.

Impact of prior anti-TNFα therapy on response to subsequent VDZ treatment. (A) Impact of anti-TNFα duration on clinical remission rate at week 54 of treatment with VDZ for ulcerative colitis. (B) Impact of anti-TNFα duration on VDZ discontinuation rate within 3 months. P-values shown are across all groups in each figure panel. TNFα, tumor necrosis factor α; VDZ, vedolizumab.

Table 1.

Patient Baseline Demographic and Clinical Characteristics

Variable	Biologic-naïve patients (n = 197)	Biologic-non-naïve patients (n = 173)	P-value
Sex			NS
Male	109 (55.3)	94 (54.3)
Female	88 (44.7)	79 (45.7)
Age (yr), mean ± SD
At UC diagnosis^a	40.0 ± 16.7	34.7 ± 15.5	< 0.01
At first dose of VDZ	48.7 ± 17.0	44.5 ± 15.7	< 0.05
BMI (kg/m²), mean ± SD^a	21.6 ± 4.0	21.5 ± 3.8	NS
Duration of UC (yr), mean ± SD^a	8.7 ± 8.6	9.9 ± 7.7	NS
Symptoms
Bloody stool	142 (72.1)	100 (57.8)	< 0.01
Abdominal pain	79 (40.1)	70 (40.5)	NS
Proctalgia	4 (2.0)	4 (2.3)	NS
Diarrhea	118 (59.9)	96 (55.5)	NS
UC disease type			NS
Pancolitis	144 (73.1)	123 (71.1)
Left-sided colitis	45 (22.8)	47 (27.2)
Proctitis	7 (3.6)	1 (0.6)
Right-sided or segmental colitis	0	1 (0.6)
Unknown	1 (0.5)	1 (0.6)
Modified Charlson score, mean ± SD	0.5 ± 1.3	0.3 ± 0.8	< 0.05
Extraintestinal manifestations	24 (12.2)	25 (14.5)	NS
Partial Mayo score, mean ± SD	4.5 ± 2.2	4.5 ± 2.2	NS
Complete Mayo score^a
Mean ± SD	6.7 ± 2.4	6.8 ± 2.3	NS
Non-biologic therapies^b
5-Aminosalicylic acid	140 (71.1)	124 (71.7)	NS
Corticosteroids	111 (56.3)	75 (43.4)	< 0.05
Immunomodulators^c	50 (25.4)	55 (31.8)	NS
Hemoglobin (g/mL)^a
Mean ± SD	12.50 ± 2.00	12.28 ± 1.82	NS
Albumin (g/mL)^a
Mean ± SD	3.75 ± 0.63	3.79 ± 0.54	NS
CRP (mg/dL)^a
Mean ± SD	1.051 ± 2.178	0.933 ± 1.845	NS

Values are presented as number (%) unless otherwise indicated.

^a The number of patients with available data for each variable was as follows: Age at UC diagnosis: biologic-naïve (n=196), BMI: biologic-naïve (n=165), biologic-non-naïve (n=147), Duration of UC: biologic-naïve (n=196), Complete Mayo score: biologic-naïve (n=168), biologic-non-naïve (n=136), Hemoglobin: biologic-naïve (n=195), biologic-non-naïve (n=168), Albumin: biologic-naïve (n=191), biologic-non-naïve (n=165), CRP: biologic-naïve (n=194), biologic-non-naïve (n=166).

^b At the first dose of VDZ, i.e., concomitant.

^c Azathioprine and mercaptopurine.

SD, standard deviation; UC, ulcerative colitis; VDZ, vedolizumab; BMI, body mass index; CRP, C-reactive protein; NS, nonsignificant.

Table 2.

Characteristics of Prior Biologics in the Biologic-Non-Naïve Group of Patients with UC

Variable	Biologic-non-naïve patients (n = 173)	Biologics before VDZ treatment^a			Other advanced therapies before VDZ treatment
Variable	Biologic-non-naïve patients (n = 173)	Infliximab	Adalimumab	Golimumab	Tofacitinib
Number of biologic failures
1	104 (60.1)
≥2	69 (39.9)
Prior tofacitinib therapy	15 (8.7)
Time between tofacitinib discontinuation and first dose of VDZ (mo) (n = 14)	1.66 ± 2.24
Prior anti-TNFα therapy	171 (98.8)
Duration of anti-TNFα therapy (mo) (n = 162)	21.49 ± 25.95
Time between anti-TNFα discontinuation and first dose of VDZ (mo) (n = 164)	12.38 ± 20.32
Number of patients^b		97 (56.1)	88 (50.9)	59 (34.1)	15 (8.7)
Treatment duration (mo)^c		18.80 ± 27.43	16.74 ± 21.29	10.38 ± 11.05	3.56 ± 3.65
Reasons for discontinuation^d,e
Remission		7 (7.2)	0	2 (3.4)	0
Adverse events		26 (26.8)	9 (10.2)	3 (5.1)	3 (20.0)
Primary nonresponse		31 (32.0)	29 (33.0)	22 (37.3)	8 (53.3)
Loss of response		32 (33.0)	44 (50.0)	28 (47.5)	4 (26.7)
Patient request		4 (4.1)	6 (6.8)	3 (5.1)	0
Unknown		2 (2.1)	4 (4.5)	2 (3.4)	0
Other		0	2 (2.3)	0	0

Values are presented as number (%) or mean±standard deviation.

^a Individual patients may have received more than 1 prior biologic therapy. None of the patients who received biologics before VDZ received ustekinumab (i.e., n=0).

^b Percentage of biologic-non-naïve group.

^c The number of patients treated with each agent was as follows: infliximab (n=90), adalimumab (n=84), golimumab (n=51), and tofacitinib (n=14).

^d Percentages in this section are percentages of each biologic-type group.

^e Reasons for discontinuation were accumulated from all time points of anti-TNFα therapy discontinuation.

UC, ulcerative colitis; VDZ, vedolizumab; TNFα, tumor necrosis factor α.

Table 3.

Predictors of Clinical Remission up to Week 54 of VDZ Treatment for Ulcerative Colitis: Univariate and Multivariate Analyses

Variable	Univariate analysis		Multivariate analysis
Variable	OR (95% CI)	P-value	OR (95% CI)	P-value
Sex (male vs. female)	0.670 (0.419–1.071)	0.093
Median age at first dose of VDZ (≥ 46 yr vs. < 46 yr)	0.827 (0.522–1.310)	0.418
Median disease duration (≥ 7.36 yr vs. < 7.36 yr)	1.482 (0.933–2.354)	0.095
Duration of anti-TNFα treatment				0.026
≥ 3 mo vs. < 3 mo	2.714 (1.227–6.004)	0.007	2.209 (0.935–5.217)
0 mo vs. < 3 mo	3.245 (1.512–6.962)		3.087 (1.347–7.070)
Concomitant use of tacrolimus (yes vs. no)^a	1.174 (0.511–2.695)	0.706
Concomitant use of corticosteroid (yes vs. no)	1.072 (0.678–1.697)	0.766
Concomitant use of IM (yes vs. no)^b	1.357 (0.801–2.300)	0.256
Partial Mayo score (≥ 5 vs. ≤ 4)	0.363 (0.221–0.594)	< 0.001	0.412 (0.240–0.707)	0.001
Endoscopic findings
MES 2 vs. MES 0 or 1	0.875 (0.384–1.992)	0.191
MES 3 vs. MES 0 or 1	0.559 (0.238–1.313)
Hemoglobin (< 10 g/dL vs. ≥ 10 g/dL)	0.340 (0.713–0.668)	0.001	0.457 (0.203–1.032)	0.060
Albumin (< 3.0 g/dL vs. ≥ 3.0 g/dL)	0.213 (0.102–0.441)	< 0.001	0.362 (0.155–0.845)	0.019
CRP (≥ 0.26 mg/dL vs. < 0.26 mg/dL)	0.526 (0.327–0.846)	0.008	0.744 (0.435–1.272)	0.280

^a The number of patients using tacrolimus was n=40 within 3 months of starting VDZ treatment.

^b Azathioprine and mercaptopurine.

VDZ, vedolizumab; OR, odds ratio; CI, confidence interval; TNFα, tumor necrosis factor α; IM, immunomodulator; MES, Mayo Endoscopic Score; CRP, C-reactive protein.

REFERENCES

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2. Raine T, Bonovas S, Burisch J, et al. ECCO guidelines on therapeutics in ulcerative colitis: medical treatment. J Crohns Colitis 2022;16:2–17.PubMed
3. Roda G, Jharap B, Neeraj N, Colombel JF. Loss of response to anti-TNFs: definition, epidemiology, and management. Clin Transl Gastroenterol 2016;7:e135.Article PubMed PMC PDF
4. Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER. The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases. J Pharmacol Exp Ther 2009;330:864–875.PubMed
5. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013;369:699–710.Article PubMed
6. Attauabi M, Madsen GR, Bendtsen F, Seidelin JB, Burisch J. Vedolizumab as the first line of biologic therapy for ulcerative colitis and Crohn’s disease: a systematic review with meta-analysis. Dig Liver Dis 2022;54:1168–1178.Article PubMed
7. Pulusu SSR, Srinivasan A, Krishnaprasad K, et al. Vedolizumab for ulcerative colitis: real world outcomes from a multicenter observational cohort of Australia and Oxford. World J Gastroenterol 2020;26:4428–4441.Article PubMed PMC
8. Baumgart DC, Bokemeyer B, Drabik A, Stallmach A, Schreiber S; Vedolizumab Germany Consortium. Vedolizumab induction therapy for inflammatory bowel disease in clinical practice: a nationwide consecutive German cohort study. Aliment Pharmacol Ther 2016;43:1090–1102.Article PubMed
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The duration of prior anti-tumor necrosis factor agents is associated with the effectiveness of vedolizumab in patients with ulcerative colitis: a real-world multicenter retrospective study

DOI: https://doi.org/10.5217/ir.2024.00126

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The duration of prior anti-tumor necrosis factor agents is associated with the effectiveness of vedolizumab in patients with ulcerative colitis: a real-world multicenter retrospective study

Fig. 1. Patient flow diagram. VDZ, vedolizumab; UC, ulcerative colitis.

Fig. 2. Rates of clinical remission at weeks 2, 6, 14, 30, and 54 among biologic-naïve patients (n=197) and biologic-non-naïve patients (n=173) receiving VDZ therapy for ulcerative colitis. aORs of the VDZ-treated group after adjusting for covariates (ORs of biologic-naïve vs. biologic-non-naïve), from the logistic regression model with time to clinical remission (proportion) as the objective variable and the VDZ-treated group and covariates (confounding factors) as explanatory variables. VDZ, vedolizumab; OR, odds ratio; CI, confidence interval.

Fig. 3. Impact of prior anti-TNFα therapy on response to subsequent VDZ treatment. (A) Impact of anti-TNFα duration on clinical remission rate at week 54 of treatment with VDZ for ulcerative colitis. (B) Impact of anti-TNFα duration on VDZ discontinuation rate within 3 months. P-values shown are across all groups in each figure panel. TNFα, tumor necrosis factor α; VDZ, vedolizumab.

Fig. 1.

Fig. 2.

Fig. 3.

The duration of prior anti-tumor necrosis factor agents is associated with the effectiveness of vedolizumab in patients with ulcerative colitis: a real-world multicenter retrospective study

Variable	Biologic-naïve patients (n = 197)	Biologic-non-naïve patients (n = 173)	P-value
Sex			NS
Male	109 (55.3)	94 (54.3)
Female	88 (44.7)	79 (45.7)
Age (yr), mean ± SD
At UC diagnosis^a	40.0 ± 16.7	34.7 ± 15.5	< 0.01
At first dose of VDZ	48.7 ± 17.0	44.5 ± 15.7	< 0.05
BMI (kg/m²), mean ± SD^a	21.6 ± 4.0	21.5 ± 3.8	NS
Duration of UC (yr), mean ± SD^a	8.7 ± 8.6	9.9 ± 7.7	NS
Symptoms
Bloody stool	142 (72.1)	100 (57.8)	< 0.01
Abdominal pain	79 (40.1)	70 (40.5)	NS
Proctalgia	4 (2.0)	4 (2.3)	NS
Diarrhea	118 (59.9)	96 (55.5)	NS
UC disease type			NS
Pancolitis	144 (73.1)	123 (71.1)
Left-sided colitis	45 (22.8)	47 (27.2)
Proctitis	7 (3.6)	1 (0.6)
Right-sided or segmental colitis	0	1 (0.6)
Unknown	1 (0.5)	1 (0.6)
Modified Charlson score, mean ± SD	0.5 ± 1.3	0.3 ± 0.8	< 0.05
Extraintestinal manifestations	24 (12.2)	25 (14.5)	NS
Partial Mayo score, mean ± SD	4.5 ± 2.2	4.5 ± 2.2	NS
Complete Mayo score^a
Mean ± SD	6.7 ± 2.4	6.8 ± 2.3	NS
Non-biologic therapies^b
5-Aminosalicylic acid	140 (71.1)	124 (71.7)	NS
Corticosteroids	111 (56.3)	75 (43.4)	< 0.05
Immunomodulators^c	50 (25.4)	55 (31.8)	NS
Hemoglobin (g/mL)^a
Mean ± SD	12.50 ± 2.00	12.28 ± 1.82	NS
Albumin (g/mL)^a
Mean ± SD	3.75 ± 0.63	3.79 ± 0.54	NS
CRP (mg/dL)^a
Mean ± SD	1.051 ± 2.178	0.933 ± 1.845	NS

Variable	Biologic-non-naïve patients (n = 173)	Biologics before VDZ treatment^a			Other advanced therapies before VDZ treatment
Variable	Biologic-non-naïve patients (n = 173)	Infliximab	Adalimumab	Golimumab	Tofacitinib
Number of biologic failures
1	104 (60.1)
≥2	69 (39.9)
Prior tofacitinib therapy	15 (8.7)
Time between tofacitinib discontinuation and first dose of VDZ (mo) (n = 14)	1.66 ± 2.24
Prior anti-TNFα therapy	171 (98.8)
Duration of anti-TNFα therapy (mo) (n = 162)	21.49 ± 25.95
Time between anti-TNFα discontinuation and first dose of VDZ (mo) (n = 164)	12.38 ± 20.32
Number of patients^b		97 (56.1)	88 (50.9)	59 (34.1)	15 (8.7)
Treatment duration (mo)^c		18.80 ± 27.43	16.74 ± 21.29	10.38 ± 11.05	3.56 ± 3.65
Reasons for discontinuation^d,e
Remission		7 (7.2)	0	2 (3.4)	0
Adverse events		26 (26.8)	9 (10.2)	3 (5.1)	3 (20.0)
Primary nonresponse		31 (32.0)	29 (33.0)	22 (37.3)	8 (53.3)
Loss of response		32 (33.0)	44 (50.0)	28 (47.5)	4 (26.7)
Patient request		4 (4.1)	6 (6.8)	3 (5.1)	0
Unknown		2 (2.1)	4 (4.5)	2 (3.4)	0
Other		0	2 (2.3)	0	0

Variable	Univariate analysis		Multivariate analysis
Variable	OR (95% CI)	P-value	OR (95% CI)	P-value
Sex (male vs. female)	0.670 (0.419–1.071)	0.093
Median age at first dose of VDZ (≥ 46 yr vs. < 46 yr)	0.827 (0.522–1.310)	0.418
Median disease duration (≥ 7.36 yr vs. < 7.36 yr)	1.482 (0.933–2.354)	0.095
Duration of anti-TNFα treatment				0.026
≥ 3 mo vs. < 3 mo	2.714 (1.227–6.004)	0.007	2.209 (0.935–5.217)
0 mo vs. < 3 mo	3.245 (1.512–6.962)		3.087 (1.347–7.070)
Concomitant use of tacrolimus (yes vs. no)^a	1.174 (0.511–2.695)	0.706
Concomitant use of corticosteroid (yes vs. no)	1.072 (0.678–1.697)	0.766
Concomitant use of IM (yes vs. no)^b	1.357 (0.801–2.300)	0.256
Partial Mayo score (≥ 5 vs. ≤ 4)	0.363 (0.221–0.594)	< 0.001	0.412 (0.240–0.707)	0.001
Endoscopic findings
MES 2 vs. MES 0 or 1	0.875 (0.384–1.992)	0.191
MES 3 vs. MES 0 or 1	0.559 (0.238–1.313)
Hemoglobin (< 10 g/dL vs. ≥ 10 g/dL)	0.340 (0.713–0.668)	0.001	0.457 (0.203–1.032)	0.060
Albumin (< 3.0 g/dL vs. ≥ 3.0 g/dL)	0.213 (0.102–0.441)	< 0.001	0.362 (0.155–0.845)	0.019
CRP (≥ 0.26 mg/dL vs. < 0.26 mg/dL)	0.526 (0.327–0.846)	0.008	0.744 (0.435–1.272)	0.280

Table 1. Patient Baseline Demographic and Clinical Characteristics

Values are presented as number (%) unless otherwise indicated.

The number of patients with available data for each variable was as follows: Age at UC diagnosis: biologic-naïve (n=196), BMI: biologic-naïve (n=165), biologic-non-naïve (n=147), Duration of UC: biologic-naïve (n=196), Complete Mayo score: biologic-naïve (n=168), biologic-non-naïve (n=136), Hemoglobin: biologic-naïve (n=195), biologic-non-naïve (n=168), Albumin: biologic-naïve (n=191), biologic-non-naïve (n=165), CRP: biologic-naïve (n=194), biologic-non-naïve (n=166).

At the first dose of VDZ, i.e., concomitant.

Azathioprine and mercaptopurine.

SD, standard deviation; UC, ulcerative colitis; VDZ, vedolizumab; BMI, body mass index; CRP, C-reactive protein; NS, nonsignificant.

Table 2. Characteristics of Prior Biologics in the Biologic-Non-Naïve Group of Patients with UC

Values are presented as number (%) or mean±standard deviation.

Individual patients may have received more than 1 prior biologic therapy. None of the patients who received biologics before VDZ received ustekinumab (i.e., n=0).

Percentage of biologic-non-naïve group.

The number of patients treated with each agent was as follows: infliximab (n=90), adalimumab (n=84), golimumab (n=51), and tofacitinib (n=14).

Percentages in this section are percentages of each biologic-type group.

Reasons for discontinuation were accumulated from all time points of anti-TNFα therapy discontinuation.

UC, ulcerative colitis; VDZ, vedolizumab; TNFα, tumor necrosis factor α.

Table 3. Predictors of Clinical Remission up to Week 54 of VDZ Treatment for Ulcerative Colitis: Univariate and Multivariate Analyses

The number of patients using tacrolimus was n=40 within 3 months of starting VDZ treatment.

Azathioprine and mercaptopurine.

VDZ, vedolizumab; OR, odds ratio; CI, confidence interval; TNFα, tumor necrosis factor α; IM, immunomodulator; MES, Mayo Endoscopic Score; CRP, C-reactive protein.