The effectiveness of vedolizumab in advanced therapy-experienced ulcerative colitis patients: Real world data from the Inflammatory Bowel Disease of the Middle East (IBD-ME) Registry group

Abstract

Background:

Vedolizumab is an approved ulcerative colitis (UC) treatment. Multiple large randomized clinical trials have demonstrated the drug’s efficacy and safety. However, real-world data from Middle Eastern countries are spare. The study aims to evaluate the clinical efficacy of vedolizumab (VDZ) therapy in advanced therapy experienced UC patients.

Methods:

A retrospective electronic chart review of a cohort study of 153 moderately to severely active UC patients who failed or were intolerant to TNF antagonists and received vedolizumab from two large tertiary care centers was performed. Rates of clinical response and remission were retrospectively evaluated at 3,6, and 12 months post VDZ therapy using Patient Simple Clinical Colitis Activity Index (P-SCCAI); clinical response was defined as a decrease in P-SCCAI ≥3, and clinical remission was defined as a P-SCCAI score of ≤3 points. Logistic regression analysis was used to identify predictors of response to vedolizumab.

Results:

A total of 153 UC patients had sufficient data for analysis. Clinical remission rates were 61.9% for patients on vedolizumab every 8 weeks and 89.3% for those receiving every 4 (Q4) weeks dosing. A significant reduction in CRP and improvement of albumin post vedolizumab treatment were observed, and corticosteroids were stopped in most patients. In a multiple logistic regression analysis, several factors were found to influence the clinical effectiveness of VDZ in inducing remission. Female gender was associated with a higher likelihood of remission [OR =3.09, 95% CI = (1.05–9.13), P = 0.04]. Conversely, a greater number of biologics used prior to VDZ treatment was associated with a lower likelihood of remission [OR =0.418, 95% CI = (0.203–0.859), P = 0.017]. Patients with extensive disease (E3) had an increased likelihood of remission [OR =3.81, 95% CI = (1.32–10.97), P = 0.0129]. Additionally, a VDZ dosing frequency of Q4 weeks was associated with a significantly higher likelihood of remission [OR =6.08, 95% CI = (1.73–21.39), P = 0.0049]. No significant safety signals were reported.

Conclusions:

In this current real-world study, vedolizumab effectively achieved clinical response and remission in most advanced therapy experienced UC patients treated for up to 12 months. Future studies with larger sample sizes and more robust study designs should be conducted to further validate the results of this study.

INTRODUCTION

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) that mainly affects the rectum and colon in the form of continuous inflammation, which leads to significant healthcare challenges and impacts on the quality of patients’ lives.[1,2,3,4] While UC shares common pathophysiological mechanisms worldwide, the disease’s epidemiology, clinical presentation, and treatment patterns may exhibit regional variations influenced by genetic, environmental, and sociodemographic factors.[5,6,7] The disease incidence is rising steadily across the Middle East, particularly in the Kingdom of Saudi Arabia (KSA).[8,9,10,11] This growing incidence underscores the importance of region-specific research to understand UC’s impact on public health and healthcare expenditure in the Middle East, including KSA.[12]

In the management of UC, therapeutic strategies are designed to achieve and maintain clinical remission, alleviate symptoms, and enhance patients’ quality of life.[13] Conventional treatments such as 5-amino salicylates (5ASA), corticosteroids, immunomodulators, and advanced therapies such Anti-TNFs, vedolizumab, ustekinumab, and JAK inhibitors are the mainstay of UC therapy, guided by local and international guidelines.[14,15] However, the availability and utilization of these treatments can be significantly influenced by regional factors such as variations in drug accessibility, regulatory approval processes, and healthcare reimbursement policies. These factors pose unique challenges to UC management in the Middle East, including Saudi Arabia.

Tumor necrosis factor alpha (TNF-α) antagonists have been found to be effective for both inducing and maintaining remission in UC[16,17,18,19] and have significantly transformed the treatment of patients with IBD. However, this class of medication has several limitations, including increasing the risk of severe infections and malignancies and the potential for treatment failure due to primary or secondary loss of response.[20] As a result, new treatment options have been developed, one of which is vedolizumab (VDZ), which is a humanized monoclonal antibody that specifically recognizes the α4β7 heterodimer and selectively blocks gut lymphocyte trafficking without interfering with trafficking to the central nervous system.[21] In the GEMINI 1 study, a randomized, double-blind, placebo-controlled trial of VDZ in UC, the response rate for induction at week 6 was 47.1%, and that for maintenance at week 52 was 41.8%.[22]

In the context of the Middle East, including KSA, real-world evidence regarding the short- and long-term effectiveness and safety of biological therapies remains limited, necessitating region-specific research initiatives that address existing knowledge gaps and optimize UC management strategies in local populations. Accordingly, we present a retrospective cohort of UC patients who failed or showed intolerance to biologics or advanced therapy and were treated with VDZ. The study aimed to evaluate the clinical effectiveness of VDZ as a treatment for Saudi adult patients with UC.

PATIENTS AND METHODS

This retrospective review targeted adults diagnosed with UC, identified through electronic health records through the Inflammatory Bowel Disease Information System (IBDIS), from two University hospitals in two large cities (King Khalid University Medical City [KSUMC], King Saud University Riyadh, Saudi Arabia, and King Abdulaziz University (KAUH), Jeddah, Saudi Arabia. IBDIS is a comprehensive electronic database comprising nine sections encompassing all aspects of IBD. These sections include epidemiological data, symptoms, laboratory and radiological investigations, complications, and treatment options for individuals with IBD. Inclusion criteria comprised individuals aged >16 exhibiting refractory symptoms either clinically or endoscopically or demonstrating intolerance to TNF-α antagonists and were subsequently initiated on VDZ. Patients were followed up for a minimum of 12 months post VDZ initiation. Exclusion criteria: patients diagnosed with CD or indeterminate colitis and patients who stopped using vedolizumab due to allergy. The collected data included variables such as age, gender, disease duration, severity at diagnosis, family history, cigarette smoking status, perianal disease presence, disease behavior, and previous and concurrent medication for UC, including corticosteroids, budesonide, immunomodulators, and anti-TNF or advanced therapy. Laboratory parameters such as hemoglobin, albumin, and C-reactive protein (CRP) levels were also extracted.

Assessments were conducted at weeks 12, 24, and 52 post VDZ initiation. Clinical remission and response rates were evaluated using specific criteria, where a clinical response was defined as a decrease in Patient Simple Clinical Colitis Activity Index (P-SCCAI) ≥3, and clinical remission was defined as a P-SCCAI score of ≤3 points. The P-SCCAI is a translated version of the original Simple Clinical Colitis Activity Index (SCCAI) designed for patients. It is used to assess UC disease activity during remission. It consists of four domains: bowel frequency during the day, bowel frequency during the night, blood in stool, and general well-being. Each domain has one item. The domain “urgency of defecation” includes three items. Additionally, there is a domain called “extracolonic features” that comprises four extracolonic features: erythema nodosum, arthritis, uveitis, and pyoderma gangrenosum. The PSCCAI is comparable to the clinician-based SCCAI and biomarkers in detecting UC activity.[23] The study also documented glucocorticoid-free remission rates at 3, 6, and 12 months as well as at the end of the follow-up period, based on data from a single center (KSUMC).

Statistical analysis

Descriptive statistics were utilized to thoroughly summarize the characteristics of the study population. Continuous variables were summarized using measures such as means, standard deviations (SDs), medians, interquartile ranges (IQRs), minimum and maximum values, and 95% confidence intervals (CIs) where appropriate. Categorical variables were summarized using frequencies and percentages. Hypothesis testing was performed using a comprehensive range of appropriate statistical tests based on the nature of the data and research questions. The paired t-test was employed to compare means between two related groups, while Fisher’s exact test was utilized for categorical variables with small sample sizes. Additionally, a one-way analysis of variance (ANOVA) was conducted to assess differences in means among multiple groups. Univariate and multiple logistic regression analyses were conducted to identify significant clinical response and remission predictors. Odds ratios (ORs) and their corresponding 95% CIs were calculated. Covariates included demographic factors, disease characteristics, treatment regimens, and other relevant variables. All statistical analyses were done using SAS^® version 9.4 (SAS institute, Cary, NC, USA). A significance threshold of P value = 0.05 was adopted for all statistical tests, indicating statistical significance. Multiple imputation by fully conditional specification was utilized for missing lab data.

Ethical considerations

This study adhered to the ethical principles outlined in the Declaration of Helsinki and was conducted by established research protocols. Approval for the study protocol was obtained from the Ethical Committee of the Institute for Inflammatory Bowel Disease (IBD) Database Registry; IRB project number E-11-538. The confidentiality and privacy of participant data were rigorously maintained throughout the study, with all data handling procedures conducted in compliance with relevant data protection regulations and guidelines.

RESULTS

Demographic and clinical characteristics of study participants

This study included a total of 153 patients, with 51.6% being males. The majority of the enrolled patients were aged 25 to 45, comprising 68.7% of the study population. Disease duration varied among participants, with 47% reporting a duration of 5 to 10 years and 31.3% reporting a duration exceeding 10 years. The prevalence of smoking among the study cohort was low, with 84.9% classified as nonsmokers. Regarding disease location, 54.9% of the patient population had left-sided colitis, and 41.8% had extensive colitis. Extraintestinal systems manifestations (EIMs) were identified in 37.2% of the study cohort, predominantly affecting the musculoskeletal (20.2%). Approximately 30.7% of the patients had an intolerance to anti-TNFs. Among our cohort 26.1% failed infliximab, 13% failed adalimumab, 1.3% failed ustekinumab, and 28.1% failed more than 2 advanced therapies. Concurrent use of immunomodulators was observed in 47.6% of patients, with thiopurines being the most utilized (45.7%). Corticosteroid therapy was administered to 29.4% of patients, with 24.1% receiving a dosage of 10–20 mg and 5.2% receiving a dosage exceeding 20 mg daily. Most patients (81.7%) received VDZ at 8-week intervals, while 18.3% were administered VDZ at 4-week intervals [Table 1].

Table 1.

Patient baseline characteristics of study participants

Characteristic	n (%)
Age
<25 yrs.	40 (26.14)
25-55 yrs.	105 (68.63)
>55 yrs.	8 (5.23)
Duration of illness
<5 yrs.	33 (21.57)
≥5-10 yrs.	72 (47.06)
>10 yrs.	48 (31.37)
Gender
Male	79 (51.63)
Female	74 (48.37)
Smoking status
Active smokers	15 (9.80)
Passive smokers	2 (1.31)
Ex-smokers	6 (3.92)
Nonsmokers	130 (84.97)
Family history of ulcerative colitis
Yes	27 (17.65)
No	126 (82.35)
Disease location
Ulcerative proctitis	5 (3.27)
Left-sided colitis	84 (54.90)
Extensive colitis	64 (41.83)
Extraintestinal manifestations
Bone and Joints	31 (20.26)
Skin	8 (5.23)
Primary sclerosing cholangitis (PSC)	4 (2.61)
Aphthous stomatitis	4 (2.61)
Previous treatment with immunomodulators
No previous treatment with immunomodulators	80 (52.29)
Thiopurine	70 (45.75)
Methotrexate	3 (1.96)
Previous biologic therapy
Intolerance to treatment with biologics	46 (30.07)
Infliximab	40 (26.14)
Adalimumab	20 (13.07)
Ustekinumab	2 (1.31)
Tofacitinib	1 (0.65)
Failed two biologic medications (Anti-TNFs)	28 (18.30)
Failed three or more biologic medications (Anti-TNFs, IL 12, 23 and JAKi)	15 (9.80)
Disease severity based on Mayo score
Inactive disease	3 (1.96)
Mild	30 (19.61)
Moderate	65 (42.48)
Severe	55 (35.95)
Concurrent use of corticosteroids
Yes	45 (29.41)
No	108 (70.59)
Corticosteroids dosage
10-20 mg	37 (24.18)
>20 mg	8 (5.23)
Vedolizumab maintenance dosage frequency
Every 4 weeks	28 (18.30)
Every 8 weeks	125 (81.70)

Study outcomes

Clinical efficacy

Clinical efficacy outcomes were assessed using biochemical markers and clinical response using CRP, albumin levels, and the P-SCCAI, at the end of the follow-up period, and compared to the baseline. The results are summarized in Table 2.

Table 2.

Different laboratory and disease severity measures differ at baseline and 12-month follow-up

Measure	Baseline value	12-Month value	Difference (95% CI)	P
Albumin (g/L)	36.39±7.02	38.65±6.67	–2.26 (–3.56 - –0.97)	0.0007
CRP (mg/L)	19.50±35.12	11.16±13.98	8.34 (2.66-14.01)	0.0042
Patient Simple Clinical Colitis Activity Index (P-SCCAI)	7.69±4.28	0.96±1.71	6.73 (6.06±7.40)	<0.0001

The baseline CRP level was 19.50 ± 35.12, and it decreased significantly to 11.16 ± 13.98 after 12 months of VDZ therapy, indicating a substantial reduction in inflammation (difference =8.34, 95% CI: 2.66–14.01, P = 0.004) as shown in Figure 1. Additionally, the baseline albumin level increased from 36.39 ± 7.02 to 38.65 ± 6.67 after 12 months of VDZ therapy, demonstrating an improvement in nutritional status (difference = –2.26, 95% CI: –3.56 to –0.97, P = 0.0007). The baseline P-SCCAI score was 7.69 ± 4.28, and it decreased to 0.96 ± 1.71 after 12 months of VDZ therapy, reflecting a notable reduction in disease activity (difference = 6.73, 95% CI: 6.73–7.40, P < 0.0001) as shown in Figure 2. Glucocorticoid-free remission data analysis from KSUMC revealed a decreasing trend in percentage over the follow-up period, with a particularly intriguing spike at 12 months. The percentages of glucocorticoid (GC)-free remission at 3 months, 6 months, and 12 months were 80.9%, 88.1%, and 90.1%, respectively.

Figure 1.

The mean C-reactive protein (CRP) levels at baseline and 3 months, 6 months, and 12 months later

Figure 2.

The mean Patient Simple Clinical Colitis Activity Index (P-SCCAI) scores at baseline, 6 months, and 12 months

The cross-tabulation analyses revealed significant P values for clinical response and clinical remission when comparing 3 months to 6 and 12 months. However, the percentages at the end of the follow-up period did not significantly correlate with values at 3 months. The frequency of VDZ dosing significantly affected the remission rate in less than 20% of our cohort [Figure 3]. Clinical remission rates were 61.9% for patients receiving VDZ every 8 weeks, which increased to 89.3% for those on VDZ every 4 weeks.

Figure 3.

Remission rates across dosing frequency of vedolizumab (4-week dosing vs 8-week dosing)

Safety

During the follow-up period, no instances of adverse events, such as malignancies or infections requiring antibiotic treatment, were reported among the study participants. However, it is imperative to note that adverse events were not absent, albeit their incidence was minimal. Of note, three patients reported experiencing fatigue, two patients reported palpitations, and one patient had an exacerbation of sinusitis during treatment with VDZ. Notably, all reported adverse events were categorized as mild and did not necessitate treatment discontinuation. Otherwise, no serious adverse events, such as malignancies or infections, were reported.

Predictors of effectiveness

Our multiple logistic regression analysis provides interesting insights on the clinical effectiveness of VDZ in inducing remission. The following variables were found to have a significant impact: female gender, with more than three times higher odds of achieving clinical remission than their male counterparts (OR 3.09, 95% CI 1.05–9.13, P 0.040); the number of biologics used prior to VDZ, which inversely affects the odds of achieving clinical remission (OR 0.41, 95% CI 0.20–0.85, P 0.017); disease extensions (E3), which is associated with higher odds of clinical remission (OR 3.81, 95% CI 1.32–10.9, P 0.012); and the VDZ dose frequency, with a 4-week frequency showing more than 6 times higher odds of achieving clinical remission than an 8-week frequency (OR 6.08, 95% CI [1.73- 21.3], P 0.004). These results are shown in Table 3.

Table 3.

The odds of achieving clinical remission (Patient Simple Clinical Colitis Activity Index [P-SCCAI] <3 points)

Variable	Odds ratio (OR)	95% Confidence Limits (95% CI)		P
		Lower	Upper
Gender (Female vs. Male)	3.099	1.052	9.132	0.0402*
Age	1.036	0.990	1.083	0.1248
Number of biologics used before	0.418	0.203	0.859	0.0176*
Concurrent use of corticosteroids	1.515	0.470	4.890	0.4868
Disease location (Extensive colitis vs. ulcerative proctitis and left-sided colitis)	3.818	1.328	10.977	0.0129*
Disease duration in years	0.997	0.970	1.024	0.8074
Vedolizumab dosage frequency (every 4 weeks vs. every 8 weeks)	6.087	1.731	21.396	0.0049*
Mayo Score (Severe vs. mild and moderate)	0.955	0.483	1.886	0.8935

*P<0.05

DISCUSSION

This study assessed the real-world effectiveness and safety of VDZ in long-standing UC patients who had failed or were intolerant to advanced therapy. Notably, it is the first study conducted in Saudi Arabia. As evaluated by biochemical and clinical parameters, the clinical efficacy outcomes demonstrated significant improvements in disease activity following VDZ therapy. The reduction in CRP levels, elevation in serum albumin concentrations, and a decrease in P-SCCAI scores signify effective suppression of inflammation and potential restoration of mucosal integrity. Furthermore, the absence of adverse events requiring treatment cessation or serious complications underscores the safety profile of VDZ in anti-TNF-experienced/intolerant UC patients. The low rate of adverse effects favors the tolerability of VDZ therapy in this population. Based on multiple studies, VDZ represents an effective and safe treatment option for patients with moderate–severe UC.[24,25,26,27] A comparable real-life study conducted across multiple Belgian IBD centers clearly demonstrated that VDZ was an effective therapy for approximately 70% of UC patients who were resistant or intolerant to at least two TNF antagonists. However, the study had a shorter duration of follow-up, lasting up to 14 weeks.[28] Similar findings were published in a retrospective Korean study that examined the real-world effectiveness and safety outcomes of VDZ in Korean UC patients who had failed anti-TNF therapy. The study included 105 patients and found that VDZ was effective and well-tolerated within the first 14 weeks of use in a real-world setting. It is important to note that these studies differed from the current study in terms of the shorter duration of follow-up, ranging from 10 to 14 weeks.[29] Another study aimed to compare the effectiveness of IFX versus VDZ in 59 UC patients who were induced with either IFX or VDZ. The study found that 66.7% of patients induced with IFX and 78.1% induced with VDZ were clinical responders. The response rates per 100 person-weeks were similar for VDZ and IFX. The study concluded that there was no statistically significant difference in the effectiveness of VDZ compared to IFX in terms of inducing clinical response (incidence rate ratio: 0.97, 95% confidence interval: 0.53–1.77).[30] A recent study compared VDZ to ADA in 161 UC refractory patients who had failed or were intolerant to IFX. The authors concluded that VDZ might be the therapy of choice for UC patients who experienced secondary failure with IFX.[31] Another real-world data study conducted in Germany examined clinical remission in 133 UC patients, including biologic-naïve patients and those with prior anti-TNF failure. Clinical remission was defined as a total Mayo score ≤2 with no individual subscore >1 or a partial Mayo score ≤2 with no individual subscore >1. In the biologic-naïve subgroup, the estimated rates of patients achieving clinical remission by week 26 were 50.1% for VDZ and 31.5% for anti-TNF agents. In the subgroup with one prior anti-TNF agent, clinical remission was estimated to have been achieved by 55.5% of VDZ patients compared to 30.7% of anti-TNF patients.[32] These comparative effectiveness results were consistent with our results and other published studies. In a similar study from Kuwait that evaluated the effectiveness of UST and VDZ in IBD patients who had previously received at least one anti-TNF agent, the primary outcomes measured were the percentage of hospitalization, surgery, steroid-free remission, and mucosal healing. Mucosal healing was defined as a Mayo score of 0 or 1 in UC patients. The study demonstrated the effectiveness of VDZ in patients with IBD after failing anti-TNF therapy.[33]

The VICTORY study investigated the predictors of response and remission in UC patients treated with VZD. It revealed that prior failure of TNF antagonists, higher baseline CRP levels, higher disease activity scores at the beginning of the study, and longer disease duration were associated with decreased response rates to VDZ. These findings offer a ray of hope for clinicians as they can now identify patients who are more likely to benefit from VDZ therapy and optimize treatment strategies for IBD.[34]

The current study offers several advantages. It utilizes patient-reported outcomes and CRP levels, which are valuable parameters for evaluating the real-life experiences of UC patients. Additionally, the study provides important clinical implications as it helps guide physicians on the most appropriate second-line therapy after failing an anti-TNF agent. However, it is essential to acknowledge the study’s limitations, including its retrospective design and the lack of robust endpoints, such as endoscopic remission determined by colonoscopy. Additionally, the duration of follow-up was relatively short, with a maximum of 12 months. Future research endeavors should focus on prospective, multicenter studies with larger patient cohorts to validate and extend the current findings.

To summarize, in this real-world study, VDZ effectively achieved clinical response and remission in most UC patients who were refractory or intolerant to advanced therapy and were treated for up to 12 months. The remission rate was significantly influenced by female gender, number of previously used biologics, and VDZ frequency every 4 weeks.

Conflicts of interest

Dr. Nahla Azzam has served on advisory boards and received speaker and consultation fees from Abbvie, Takeda, Janssen, Lilly, Ferring, Falk, Sandoz, Hikma, Pfizer, BMS, and Organon.

Dr. Mahmoud Mosli has served on advisory boards and received speaker and consultation fees from Abbvie, Takeda, Janssen, Lilly, Ferring, Falk, Sandoz, Sanofi, Hikma, Pfizer, BMS, and Organon. Dr. Mosli has received research funding from Celgene, Pfizer, and Takeda.

Dr Majid Almadi serves on a data safety monitoring board, also served on advisory boards for Pfizer, Alhikma, Jansen, and AbbVie, and is the current President of the Saudi Gastroenterology Association.

Dr Heba Alfarhan served on advisory boards and received speaker and consultation fees from Takeda, Pfizer, Alhikma, Jansen, Bristol-Mayers Squibb, Ferring and AbbVie, and is the current President of the Kuwait Gastroenterology Association.

The rest of the authors have no conflict of interest related to this study.

Funding Statement

Nil.