Treatment of Vedolizumab With Exclusive Enteral Nutrition in Adult Patients With Moderate to Severe Crohn's Disease (Crohn Exclusive Enteral Nutrition Study)

Abstract

INTRODUCTION:

Despite increasing studies confirming the efficacy of vedolizumab (VDZ) in Crohn's disease (CD), improving the responses to this biologic agent remains challenging in clinical practice. In this article, we investigated the efficacy of combined treatment of VDZ and 16-week exclusive enteral nutrition (EEN) in moderately to severely active CD.

METHODS:

From October 2020 to October 2023, 81 patients with moderately to severely active CD treated with VDZ from 2 inflammatory bowel disease centers were retrospectively selected. Forty-one patients received treatment of VDZ with concomitant 16-week EEN (VDZ + EEN cohort), and 40 patients received VDZ treatment alone (VDZ cohort). Clinical and biological outcomes were evaluated. Endoscopic response and mucosal healing were assessed by colonoscopy at weeks 16 and 52.

RESULTS:

There was no statistically significant difference between 2 groups at baseline for demographic and clinical characteristics. Compared with patients treated with VDZ alone, patients in the VDZ + EEN cohort achieved higher rates of clinical response (84.2% vs 40.0%), clinical remission (81.6% vs 30.0%), endoscopic response (91.4% vs 34.6%), including mucosal healing (85.7% vs 26.9%) at week 16. The superiority of VDZ + EEN treatment sustained in maintenance, with 76.7% (vs 33.3%) clinical response, 70.0% (vs 26.7%) clinical remission, 76.9% (vs 33.3%) endoscopic response, and 61.5% (vs 26.7%) mucosal healing at week 52. None of the patients experienced severe adverse events.

DISCUSSION:

VDZ with concomitant 16-week EEN might be an effective and optimized approach with solid efficacy in the induction and maintenance treatment of active CD.

INTRODUCTION

Crohn's disease (CD) is a chronic progressive and relapsing inflammatory bowel disease (IBD) that can affect the entire intestinal tract and lead to bowel damage and disability with the development of disease (1). Emerging biologics and small-molecule drugs have been approved for IBD therapy and have changed the disease's clinical status. However, an irrefutable fact is that most biologics including vedolizumab (VDZ) remain at a standstill regarding the response and remission in many cases (2). As a gut-selective monoclonal anti-α4β7-integrin humanized antibody that selectively blocks T-lymphocyte trafficking into the gastrointestinal mucosa, VDZ has been verified as a targeted therapy of moderately to severely active CD (3). Pivotal randomized clinical trials and real-world clinical practice confirmed the promising effects of VDZ on CD clinical outcomes, including increased rates of corticosteroid-free remission and mucosal healing (4–6). However, rates of endoscopic remission to VDZ treatment rarely exceed 30% (7,8). Therefore, how to improve the efficacy of VDZ in moderately to severely active CD is a clinical challenge.

Although many strategies such as intensive treatment based on inflammatory burden, therapeutic drug monitoring, switching or sequential therapy, and dual-targeted therapy have been explored to overcome the existing ceiling of IBD treatment, the long-term response rate is still unsatisfactory and also limited by adverse effects and cost (9,10). Exclusive enteral nutrition (EEN) is another optimization option that assists in intestinal recovery and leads to direct anti-inflammatory effects in the gut (11–14). Currently, EEN has been suggested as the first-line therapy to induce remission of pediatric CD and has been shown to be more effective than steroids in improving pediatric growth and mucosal healing (11–14). Despite evidence of EEN in adults CD patients with stricturing and other complex disease such as abscesses, postoperative recurrences, and fistulizing variants, especially when combined with biologics, the efficacy of EEN is often underestimated in clinical practice. Till now, EEN is still recommended as an adjuvant therapy in adult CD (15). Previous studies indicated that EEN was an effective concomitant therapy with infliximab during induction and treatment in active and complex CD (16,17). Several evidence also supported concomitant use of EEN as an independent factor associated with sustained response to infliximab (17–19). These results indicated that concomitant EEN treatment might be a potential strategy to promote the efficacy of VDZ in adult CD.

In the study, we reported on the real-world cohort of adult patients with active CD to receive VDZ with or without concomitant 16-week EEN. The efficacy and safety of this combined therapeutic strategy were evaluated.

METHODS

Patients

In this retrospective cohort study, a total of 81 patients with active moderate-to-severe CD (defined as CD Activity Index [CDAI] ≥220) were selected from October 2020 to October 2023 at the IBD center of Renmin Hospital of Wuhan University and First Hospital of Jingzhou City, Hubei, to receive VDZ treatment with (VDZ + EEN cohort) or without (VDZ cohort) concomitant use of 16-week EEN in inducing therapy (Figure 1). Patients without moderate or severe disease as per CDAI, EEN lasting less than 16 weeks, or with a confirmed diagnosis of ulcerative colitis, pouch, ostomy, or prior extensive bowel resection were excluded from the study.

Figure 1.

Therapeutic strategy and flow chart of study. (a) Therapeutic strategy in patients with moderate to severe CD treated by VDZ with or without concomitant EEN. (b) Flow chart of study. CD, Crohn's disease; EEN, exclusive enteral nutrition; VDZ, vedolizumab.

VDZ combined EEN and VDZ alone would be recommended to all patients with CD, and patients made the final decisions about the therapeutic strategy. VDZ treatment was performed according to the approved standard protocol as 300 mg intravenous infusions on day 1 and at weeks 2, 6, and 14, followed by maintenance doses every 8 weeks. Some patients in VDZ cohort have received short-term intravenous corticosteroid to help to alleviate symptoms. Patients in VDZ + EEN cohort were treated with 16-week EEN since VDZ introduction (day 1) by a formulation of total protein enteral nutrition powder (Nutrison, NUTRICIA, Netherland or Ensure, Abbott Laboratories B.V) with a caloric requirement of 120% of daily (based on ideal body weight) (14). The full volume of EEN feeds was reached and tolerated within 48–72 hours after initiation. Once EEN commenced, patients were assessed by certificated dietitians on return visit. In the meantime, they could report any problem during follow-up. Volumes could be increased if the patient was hungry and the rate could be decreased if there were side effects, such as discomfort or distension. Other than formula, patients were allowed to consume only water orally. The route of EEN administration was oral for all patients. After 16 weeks of EEN, patients were gradually switched to an open diet according to diet education and guidance of the IBD Medical Center, Wuhan University of Renmin Hospital. The duration of follow-up was 52 weeks. Patients and physicians engaged in close communication through the online group. Patients who were intolerant of EEN would receive appropriate feedback in time. Second, during the follow-up, medical teams consistently collected the information about the patient's prescription including the dosage of EEN they took and recorded their compliance.

The flowchart of the study is shown in Figure 1. This study was approved by the ethics committee of Renmin Hospital of Wuhan University (#WDRY2022-K140).

Data collection

The inclusion date coincided with the time of the first intravenous VDZ injection. Patients were followed up until October 2023 if no events occurred. Data were retrospectively extracted from each patient's medical record and database from the IBD center of Renmin Hospital of Wuhan University. Data of patients included age, sex, disease activity, medication, and body composition. Data were updated in a standardized format.

Clinical outcomes

Clinical response was defined as a decrease in CDAI by 70 points or more from the baseline. Clinical remission was defined as an absolute reduction of CDAI to <150 after the intervention. Clinical response and clinical remission were assessed at weeks 16 and 52 from the start of VDZ induction. VDZ failure was defined as (i) withdrawal of VDZ due to loss of response (defined as an initial response to VDZ with a loss of response during the maintenance phase according to physician assessment) or (ii) intolerance, and/or (iii) the need for surgery. In addition, clinical outcomes and the levels of inflammatory biomarkers including fecal calprotectin (FC) were assessed at weeks 16 and 52.

Endoscopic outcomes

Endoscopic outcomes including endoscopic response (defined as a ΔSimple Endoscopic Score for CD score ≤6) and mucosal healing (defined as a lack of any visible ulcerations) were evaluated at weeks 16 and 52 for colorectal and terminal ileum lesions.

Safety assessments

Safety data were recorded retrospectively from the medical records for each patient. We also collected safety outcomes including patient-reported adverse events, serious adverse events requiring hospitalization or treatment discontinuation, and CD-related surgery.

Statistical analysis

Descriptive statistics for demographic and clinical characteristics include mean (SD) or median (interquartile range [IQR]) for continuous variables and frequency distributions for categorical data. The Kaplan-Meier method was used to assess cumulative VDZ failure-free persistence every 4 weeks after treatment was begun and at the end of follow-up. Continuous variables were compared using t-tests or Wilcoxon matched pairs signed rank tests for parametric and nonparametric data, respectively. P < 0.05 was considered to be significant. Analyses were conducted using SPSS 24.0 (IBM, Chicago, IL).

RESULTS

Patient characteristics

A total of 81 patients with moderately to severely active CD including 40 patients in VDZ cohort and 41 patients in VDZ + EEN cohort were retrospectively selected between October 2020 and October 2023. There was no statistically significant difference between 2 cohorts at baseline in terms of relevant demographic and clinical characteristics including age and sex (Table 1). The mean duration of disease, surgical history, extraintestinal manifestations, CD behavior, site of involvement, and perianal disease also did not differ between 2 cohorts. In both cohorts, most patients had a noncomplicated phenotype. Around 60% patients had nonstricturing and nonpenetrating disease, nearly 30% with severe activity, about 20% patients had received anti-tumor necrosis factor and over 10% had undergone CD-specific surgery in the past. No significant differences were shown between VDZ and VDZ + EEN cohorts regarding previous history of immunosuppression and biomarker levels (CRP, erythrocyte sedimentation rate, and FC).

Table 1.

Phenotype and clinical characteristics of study patients at diagnosis (n = 81)

Characteristics	VDZ (n = 40)	VDZ + EEN (n = 41)	P value
Age, yr (mean ± SD)	33 ± 6.1	34 ± 9.2	0.710
Sex
Male	27 (67.5)	29 (70.7)	0.753
Female	13 (32.5)	12 (29.3)
Active smoker			0.678
Smoker	1 (2.5)	1 (2.4)
Nonsmoker	35 (87.5)	38 (92.7)
Former smoker	4 (10.0)	2 (4.9)
Disease duration, yr (IQR)	3.5 (1–17)	3.0 (1–8)	0.350
Surgical resection	5 (12.5)	4 (9.8)	0.694
CD, age at diagnosis			0.750
A1	0 (0)	0 (0)
A2	29 (72.5)	31 (75.6)
A3	11 (27.5)	10 (24.4)
Location			0.897
L1	5 (15.6)	7 (25.0)
L2	4 (10.0)	5 (12.2)
L3	31 (77.5)	28 (68.3)
L4	1 (2.5)	1 (2.4)
Behavior			0.847
B1	26 (65.0)	28 (68.3)
B2	10 (25.0)	14 (34.1)
B3	5 (12.5)	5 (12.2)
Disease activity			0.943
Moderate	28 (70.0)	29 (70.7)
Severe	12 (30.0)	12 (29.3)
Perianal disease	3 (7.5)	3 (7.3)	0.975
Extraintestinal manifestation	2 (5.0)	1 (2.4)	0.542
Malnutrition	12 (30.0)	14 (34.14)	0.690
Previous treatment
Steroids	30 (75.0)	2 (4.88)	<0.0001
Azathioprine	8 (20.0)	9 (22.0)	0.830
Anti-TNFα biologics (infliximab, adalimumab)	13 (32.5)	13 (31.7)	0.939
Immunomodulators at baseline
Yes	1 (2.5)	2 (4.9)	0.571
CRP at baseline			0.753
<5 mg/L	4 (10.0)	5 (12.2)
≥5 mg/L	36 (90.0)	36 (87.8)
FC at baseline			0.718
< 60 µg/g	3 (7.5)	4 (9.8)
≥ 60 µg/g	37 (90.6)	37 (90.2)

Data are presented as number (%) unless otherwise indicated. Montreal classification of CD: age at diagnosis: A1 (below 16 yr), A2 (between 17 and 40 yr), and A3 (above 40 yr); disease location: L1 (terminal ileum), L2 (colon), L3 (ileocolon), L4 (upper gastrointestinal tract), and p (perianal disease modifier); disease behavior: B1 (nonstricturing and nonpenetrating), B2 (structuring), and B3 (penetrating).

5-ASA, 5-aminosalicylic acid; CD, Crohn's disease; CRP, C-reactive protein; EEN, exclusive enteral nutrition; FC, fecal calprotectin; IQR, interquartile range; TNF, tumor necrosis factor; VDZ, vedolizumab.

Clinical outcomes

In current 2 cohorts, patients treated by VDZ + EEN achieved significantly higher clinical response (84.2% [32/38] vs 40.0% [12/30], P < 0.001) and clinical remission (81.6% [31/38] vs 30.0% [9/30], P < 0.001) compared with VDZ cohort at week 16 (Figure 2). The superiority of clinical outcomes in VDZ + EEN cohort sustained in maintenance, with 76.7% (23/30, P = 0.005) clinical response and 70.0% (21/30, P = 0.006) clinical remission at week 52 which was significantly greater than that in VDZ cohort (33.3% [5/15] clinical response and 26.7% [4/15] clinical remission).

Figure 2.

Clinical responses and clinical remission in moderate to patients with severe Crohn's disease after treatment of VDZ with or without concomitant EEN. Clinical response (a) and clinical remission (b) were assessed at weeks 16 and 52 after VDZ treatment with or without concomitant EEN. EEN, exclusive enteral nutrition; VDZ, vedolizumab.

We further evaluated the efficacy of the current treatment strategy using sensitive biomarker levels (FC). 92.1% (35/38) and 70.0% (21/30) patients in VDZ + EEN cohort reached normal FC levels at weeks 16 and 52, respectively, while 40% (12/30 at weeks 16 and 6/15 at week 52) patients in VDZ cohort obtained FC normalization.

Endoscopic outcomes

Endoscopic outcomes are shown in Figure 3. For patients with colorectal lesions, 91.4% (32/35, P < 0.001) and 76.9% (20/26, P = 0.006) achieved endoscopic response at weeks 16 and 52, respectively, when compared with patients in VDZ cohort (34.6% [9/26] at week 16 and 33.3% [5/15] at week 52). Mucosal healing was observed in 85.7% (30/35, P < 0.001) at week 16 and 61.5% (16/26, P = 0.031) at week 52, respectively. In VDZ cohort, 26.9% (7/26) and 26.7% (4/15) patients obtained mucosal healing at weeks 16 and 52, respectively.

Figure 3.

Endoscopic response and mucosal healing of CD patients with VDZ treatment. Endoscopic response (a) and mucosal healing (b) were evaluated at weeks 16 and 52 after VDZ introduction for patients with CD. CD, Crohn's disease; EEN, exclusive enteral nutrition; VDZ, vedolizumab.

In relation to terminal ileum disease, VDZ + EEN treatment showed significantly improved endoscopic results. Endoscopic response was achieved in 88.0% (22/25, P < 0.001) and 73.7% (14/19, P = 0.013) patients at weeks 16 and 52, respectively, while patients in VDZ cohort only achieved 27.3% (6/22) at week 16 and 27.3% (3/11) at week 52. In VDZ + EEN cohort, 80.0% (20/25) (vs 18.2% [4/22], P < 0.001) and 57.9% (11/19) (vs 18.2% [2/11], P = 0.034) patients obtained mucosal healing at weeks 16 and 52, respectively, when compared with patients treated with VDZ alone (Figure 4).

Figure 4.

Relapse-free rate of Crohn's disease patients with VDZ treatment. EEN, exclusive enteral nutrition; VDZ, vedolizumab.

VDZ discontinuation and adverse events after treatment

Discontinuation of VDZ after treatment occurred in 11 (26.8%) patients in VDZ + EEN cohort and 28 (70%) patients in VDZ cohort during the follow-up. Mean time from initial therapy to discontinuation of VDZ was 9.7 months (IQR, 5–12 months) for VDZ + EEN–treated patients and 7.6 months (IQR, 3–12 months) for VDZ-treated patients without EEN. The most common reason was failure or loss of response to the drug (7 patients in VDZ + EEN cohort and 22 patients in VDZ cohort). Other reasons were need for surgery (2 patients in VDZ + EEN cohort and 5 patients in VDZ cohort) and patient's self-decision (2 patients in VDZ + EEN cohort and 1 patient in VDZ cohort). None of the patients developed serious adverse events. Overall, gastrointestinal intolerance was the most common adverse event for patients treated by VDZ + EEN. Of these, 8 (19.5%) patients presented mild EEN-related diarrhea but never stopped enteral nutrition until 16 weeks later.

DISCUSSION

Although the randomized placebo-controlled trials confirmed the efficacy and safety of VDZ in CD, improving responses to this biologic agent remains challenging in clinical practice. In the GEMINI 2 pivotal phase 3 clinical trial of VDZ for CD, approximately one-third of patients with active CD achieved corticosteroid-free remission at week 52 (5). Similar results were supported in real-word and meta-analysis of observational studies (20,21). These data underscored that while a substantial proportion of treatment-resistant patients respond to VDZ therapy, the majority did not. Albeit dose escalation by an additional dose at week 10 or shortening infusion intervals from every 8 weeks to every 4 weeks increased clinical response rates of patients with CD who had not responded in standard administration, endoscopic healing was still limited (22). Therefore, it is critical but challenging to explore an effective optimization strategy to improve clinical and endoscopic outcomes in VDZ induction and long-term maintenance.

Multiple factors may contribute to nonresponse or insufficient response of biological agents, including concurrent intestinal infection, inadequate therapeutic drug concentrations, and importantly inflammatory burden (23). There were various strategies which had been tested for the management of CD, but the principle behind all these strategies involved the enrichment and depletion of anti-inflammatory and proinflammatory components, respectively (24). Although the precise etiopathogenesis of CD remained unknown, a number of lines of evidence showed that inappropriate diet was an important factor responsible for the onset of CD (25).

Dietary manipulation was considered a more physiological and safer strategy to manage the CD-associated inflammation, with an additional advantage of improving the nutritional status of these patients (26). The ability of EEN in inducing the clinical response and supporting nutritional built-up made it an important therapeutic option both as an adjunct or exclusively in the management of CD (27). Recent cohort studies confirmed the role of 8-week EEN in inducing clinical remission for complicated CD (26). Although the optimistic role of EEN in biologics induction and maintenance therapy for pediatric luminal CD was already established (28–30), the evidence for adult CD was heterogeneous, with meta-analysis reporting it as inferior to steroids (31). Till now, the recommended duration of EEN for inducing CD remission was 8–12 weeks (31,32). However, recent findings by Logan et al showed that after ending 8-week EEN, the reduction in FC disappeared rapidly after food reintroduction (33). These results indicated that 8-week EEN did not predict the length of remission. Seldom studies explored if a longer duration of EEN was more beneficial in CD treatment. Here, we extended the duration of EEN to 16 weeks for active CD induction and assessed the efficacy of combined treatment with VDZ and concomitant 16-week EEN in clinical and endoscopic outcomes.

Our data on clinical response confirmed the efficacy of current combined treatment. At week 16, 84.2% (32/38) reached clinical response, including 81.65% (31/38) clinical remission. Furthermore, clinical response remained relatively stable in the long-term (76.7% [23/30] at week 52), and clinical remission reached 70.0% (21/30). Furthermore, deep biologic remission was achieved by sustained reducing inflammatory indices FC (from 92.1% normalization at week 16 to 70% at week 52).

Endoscopic assessment further supported our combined therapeutic strategy of VDZ and EEN in the active CD induction regimen. 32 of 35 (91.4%) patients with colorectal lesions achieved endoscopic response. More importantly, mucosal healing was reached in 85.7% (30/35) patients. In maintenance, endoscopic response and mucosal healing were still relatively stable. At week 52, 76.9% (20/26) of patients with colonic lesions achieved endoscopic response and 61.5% (16/26) for mucosal healing. Sufficient reduction of bowel inflammatory burden by 16-week EEN and VDZ in induction most possibly contributed to these sustained clinical and endoscopic outcomes in the long-term regimen.

Involvement of the small intestine induced a much poorer nutrition status and isolated ileal CD had a lower response or remission with the biologic intervention than colonic CD (34). Although the role of EEN in small intestine involvement of adult CD was not well established, some studies observed that mucosa healing was more common in terminal ileum than colon after taking EEN (35). Therefore, we further explored the endoscopic outcomes of terminal ileum lesions. Our results indicated that patients in VDZ + EEN cohort achieved higher levels of endoscopic response (88.0% [22/25] at week 16 and 73.7% [14/19] at week 52) and mucosal healing (80.0% [20/25] at week 16 and 57.9% [11/19] at week 52). Such high rates of endoscopic response and mucosal healing for terminal ileum lesions supported the optimized efficacy of combined therapeutic strategy with VDZ and concomitant EEN treatment.

Our study provided informative findings regarding the efficiency of VDZ optimization by combined treatment with 16-week EEN in moderate to severe CD. Nevertheless, there are still limitations of this study that need to be considered. The main limitation was the retrospective design and small sample size. However, it was important to note that the data were collected from 2 large Chinese IBD regional centers with admitted IBD clinical treatment and research capabilities. Furthermore, patients selected in our study were young populations with a mean age of 33 years, relatively short disease duration (about 3 years), predominantly noncomplex biological behavior phenotype (around 60%) and a high proportion of patients with VDZ treatment at first-line (around 60%). These factors also contributed to significant efficacy of VDZ in this study. Nevertheless, better matched, prospective, and a larger scale of multicenter cohort study for a longer follow-up time required in the future. In this study, a certain and constant amount of EEN was started at the beginning of VDZ treatment with a duration of 16 weeks. Thus, it would be of value to further evaluate whether 16-week EEN was more effective than shorter EEN administrations in active patients with CD.

In conclusion, our results provided evidence that combined treatment with VDZ and concomitant 16-week EEN was an efficient optimization method with promising clinical outcomes in patients with moderately and severely active CD. The study also provided insight and reference for the optimization of other biological agents.

CONFLICTS OF INTEREST

Guarantor of the article: Ping An, MD.

Specific author contributions: J.W., J.L., A.Y., Y.X.: study concept and design, data analysis, and manuscript preparation. L.Z., H.R., J.K., J.S., Q.Z., Y.W.: data collection. W.W., J.Z., Z.T., H.W.: data analysis. P.A.: study concept and design, manuscript preparation, patient identification, coordination of image evaluation by endoscopists, and critical revision of the manuscript. All authors approved the final draft that is submitted.

Financial support: This study was funded by the National Natural Science Foundation of China (Grant Number 82170632 [to Ping An]), the Fundamental Research Funds for the·Central·Universities (Grant Number 2042024kf0040 [to Ping An]), Teaching and Research Project of Wuhan University School of Medicine (Grant Number 2021033 [to Ping An]), Interdisciplinary Innovative Talents Foundation from Renmin Hospital of Wuhan University (Grant Number JCRCZN-2022-004 [to Ping An]), Clinical Nursing Special Research Incubation Foundation of Wuhan University (Grant Number LCHL202313 [to Juan Su]), and Natural Science Foundation of Hubei Province (Grant Number 2021CFB454 [to Yaqing Xu]).

Potential competing interests: None to report.

Data availability statements: Data will be available upon reasonable request from corresponding author.

Study Highlights.

WHAT IS KNOWN

• ✓ The response to vedolizumab in Crohn's disease is challenging to improve.

• ✓ The efficacy of combined treatment of vedolizumab and exclusive enteral nutrition remains unclear.

WHAT IS NEW HERE

• ✓ Vedolizumab with concomitant 16-week exclusive enteral nutrition might be an effective approach in the induction and maintenance treatment of active Crohn's disease.