Effectiveness of biologics for endoscopic healing in patients with isolated proximal small bowel Crohn’s disease

Abstract

BACKGROUND

Endoscopic healing (EH) is a key therapeutic target in Crohn’s disease (CD). Proximal small bowel (SB) lesions in patients with CD are associated with a significant risk of strictures and bowel resection. Assessing SB in patients with CD is necessary because of its significant therapeutic implications. The advent of biologic therapies, including infliximab, ustekinumab, and vedolizumab, has significantly altered CD treatment. However, data on the efficacy of biologics in achieving EH, specifically in the proximal SB of patients with CD, remain limited.

AIM

To assess the effectiveness of biologics for EH in patients with jejunal and/or proximal ileal CD.

METHODS

Between 2017 and 2023, we retrospectively included 110 consecutive patients with isolated proximal SB CD, identified through baseline balloon-assisted enteroscopy. These patients completed 1-year of treatment with infliximab, ustekinumab, or vedolizumab, and underwent a second balloon-assisted enteroscopy at 1 year. Complete EH was defined as a modified Simple Endoscopic Score for CD (SES-CD) of < 3, while EH of the jejunum and proximal ileum was defined as a segmental modified SES-CD of 0.

RESULTS

In total, 64 patients were treated with infliximab, 28 with ustekinumab, and 18 with vedolizumab. The complete EH rate at 1 year was 20.9% (23/110), with 29.6% (19/64) for infliximab, 10.7% (3/28) for ustekinumab, and 5.5% (1/18) for vedolizumab. The median modified SES-CD significantly decreased compared to baseline [5 (2-8) vs 8 (6-9), P < 0.001]. The jejunal and proximal ileal EH rates at 1 year were 30.8% (12/39) and 15.5% (16/103), respectively. Multiple logistic regression analysis showed that stricturing or penetrating disease [odds ratio (OR) = 0.261, 95%CI: 0.087-0.778, P = 0.016], prior exposure to biologics (OR = 0.080, 95%CI: 0.010-0.674, P = 0.020), and moderate-to-severe endoscopic disease (OR = 0.277, 95%CI: 0.093-0.829, P = 0.022) were associated with a lower likelihood of achieving EH at 1 year.

CONCLUSION

Only 20.9% of patients with isolated proximal SB CD achieved complete EH after 1 year of biologic therapy.

Key Words: Crohn’s disease; Isolated proximal small bowel disease; Endoscopic healing; Biologics; Balloon-assisted enteroscopy

Core Tip: Endoscopic healing (EH) is a key treatment target for Crohn’s disease (CD), but limited data are available on isolated proximal small bowel (SB) disease. This retrospective study analyzed the data of patients with isolated proximal SB CD identified through balloon-assisted enteroscopy. We aimed to evaluate the effectiveness of biologics for EH in patients with jejunal and proximal ileal CD at 1 year. The results showed that 20.9% of patients achieved complete EH after 1-year biologic therapy. Failure to achieve complete EH was significantly associated with stricturing or penetrating disease, prior exposure to biologics, and moderate-to-severe endoscopic disease.

INTRODUCTION

Crohn’s disease (CD) is a chronic, progressive, and destructive bowel disease that impacts the entire gastrointestinal system, primarily affecting the terminal ileum and colon[1,2]. The advent of biological therapies, including infliximab, ustekinumab, and vedolizumab, has significantly altered CD treatment. Endoscopic healing (EH) is a key goal in CD management, with numerous studies demonstrating its association with favorable outcomes[3,4]. However, most majority of the available evidence on EH relies on ileocolonoscopic data, which can overlook small bowel (SB) lesions because the disease can skip the distal ileum[5]. Proximal SB involvement occurs in approximately 15% of patients with CD[6,7]. While these proximal SB lesions are less common, they are associated with a higher risk of stricturing or penetrating complications in the course of the disease than colonic or distal ileal CD[8-10]. Therefore, evaluating the proximal SB is essential for CD management due to its significant therapeutic implications. However, data on the efficacy of biologics in achieving EH specifically in the proximal SB of patients with CD, remain limited.

Balloon-assisted enteroscopy (BAE) enables the evaluation of areas of the proximal SB that are not accessible through conventional colonoscopy[11]. Its introduction has significantly enhanced the detection of SB mucosal lesions[12]. Therefore, this study retrospectively analyzed data from patients with isolated proximal SB CD, who underwent BAE after receiving 1 year of treatment with infliximab, ustekinumab, or vedolizumab.

We aimed to evaluate the effectiveness of these biologics for EH in patients with jejunal and proximal ileal CD at 1 year.

MATERIALS AND METHODS

Patients and study design

This retrospective, longitudinal cohort study was conducted at a single tertiary referral hospital in China. Consecutive adult patients with isolated proximal SB CD, identified through baseline BAE assessments, were included between 2017 and 2023. The inclusion criteria were as follows: (1) Patients only had isolated proximal SB disease without terminal ileal and/or colonic involvement; (2) Presence of at least one segment with a modified Simple Endoscopic Score for CD (SES-CD) of ≥ 3 and any ulcer size upon baseline BAE evaluation; (3) Initiation of therapy with infliximab, ustekinumab, or vedolizumab, and (4) Undergoing a follow-up BAE evaluation 1 year after starting treatment. We excluded patients who had an ileocolonic stoma, were concurrently using exclusive enteral nutrition, or had switched to an alternative treatment before undergoing the second BAE.

The selection of biologics for patients was guided by guidelines and also took into account individual patient preferences. Each biologic was administered following guidelines[13-15]. For infliximab induction, patients followed standard induction (standard doses at weeks 0, 2, and 6) and maintenance (5 mg/kg intravenously every 8 weeks) protocols. For ustekinumab, a single intravenous dose (approximately 6 mg/kg) was administered for induction, followed by a subcutaneous maintenance injection of 90 mg every 8 weeks. For vedolizumab, patients received 300 mg intravenously at weeks 0, 2, and 6, and every 8 weeks thereafter. For patients experiencing a loss of response to biologics therapy, dose optimization of infliximab was performed to shorten the treatment intervals or increase the dose. In contrast, dose optimization of vedolizumab and ustekinumab shortened the treatment intervals. Dose optimization depends on the clinician's assessment. All the biologics used is originators.

This study was approved by the Ethics Committee of the Sixth Affiliated Hospital of Sun Yat-sen University (ID: 2023ZSLYEC-609). Informed consent from patients was waived because the study was retrospective, and all patient data were fully de-identified.

BAE procedure and evaluation

All patients underwent a BAE (EN-450P5 or EN-580T, Fujifilm, Tokyo, Japan). The BAE procedures were performed and evaluated by two experienced endoscopists. We calculated the length of the SB examined by counting the number of over-tube strokes[16]. The SB was divided into 3 segments: The terminal ileum (≤ 30 cm from the ileocecal valve), the proximal ileum (30-300 cm from the ileocecal valve), and the jejunum (the proximal part of SB, excluding the section defined as the proximal ileum and duodenum) (Supplementary Table 1)[15,17]. Isolated proximal SB was defined as an SB > 30 cm away from the ileocecal valve.

BAE evaluations of the SB were performed using the modified SES-CD. This scoring system assesses SB lesion activity based on four endoscopic variables: The size of ulcers, the proportion of the ulcerated surface, the proportion of the affected surface, and the presence of stenosis. Each variable was scored on a scale of 0-3 for each of the three segments, and the total score for each segment ranged from 0 to 12 (Supplementary Table 1)[17,18]. The overall modified SES-CD score was then calculated as the sum of the scores for each SB segment. The size of ulcers was classified as 0 (none), 1 (small, from 0.1 to < 0.5 cm), 2 (large, from 0.5 to 2 cm), and 3 (very large, > 2 cm). Figure 1 shows the representative BAE images of patients with different modified SES-CD scores.

Figure 1 Representative of balloon-assisted enteroscopy images with modified Simple Endoscopic Score for Crohn’s disease scores of 1, 2, or 3. A: Small ulcers; B: Large ulcer; C: Very large ulcer; D: Ulcerated surface < 10%; E: Ulcerated surface 10%-30%; F: Ulcerated surface > 30%; G: Single stenosis which can be passed; H: Multiple stenosis which can be passed; I: Stenosis which could not be passed.

Endpoints and definitions

The primary outcome of this study was to analyze the efficacy of three approved biologics for CD in achieving 1 year of complete EH, defined as a completely modified SES-CD < 3. One-year EH of the jejunum and proximal ileum was separately defined as a modified SES-CD of 0 in the segment assessed[19]. The secondary outcomes were the rate of endoscopic response (ER) rates and complete ulcer healing at 1 year. ER was defined as a reduction in the modified SES-CD score by more than 50% at both the complete and segmental levels[20]. Complete ulcer healing was defined as no inflammatory changes present, including erosions and ulcerations[18].

Statistical analysis

Descriptive data were presented as mean ± SD or median with interquartile range (IQR). Categorical data were represented as case numbers and proportions. Comparisons were made using Student’s t-test or Mann-Whitney U test for continuous data and the χ² test or Fisher’s exact test for categorical data. The correlations between endoscopic findings and variables such as C-reactive protein (CRP) or Harvey-Bradshaw Index (HBI) were determined using the Spearman rank correlation test. For the evaluation of risk factors, univariate analysis was conducted using the χ² test, and multiple logistic regression was employed for multivariate analysis to identify independent predictors. The level of statistical significance was set at P < 0.05. All statistical analyses were performed using SPSS Statistics version 25.0.

RESULTS

Patients

Of the 205 patients with active isolated proximal SB CD, 95 patients were excluded for various reasons. Ultimately, we assessed 110 patients who finished 1 year of biologics treatment and underwent a follow-up BAE evaluation after 1 year. The process of patient selection is illustrated in Figure 2. Baseline characteristics are summarized in Table 1. The median age was 33 years (IQR: 25-39), and 88 (80.0%) patients were male. The median disease duration was 1.1 years (IQR: 0.4-2.5), and 33 (30.0%) patients had prior exposure to biologics. The proximal ileum was the most frequently affected bowel segment in proximal SB CD, observed in 103 (93.6%) patients, while jejunal involvement was observed in 39 (35.5%). Stricturing and penetrating diseases were present in 62 (56.4%) and 18 (16.4%) patients, respectively. Regarding biologic treatments, 64 (58.2%), 28 (25.5%), and 18 (16.4%) patients were treated with infliximab, ustekinumab, and vedolizumab, respectively. The baseline characteristics of patients stratified by biologics are summarized in Supplementary Table 2.

Figure 2 The flow of enrolled patients in this study. Active endoscopic disease was defined as having a modified simple endoscopic score for Crohn’s disease ≥ 3, accompanied by any size ulcer. BAE: Balloon-assisted enteroscopy; SB: Small bowel; CD: Crohn’s disease; SES-CD: Simple endoscopic score for Crohn’s disease.

Table 1 Baseline clinical features, n (%).

Variables	All patients (n = 110)
Male	88 (80.0)
Age, years, median (IQR)	33 (25-39)
Disease duration, years, median (IQR)	1.1 (0.4-2.5)
Smoking history	18 (16.4)
Disease behavior
Bl: Inflammatory	30 (27.3)
B2: Stricturing	62 (56.4)
B3: Penetrating	18 (16.4)
Perianal disease	65 (59.1)
HBI, median (IQR)	7 (5-7)
HBI > 4	94 (85.5)
CRP, mg/L, median (IQR)	2.1 (0.6-8.9)
Albumin, g/L, median (IQR)	39 (36-42)
Hemoglobin, g/L, median (IQR)	129 (112-139)
Prior biologic exposure	33 (30.0)
Current biologic therapy
Infliximab	64 (58.2)
Ustekinumab	28 (25.5)
Vedolizumab	18 (16.4)
Concomitant treatment
Steroids	3 (2.7)
Immunomodulator	34 (30.9)
Baseline BAE evaluation
Modified SES-CD, median (IQR)	8 (6-9)
Bowel segment with active disease1
Jejunum	39 (35.5)
Proximal ileum	103 (93.6)
Very large ulcers (> 2.0 cm)
Jejunum	11/39 (28.2)
Proximal ileum	35/103 (34.0)
Dose optimization	7 (6.4)

¹Bowel segment with active disease was defined as having a segmental modified simple endoscopic score for Crohn’s disease ≥ 3, accompanied by any size ulcer.

IQR: Interquartile range; HBI: Harvey-Bradshaw Index; CRP: C-reactive protein; BAE: Balloon-assisted enteroscopy; SES-CD: Simple endoscopic score for Crohn’s disease.

BAE findings at baseline

At baseline assessment, all patients underwent transanal and transoral BAE, and the scope reached the entire intestine in 48 (43.6%) patients. Overall, all patients had ulcer lesions at proximal SB, 73 (66.4%) had stricturing disease and 74 (67.3%) had moderate-to-severe endoscopic activity (modified SES-CD ≥ 7). The median total modified SES-CD was 8 (IQR: 6-9). The median segmental modified SES-CD for the jejunum was 4 (IQR: 3-5), and that for the proximal ileum was 6 (IQR: 5-7).

Complete endoscopic outcomes at 1 year

During the second examination, all patients underwent transanal and transoral BAE, and the scope reached the entire intestine in 57 (51.8%) patients. Figure 3 shows that 20.9% (23/110) of the patients achieved complete EH at 1 year. Patients treated with infliximab demonstrated the numerically highest EH rate at 1 year [29.6% (19/64)], followed by those treated with ustekinumab [10.7% (3/28)] and vedolizumab [5.5% (1/18)]. Similar trends were observed for achieving ER. In total, 33.6% (37/110) of patients achieved ER: 42.2% (27/64) in the infliximab-, 28.6% (8/28) in the ustekinumab-, and 11.1% (2/18) in the vedolizumab-treated patients (Figure 4A, Supplementary Table 3). Patients treated with infliximab had a significantly higher ER rate than patients treated with vedolizumab (P = 0.015). The median modified SES-CD significantly decreased at 1 year compared to baseline [5 (IQR: 2-8) vs 8 (IQR: 6-9), P < 0.001].

Figure 3 The rates of endoscopic healing, endoscopic response, and ulcer healing in patients with isolated proximal small bowel Crohn’s disease after 1 year of biologic therapy. ^aP < 0.05.

Figure 4 The ability of infliximab, ustekinumab, and vedolizumab to achieve endoscopic outcomes in patients with isolated proximal small bowel Crohn’s disease after 1 year of therapy. A: Complete; B: Jejunum; C: Proximal ileum. ^aP < 0.05.

Figures 3 and 4A summarizes the rates of complete ulcer healing among all patients. At 1 year, the complete ulcer healing rates for patients was 27.3% (30/110). Patients treated with infliximab demonstrated the numerically highest ulcer healing rate at 1 year [35.9% (23/64)], followed by those treated with ustekinumab [17.9% (5/28)] and vedolizumab [11.1% (2/18)]. At baseline, 35 patients had very large ulcers and 49 had large ulcers. The complete ulcer healing rates for patients with very large or larger ulcers were 17.9% (15/84): Very large 22.9% (8/35) and large 14.3% (7/49). Notably, among patients with large or very large ulcers, those treated with infliximab showed a significantly higher complete ulcer healing rate [31.8% (14/44)] than those treated with ustekinumab [4.0% (0/25), P = 0.017] and vedolizumab [0.0% (0/15), P = 0.013]. For detailed complete ulcer healing rates for patients with very large and large ulcers, respectively (Supplementary Table 4).

Segmental endoscopic outcomes at 1 year

In total, 39 patients had a jejunum with segmental modified SES-CD ≥ 3. Among these, 12 (30.8%) achieved jejunal EH, 17 (43.6%) achieved ER, and 14 (35.9%) achieved ulcer healing at 1 year (Figure 3). Vedolizumab-treated patients demonstrated the lowest rate of jejunal EH at 1 year [9.1% (1/11)]. Compared to vedolizumab, the highest rate of jejunal EH at 1 year was observed in infliximab-treated patients [53.3% (8/15), P = 0.036], followed by ustekinumab-treated patients [23.1% (3/13), P = 0.596; Figure 4B, Supplementary Table 3]. Similar trends were observed in ulcer healing outcomes, while the rates of ER were comparable between infliximab- and ustekinumab-treated patients and were numerically higher than those in vedolizumab-treated patients (Figure 4B and Supplementary Table 3). The median jejunal modified SES-CD significantly decreased at 1 year compared to baseline [4 (IQR: 3-5) to 3 (IQR: 0-4), P < 0.001; Supplementary Figure 1].

Additionally, 103 patients had a proximal ileum with segmental modified SES-CD ≥ 3. Of these, 16 (15.5%) achieved proximal ileal EH, 23 (22.3%) achieved ER, and 18 (17.5%) achieved ulcer healing at 1 year, respectively (Figure 3). Vedolizumab-treated patients demonstrated the lowest rate of proximal ileal EH at 1 year [5.5% (1/18)], although this was not statistically significant compared with the infliximab- [22.4% (13/58), P = 0.107] and ustekinumab-treated patients [7.4% (2/27), P = 0.807; Figure 4C and Supplementary Table 3]. Similar trends were observed in ER and ulcer healing outcomes (Figure 4C and Supplementary Table 3). The median proximal ileal modified SES-CD significantly decreased at 1 year compared to baseline [6 (IQR: 5-7) to 5 (IQR: 3-6), P < 0.001; Supplementary Figure 1].

Notably, significant differences were observed in segmental EH rates between the jejunum and proximal ileum [30.8% (12/39) vs 15.5% (16/103), P = 0.042; Figure 3]. Similar trends were observed in segmental ER rates [43.6% (17/39) vs 22.3% (23/103), P = 0.012] and in segmental ulcer healing rate [35.9% (14/39) vs 17.5% (18/103), P = 0.012] between the two segments (Figure 3).

Supplementary Table 4 summarizes the rates of ulcer healing in the jejunum and the proximal ileum after 1 year of biologic therapy. At baseline, 11 patients had very large ulcers in the jejunum and 35 patients in proximal ileum. There was no significant difference in the rate of complete ulcer healing between the jejunum and proximal ileum at 1 year [27.3% (3/11) vs 17.1% (6/35), P = 0.664]. Similar results were observed between the jejunum and proximal ileum which had large ulcers at baseline [27.8% (5/18) vs 15.2% (7/46), P = 0.247].

HBI and CRP findings at 1 year

At 1 year, 67.3% (74/110) of patients were in clinical remission (HBI < 4) and 74.5% (82/110) were in biochemical remission (CRP ≤ 3mg/L). The median HBI significantly decreased at 1 year compared to that at baseline [3 (2-4) vs 7 (5-7), P < 0.001]. The correlation between the total modified SES-CD and HBI scores was weak both at baseline (r = 0.172, P = 0.072) and 1 year (r = 0.214, P < 0.05). Similarly, the median CRP level significantly decreased compared to that at baseline [0.8 (0.5-3.2) vs 2.1 (0.6-8.9) mg/L, P < 0.001]. The correlation between the total modified SES-CD and CRP levels was also weak at both baseline (r = 0.196, P < 0.05) and 1 year (r = 0.160, P = 0.095; Supplementary Figures 2 and 3).

Predictive factors for failure of EH

In multivariate logistic regression analysis, the following factors were identified as risk factors for achieving complete EH: Stricturing or penetrating behavior [odds ratio (OR) = 0.261, 95%CI: 0.087-0.778, P = 0.016], prior exposure to biologics (OR = 0.080, 95%CI: 0.010-0.674, P = 0.020), and moderate-to-severe endoscopic disease (OR = 0.277, 95%CI: 0.093-0.829, P = 0.022; Table 2). The rates of complete EH were 70.0% (7/10) for the patients with none of these risk factors, 33.3% (5/15) for 1 factor, 13.5% (5/37) for 2 factors, and 0 for 3 factors (Figure 5). With each added risk factor, the likelihood of achieving complete EH decreases by 76.1%, as indicated by an OR of 0.239 (95%CI: 0.112-0.509, P < 0.001).

Figure 5 The likelihood of achieving complete endoscopic healing is stratified by the number of risk factors. Stricturing or penetrating behavior, prior exposure to biologics, and moderate-to-severe endoscopic disease were identified as risk factors for achieving complete endoscopic healing.

Table 2 Risk for failure to achieve complete endoscopic healing after one-year biologic therapy.

Variables	Univariate analysis			Multivariate analysis
	OR	95%CI	P value	aOR	95%CI	P value
Male	1.863	0.500-6.944	0.354
Age > 40	0.457	0.097-2.161	0.323
Disease duration > 2 years	0.578	0.207-1.612	0.295
Active smoker	0.423	0.090-1.988	0.276
B2/3 behavior	0.191	0.066-0.559	< 0.001	0.261	0.087-0.778	0.016
Perianal involvement	0.434	0.156-1.207	0.434
Prior biologic exposure	0.078	0.010-0.607	0.015	0.080	0.010-0.674	0.020
Immunomodulator use	0.271	0.075-0.985	0.047	0.448	0.108-1.860	0.269
Moderate-to-severe endoscopic disease1	3.617	1.396-9.374	0.008	0.277	0.093-0.829	0.022
Prior intestinal resection	0.350	0.042-2.886	0.329
Dose optimization	1.630	0.186-14.256	0.659
Type of biological therapies (IFX reference)
Vedolizumab	0.139	0.017-1.123	0.064
Ustekinumab	0.533	0.277-1.027	0.060

¹Moderate-to-severe endoscopic disease was defined as the modified simple endoscopic score for Crohn’s disease ≥ 7.

OR: Odds ratio; IFX: Infliximab; aOR: Adjusted odds ratio.

Safety assessment

No serious adverse events were observed in all patients during the use of the 3 different biologics. Only two patients treated with infliximab experienced adverse reactions. One patient had a positive T-SPOT test at the 24 weeks of assessment, but pulmonary computed tomography and other examinations did not show tuberculosis activation, hence isoniazid was administered orally for prophylactic anti-tuberculosis treatment, and continued infliximab treatment. The other case was a definite pulmonary infection. After regular anti-infection treatment, the patient recovered and was allowed to continue infliximab treatment.

DISCUSSION

To our knowledge, this is the first study to evaluate the effectiveness of biologics in achieving EH in patients with isolated proximal SB CD. Our findings revealed that only 20.9% of patients with isolated proximal SB CD achieved complete EH after 1 year of biological therapy. At segmental level analyses, 30.8% and 15.5% of the jejunum and proximal ileum, respectively, achieved segmental EH at 1 year. Additionally, failure to achieve complete EH was significantly associated with stricturing or penetrating disease, prior exposure to biologics, and moderate-to-severe endoscopic disease. Our study underscores the nuanced challenges in achieving EH in isolated proximal SB CD, emphasizing the need for tailored treatment strategies that consider individual patient risk factors and disease characteristics.

Several cohort studies have suggested that SB lesions do not heal as well as the colon after receiving biological therapy[21,22]. Indeed, many studies have primarily focused on lesions in the terminal ileum and colon, thus potentially overlooking lesions in the jejunum and proximal ileum[23]. Specifically, conventional ileocolonoscopy cannot assess the ER to therapy in patients with isolated proximal SB CD. Differences in physiological structure and function between the proximal SB and the terminal ileum may also cause different responses to biologics. To address this gap, our study focused on patients with isolated proximal SB CD to evaluate the effectiveness of the ER provided by biologics for proximal SB lesions.

After 1 year of biological treatment, the complete EH rate in patients with isolated proximal SB CD was 20.9% (23/110) and the ER rate was 33.6% (37/110). Takenaka et al[18] reported that 36% (41/114) of patients had SB EH during infliximab maintenance therapy based on BAE evaluation. Similarly, a subsequent study by Han et al[24] revealed SB endoscopic remission rate of 38% (41/108) and EH rate of 27.8% (30/108) after treatment with infliximab. Our rates are relatively low compared to those reported in several previous studies[25-27]. However, previous studies primarily utilized ileocolonoscopy or retrograde BAE for their assessments, which may not have accurately evaluated lesions in the jejunum and proximal ileum, potentially leading to overestimating the EH rate. In our study, we found infliximab-treated patients had a numerically higher 1-year EH rate in proximal SB compared to ustekinumab- and vedolizumab-treated patients. The effect of infliximab on large and very large ulcers is better than that of vedolizumab and ustekinumab. It seems that infliximab has a priority effect, but there may be the influence of the following factors. Notably, 55.6% (10/18) of vedolizumab- and 46.4% (13/28) of ustekinumab-treated patients in our study had previously failed to respond to infliximab, resulting in lower complete EH rates [vedolizumab: 0% (0/10) and ustekinumab: 7.7% (1/13)]. Therefore, caution is warranted when interpreting the superiority of infliximab for proximal SB CD. Furthermore, patients with active endoscopic disease in the jejunum showed better healing outcomes compared to those with proximal ileum lesions after 1 year, possibly because the jejunum had lower baseline segmental modified SES-CD scores [4 (IQR: 3-5) vs 6 (IQR: 5-7), P < 0.001].

Predictors of failure to achieve EH have been reported in several studies. De Cruz et al[28] identified factors like young age at diagnosis, the presence of a perianal fistula, delayed treatment, and smoking as predictors of poor outcomes. Freeman[29] further reported that complicated disease behavior and proximal SB involvement are also associated with poor outcomes. Our study found that stricturing or penetrating disease, prior exposure to biologics, and moderate-to-severe endoscopic disease were significantly associated with the failure to achieve EH in patients with proximal SB CD. With each added risk factor, the likelihood of achieving complete EH decreases by 76.1%. Notably, 77.3% (85/110) of patients presented with two or more risk factors, likely contributing to the poor response observed in a large percentage of our study population. Furthermore, previous research has also indicated that proximal SB lesions are typically associated with poorer prognoses[7]. Proximal SB CD, particularly with jejunal lesions, is more likely to develop into stricturing or penetrating disease, typically resulting in a poorer prognosis[8,30]. Thus, early intervention, before the progression to complicated stricturing or penetrating disease, may improve endoscopic outcomes for patients with SB CD treated with biologics. Additionally, our univariate analysis identified the absence of concomitant immunomodulator use as a risk factor for failing to achieve EH. Previous studies have also indicated that higher concentrations of biologics are necessary to achieve EH in SB lesions[31]. Therefore, therapeutic drug monitoring and combination therapies may also improve the endoscopic outcomes in SB CD.

Our results also indicate that neither HBI nor CRP levels adequately reflect the endoscopic disease activity in SB CD, aligning with previous studies[32]. Previous research has suggested a poor consistency between fecal calprotectin levels and SB lesions[33]. Therefore, using BAE to monitor the ER in patients with isolated proximal SB CD is clinically important, particularly in those with stricture complications treated endoscopically[34]. However, frequent BAE may be challenging for some patients to tolerate; thus, imaging examination may become a more common clinical practice for managing proximal SB CD. Despite this potential shift, high-quality data comparing the consistency of BAE findings with imaging results are lacking. Furthermore, the differences in prognosis between enteroscopic and imaging evaluations remain unclear, emphasizing the need for future research.

This study had a few limitations. Despite reaching statistical significance, the relatively small sample size and uneven baselines of various biologics limited the accuracy of comparisons. Additionally, some patients did not undergo follow-up BAE after 1 year of treatment, and others dropped out early because of treatment ineffectiveness or adverse effects. Finally, we did not compare lesions at other sites of CD, as this was not the focus of the current study.

CONCLUSION

This study advances our understanding of the effectiveness of biologic therapy for patients with isolated proximal SB CD, highlighting the distinct challenges in achieving EH. Our findings reveal a relatively low EH rate of 20.9% in this cohort, which is significantly associated with stricturing or penetrating disease, prior exposure to biologics, and moderate-to-severe endoscopic disease. Early intervention before the development of complicated stricturing or penetrating disease, along with therapeutic drug monitoring and combination therapies, may improve endoscopic outcomes in SB CD. Additionally, infliximab seemingly displayed superior effectiveness in achieving endoscopic improvement than ustekinumab and vedolizumab in SB CD, especially in patients with large or very large ulcers. Future studies should focus on expanding the sample size, comparing the accuracy of different diagnostic modalities, and assessing the effectiveness of combination therapies in SB CD. Such research is crucial for developing more nuanced and effective treatment protocols for patients with CD, particularly for those with less common manifestations of the disease.