Inflammatory bowel diseases (IBD), which encompass Crohn’s disease (CD) and ulcerative colitis (UC), are chronic and disabling inflammatory gastrointestinal disorders. In contrast to UC in which lesions are strictly limited to the colon, CD is more heterogeneous and can affect the entire gastrointestinal tract, from the mouth to the anus. The Montreal classification of CD distinguishes anatomical disease location in the ileum (L1), colon (L2), and both the ileum and colon (L3)[1], each accounting for approximately one-third of patients who are diagnosed with CD[2]. About 10%–15% of patients have associated upper gastrointestinal lesions (L4)[3], which are isolated in 2%–3% of cases[4]. It has been demonstrated that jejunal disease is a significantly greater risk factor for stricturing disease and multiple abdominal surgeries than either esophagogastroduodenal or ileal (without proximal) disease[5-7].

Assessment of the small bowel (SB) in patients with suspected or diagnosed CD is necessary because complete visualization of the entire length of the SB may have a significant impact on prognosis with potential therapeutic implications[8]. Device-assisted enteroscopy should be performed only when endoscopic therapy is indicated, because of its invasive nature[9]. Cross-sectional imaging (magnetic resonance enterography and computed tomography enterography) is highly accurate for the diagnosis of obstructive and fistulizing SB CD. Computed tomography enterography (CTE) is less suitable than magnetic resonance enterography (MRE) for follow-up monitoring because radiation exposure should be considered. Since its first approval by the Food and Drug Administration (FDA) in August 2001, small bowel capsule endoscopy (SBCE) has become an important tool for assessing the SB, and it is particularly useful in areas of the gastrointestinal tract that are not accessible to conventional endoscopy. In a recent prospective study assessing whether SBCE or MRE that was performed after the initial diagnosis may alter the original disease classification, SBCE was more sensitive for detection of previously unrecognized locations, while MRE was superior for detection of phenotype shift[10]. Therefore, SBCE and MRE are probably complementary, because MRE assesses transmural involvement, while SBCE allows direct visualization of the mucosal surface of the SB. Five main lesions are associated with CD, although not specific – edema, aphthoid erosions, superficial and deep ulcerations, and stenosis (Figure 1).

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Figure 1 Small bowel capsule endoscopy findings associated with Crohn’s disease. A: Edema; B: Aphthoid erosion; C: Superficial ulceration; D: Deep ulceration; E: Stenosis.

Until recently, therapeutic strategies relied on a progressive and step-wise approach that was based solely on IBD-related symptoms. However, evidence is now accumulating that demonstrates the weak correlation that exists between symptoms and endoscopic disease activity in patients with CD[11-13]. Thus, the “treat-to-target” paradigm was developed in 2015, and it is based on regular and objective assessment of disease activity, and subsequent adjustment of the treatment[14]. The treatment goal has evolved to a new concept, which is achieving and maintaining deep remission, combining both clinical and endoscopic remission[15]. In patients with CD, the STRIDE consensus defined endoscopic remission as resolution of ulceration at ileocolonoscopy or resolution of inflammation findings on cross-sectional imaging when endoscopy cannot adequately evaluate inflammation[15]. However, as discussed above, MRE may often underestimate mucosal lesions, and SBCE could play a key role to play in this tight monitoring of patients with CD.

Both European and American guidelines now recognize SBCE as a useful adjunct in diagnosising SB CD in patients in whom there is a high clinical suspicion for CD, because it has a high negative predictive value in this indication[9,16]. In 2009, an international consensus aimed to define the role of SBCE in the follow-up of patients with IBD, suggesting that SBCE “may identify lesions in the small bowel that have not been detected by ileocolonoscopy after ileocolic resection” and that it “has a potential role in the assessment of mucosal healing after drug therapy”, but there was little of evidence to support this suggestion[17]. At that time, there is no recommendation for the use of SBCE during patient follow-up.

Here, we conducted a systematic literature review that aimed to investigate the impact of SBCE in a treat-to-target strategy in patients with CD.

An electronic literature search was conducted in PubMed and the Cochrane library using the following search terms: “capsule endoscopy”, in combination with “Crohn’s disease” or “inflammatory bowel disease” or “ileitis” or “enteritis”, and with synonyms of “treat-to-target” or “monitoring” or “post-operative recurrence”. The search was conducted in early February 2019 and included citations beginning from January 1, 2000. We restricted our search to studies that were published in English and we excluded studies related to animal research. Supplementary Table 1 provides the PubMed literature search strategy in detail. Duplicate articles identified in both PubMed and Cochrane library were manually deleted. To identify additional relevant studies, we checked the reference lists of the selected articles.

Two authors independently reviewed the titles and abstracts of articles that were identified by the search strategy after duplicates were removed (CLB and AB). Any disagreements regarding the inclusion of articles were solved by discussion until consensus was reached. Reviewers were not blinded to the study authors’ affiliation or journal name. Following the initial screening of abstracts, all articles containing information about SBCE in the context of treat-to-target strategy in patients with CD were included. Studies without any outcome related to treat-to-target strategy or to CD were excluded, as were studies related to pediatric populations and reviews, meta-analyses, editorials, and letters to the editor. Full-text articles were retrieved, and reference lists were screened manually to identify additional studies.

The following data were extracted for each included study: Name of the first author, year of publication, study design, patient population and sample size, capsule endoscopy findings, and comparator modality, if applicable. For studies assessing disease reclassification, the impact of SBCE findings in patient management was reported. For studies assessing mucosal healing during treatment, ongoing treatment and prior biologic exposure were noted. For studies assessing the use of SBCE in the post-operative setting, risk factors for post-operative recurrence, indications for surgery, interval between surgery and endoscopic re-assessment, post-operative prophylactic treatment, and the rate of clinical recurrence were noted.

The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses was used to conduct and report the results of this review[18]. The first part of this systematic review focused on the indexes that were used to describe CD lesions at small bowel capsule endoscopy. The findings were then organized according to the context of SBCE use when monitoring a patient who was diagnosed with inflammatory bowel disease, as follows: (1) Reclassifying disease location or phenotype; (2) Assessing mucosal healing in patients with CD; and (3) Monitoring patients in the post-operative setting.

There were 153 studies identified after the electronic search. Seven additional studies were identified from a review of the reference lists from included articles. Based on the information provided in the abstracts, 103 studies were excluded, as well as seven duplicates. Fifty articles were then selected for full-text review. Among those articles, three were excluded, and 47 articles were finally included in this review. The PRISMA diagram describing the article search process is presented in Figure 2.

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Figure 2 Preferred reporting items for systematic reviews and meta-analyses diagram.

Supplementary Table 2 summarizes the studies that assessed the two indexes that have been developed to date to describe CD lesions at SBCE. The first index is the Lewis score, which was developed in 2007[19] and validated in 2014, and it has excellent interobserver agreement in patients with known SB CD[20]. A score below 135 is considered to be normal, while a score above 790 reflects moderate to severe inflammation. Between these two values, SB inflammation is considered to be mild[19]. This score was also useful as a diagnostic tool for patients with suspected CD, with a sensitivity and positive predictive value of 82.6%, and a specificity and negative predictive value of 87.9%[21].

The second index was developed in 2008 and it is called Capsule Endoscopy Crohn’s Disease Activity Index (CECDAI). It ranges from 0 to 36, and the correlation between two observers is also excellent[22]. This score was validated in 2012 in a cohort of 50 patients with known SB CD[23]. Two recent studies showed a significant correlation between the Lewis and CECDAI scores in patients with known SB CD, with correlation coefficients of r = 0.632 (P < 0.0001)[24] and r = 0.81 (P = 0.0001)[25], respectively. Lewis score thresholds of 135 and 790 correspond with CECDAI levels of 3.8 and 5.8, respectively[24].

Compared to the MRE scores, the Lewis score was significantly correlated with both MaRIA and Clermont scores (r = 0.50, P = 0.001 and r = 0.53, P = 0.001, respectively), especially for detecting moderate to severe inflammation[26]. However, the Lewis score was weakly correlated with clinical activity as measured by the Harvey Bradshaw index (r = 0.213, P = 0.019) and no correlation was found between CD activity index (CDAI) and the CECDAI[23]. The Lewis score moderately correlated with C-reactive protein (r = 0.326, P < 0.001)[27], and a moderate correlation was demonstrated between SBCE scores and fecal calprotectin (r = 0.48, P = 0.001 for Lewis score, and r = 0.53, P = 0.001 for CECDAI)[25].

Table 1 describes the key studies that show the potential impact of SBCE on disease reclassification of patients suspected or diagnosed with IBD, and gives an overview of the subsequent therapeutic management. Most of those studies focused on reclassifying the CD location by assessing SB in patients with known or suspected CD. All showed positive SBCE findings, including jejunal lesions that had not previously been visualized using conventional endoscopy or imaging. All of the studies that compared SBCE to other diagnostic modalities showed a significant incremental diagnostic yield of SBCE. Compared to push enteroscopy, SBCE had an incremental diagnostic yield of 63.6% in patients with known CD, although the difference was not significant in patients with suspected CD[28]. Two studies compared the diagnostic yield of SBCE to that of enteroclysis, and both demonstrated a significant incremental diagnostic yield of 62.0%[28] and 33.4%[29] in patients with known CD. In patients with suspected CD and negative ileocolonoscopy, an intestinal ultrasound and SBCE had a similar diagnostic yield (38%)[30]. However, in patients with known CD of the distal ileum, SBCE had an incremental diagnostic yield of 41% compared to the small intestine contrast ultrasonography (SICUS) for the detection of upper SB lesions, while the detection rate of distal SB lesions was similar for both modalities (93%)[31]. Compared to cross-sectional imaging, three studies demonstrated that SBCE was superior in detecting SB lesions[10,32,33], with an incremental diagnostic yield up to 31.9%[33], especially for the detection of proximal SB CD location[10,33]. However, the lesions that were considered for the diagnosis of CD varied greatly from one study to another, making it difficult to compare these studies.

A single study focused on the comparison of SBCE findings between CD patients with and without perianal disease, showing that patients with perianal involvement had significantly more relevant SB lesions (94.1% vs 66.6%, P = 0.03) and higher inflammatory activity with a Lewis score ≥ 135 (94.1% vs 64.8%, P = 0.03), especially in proximal SB segments, compared to patients without perianal CD[34].

Only three of the included studies focused on reclassifying the IBD type in patients who were diagnosed with IBD-unclassified, indeterminate colitis or pouchitis. The lesions that were considered for the diagnosis of CD were very different depending on the study. However, SBCE detected SB lesions allowing the physician to suspect or even make the diagnosis of CD in 16.7% to 50.0% of patients with IBD-unclassified or indeterminate colitis, and up to 65.2% of patients who were diagnosed with pouchitis following ileo-anal anastomosis[35-37].

For the impact on therapeutic management, most of the studies showed that SBCE findings led to a change in the dose or change of immunomodulatory agent, initiation of biologic treatment, or avoidance of surgery, in more than one-third of patients, and even in 100% of patients in four studies[38-41].

Table 2 summarizes the nine studies that evaluated the use of SBCE to assess mucosal healing in patients who were diagnosed with CD. All but one study had a prospective design. Most of these studies did not evaluate a specific treatment, except for two studies, one of which focused on adalimumab and azathioprine[42] and the other that focused on certolizumab pegol[43]. Another study was a sub-study of a prospective, randomized, double blind placebo-controlled study that assessed the safety, tolerability and efficacy of glatiramer acetate (Copaxone^®)[44]. In three of the nine included studies, there was no comparison between SBCE findings at baseline and during follow-up, because the included patients-most of whom were in clinical remission-had only one SBCE after treatment[45-47]. The SBCE findings that were considered for the assessment of mucosal healing differed according to the studies, although most of them were based on the calculation of the Lewis score, with a normal value below 135.

Overall, despite high heterogeneity in these studies, the results indicated that mucosal healing can be evaluated by SBCE to monitor the effect of medical treatment in patients with CD, with a significant correlation between the Lewis score and fecal calprotectin (r = 0.82, P < 0.0001)[46], while there was no significant correlation between this score and clinical activity as measured by the CDAI[44,47].

Only seven of the included studies focused on the monitoring of patients with CD in the post-operative setting. The results are summarized in Table 3. All but one of the studies were prospective, and they all had small-sized cohorts with less than 35 patients. The single retrospective study included 83 patients with no risk factor for post-operative recurrence. The design methodology varied greatly between studies, making them difficult to compare. First, indications for surgery were different depending on the study, with varying proportions of treatment failure, stenosis, and fistula or abscess. The existence of risk factors for post-operative recurrence was also variable between studies, especially for smoking (range, 11%–50%) and penetrating phenotype (range, 7%–58%). In some studies, post-operative prophylactic treatment was forbidden, while others allowed the use of immunosuppressive drugs or biologics. The interval between surgery and the endoscopic re-assessment was also extremely variable, ranging from less than 3 mo to 1 year. Finally, SBCE findings that were considered for defining post-operative recurrence were also different across studies, and they were mostly based on the Lewis score (≥ 135) or the Rutgeerts score (≥ i,1 or i,2)[48].

All but one study compared SBCE to ileocolonoscopy, which is the current gold standard for assessing post-operative recurrence in patients with CD. Although two studies showed that the sensitivity of SBCE in detecting recurrence in the neoterminal ileum was not superior to that of ileo-colonoscopy[49,50], the other studies showed that SBCE could detect post-operative recurrence more frequently than ileo-colonoscopy[51-54], and with a better tolerance[51]. Moreover, two studies demon-strated that SBCE detected lesions outside the scope of ileocolonoscopy in more than half of the patients[49,51], which might be a substantial advantage as compared to conventional endoscopy because of the prognostic impact of these lesions on therapeutic management.

The retrospective study was also interesting and evaluated the impact of SBCE findings on clinical outcomes in asymptomatic patients without medical prophylaxis after ileocolonic resection. Two groups of patients were compared. Group 1 underwent ileocolonoscopy and SBCE within 1 year after surgery, whereas group 2 only had ileocolonoscopy. Patients with endoscopic recurrence detected by either ileocolonoscopy or SBCE received azathioprine or infliximab. One year later, disease activity was re-assessed by ileocolonoscopy. The clinical recurrence rate was 2.7% in group 1 compared with 21.7% in group 2 (P = 0.019), and the endoscopic recurrence rates were 21.6% and 43.5% (P = 0.036), respectively[54], suggesting that SBCE could be useful in detecting post-operative recurrence especially in patients without pharmacological prophylaxis.

This is reinforced by the results of another study that aimed to assess residual SB lesions in 25 CD patients immediately after surgery (< 3 mo). The mean Lewis score was 751.3, and 84.0% had endoscopic activity, and these residual lesions, especially in the distal SB, were associated with postoperative clinical recurrence[55], suggesting that SBCE could be used to detect very early post-operative recurrence, particularly in patients without any risk factors who do not necessarily require prophylactic treatment according to the current guidelines.

Crohn’s disease (CD) may affect any part of the digestive tract. Proximal small bowel (SB) lesions, especially jejunal lesions, are associated with an increased risk of stricturing disease and abdominal surgeries compared to esophagogastroduodenal or ileocolonic disease. Thus, assessing the SB may have a significant impact on prognosis. The treat-to-target paradigm was developed in 2015 because of the poor correlation that exists between symptoms and endoscopic disease activity in patients with CD. This concept is based on regular and objective assessment of disease activity and subsequent adjustment of treatment, with the final aim of reaching both clinical and endoscopic remission. Until now, the treat-to-target strategy is based on the assessment of mucosal lesions seen by endoscopy into the ileum and the colon and for the SB by trans-sectional imaging techniques.

The small bowel capsule endoscopy (SBCE) has a higher diagnostic yield compared to the imaging techniques such as the magnetic resonance imaging with enterography (MRE) to detect mucosal lesions especially for the proximal part of the SB and might be more accurate in a treat-to-target strategy. SBCE and MRE are probably complementary, as MRE assesses transmural involvement, while SBCE allows a direct visualization of the mucosal surface of the entire SB. However, there is no recommendation regarding the use of SBCE during patient follow-up.

To investigate the impact of SBCE in a treat-to-target strategy in patients with CD.

An electronic search of the literature was conducted using PubMed and Cochrane library focusing on studies regarding SBCE in the tight monitoring of patients with CD. All articles containing information about SBCE in the context of treat-to-target strategy in patients with CD were included. Full-text articles were retrieved, reference lists were screened manually to identify additional studies.

Forty-seven articles were included in total. Twenty-two studies demonstrated the usefulness of SBCE on disease reclassification of patients suspected or diagnosed with CD, with a significant incremental diagnostic yield compared to other diagnostic modalities. Nine studies showed that mucosal healing can be evaluated by SBCE to monitor the effect of medical treatment. Seven studies demonstrated that SBCE could detect post-operative recurrence to a similar extent as ileocolonoscopy, and proximal SB lesions beyond the reach of the colonoscope in more than half of the patients.

This systematic review provided a global overview of the published studies assessing the use of SBCE in the tight monitoring of patients with CD. SBCE might be incorporated in the treat-to-target algorithm and could be useful for refining disease location and prognosis, assessing mucosal healing in patients under treatment, and monitoring patients in the post-operative setting.

Randomized controlled trials are required to confirm the reliability of SBCE in the treat-to-target algorithm of patients with CD. In addition, the development of pan-enteric video capsule endoscopy should allow to broaden its indications, all the more so as artificial intelligence is expected to help reduce the burden of capsule endoscopists by automatically detecting and classifying lesions.