ORIGINAL ARTICLE
Small Bowel Capsule Endoscopy in the Management of Established Crohn’s Disease: Clinical Impact, Safety, and Correlation with Inflammatory Biomarkers Uri Kopylov, MD,* Artur Nemeth, MD,† Anastasios Koulaouzidis, MD,‡ Richard Makins, MD,§ Gary Wild, MD,* Waqqas Afif, MD,* Alain Bitton, MD,* Gabriele Wurm Johansson, MD,† Talat Bessissow, MD,* Rami Eliakim, MD,k Ervin Toth, MD,† and Ernest G. Seidman, MD*
Background: Multiple studies have established the superior diagnostic accuracy of video capsule endoscopy (VCE) for the diagnosis of small bowel (SB) Crohn’s disease (CD). However, data on the clinical impact of VCE in patients with established CD are scarce. The aim of this study was to examine the impact and safety of VCE on the clinical management of patients with established CD.
Methods: A retrospective, multicenter, cross-sectional study. The study cohort included consecutive patients with established SB CD who underwent VCE in 4 tertiary referral centers (1 Canada, 1 Sweden, and 2 United Kingdom) from January 2008 to October 2013. Patients were excluded if VCE was performed as a part of the initial diagnostic workup. The presence of SB mucosal inflammation was quantified using the Lewis score. Inflammatory biomarkers (C-reactive protein and fecal calprotectin) were measured and correlated with the Lewis score. Results: The study included 187 patients. No SB inflammation was observed in 28.4%, mild-to-moderate inflammation in 26.6%, and moderate-tosevere inflammation in 45% of the patients (median Lewis score, 662; range, 0–6400). A change in management was recommended in 52.3% of the patients based on VCE findings. Elevated C-reactive protein, fecal calprotectin, or the combination of both were poorly correlated with significant SB inflammation. SB capsule retention occurred in 4 patients (2.1%). Conclusions: VCE in patients with established CD is safe, and the results often have a significant clinical impact. VCE should not be limited to CD patients with positive inflammatory markers because their predictive value for significant SB inflammation is poor. (Inflamm Bowel Dis 2015;21:93–100) Key Words: Crohn’s disease, capsule endoscopy, fecal calprotectin, patency capsule
V
ideo capsule endoscopy (VCE) enables excellent visualization of the small bowel (SB) mucosa. Since its introduction into clinical practice in 2000, VCE has become an important modality for the diagnostic workup of obscure gastrointestinal bleeding, SB tumors, and inflammation. The diagnosis of SB Crohn’s disease
Received for publication July 28, 2014; Accepted October 11, 2014. From the *Division of Gastroenterology, McGill University Health Center, Montreal, QC, Canada; †Department of Gastroenterology, Skåne University Hospital, Malmö, Lund University, Lund, Sweden; ‡Endoscopy Unit, Centre for Liver and Digestive Disorders, The Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; §Department of Gastroenterology, Gloucestershire Hospitals NHS Foundation Trust, Chetlenham, United Kingdom; and kDepartment of Gastroenterology, Chaim Sheba Medical Center, Tel Hashomer, Israel. A. Koulaouzidis, ESGE Given Imaging research grant 2011, Lecture honoraria from Dr Falk Pharma, Travel grant/support from Dr Falk Pharma, Abbott, MSD, Material support for research from SynMed. R. Makins, teaching fees from Intromedic. E. Toth, speaker’s honorarium from Given Imaging. E. G. Seidman, speaker’s bureau and research grant support from Given Imaging. The authors have no conflicts of interest to disclose. Reprints: Uri Kopylov, MD, McGill Center for IBD Research, McGill University Health Center, 1650 Cedar Avenue, C1.145, Montreal H3G 1A4, QC, Canada (e-mail: [email protected]). Copyright © 2014 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000255 Published online 26 November 2014.
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(CD) is among the prime indications for VCE, as one third of patients with CD have only SB involvement.1,2 In particular, the diagnosis will be missed if the terminal ileum is not involved.3,4 To date, several studies compared the diagnostic accuracy of VCE for CD with that of other imaging modalities. Its superiority over SB follow-through and computed tomography enterography has been repeatedly demonstrated.3,5–8 Magnetic resonance enterography (MRE) and VCE have a comparable diagnostic accuracy. However, VCE is more sensitive for detection of subtle mucosal inflammation9,10 and for proximal SB involvement.11 In addition to establishing the diagnosis of CD, VCE also has a role in monitoring CD activity and detection of complications.12 However, one of the main limiting factors of its use in established SB CD is the risk of capsule retention. The latter was reported to be as high as 13% in early studies.13,14 In addition, the available scoring systems for quantification of SB inflammation (Lewis score15 [LS] and Capsule Endoscopy Crohn’s Disease Activity Index16) have not been extensively validated for the indication of monitoring of CD in large-scale clinical trials.3,17 The aim of this study was to describe the clinical impact and the safety of VCE in a large multicenter cohort of patients with established CD. In addition, we aimed to evaluate the www.ibdjournal.org |
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diagnostic accuracy of inflammatory biomarkers for prediction of significant SB inflammation.
METHODS Patient Selection This was a retrospective, multicenter, cross-sectional study. The study cohort included consecutive patients with established CD who underwent VCE in 4 academic referral centers (1 each in Canada and Sweden, 2 in the United Kingdom) from January 2008 to October 2013. Patients who underwent VCE for the initial diagnostic workup of CD were excluded. The clinical and demographic data were extracted from the patient’s files and electronic records. The study was approved by the local ethics review board and was conducted in accordance with the Helsinki declaration principles.
Capsule Endoscopy The studies were performed using different models of SB capsule endoscopes (PillCam SB1/2; GivenImaging Ltd., Yoqneam, Israel), (MiroCam; Intromedic Co., Seoul, South Korea), and (EndoCapsule; Olympus Co., Tokyo, Japan) according to the availability in each participating center. The studies were independently reviewed by experienced capsule endoscopists (E.G.S., A.K., E.T., R.M.). Mucosal inflammation was graded using the LS15; Normal VCE was defined as LS ,135, mild-to-moderate inflammation as 135 # LS , 790, and moderate-to-severe as LS $790. For the purpose of this study, we have used the cutoff value of 790 to define significant inflammation.
Patency Capsule Patency capsule (PC) examinations were performed in accordance with the policy of each center. In one center (Montreal), PC was performed for each established CD patient. In other centers, PC was offered only to high-risk patients (history of SB obstruction, abdominal surgery, significantly elevated inflammatory markers). If PC was not excreted in accordance to the manufacturer’s instructions, diagnostic VCE was not performed.
Inflammatory Biomarkers Fecal calprotectin (FCP) was measured by enzyme-linked immunosorbent assay (ELISA) or Quantum Blue Rapid test (Buhlmann Laboratories, Basel, Switzerland) in accordance to the manufacturer’s instructions. For ELISA, values ,50 mg/g were considered negative and positive if . 200 mg/g. For the rapid test, values ,30 mg/g were considered negative and positive if . 100 mg/g. C-reactive protein (CRP) .5 g/dL was defined as positive. Clinical impact was defined as a change in CD-related therapy (escalation/de-escalation of anti-inflammatory therapy, dose adjustment, referral for surgery) that was recommended after the VCE results (at the next clinic visit or within 3 mo of the procedure).
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Statistical Analysis We evaluated VCE diagnostic accuracy and correlation of elevated biomarkers (FCP, CRP, and combination) with significant SB inflammation (LS .790). Sensitivity, specificity, negative predictive value, and positive predictive value as well as Spearman’s rank (r) correlation were calculated. R values ,0.3 were considered as weak-to-low correlation, 0.3 to 0.49 as low-to-moderate, 0.5 to 0.69 as moderate, and $0.7 as strong correlation.18 A two-tailed P value ,0.05 was considered statistically significant. Receiver operating characteristic curve was constructed for correlation of ELISA and FCP with LS .790, and area under the curve (AUC) was calculated. An AUC of 0.6 to 0.7 was considered poor and 0.9 to 1 was considered as excellent correlation. The analysis was performed using IBM SPSS statistic (version 20.0; Armonk, NY).
RESULTS
One hundred eighty-seven (n ¼ 187) patients were included in the study. Their clinical and demographic characteristics and the indications for VCE are described in Table 1. The LS was available in 169 of 187 patients. VCE was normal (LS ,135) in 28.4%; VCE findings consistent with mild inflammation were observed in 26.6% and moderate-to-severe inflammation in 45% of the patients. A change in therapeutic management of CD was recommended as a result of VCE findings in 99 of 187 (52.3%) patients; 8 patients refused to change their treatment. The therapeutic yield was marginally higher in patients with known SB CD as compared with patients with isolated colonic CD (as established before VCE). However, the difference did not reach statistical significance (58.8% versus 51.1%, P ¼ NS). In patients with no SB inflammation (LS ,135), a therapeutic change was recommended in 14.5%. Among those with mild inflammation (LS, 135–790) and moderate-to-severe inflammation (LS .790), therapeutic changes were recommended in 48.1% and 87.1%, respectively. The recommended change included intensification or initiation of anti-inflammatory treatment in 82.5% of patients. A biologic was started in 29.6%, and a dose of a biologic was increased in 4.4% of the patients; an immunomodulator was initiated in 36.3% of the patients. A surgical intervention was suggested in 2.2% of the patients. The recommended therapeutic changes stratified by referral indication and LS are described in detail in Tables 2 and 3.
Disease Location and Phenotype Among the 121 patients with an abnormal VCE, SB findings in all 3 tertiles were demonstrated in 65% of the cases. The third tertile was involved in 88%, whereas proximal (first tertile) inflammation was demonstrated in 49.6% of the patients. In 11 of 43 (25.6%) patients diagnosed with colonic CD, previously undetected SB CD was demonstrated by VCE. Ileocolonoscopy results (within a year of VCE) were available for 97 patients. In 45 patients, no active endoscopic SB disease was demonstrated on ileocolonoscopy. In 30 of 45 (66.6%) of these patients, moderate-to-severe SB inflammation was detected
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TABLE 1. Demographic and Clinical Characteristics of CD Patients Undergoing VCE Gender M/F (%) Age at VCE, mean 6 SD, yr Duration of disease, mean 6 SD, yr Montreal classification (%) Age at onset A1 (,17) A2 (17–40) A3 (.40) Location L1 (SB) L2 (colon) L3 (ileocolonic) Phenotype B1 (luminal) B2 (penetrating) B3 (stricturing) History of surgery Medications Anti-TNFs Infliximab Adalimumab Thiopurines 5-ASA Corticosteroids Indication for VCE (%) Abdominal pain Diarrhea Anemia Weight loss OGIB Obstructive symptoms Evaluation of disease extent Re-evaluation of disease activity/extenta Monitoring of mucosal healing/response to medical therapy Monitoring of postoperative recurrence Suspected IBS-related symptoms
75 (40.1)/112 (59.9) 35.6 6 14.5 7.3 6 8.0
35 (18.7) 112 (59.9) 40 (21.4) 71 (38) 43 (23) 73 (39) 149 30 8 47
(79.7) (16) (4.3) (25.1)
36 20 58 57 51
(19.2) (10.7) (1) (30.7) (27.3)
56 28 9 3 5 5 56 10 9
(29.9) (56.6) (4.8) (1.6) (2.7) (2.7) (29.9) (5.3) (4.8)
4 (2.1) 2 (1.1)
IBS, irritable bowel disease; OGIB, obscure gastrointestinal bleeding. a In patients with quiescent disease.
by VCE (Table 4). Eight patients (4.2%) were identified as having a stricturing (B2) disease before the procedure; only 1 of these patients had a postoperative anastomotic stricture identified by VCE. In addition, strictures were identified in 7 of 179 (3.9%) of the patients previously characterized as having a luminal or fistulizing phenotype. SB imaging (computed tomography enterography/MRE) results within 6 months of the VCE were available for 35 patients. Significant SB pathology was demonstrated in 15 (42.9%)
patients. In 10 of 15 (66.7%) of these patients, significant SB inflammation was demonstrated by VCE, and mild-to-moderate inflammation was shown in additional 3 (20%) of the patients.
Correlation with Inflammation Biomarkers CRP was available for 83% (elevated in 48%) of the patients and FCP for 66.3% (elevated in 60.6%). FCP was measured by ELISA in 95.5% and by the rapid test quantum blue rapid semiquantitative FCP assay (QB) in 4.5% of the cases. Both markers were available for 54.5% (positive in 50.9%) of the patients. The biomarkers were obtained 4.5 6 62.9 days before VCE. Sensitivity, specificity, positive predictive values, negative predictive values, and correlation values of elevated biomarkers for detection of significant SB inflammation are shown in Table 5. Poor correlation with significant SB inflammation was demonstrated for elevated FCP (ELISA .200 mg/g, QB .100 mg/g; r ¼ 0.164, P ¼ 0.07; sensitivity, 69.8%, specificity, 46.5%), elevated CRP (r ¼ 0.3; P ¼ 0.01; sensitivity, 60.5%, specificity, 70.3%), or combination of both elevated markers (r ¼ 0.2; P ¼ 0.14). A negligible improvement in the correlation was achieved if patients with exclusively colonic CD (determined before VCE) were excluded. However, neither of the markers nor their combination reached a level of correlation greater than 0.4. We performed additional analyses using ELISA FCP results only (.200 mg/g), “grey zone” FCP values (30–100 mg/g for QB or 50–200 mg/g for ELISA and LS .135) as a cutoff value of significant inflammation. Nevertheless, no significant improvement in diagnostic accuracy was achieved (data not shown). We constructed a receiver operating characteristic for FCP and CRP as a predictor of significant SB inflammation. As QB is a semiquantitative rest, only patients with ELISA FCP results were included (n ¼ 112). The AUC was 0.63, and with exclusion of patients without known SB disease was 0.64 (Fig. 1), which corresponds to poor detection accuracy. For CRP, the AUC was 0.66. The cutoff value associated with the optimal combination of sensitivity and specificity was 275 mg/g. Nevertheless, the diagnostic accuracy was not significantly improved using this cutoff (Table 5).
Safety Capsule retention in the SB occurred in 4 (2.1%) patients. In 3 cases, the capsule was expelled after a course of corticosteroids. In the 1 other patient with a known stricturing phenotype, the capsule was retained at the anastomotic site in the neoterminal ileum, necessitating endoscopic removal. This patient did not undergo a prior PC. In an additional patient, the capsule was retained in the esophagus and was reinserted endoscopically. None of the patients required surgical intervention. A PC was performed in 77 (41%) of the patients. In one center (Montreal), PC was administered routinely to all patients with known CD. PC was successfully excreted within 30 hours in 91.6% of the patients; all of them proceeded to diagnostic capsule. In patients with stricturing disease, a PC was performed in 2 (25%) and was successfully excreted by both. One case of www.ibdjournal.org |
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TABLE 2. Association of VCE Results and Therapeutic Recommendations According to Referral Indications in CD Therapeutic Change Recommended LS ,135 N (%)
Indication Abdominal pain Diarrhea Anemia Weight loss OGIB Obstructive symptoms Evaluation of disease extent Re-evaluation of disease activity/extent Monitoring of mucosal healing/response to medical therapy Monitoring of postoperative recurrence Suspected IBS-related symptoms
LS 135–790 N (%)
2 (40) 0 (0) 1 (20) 0 (0) 0 (0) 0 (0) 2 (40) 0 (0) 0 (0)
5 6 0 0 1 1 10 1 0
0 (0) 0 (0)
(20.8) (25) (0) (0) (4.2) (4.2) (41.7) (4.2) (0)
0 (0) 0 (0)
Therapeutic Change not Recommended
LS .790 N (%)
LS ,135 N (%)
22 11 2 1 1 1 19 4 5
15 1 2 1 2 1 2 1 1
(32.4) (16.2) (2.9) (1.5) (1.5) (1.5) (27.9) (5.9) (7.4)
2 (2.9) 0 (0)
(34.9) (2.3) (4.7) (2.3) (4.7) (2.3) (4.7) (2.3) (2.3)
1 (2.3) 2 (4.7)
LS 135–790 N (%) 5 5 2 0 0 2 4 1 2
(23.8) (23.8) (9.5) (0) (0) (9.5) (19) (4.8) (9.5)
LS .790 N (%) 1 (12.5) 2 (25) 1 (12.5) 0 (0) 1 (12.5) 0 (0) 1 (12.5) 1 (12.5) 1 (12.5)
0 (0) 0 (0)
0 (0) 0 (0)
IBS, irritable bowel disease; LS, Lewis score of severity of SB lesions seen on videocapsule.
transient symptomatic SB obstruction occurred after ingestion of a PC and was resolved spontaneously. One case of retention (2%) of the diagnostic capsule occurred in a patient who had successfully excreted the PC.
DISCUSSION
Our findings in a large cohort of patients with established CD followed in tertiary referral settings demonstrate that VCE is associated with a significant clinical impact. Furthermore, VCE was associated with an excellent safety profile with an SB retention rate of only 2.1% and need for endoscopic intervention in 0.5% of the patients. To the best of our knowledge, this is the largest study evaluating the impact of VCE on the management of established CD patients so far and the first one to systematically use a unified scoring system (LS) and to establish the correlation of inflammatory biomarkers with LS.
VCE is established as an important clinical tool for diagnosis of SB CD, with significantly higher diagnostic yield in comparison with other traditional cross-sectional imaging modalities.3,10 An exception is MRE, which is equally accurate, especially for distal SB involvement.11 Both cross-sectional imaging and VCE can be used for monitoring of established CD.19–21 MRE is superior to diagnose penetrating and stenotic complications (the latter being a relative contraindication for VCE).19 Moreover, MRE is not associated with a risk of retention, and VCE may be especially useful in several particular clinical scenarios, mostly those requiring accurate visualization of subtle mucosal inflammation, such as unexplained anemia, monitoring of mucosal healing, and postoperative recurrence, and symptoms that could not be explained by endoscopic findings. Several small series have described the use of VCE for monitoring of mucosal healing22,23 and postoperative recurrence.24 In CD patients with symptoms that could not be explained by ileocolonoscopy
TABLE 3. Therapeutic Changes Stratified by VCE Results in Established CD
Lewis Score ,135 135–790 .790
None (%)
Change Recommended (%)
Biologic Started (%)
Biologic Dose Escalated
IMM Started (%)
IMM Dose Escalated (%)
Steroids (%)
Biologic Stopped (%)
Surgery (%)
Othera
43 (91.5) 22 (48.9) 9 (12.2)
4 (8.5) 23 (51.1) 64 (87.8)
0 6 (13.3) 21 (28.4)
0 0 4
1 (2.1) 10 (22.2) 23 (31.1)
0 1 (2.2) 1 (1.4)
0 3 (6.7) 10 (13.5)
1 (2.1) 0 0
0 0 2 (2.7)
2a (4) 1a (2.2) 1b (1.3)
IMM, immunomodulator. a Medications were stopped or a non–anti-inflammatory agent was added, such as antibiotics. b TPN and antibiotics were associated.
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(%)
Patient Refused Change 0 2 (4.4) 3 (4.1)
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Significant SB inflammation: Lewis score .790. PPV, positive predictive value; QB, quantum blue rapid semiquantitative FCP assay; r, spearman’s rho correlation; Sens, sensitivity; Spec, specificity.
53.8 50 67.8 63.8 0.17 0.65 60.5 70.3 5737 72.5 0.31 0.01 61.9 47.1 59.1 50 0.2 0.0.143 65.3 57.3 64 56.1 0.22 0.61 57.5 76.2 69.6 65.5 0.34 0.02 59 50 67.3 40.7 0.32 0.0016 0.07 0.02 0.164 0.25 65.2 60 48.7 60.7 43.5 52.2 69.8 68.0 All CD Known ileal CD
P r Sens Spec PPV NPV P r NPV PPV Sens Spec P r Sens Spec PPV NPV
findings, VCE diagnosed SB inflammation in 44% of the patients.25 Additionally, in patients with primarily proximal SB disease, VCE has a higher diagnostic accuracy.11 Proximal SB involvement was recently reported to be associated with an increased long-term risk of complications.26 Currently, clinical experience with VCE for monitoring of known CD for these and/or other indications is limited and lacks standardization. VCE was demonstrated to have an impact on the clinical management of both adult and pediatric CD patients and to result in a shift in the diagnosis to CD in some patients with ulcerative colitis or unclassified IBD.27–29 The largest series published so far described the results and the therapeutic impact of VCE in 126 IBD patients, including 86 with CD.30 In the latter study, VCE lead to a management change in 61.6% of the patients. In another recent study, a therapeutic change was undertaken in 53% of the 77 CD patients after VCE.25 Importantly, normal VCE results in symptomatic CD patients is also clinically useful, as it would suggest a noninflammatory etiology for the symptoms (such as a functional bowel disorder), leading to alternative treatment options. The currently available data pertaining to the optimal strategy and indications for the utilization of VCE in established CD is limited. Additional studies are required to incorporate capsule endoscopy and alternative noninvasive screening methods into clinical surveillance and monitoring protocols. One of the major issues limiting the use of VCE in established CD is the risk of retention, which was although initially reported to be as high as 13%,31 in later reports, the risk was much lower (4%–5.6%),25,32,33 especially when a PC was used. In recent meta-analyses, the rate of VCE retention in patients with suspected CD was 2.8% for adults34 and 2.5% for pediatric patients,35 respectively. Although the use of PC has been demonstrated to significantly reduce the rate of retention,36 it does not eliminate the risk completely.33 In this study, the rate of SB retention was lower than in previous reports (2.1%). Only 1 patient experienced capsule retention after timely excretion of a PC. However, we cannot evaluate the impact of PC on complication rates in our cohort, as the strategy varied between the participating centers, with only 1 administering a PC to all patients with established CD. The other centers used a PC for selected patients considered to be at a higher risk category for
P
(50.0) (33.3) (68.2) (33.3)
r
15 8 15 7
NPV
(36.7) (16.7) (18.2) (33.3)
PPV
11 4 4 7
Spec
(13.3) (50.0) (13.6) (33.3)
Sens
4 12 3 7
LS .790 N (%)
Both Markers Elevated
Ileitis Colitis Illeocolitis Normal ileocolonoscopy
135 , LS . 790 N (%)
CRP .5
LS ,135 N (%)
FCP .275 mg/g
Endoscopy Findings
Elevated FCP (.200 mg/g ELISA, .100 mg/g QB)
TABLE 4. Correlation of VCE with Ileocolonoscopy Findings in Established CD
TABLE 5. Diagnostic Performance of Inflammatory Biomarkers for Prediction of Significant Small Bowel Inflammation on VCE in Established CD
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FIGURE 1. Receiver operating characteristic (ROC) curve analysis of the diagnostic performance of ELISA FCP for detection of significant SB inflammation (LS .790) in patients with established CD (AUC ¼ 0.64).
retention. The World Organization of Digestive Endoscopy and the European Crohn’s and Colitis Organization guidelines recommend to consider PC in patients with known CD; however, it is not clear whether administration of PC will be beneficial in all CD patients or it should be limited to higher risk subgroups only. The optimal strategy for utilization of PC in this clinical situation deserves further exploration in future studies. To the best of our knowledge, our study is the first to systematically apply a widely accepted endoscopic scoring system (LS) in a large cohort of patients with established CD. Previous studies addressing a similar patient cohort used simpler qualitative scoring systems that were different for each study.22,25,30 However, the LS was developed and validated for the purpose of discrimination of SB inflammation from noninflammatory etiologies.15 Although it is frequently used for reporting SB involvement in CD, it has never been validated for the monitoring of known CD. There are, however, certain drawbacks in the utilization of LS for monitoring of established CD. Most notably, strictures are the most heavily weighted element of the LS (e.g., a simple singe ulcer yields a score of 135, whereas a single traversed stenosis is scored 18-fold higher at 2352). Because a known SB stricture will usually be a contraindication for VCE and ruling out significant stenosis is recommended before performance of diagnostic capsule examination,37 the number of CD patients with known stricturing phenotype that are eligible for VCE would be expected to be low. Consequently, in our cohort, patients with stricturing disease or strictures found on VCE were relatively rare. In addition, although the LS divides the SB into 3 tertiles that are scored separately, only the most severely involved tertile is used as the final score. Thus, a patient who has involvement in all 3 tertiles may have an LS equal to a patient who only has SB involvement limited to a single tertile. Moreover, as reported by
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the authors,15 there was a significant overlap in the scores of patients with mild and moderate-to-severe disease. The aforementioned limitations of the LS result in a relatively clear discrimination of CD patients with normal versus inflamed SB but with a more limited quantification of the inflammatory burden. In addition, there is no consensus as to what LS represents mucosal healing or postoperative recurrence, in contrast to multiple available endoscopic scores. We believe that a modified LS adjusted for monitoring of CD merits development and validation in a large-scale prospective trial. We did not find a significant correlation between inflammatory biomarkers (both CRP and FCP or a combination of both) and the presence of significant SB inflammation. FCP is a neutrophil-derived protein that is directly correlated with mucosal inflammation and provides an excellent diagnostic tool for diagnosis of CD, monitoring of mucosal healing, and prediction of relapse.38 Inflammatory biomarkers are frequently used as a screening tool before referral for VCE. However, based on our results, this strategy cannot be considered accurate for patients with known CD, as approximately 40% of the patients with significant lesions will be missed if only patients with elevated biomarkers are tested. The correlation of FCP with LS has been evaluated in patients with suspected CD in 3 studies. Koulaouzidis et al showed that FCP was significantly correlated with LS; however, this correlation was only observed in a subgroup of patients with FCP ,100 mg/g and not in patients with higher FCP values, in whom no correlation between the 2 was observed. Capsule Endoscopy Crohn’s Disease Activity Index was not correlated with FCP in cases with low- or high-FCP group.17 In a study from Finland, FCP level of 50 and 100 mg/g were both associated with poor sensitivity and moderate specificity for detection of SB inflammation.39 In an additional study evaluating patients with suspected CD, FCP .200 mg/g was associated with a positive predictive value of 78% and a negative predictive value of 100% for the diagnosis of CD (LS .135).40 In our study, the diagnostic accuracy of both FCP and CRP for prediction of significant inflammation in established CD was insufficient. We have used the LS cutoff value of 790 for definition of significant inflammation because all patients in our cohort were already diagnosed with CD, and findings consistent with mild inflammation were less likely to be of true clinical significance. In contrast to the aforementioned studies, we have used 2 different methods for measurement of FCP. However, the accuracy of the rapid semiquantitative method is comparable with ELISA, and the correlation between the methods is very good.41 To the best of our knowledge, our study is the first to evaluate this correlation in a cohort of patients with established CD. Despite the significant findings, our study has several limitations, mostly originating from the retrospective format of the study. We do not have colonoscopic or cross-sectional imaging data available for all the patients. Current imaging data were available only for a minority of patients, and in many cases, these studies were performed in an emergency setting with suboptimal visualization, precluding performing a meaningful analysis of
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correlation of VCE with imaging findings. The results of inflammatory biomarkers were available for a majority of patients. However, in some patients, changes in disease severity may have occurred during the lag period before VCE was performed. Furthermore, we did not apply a uniform strategy for referral for VCE or administration of PC. In addition, a decision to change therapy was undertaken by each treating physician on an individual case basis. Such decisions could have been influenced by additional clinical factors. A prospective study would allow for the clinical impact to be accessed more accurately by asking the clinician what their next course of action would have been in the absence of a VCE and whether VCE results have altered their decision. The limitations of the LS for the patient cohort that was evaluated in our study were discussed above. Despite the aforementioned limitations, our study provides important insight and useful data on the clinical utility and safety of VCE for management of patients with established CD.
SUMMARY VCE provides meaningful results leading to therapeutic changes in more than 50% of patients with established CD. VCE is very safe in this patient cohort, especially if preceded by PC in at least the subgroup of high-risk patients. FCP and CRP do not correlate well with significant VCE findings in patients with established CD and cannot be relied on to select patients for study.
ACKNOWLEDGMENTS Author contributions: Study design: U. Kopylov, A. Koulaouzidis, E. Toth, E. G. Seidman; data collection: U. Kopylov, A. Nemeth, G. W. Johansson, R. Makins, W. Afif, T. Bessissow; data analysis: U. Kopylov, A. Koulaouzidis, E. Toth, E. G. Seidman; manuscript drafting: U. Kopylov, E. G. Seidman; review of the manuscript for important scientific input: A. Nemeth, G. W. Johansson, R. Makins, W. Afif, T. Bessissow, A. Koulaouzidis, E. Toth, G. Wild, W. Afif, A. Bitton, R. Eliakim; guarantor of the article: U. Kopylov. All authors have reviewed and approved the manuscript.
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1. Cosnes J, Gower-Rousseau C, Seksik P, et al. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology. 2011;140: 1785–1794. 2. Wang A, Banerjee S, Barth BA, et al. Wireless capsule endoscopy. Gastrointest Endosc. 2013;78:805–815. 3. Leighton JA, Gralnek IM, Cohen SA, et al. Capsule endoscopy is superior to small-bowel follow-through and equivalent to ileocolonoscopy in suspected Crohn’s disease. Clin Gastroenterol Hepatol. 2014;12:609–615. 4. Rosa B, Moreira MJ, Rebelo A, et al. Lewis Score: a useful clinical tool for patients with suspected Crohn’s Disease submitted to capsule endoscopy. J Crohn’s Colitis. 2012;6:692–697. 5. de Melo SW Jr, Di Palma JA. The role of capsule endoscopy in evaluating inflammatory bowel disease. Gastroenterol Clinics North Am. 2012;41: 315–323. 6. Marmo R, Rotondano G, Piscopo R, et al. Meta-analysis: capsule enteroscopy vs. conventional modalities in diagnosis of small bowel diseases. Aliment Pharmacol Ther. 2005;22:595–604.
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7. Marmo R, Rotondano G, Piscopo R, et al. Capsule endoscopy versus enteroclysis in the detection of small-bowel involvement in Crohn’s disease: a prospective trial. Clin Gastroenterol Hepatol. 2005;3:772–776. 8. Triester SL, Leighton JA, Leontiadis GI, et al. A meta-analysis of the yield of capsule endoscopy compared to other diagnostic modalities in patients with non-stricturing small bowel Crohn’s disease. Am J Gastroenterol. 2006;101:954–964. 9. Tillack C, Seiderer J, Brand S, et al. Correlation of magnetic resonance enteroclysis (MRE) and wireless capsule endoscopy (CE) in the diagnosis of small bowel lesions in Crohn’s disease. Inflamm Bowel Dis. 2008;14:1219–1228. 10. Dionisio PM, Gurudu SR, Leighton JA, et al. Capsule endoscopy has a significantly higher diagnostic yield in patients with suspected and established small-bowel Crohn’s disease: a meta-analysis. Am J Gastroenterol. 2010;105:1240–1248. 11. Jensen MD, Nathan T, Rafaelsen SR, et al. Diagnostic accuracy of capsule endoscopy for small bowel Crohn’s disease is superior to that of MR enterography or CT enterography. Clin Gastroenterol Hepatol. 2011;9:124–129. 12. Kopylov U, Seidman EG. Capsule endoscopy in inflammatory bowel disease. World J Gastroenterol. 2014;20:1155–1164. 13. Mow WS, Lo SK, Targan SR, et al. Initial experience with wireless capsule enteroscopy in the diagnosis and management of inflammatory bowel disease. Clin Gastroenterol Hepatol. 2004;2:31–40. 14. Cheifetz AS, Kornbluth AA, Legnani P, et al. The risk of retention of the capsule endoscope in patients with known or suspected Crohn’s disease. Am J Gastroenterol. 2006;101:2218–2222. 15. Gralnek IM, Defranchis R, Seidman E, et al. Development of a capsule endoscopy scoring index for small bowel mucosal inflammatory change. Aliment Pharmacol Ther. 2008;27:146–154. 16. Niv Y, Ilani S, Levi Z, et al. Validation of the Capsule Endoscopy Crohn’s Disease Activity Index (CECDAI or Niv score): a multicenter prospective study. Endoscopy. 2012;44:21–26. 17. Koulaouzidis A, Douglas S, Plevris JN. Lewis score correlates more closely with fecal calprotectin than Capsule Endoscopy Crohn’s Disease Activity Index. Dig Dis Sci. 2012;57:987–993. 18. Fleiss JL. Statistical Methods for Rates and Proportions. 2nd ed. New York, NY: John Wiley; 1981, pp. 38–46. 19. Annese V, Daperno M, Rutter MD, et al. European evidence based consensus for endoscopy in inflammatory bowel disease. J Crohn’s Colitis. 2013;7:982–1018. 20. Panes J, Bouhnik Y, Reinisch W, et al. Imaging techniques for assessment of inflammatory bowel disease: joint ECCO and ESGAR evidence-based consensus guidelines. J Crohn’s Colitis. 2013;7:556–585. 21. Amitai MM, Ben-Horin S, Eliakim R, et al. Magnetic resonance enterography in Crohn’s disease: a guide to common imaging manifestations for the IBD physician. J Crohn’s Colitis. 2013;7:603–615. 22. Efthymiou A, Viazis N, Mantzaris G, et al. Does clinical response correlate with mucosal healing in patients with Crohn’s disease of the small bowel? A prospective, case-series study using wireless capsule endoscopy. Inflamm Bowel Dis. 2008;14:1542–1547. 23. Niv E, Fishman S, Kachman H, et al. Sequential capsule endoscopy of the small bowel for follow-up of patients with known Crohn’s disease. J Crohn’s Colitis. [published online ahead of print March 22, 2014]. doi: 10.1016/j.crohns.2014.03.003. 24. Bourreille A, Jarry M, D’Halluin PN, et al. Wireless capsule endoscopy versus ileocolonoscopy for the diagnosis of postoperative recurrence of Crohn’s disease: a prospective study. Gut. 2006;55:978–982. 25. Dussault C, Gower-Rousseau C, Salleron J, et al. Small bowel capsule endoscopy for management of Crohn’s disease: a retrospective tertiary care centre experience. Dig Liver Dis. 2013;45:558–561. 26. Lazarev M, Huang C, Bitton A, et al. Relationship between proximal Crohn’s disease location and disease behavior and surgery: a crosssectional study of the IBD Genetics Consortium. Am J Gastroenterol. 2013;108:106–112. 27. Cohen SA, Gralnek IM, Ephrath H, et al. The use of a patency capsule in pediatric Crohn’s disease: a prospective evaluation. Dig Dis Sci. 2011;56: 860–865. 28. Gralnek IM, Cohen SA, Ephrath H, et al. Small bowel capsule endoscopy impacts diagnosis and management of pediatric inflammatory bowel disease: a prospective study. Dig Dis Sci. 2012;57:465–471. www.ibdjournal.org |
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29. Min SB, Le-Carlson M, Singh N, et al. Video capsule endoscopy impacts decision making in pediatric IBD: a single tertiary care center experience. Inflamm Bowel Dis. 2013;19:2139–2145. 30. Long MD, Barnes E, Isaacs K, et al. Impact of capsule endoscopy on management of inflammatory bowel disease: a single tertiary care center experience. Inflamm Bowel Dis. 2011;17:1855–1862. 31. Kornbluth A, Colombel JF, Leighton JA, et al. ICCE consensus for inflammatory bowel disease. Endoscopy. 2005;37:1051–1054. 32. Esaki M, Matsumoto T, Watanabe K, et al. Use of capsule endoscopy in patients with Crohn’s disease in Japan: a multicenter survey. J Gastroenterol Hepatol. 2014;29:96–101. 33. Eliakim R. Video capsule endoscopy of the small bowel. Curr Opin Gastroenterol. 2013;29:133–139. 34. Liao Z, Gao R, Xu C, et al. Indications and detection, completion, and retention rates of small-bowel capsule endoscopy: a systematic review. Gastrointest Endosc. 2010;71:280–286. 35. Cohen SA, Klevens AI. Use of capsule endoscopy in diagnosis and management of pediatric patients, based on meta-analysis. Clin Gastroenterol Hepatol. 2011;9:490–496.
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36. Herrerias JM, Leighton JA, Costamagna G, et al. Agile patency system eliminates risk of capsule retention in patients with known intestinal strictures who undergo capsule endoscopy. Gastrointest Endosc. 2008; 67:902–909. 37. Bourreille A, Ignjatovic A, Aabakken L, et al. Role of small-bowel endoscopy in the management of patients with inflammatory bowel disease: an international OMED-ECCO consensus. Endoscopy. 2009;41:618–637. 38. Kopylov U, Rosenfeld G, Bressler B, et al. Clinical utility of fecal biomarkers for the diagnosis and management of inflammatory bowel disease. Inflamm Bowel Dis. 2014;20:742–756. 39. Sipponen T, Haapamaki J, Savilahti E, et al. Fecal calprotectin and S100A12 have low utility in prediction of small bowel Crohn’s disease detected by wireless capsule endoscopy. Scand J Gastroenterol. 2012;47:778–784. 40. Koulaouzidis A, Douglas S, Rogers MA, et al. Fecal calprotectin: a selection tool for small bowel capsule endoscopy in suspected IBD with prior negative bi-directional endoscopy. Scand J Gastroenterol. 2011;46:561–566. 41. Otten CMT, Kok L, Witteman BJM, et al. Diagnostic performance of rapid tests for detection of fecal calprotectin and lactoferrin and their ability to discriminate inflammatory from irritable bowel syndrome. Clin Chem Lab Med. 2008;46:1275–1280.
Small Bowel Capsule Endoscopy in the Management of Established Crohn’s Disease: Clinical Impact, Safety, and Correlation with Inflammatory Biomarkers Uri Kopylov, MD,* Artur Nemeth, MD,† Anastasios Koulaouzidis, MD,‡ Richard Makins, MD,§ Gary Wild, MD,* Waqqas Afif, MD,* Alain Bitton, MD,* Gabriele Wurm Johansson, MD,† Talat Bessissow, MD,* Rami Eliakim, MD,k Ervin Toth, MD,† and Ernest G. Seidman, MD*
Background: Multiple studies have established the superior diagnostic accuracy of video capsule endoscopy (VCE) for the diagnosis of small bowel (SB) Crohn’s disease (CD). However, data on the clinical impact of VCE in patients with established CD are scarce. The aim of this study was to examine the impact and safety of VCE on the clinical management of patients with established CD.
Methods: A retrospective, multicenter, cross-sectional study. The study cohort included consecutive patients with established SB CD who underwent VCE in 4 tertiary referral centers (1 Canada, 1 Sweden, and 2 United Kingdom) from January 2008 to October 2013. Patients were excluded if VCE was performed as a part of the initial diagnostic workup. The presence of SB mucosal inflammation was quantified using the Lewis score. Inflammatory biomarkers (C-reactive protein and fecal calprotectin) were measured and correlated with the Lewis score. Results: The study included 187 patients. No SB inflammation was observed in 28.4%, mild-to-moderate inflammation in 26.6%, and moderate-tosevere inflammation in 45% of the patients (median Lewis score, 662; range, 0–6400). A change in management was recommended in 52.3% of the patients based on VCE findings. Elevated C-reactive protein, fecal calprotectin, or the combination of both were poorly correlated with significant SB inflammation. SB capsule retention occurred in 4 patients (2.1%). Conclusions: VCE in patients with established CD is safe, and the results often have a significant clinical impact. VCE should not be limited to CD patients with positive inflammatory markers because their predictive value for significant SB inflammation is poor. (Inflamm Bowel Dis 2015;21:93–100) Key Words: Crohn’s disease, capsule endoscopy, fecal calprotectin, patency capsule
V
ideo capsule endoscopy (VCE) enables excellent visualization of the small bowel (SB) mucosa. Since its introduction into clinical practice in 2000, VCE has become an important modality for the diagnostic workup of obscure gastrointestinal bleeding, SB tumors, and inflammation. The diagnosis of SB Crohn’s disease
Received for publication July 28, 2014; Accepted October 11, 2014. From the *Division of Gastroenterology, McGill University Health Center, Montreal, QC, Canada; †Department of Gastroenterology, Skåne University Hospital, Malmö, Lund University, Lund, Sweden; ‡Endoscopy Unit, Centre for Liver and Digestive Disorders, The Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; §Department of Gastroenterology, Gloucestershire Hospitals NHS Foundation Trust, Chetlenham, United Kingdom; and kDepartment of Gastroenterology, Chaim Sheba Medical Center, Tel Hashomer, Israel. A. Koulaouzidis, ESGE Given Imaging research grant 2011, Lecture honoraria from Dr Falk Pharma, Travel grant/support from Dr Falk Pharma, Abbott, MSD, Material support for research from SynMed. R. Makins, teaching fees from Intromedic. E. Toth, speaker’s honorarium from Given Imaging. E. G. Seidman, speaker’s bureau and research grant support from Given Imaging. The authors have no conflicts of interest to disclose. Reprints: Uri Kopylov, MD, McGill Center for IBD Research, McGill University Health Center, 1650 Cedar Avenue, C1.145, Montreal H3G 1A4, QC, Canada (e-mail: [email protected]). Copyright © 2014 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000255 Published online 26 November 2014.
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(CD) is among the prime indications for VCE, as one third of patients with CD have only SB involvement.1,2 In particular, the diagnosis will be missed if the terminal ileum is not involved.3,4 To date, several studies compared the diagnostic accuracy of VCE for CD with that of other imaging modalities. Its superiority over SB follow-through and computed tomography enterography has been repeatedly demonstrated.3,5–8 Magnetic resonance enterography (MRE) and VCE have a comparable diagnostic accuracy. However, VCE is more sensitive for detection of subtle mucosal inflammation9,10 and for proximal SB involvement.11 In addition to establishing the diagnosis of CD, VCE also has a role in monitoring CD activity and detection of complications.12 However, one of the main limiting factors of its use in established SB CD is the risk of capsule retention. The latter was reported to be as high as 13% in early studies.13,14 In addition, the available scoring systems for quantification of SB inflammation (Lewis score15 [LS] and Capsule Endoscopy Crohn’s Disease Activity Index16) have not been extensively validated for the indication of monitoring of CD in large-scale clinical trials.3,17 The aim of this study was to describe the clinical impact and the safety of VCE in a large multicenter cohort of patients with established CD. In addition, we aimed to evaluate the www.ibdjournal.org |
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diagnostic accuracy of inflammatory biomarkers for prediction of significant SB inflammation.
METHODS Patient Selection This was a retrospective, multicenter, cross-sectional study. The study cohort included consecutive patients with established CD who underwent VCE in 4 academic referral centers (1 each in Canada and Sweden, 2 in the United Kingdom) from January 2008 to October 2013. Patients who underwent VCE for the initial diagnostic workup of CD were excluded. The clinical and demographic data were extracted from the patient’s files and electronic records. The study was approved by the local ethics review board and was conducted in accordance with the Helsinki declaration principles.
Capsule Endoscopy The studies were performed using different models of SB capsule endoscopes (PillCam SB1/2; GivenImaging Ltd., Yoqneam, Israel), (MiroCam; Intromedic Co., Seoul, South Korea), and (EndoCapsule; Olympus Co., Tokyo, Japan) according to the availability in each participating center. The studies were independently reviewed by experienced capsule endoscopists (E.G.S., A.K., E.T., R.M.). Mucosal inflammation was graded using the LS15; Normal VCE was defined as LS ,135, mild-to-moderate inflammation as 135 # LS , 790, and moderate-to-severe as LS $790. For the purpose of this study, we have used the cutoff value of 790 to define significant inflammation.
Patency Capsule Patency capsule (PC) examinations were performed in accordance with the policy of each center. In one center (Montreal), PC was performed for each established CD patient. In other centers, PC was offered only to high-risk patients (history of SB obstruction, abdominal surgery, significantly elevated inflammatory markers). If PC was not excreted in accordance to the manufacturer’s instructions, diagnostic VCE was not performed.
Inflammatory Biomarkers Fecal calprotectin (FCP) was measured by enzyme-linked immunosorbent assay (ELISA) or Quantum Blue Rapid test (Buhlmann Laboratories, Basel, Switzerland) in accordance to the manufacturer’s instructions. For ELISA, values ,50 mg/g were considered negative and positive if . 200 mg/g. For the rapid test, values ,30 mg/g were considered negative and positive if . 100 mg/g. C-reactive protein (CRP) .5 g/dL was defined as positive. Clinical impact was defined as a change in CD-related therapy (escalation/de-escalation of anti-inflammatory therapy, dose adjustment, referral for surgery) that was recommended after the VCE results (at the next clinic visit or within 3 mo of the procedure).
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Statistical Analysis We evaluated VCE diagnostic accuracy and correlation of elevated biomarkers (FCP, CRP, and combination) with significant SB inflammation (LS .790). Sensitivity, specificity, negative predictive value, and positive predictive value as well as Spearman’s rank (r) correlation were calculated. R values ,0.3 were considered as weak-to-low correlation, 0.3 to 0.49 as low-to-moderate, 0.5 to 0.69 as moderate, and $0.7 as strong correlation.18 A two-tailed P value ,0.05 was considered statistically significant. Receiver operating characteristic curve was constructed for correlation of ELISA and FCP with LS .790, and area under the curve (AUC) was calculated. An AUC of 0.6 to 0.7 was considered poor and 0.9 to 1 was considered as excellent correlation. The analysis was performed using IBM SPSS statistic (version 20.0; Armonk, NY).
RESULTS
One hundred eighty-seven (n ¼ 187) patients were included in the study. Their clinical and demographic characteristics and the indications for VCE are described in Table 1. The LS was available in 169 of 187 patients. VCE was normal (LS ,135) in 28.4%; VCE findings consistent with mild inflammation were observed in 26.6% and moderate-to-severe inflammation in 45% of the patients. A change in therapeutic management of CD was recommended as a result of VCE findings in 99 of 187 (52.3%) patients; 8 patients refused to change their treatment. The therapeutic yield was marginally higher in patients with known SB CD as compared with patients with isolated colonic CD (as established before VCE). However, the difference did not reach statistical significance (58.8% versus 51.1%, P ¼ NS). In patients with no SB inflammation (LS ,135), a therapeutic change was recommended in 14.5%. Among those with mild inflammation (LS, 135–790) and moderate-to-severe inflammation (LS .790), therapeutic changes were recommended in 48.1% and 87.1%, respectively. The recommended change included intensification or initiation of anti-inflammatory treatment in 82.5% of patients. A biologic was started in 29.6%, and a dose of a biologic was increased in 4.4% of the patients; an immunomodulator was initiated in 36.3% of the patients. A surgical intervention was suggested in 2.2% of the patients. The recommended therapeutic changes stratified by referral indication and LS are described in detail in Tables 2 and 3.
Disease Location and Phenotype Among the 121 patients with an abnormal VCE, SB findings in all 3 tertiles were demonstrated in 65% of the cases. The third tertile was involved in 88%, whereas proximal (first tertile) inflammation was demonstrated in 49.6% of the patients. In 11 of 43 (25.6%) patients diagnosed with colonic CD, previously undetected SB CD was demonstrated by VCE. Ileocolonoscopy results (within a year of VCE) were available for 97 patients. In 45 patients, no active endoscopic SB disease was demonstrated on ileocolonoscopy. In 30 of 45 (66.6%) of these patients, moderate-to-severe SB inflammation was detected
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TABLE 1. Demographic and Clinical Characteristics of CD Patients Undergoing VCE Gender M/F (%) Age at VCE, mean 6 SD, yr Duration of disease, mean 6 SD, yr Montreal classification (%) Age at onset A1 (,17) A2 (17–40) A3 (.40) Location L1 (SB) L2 (colon) L3 (ileocolonic) Phenotype B1 (luminal) B2 (penetrating) B3 (stricturing) History of surgery Medications Anti-TNFs Infliximab Adalimumab Thiopurines 5-ASA Corticosteroids Indication for VCE (%) Abdominal pain Diarrhea Anemia Weight loss OGIB Obstructive symptoms Evaluation of disease extent Re-evaluation of disease activity/extenta Monitoring of mucosal healing/response to medical therapy Monitoring of postoperative recurrence Suspected IBS-related symptoms
75 (40.1)/112 (59.9) 35.6 6 14.5 7.3 6 8.0
35 (18.7) 112 (59.9) 40 (21.4) 71 (38) 43 (23) 73 (39) 149 30 8 47
(79.7) (16) (4.3) (25.1)
36 20 58 57 51
(19.2) (10.7) (1) (30.7) (27.3)
56 28 9 3 5 5 56 10 9
(29.9) (56.6) (4.8) (1.6) (2.7) (2.7) (29.9) (5.3) (4.8)
4 (2.1) 2 (1.1)
IBS, irritable bowel disease; OGIB, obscure gastrointestinal bleeding. a In patients with quiescent disease.
by VCE (Table 4). Eight patients (4.2%) were identified as having a stricturing (B2) disease before the procedure; only 1 of these patients had a postoperative anastomotic stricture identified by VCE. In addition, strictures were identified in 7 of 179 (3.9%) of the patients previously characterized as having a luminal or fistulizing phenotype. SB imaging (computed tomography enterography/MRE) results within 6 months of the VCE were available for 35 patients. Significant SB pathology was demonstrated in 15 (42.9%)
patients. In 10 of 15 (66.7%) of these patients, significant SB inflammation was demonstrated by VCE, and mild-to-moderate inflammation was shown in additional 3 (20%) of the patients.
Correlation with Inflammation Biomarkers CRP was available for 83% (elevated in 48%) of the patients and FCP for 66.3% (elevated in 60.6%). FCP was measured by ELISA in 95.5% and by the rapid test quantum blue rapid semiquantitative FCP assay (QB) in 4.5% of the cases. Both markers were available for 54.5% (positive in 50.9%) of the patients. The biomarkers were obtained 4.5 6 62.9 days before VCE. Sensitivity, specificity, positive predictive values, negative predictive values, and correlation values of elevated biomarkers for detection of significant SB inflammation are shown in Table 5. Poor correlation with significant SB inflammation was demonstrated for elevated FCP (ELISA .200 mg/g, QB .100 mg/g; r ¼ 0.164, P ¼ 0.07; sensitivity, 69.8%, specificity, 46.5%), elevated CRP (r ¼ 0.3; P ¼ 0.01; sensitivity, 60.5%, specificity, 70.3%), or combination of both elevated markers (r ¼ 0.2; P ¼ 0.14). A negligible improvement in the correlation was achieved if patients with exclusively colonic CD (determined before VCE) were excluded. However, neither of the markers nor their combination reached a level of correlation greater than 0.4. We performed additional analyses using ELISA FCP results only (.200 mg/g), “grey zone” FCP values (30–100 mg/g for QB or 50–200 mg/g for ELISA and LS .135) as a cutoff value of significant inflammation. Nevertheless, no significant improvement in diagnostic accuracy was achieved (data not shown). We constructed a receiver operating characteristic for FCP and CRP as a predictor of significant SB inflammation. As QB is a semiquantitative rest, only patients with ELISA FCP results were included (n ¼ 112). The AUC was 0.63, and with exclusion of patients without known SB disease was 0.64 (Fig. 1), which corresponds to poor detection accuracy. For CRP, the AUC was 0.66. The cutoff value associated with the optimal combination of sensitivity and specificity was 275 mg/g. Nevertheless, the diagnostic accuracy was not significantly improved using this cutoff (Table 5).
Safety Capsule retention in the SB occurred in 4 (2.1%) patients. In 3 cases, the capsule was expelled after a course of corticosteroids. In the 1 other patient with a known stricturing phenotype, the capsule was retained at the anastomotic site in the neoterminal ileum, necessitating endoscopic removal. This patient did not undergo a prior PC. In an additional patient, the capsule was retained in the esophagus and was reinserted endoscopically. None of the patients required surgical intervention. A PC was performed in 77 (41%) of the patients. In one center (Montreal), PC was administered routinely to all patients with known CD. PC was successfully excreted within 30 hours in 91.6% of the patients; all of them proceeded to diagnostic capsule. In patients with stricturing disease, a PC was performed in 2 (25%) and was successfully excreted by both. One case of www.ibdjournal.org |
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TABLE 2. Association of VCE Results and Therapeutic Recommendations According to Referral Indications in CD Therapeutic Change Recommended LS ,135 N (%)
Indication Abdominal pain Diarrhea Anemia Weight loss OGIB Obstructive symptoms Evaluation of disease extent Re-evaluation of disease activity/extent Monitoring of mucosal healing/response to medical therapy Monitoring of postoperative recurrence Suspected IBS-related symptoms
LS 135–790 N (%)
2 (40) 0 (0) 1 (20) 0 (0) 0 (0) 0 (0) 2 (40) 0 (0) 0 (0)
5 6 0 0 1 1 10 1 0
0 (0) 0 (0)
(20.8) (25) (0) (0) (4.2) (4.2) (41.7) (4.2) (0)
0 (0) 0 (0)
Therapeutic Change not Recommended
LS .790 N (%)
LS ,135 N (%)
22 11 2 1 1 1 19 4 5
15 1 2 1 2 1 2 1 1
(32.4) (16.2) (2.9) (1.5) (1.5) (1.5) (27.9) (5.9) (7.4)
2 (2.9) 0 (0)
(34.9) (2.3) (4.7) (2.3) (4.7) (2.3) (4.7) (2.3) (2.3)
1 (2.3) 2 (4.7)
LS 135–790 N (%) 5 5 2 0 0 2 4 1 2
(23.8) (23.8) (9.5) (0) (0) (9.5) (19) (4.8) (9.5)
LS .790 N (%) 1 (12.5) 2 (25) 1 (12.5) 0 (0) 1 (12.5) 0 (0) 1 (12.5) 1 (12.5) 1 (12.5)
0 (0) 0 (0)
0 (0) 0 (0)
IBS, irritable bowel disease; LS, Lewis score of severity of SB lesions seen on videocapsule.
transient symptomatic SB obstruction occurred after ingestion of a PC and was resolved spontaneously. One case of retention (2%) of the diagnostic capsule occurred in a patient who had successfully excreted the PC.
DISCUSSION
Our findings in a large cohort of patients with established CD followed in tertiary referral settings demonstrate that VCE is associated with a significant clinical impact. Furthermore, VCE was associated with an excellent safety profile with an SB retention rate of only 2.1% and need for endoscopic intervention in 0.5% of the patients. To the best of our knowledge, this is the largest study evaluating the impact of VCE on the management of established CD patients so far and the first one to systematically use a unified scoring system (LS) and to establish the correlation of inflammatory biomarkers with LS.
VCE is established as an important clinical tool for diagnosis of SB CD, with significantly higher diagnostic yield in comparison with other traditional cross-sectional imaging modalities.3,10 An exception is MRE, which is equally accurate, especially for distal SB involvement.11 Both cross-sectional imaging and VCE can be used for monitoring of established CD.19–21 MRE is superior to diagnose penetrating and stenotic complications (the latter being a relative contraindication for VCE).19 Moreover, MRE is not associated with a risk of retention, and VCE may be especially useful in several particular clinical scenarios, mostly those requiring accurate visualization of subtle mucosal inflammation, such as unexplained anemia, monitoring of mucosal healing, and postoperative recurrence, and symptoms that could not be explained by endoscopic findings. Several small series have described the use of VCE for monitoring of mucosal healing22,23 and postoperative recurrence.24 In CD patients with symptoms that could not be explained by ileocolonoscopy
TABLE 3. Therapeutic Changes Stratified by VCE Results in Established CD
Lewis Score ,135 135–790 .790
None (%)
Change Recommended (%)
Biologic Started (%)
Biologic Dose Escalated
IMM Started (%)
IMM Dose Escalated (%)
Steroids (%)
Biologic Stopped (%)
Surgery (%)
Othera
43 (91.5) 22 (48.9) 9 (12.2)
4 (8.5) 23 (51.1) 64 (87.8)
0 6 (13.3) 21 (28.4)
0 0 4
1 (2.1) 10 (22.2) 23 (31.1)
0 1 (2.2) 1 (1.4)
0 3 (6.7) 10 (13.5)
1 (2.1) 0 0
0 0 2 (2.7)
2a (4) 1a (2.2) 1b (1.3)
IMM, immunomodulator. a Medications were stopped or a non–anti-inflammatory agent was added, such as antibiotics. b TPN and antibiotics were associated.
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(%)
Patient Refused Change 0 2 (4.4) 3 (4.1)
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Significant SB inflammation: Lewis score .790. PPV, positive predictive value; QB, quantum blue rapid semiquantitative FCP assay; r, spearman’s rho correlation; Sens, sensitivity; Spec, specificity.
53.8 50 67.8 63.8 0.17 0.65 60.5 70.3 5737 72.5 0.31 0.01 61.9 47.1 59.1 50 0.2 0.0.143 65.3 57.3 64 56.1 0.22 0.61 57.5 76.2 69.6 65.5 0.34 0.02 59 50 67.3 40.7 0.32 0.0016 0.07 0.02 0.164 0.25 65.2 60 48.7 60.7 43.5 52.2 69.8 68.0 All CD Known ileal CD
P r Sens Spec PPV NPV P r NPV PPV Sens Spec P r Sens Spec PPV NPV
findings, VCE diagnosed SB inflammation in 44% of the patients.25 Additionally, in patients with primarily proximal SB disease, VCE has a higher diagnostic accuracy.11 Proximal SB involvement was recently reported to be associated with an increased long-term risk of complications.26 Currently, clinical experience with VCE for monitoring of known CD for these and/or other indications is limited and lacks standardization. VCE was demonstrated to have an impact on the clinical management of both adult and pediatric CD patients and to result in a shift in the diagnosis to CD in some patients with ulcerative colitis or unclassified IBD.27–29 The largest series published so far described the results and the therapeutic impact of VCE in 126 IBD patients, including 86 with CD.30 In the latter study, VCE lead to a management change in 61.6% of the patients. In another recent study, a therapeutic change was undertaken in 53% of the 77 CD patients after VCE.25 Importantly, normal VCE results in symptomatic CD patients is also clinically useful, as it would suggest a noninflammatory etiology for the symptoms (such as a functional bowel disorder), leading to alternative treatment options. The currently available data pertaining to the optimal strategy and indications for the utilization of VCE in established CD is limited. Additional studies are required to incorporate capsule endoscopy and alternative noninvasive screening methods into clinical surveillance and monitoring protocols. One of the major issues limiting the use of VCE in established CD is the risk of retention, which was although initially reported to be as high as 13%,31 in later reports, the risk was much lower (4%–5.6%),25,32,33 especially when a PC was used. In recent meta-analyses, the rate of VCE retention in patients with suspected CD was 2.8% for adults34 and 2.5% for pediatric patients,35 respectively. Although the use of PC has been demonstrated to significantly reduce the rate of retention,36 it does not eliminate the risk completely.33 In this study, the rate of SB retention was lower than in previous reports (2.1%). Only 1 patient experienced capsule retention after timely excretion of a PC. However, we cannot evaluate the impact of PC on complication rates in our cohort, as the strategy varied between the participating centers, with only 1 administering a PC to all patients with established CD. The other centers used a PC for selected patients considered to be at a higher risk category for
P
(50.0) (33.3) (68.2) (33.3)
r
15 8 15 7
NPV
(36.7) (16.7) (18.2) (33.3)
PPV
11 4 4 7
Spec
(13.3) (50.0) (13.6) (33.3)
Sens
4 12 3 7
LS .790 N (%)
Both Markers Elevated
Ileitis Colitis Illeocolitis Normal ileocolonoscopy
135 , LS . 790 N (%)
CRP .5
LS ,135 N (%)
FCP .275 mg/g
Endoscopy Findings
Elevated FCP (.200 mg/g ELISA, .100 mg/g QB)
TABLE 4. Correlation of VCE with Ileocolonoscopy Findings in Established CD
TABLE 5. Diagnostic Performance of Inflammatory Biomarkers for Prediction of Significant Small Bowel Inflammation on VCE in Established CD
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FIGURE 1. Receiver operating characteristic (ROC) curve analysis of the diagnostic performance of ELISA FCP for detection of significant SB inflammation (LS .790) in patients with established CD (AUC ¼ 0.64).
retention. The World Organization of Digestive Endoscopy and the European Crohn’s and Colitis Organization guidelines recommend to consider PC in patients with known CD; however, it is not clear whether administration of PC will be beneficial in all CD patients or it should be limited to higher risk subgroups only. The optimal strategy for utilization of PC in this clinical situation deserves further exploration in future studies. To the best of our knowledge, our study is the first to systematically apply a widely accepted endoscopic scoring system (LS) in a large cohort of patients with established CD. Previous studies addressing a similar patient cohort used simpler qualitative scoring systems that were different for each study.22,25,30 However, the LS was developed and validated for the purpose of discrimination of SB inflammation from noninflammatory etiologies.15 Although it is frequently used for reporting SB involvement in CD, it has never been validated for the monitoring of known CD. There are, however, certain drawbacks in the utilization of LS for monitoring of established CD. Most notably, strictures are the most heavily weighted element of the LS (e.g., a simple singe ulcer yields a score of 135, whereas a single traversed stenosis is scored 18-fold higher at 2352). Because a known SB stricture will usually be a contraindication for VCE and ruling out significant stenosis is recommended before performance of diagnostic capsule examination,37 the number of CD patients with known stricturing phenotype that are eligible for VCE would be expected to be low. Consequently, in our cohort, patients with stricturing disease or strictures found on VCE were relatively rare. In addition, although the LS divides the SB into 3 tertiles that are scored separately, only the most severely involved tertile is used as the final score. Thus, a patient who has involvement in all 3 tertiles may have an LS equal to a patient who only has SB involvement limited to a single tertile. Moreover, as reported by
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the authors,15 there was a significant overlap in the scores of patients with mild and moderate-to-severe disease. The aforementioned limitations of the LS result in a relatively clear discrimination of CD patients with normal versus inflamed SB but with a more limited quantification of the inflammatory burden. In addition, there is no consensus as to what LS represents mucosal healing or postoperative recurrence, in contrast to multiple available endoscopic scores. We believe that a modified LS adjusted for monitoring of CD merits development and validation in a large-scale prospective trial. We did not find a significant correlation between inflammatory biomarkers (both CRP and FCP or a combination of both) and the presence of significant SB inflammation. FCP is a neutrophil-derived protein that is directly correlated with mucosal inflammation and provides an excellent diagnostic tool for diagnosis of CD, monitoring of mucosal healing, and prediction of relapse.38 Inflammatory biomarkers are frequently used as a screening tool before referral for VCE. However, based on our results, this strategy cannot be considered accurate for patients with known CD, as approximately 40% of the patients with significant lesions will be missed if only patients with elevated biomarkers are tested. The correlation of FCP with LS has been evaluated in patients with suspected CD in 3 studies. Koulaouzidis et al showed that FCP was significantly correlated with LS; however, this correlation was only observed in a subgroup of patients with FCP ,100 mg/g and not in patients with higher FCP values, in whom no correlation between the 2 was observed. Capsule Endoscopy Crohn’s Disease Activity Index was not correlated with FCP in cases with low- or high-FCP group.17 In a study from Finland, FCP level of 50 and 100 mg/g were both associated with poor sensitivity and moderate specificity for detection of SB inflammation.39 In an additional study evaluating patients with suspected CD, FCP .200 mg/g was associated with a positive predictive value of 78% and a negative predictive value of 100% for the diagnosis of CD (LS .135).40 In our study, the diagnostic accuracy of both FCP and CRP for prediction of significant inflammation in established CD was insufficient. We have used the LS cutoff value of 790 for definition of significant inflammation because all patients in our cohort were already diagnosed with CD, and findings consistent with mild inflammation were less likely to be of true clinical significance. In contrast to the aforementioned studies, we have used 2 different methods for measurement of FCP. However, the accuracy of the rapid semiquantitative method is comparable with ELISA, and the correlation between the methods is very good.41 To the best of our knowledge, our study is the first to evaluate this correlation in a cohort of patients with established CD. Despite the significant findings, our study has several limitations, mostly originating from the retrospective format of the study. We do not have colonoscopic or cross-sectional imaging data available for all the patients. Current imaging data were available only for a minority of patients, and in many cases, these studies were performed in an emergency setting with suboptimal visualization, precluding performing a meaningful analysis of
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correlation of VCE with imaging findings. The results of inflammatory biomarkers were available for a majority of patients. However, in some patients, changes in disease severity may have occurred during the lag period before VCE was performed. Furthermore, we did not apply a uniform strategy for referral for VCE or administration of PC. In addition, a decision to change therapy was undertaken by each treating physician on an individual case basis. Such decisions could have been influenced by additional clinical factors. A prospective study would allow for the clinical impact to be accessed more accurately by asking the clinician what their next course of action would have been in the absence of a VCE and whether VCE results have altered their decision. The limitations of the LS for the patient cohort that was evaluated in our study were discussed above. Despite the aforementioned limitations, our study provides important insight and useful data on the clinical utility and safety of VCE for management of patients with established CD.
SUMMARY VCE provides meaningful results leading to therapeutic changes in more than 50% of patients with established CD. VCE is very safe in this patient cohort, especially if preceded by PC in at least the subgroup of high-risk patients. FCP and CRP do not correlate well with significant VCE findings in patients with established CD and cannot be relied on to select patients for study.
ACKNOWLEDGMENTS Author contributions: Study design: U. Kopylov, A. Koulaouzidis, E. Toth, E. G. Seidman; data collection: U. Kopylov, A. Nemeth, G. W. Johansson, R. Makins, W. Afif, T. Bessissow; data analysis: U. Kopylov, A. Koulaouzidis, E. Toth, E. G. Seidman; manuscript drafting: U. Kopylov, E. G. Seidman; review of the manuscript for important scientific input: A. Nemeth, G. W. Johansson, R. Makins, W. Afif, T. Bessissow, A. Koulaouzidis, E. Toth, G. Wild, W. Afif, A. Bitton, R. Eliakim; guarantor of the article: U. Kopylov. All authors have reviewed and approved the manuscript.
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