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Aims To assess residual lesions in small bowel immediately after surgery. Methods Capsule endoscopy (CE) was performed immediately after surgery (<3months), and endoscopic activity was assessed using the Lewis score (LS) composed of the highest tertile score (in rst, second, and third tertile) and the stenosis score (in whole small intestine). The relationship between these residual lesions and postoperative clinical recurrence was prospectively evaluated.

Results After assessing patency using a patency capsule, CE was performed in 25 patients. The mean LS was 751.3, and 84.0% (21/25) had endoscopic activity. These lesions were detected by preoperative examinations in 0% and by a serosal side view during surgery in 16.0%. Regarding the cumulative clinical recurrence rate according to endoscopic severity (normal, mild, and moderate-to-severe) immediately after surgery, no signicant di erence was found. However, comparing groups divided according to the highest tertile score, the cumulative clinical recurrence rate was signicantly higher in the group with the highest third tertile score. Furthermore, patients with ulcers in the third tertile had a signicantly higher recurrence rate.

Conclusions Many cases with CD had endoscopic activity immediately after “curative” surgery. These residual lesions, especially in the distal small intestine, were associated with postoperative clinical recurrence.

Keywords Crohn’s disease· Capsule endoscopy· Clinical recurrence· Postoperative recurrence· Residual lesion Introduction The rate of surgery for Crohn’s disease (CD) is high, with reported cumulative surgery rates of 16.3% at 1year, 33.3% at 5 years, and 46.3% at 10 years following diagnosis, respectively [ 1]. Furthermore, many cases require repeat surgery, and the cumulative repeat surgery rates are as high as 24.2 and 35.0% at 5 and 10years following their rst sur - gery, respectively [ 2]. We have also reported that 48.7% of patients require rst surgery at 5years following diagnosis, while 36.0% require repeat surgery at 5years after their rst surgery [ 3]. In order to optimize postoperative maintenance therapy depending on the activity of each case, endoscopic recurrence preceding clinical recurrence has been recog - nized to be important [ 4, 5]. Endoscopic recurrence rates in patients without symptoms have been reported to be as high as 70–90% and 85–100% at 1 and 3years following Jun Kusaka and Hisashi Shiga contributed equally to this work.

* Hisashi Shiga [email protected] -u.ac.jp; [email protected] 1 Division ofGastroenterology, Tohoku University Graduate School ofMedicine, Sendai, Japan 2 Department ofGastroenterology andNeurology, Akita University Graduate School ofMedicine, 1 -1-1 Hondo, Akita010 -8543, Japan 3 Division ofGastroenterology andHepatology, Tohoku Medical andPharmaceutical University, Sendai, Japan 4 Health Administration Center, Center fortheAdvancement ofHigher Education, Tohoku University, Sendai, Japan Vol:.(1234567890) 1 3 769 Digestive Diseases and Sciences (2018) 63:768–774 surgery, respectively [6 ]. Recently, in order to utilize endo- scopic recurrence for improving postoperative treatments, De Cruz etal. demonstrated in a multicenter randomized trial that it is useful to intensify treatments according to the endoscopic ndings at 6months following surgery [7 ]. The prospective detection of endoscopic recurrence may enable us to reconsider treatment regimens prior to clinical recur - rence, thereby improving the long-term prognosis [4 , 5 ].

However, we have some concern about the aforemen- tioned study [7 ]. First, only cases following ileocecal resec- tion were included and only colonoscopy was performed.

The rate of small bowel lesions not found on ileocolonos - copy was quite high [8 , 9]. Second, it is di cult to distin- guish endoscopic recurrence from residual lesions. We often nd residual lesions (mostly minor lesions) even after sur - gery; however, we have little knowledge about how high the rate of residual lesions is and whether these lesions have an inuence on postoperative course or not. Therefore, prior to the evaluation of postoperative endoscopic recurrence, it is necessary to perform an accurate assessment of residual lesions in small bowel immediately after surgery. In recent years, the usefulness of capsule endoscopy (CE) has been reported in the diagnosis of small bowel diseases.

Since CE is less invasive and less painful than small bowel follow-through and balloon-assisted small bowel enteros- copy, and CE has a higher detection rate of lesions compared to CT enterography (CTE) and MR enterography (MRE) [ 10– 13], it is considered to be an important modality in the diagnosis of CD. However, there have so far been few studies regarding the role of CE for CD following surgery. Thus, in order to assess any residual small bowel lesions accurately, we performed capsule endoscopy (CE) immediately after surgery in patients with CD. We also investigated the rela- tionship between such residual lesions and postoperative clinical recurrence prospectively.

Materials and Methods Subjects We included patients with CD who had undergone surgery for remission induction at Tohoku University Hospital between December 2013 and February 2016. CE was per - formed immediately following surgery (<3months after surgery), and the patients’ clinical courses were followed prospectively. CD was diagnosed based on the diagnostic criteria from the Research Group of Intractable Inamma- tory Bowel Disease organized by the Ministry of Health, Labour, and Welfare of Japan [14]. Regarding surgical pro- cedures, only patients who had undergone intestinal resec- tions were included, excluding those who had only under - gone surgery for anal lesions. Patients who had undergone colostomy or ileostomy were also included. As the disease location at diagnosis may change over time, various types of disease location were included.

The present study was approved by the ethics committee of our hospital on September 30, 2013. Written informed consent was obtained in all cases. All CEs in the present study were performed on an outpatient basis, and the exami- nations were covered by the patients’ health insurance. CE Procedure In the present study, CE was performed using either PillCam ® SB2 or SB3 (Given Imaging, Covidien Ltd., Yokneam, Israel). Prior to CE procedure, patency was assessed with a patency capsule (PC) being excreted in its original shape within 33h after swallowing. In patients who were judged to have no patency, other gastrointestinal exami- nations were performed. Regarding a bowel preparation for CE, 50mg of magne- sium citrate and 150mg of sodium picosulfate hydrate were orally administered at 14 and 13h before CE, respectively.

A high concentration of polyethylene glycol was also admin- istered 1h before CE. Two and 4h after swallowing CE, the patients were allowed to drink water and to eat, respectively.

In cases in which the capsule reached colon within 8h after swallowing, the examination was ended. If not, the examina- tion was extended to 10h. Assessment of Residual Lesions The endoscopic activity immediately after surgery was assessed by two endoscopists using the Lewis score (LS) which was reported by Gralnek etal. [15]. The small intes- tine is divided into three parts from the oral side: rst ter - tile, second tertile, and third tertile. Then, the tertile score is calculated as the sum of the inammatory parameter scores (villous appearance and ulcers) in each tertile. On the other hand, the stenosis score is calculated in whole small intes- tine (not in each tertile). The LS is the sum of the highest tertile score and the stenosis score. The LS classies the endoscopic severity into three grades: normal or physi- ological inammation (<135), mild inammation (≥135 and<790), and moderate-to-severe inammation (≥790).

Primary and Secondary Outcomes The primary outcome was the endoscopic activity imme- diately after surgery (i.e., residual lesions) using the LS.

The secondary outcomes included the relationship between clinical characteristics and residual lesions, and that between residual lesions and postoperative clinical recurrence. Post- operative clinical recurrence was dened as repeat surgery, hospitalization associated with CD or changes in the medical 1 3 770 Digestive Diseases and Sciences (2018) 63:768–774 treatments. In order to include patients with ileostomy or colostomy, we did not use the Crohn’s Disease Activity Index.

Statistical Analysis Quantitative data are shown as the mean value and stand- ard deviation. For comparisons between groups, t test, Mann–Whitney U test, or correlation analysis was used as appropriate. The cumulative clinical recurrence rate was calculated using the Kaplan–Meier method, and compari- sons between groups were performed using the log-rank test.

These analyses were all performed using the JMP Ver. 11 software program (SAS Institute Inc., Cary, NC, USA). A P value of less than 0.05 was considered to be statistically signicant.

Results Clinical Characteristics and Medical Treatments There were 46 patients with CD who underwent surgery during the study period. CE was attempted in 27 of these patients, excluding any patients who changed hospitals fol- lowing surgery, patients who did not provide their consent to undergo CE, and patients in whom more than 3 or more months had passed following surgery. The clinical characteristics of 27 patients are shown in Table 1. These patients included 24 males (88.9%) and 3 females (11.1%), with a mean age at diagnosis of 24.7 (SD, 8.0)years, age at surgery of 35.6 (8.5)years, and disease duration at surgery of 12.0 (8.5)years. The number of pre- vious surgeries was 2.1 (1-7), and 14 patients (51.9%) had no history of previous surgery for CD. The disease type included 9 ileitis type (33.3%), 17 ileocolitis type (63.0%), and 1 colitis type (3.7%), while the disease behavior included 2 penetrating type (7.4%) and 25 non-penetrating type (92.6%). There were 17 patients (63.0%) with anal lesions. Six patients (22.2%) had a smoking history, while 21 (77.8%) did not. The surgical procedures included 10 partial resections of the small intestine (37.0%), 8 ileoce- cal resections (29.6%), 6 anastomotic resections (22.2%), 3 colostomies (11.1%), 3 strictureplasties (11.1%), 2 partial colectomies (7.4%), and 2 subtotal colectomies (7.4%) with some overlapping. Following surgery, same medical treatments were contin- ued in all cases except for two patients in whom anti-tumor necrosis factor agent or immunomodulator was newly added.

There were no signicant di erences in clinical character - istics or medical treatments between the 27 patients who underwent CE and other 19 patients who were excluded. Table 1 Clinical characteristics SD standard deviation, 5-ASA 5-aminosalicylic acid, TNF tumor necrosis factor † Non-penetrating type contains inammatory and stricturing types‡ There is some overlapping Clinical characteristics N=27 Gender Male 24 (88.9%) Female 3 (11.1%) Age at diagnosis years (SD)24.7 (8.0) Age at surgery years (SD)35.6 (8.5) Disease duration at surgery years (SD)12.0 (8.5) Number of previous surgery times2.1 (1-7) 1 14 (51.9%) ≥2 13 (48.1%) Disease type Ileitis type 9 (33.3%) Ileocolitis type 17 (63.0%) Colitis type 1 (3.7%) Disease behavior Penetrating type 2 (7.4%) Non-penetrating type † 25 (92.6%) Anal lesions Present 17 (63.0%) Absent 10 (37.0%) Extraintestinal manifestations Present 2 (7.4%) Absent 25 (92.6%) Smoking history Present 6 (22.2%) Absent 21 (77.8%) Surgical procedures ‡ Partial small intestinal resection 10 (37.0%) Ileocecal resection 8 (29.6%) Anastomotic resection 6 (22.2%) Colostomy 3 (11.1%) Strictureplasty 3 (11.1%) Partial colectomy 2 (7.4%) Subtotal colectomy 2 (7.4%) Length of the residual small intestine cm (SD)291.2 (85.5) Preoperative medications ‡ 5-ASA 23 (85.2%) Anti-TNF agent 15 (55.6%) Elemental diet 7 (25.9%) Immunomodulator 4 (14.8%) Postoperative medications ‡ 5-ASA 26 (96.3%) Anti-TNF agent 16 (59.3%) Elemental diet 8 (29.6%) Immunomodulator 5 (18.5%) 1 3 771 Digestive Diseases and Sciences (2018) 63:768–774 CE Procedure Twenty-ve of 27 patients (92.6%) were diagnosed to have patency using a PC, and CE was performed at 1.8 (1.1) months following surgery. Of 25 patients in whom CE was performed, we could observe the entire small intestine in 20 patients (80.0%), and the average observation time of the small intestine was 212 (103)minutes. No adverse events such as aspiration or abdominal pain were observed. In 24 patients, the capsule endoscope was excreted within 2weeks. Although the excretion of the capsule endoscope was not conrmed within 2weeks in one case, an X-ray examination at 2weeks showed that it had already been excreted.

In two patients who were diagnosed to have no patency, narrowing or stenosis of the intestinal anastomosis was found by other examinations. Since both patients had no symptoms, they preferred to continue monitoring without any interven- tion. There has been no change in their symptoms or blood tests at 23 and 13months following CE, respectively.

Primary Outcome Regarding villous edema of which the tertile score was com- posed, the scores were 5.8 (21.9), 9.6 (30.3), and 6.7 (21.8) in the rst, second, and third tertile, respectively. Regarding ulcers of which the tertile score was composed, the scores were 176.4 (356.6), 160.2 (306.6), and 177.6 (288.9) in the rst, second, and third tertile, respectively. As the sum of the parameter scores (villous edema and ulcers), the tertile scores in the rst, second, and third tertile were 182.2 (371.6), 169.8 (313.1), and 184.3 (290.1), respectively; no signicant di er - ence was found among the three groups. The stenosis score was 182.2 (371.6). Using the highest tertile score and the ste- nosis score, the LS was 751.3 (984.0). According to the LS, 16.0, 56.0, and 28.0% were classied as normal, mild, and moderate-to-severe inammation, respectively. The details of the scores are shown in Table 2.

Prior to surgery, we performed CT in 25 patients (100%), small bowel follow-through in 22 patients (88%), colonoscopy in 12 patients (48%), and colonoscopy followed by retrograde gastrointestinal series in 11 patients (44%) with some overlap- ping. However, the recognition rate of lesions other than those resected by surgery was 0%. During surgery, residual lesions were reviewed based on the ndings of a serosal side view; however, the recognition rate was only 16.0% (4/25).

Secondary Outcomes Relationship Between Clinical Characteristics and Residual Lesions Among the clinical characteristics, patients with anal lesions had signicantly higher LS (P = 0.024) (Fig.1). There were no signicant di erences for the LS concerning age at diagnosis, age at surgery, disease duration at surgery, num- ber of previous surgeries, disease type, disease behavior, extraintestinal manifestations, or smoking history. Regard- ing medical treatments, no signicant di erence for the LS was observed.

Relationship Between Residual Lesions and Postoperative Clinical Recurrence Postoperative clinical recurrence was observed in 5 of 25 patients (Nos. 2, 9, 13, 15, and 16 in Table 2), and the time from surgery to clinical recurrence was 9.8 (4.5) months.

Regarding the cumulative clinical recurrence rate, no sig- nicant di erences were observed in clinical characteristics and medical treatments. When the cumulative clinical recur - rence rate was compared among the endoscopic severities classied by the LS (normal, mild, and moderate-to-severe), again no signicant di erence was found. However, when comparing groups divided according to the highest tertile score, the cumulative clinical recurrence rate was signi- cantly higher in the group with the highest third tertile score ( P =0.046) (Fig. 2). Furthermore, patients with ulcers in the third tertile had a signicantly higher clinical recurrence rate in comparison with the others (P =0.045) (Fig.3). Discussion Since CD often requires repeat surgery, the prevention of postoperative recurrence is an important issue. In order to prevent postoperative clinical recurrence, it is useful to detect endoscopic recurrence preceding clinical symptoms.

However, even if active lesions are detected endoscopically in postoperative follow-up study, it cannot be determined with certainty that those lesions actually represent endo - scopic recurrence. This is because a certain number of lesions may remain even after surgery. Therefore, the pre- sent pilot study was conducted in order to accurately assess the presence of any residual lesions immediately after sur - gery and to elucidate the relationship between these residual lesions and postoperative clinical recurrence prospectively. In spite of having undergone surgery, 84% with CD had endoscopic activity immediately after surgery, and the aver - age endoscopic activity was almost moderate. Such a high prevalence of residual small bowel lesions using periopera- tive endoscopy has been reported in some previous studies [ 16, 17]. Kono etal. also reported that 78.0% of the sub- jects had endoscopic activity on very early postoperative endoscopy [ 18]. These residual lesions probably have some inuence on the ndings of follow-up endoscopy after sur - gery. On the other hand, most of these residual lesions could not be detected by preoperative examinations. Preoperative 1 3 772 Digestive Diseases and Sciences (2018) 63:768–774 Table 2 Lewis scores of all cases In ve patients (Nos. 18, 20, 22, 23, and 24), we could not observe the entire small intestine during the prescribed examination time (10h) † The tertile score is calculated as the sum of the parameter scores (villous edema and ulcer). The stenosis score is calculated in whole small intestine (not in each tertile) ‡ The LS consists of the highest tertile score and the stenosis score No. 1st tertile score † 2nd tertile score † 3rd tertile score † Stenosis score † Lewis score ‡ Villous appearance UlcerVillous appearance UlcerVillous appearance Ulcer 1 8 1350 08 02352 2495 2 0 00 1358 2252352 2585 3 0 00 00 00 0 4 0 1350 6750 2250 675 5 0 00 08 0196 196 6 112 1350112 6750 2250 1462 7 0 00 00 00 0 8 0 00 00 1350 135 9 0 1350 2250 1350 225 10 0 00 00 1350 135 11 0 1350 1350 0196 331 12 0 2250 00 1350 225 13 0 00 08 1353360 3503 14 8 1350 2258 1350 225 15 0 00 00 2250 225 16 0 00 2250 13500 1350 17 0 2250 08 1350 225 18 0 00 08 00 8 19 0 00 00 00 0 20 8 1350 00 02352 2495 21 0 13500 13500 7870 1350 22 0 2258 225112 2250 337 23 8 225112 00 00 233 24 0 00 1350 00 135 25 0 00 08 2250 233 Fig. 1 Lewis scores of patients with and without anal lesions. Patients with anal lesions had signicantly higher Lewis score than those without anal lesions (P=0.024) Fig. 2 Cumulative recurrence rates comparing groups divided according to the highest tertile score. When comparing groups divided according to the highest tertile score, the cumulative recur - rence rate was signicantly higher in the patients with the highest third tertile score (P=0.046) 1 3 773 Digestive Diseases and Sciences (2018) 63:768–774 gastrointestinal examinations are limited due to the presence of stenosis or stula, and other minor lesions are thus often missed. For example, the detection rate of lesions on small bowel follow-through, which is often performed in cases with stenosis or stula, is very low compared to CE [19].

The detection rate of minor lesions on CTE and MRE is also low. It is di cult to perform CE preceding surgery due to the risk of capsule retention, while residual lesions could be non-invasively assessed on CE immediately after surgery without any stenosis or stulas.

Among the clinical characteristics, only anal lesions were signicantly associated with higher endoscopic activity immediately after surgery. Anal lesions have been reported to be a risk factor for recurrence following surgery [4 , 5].

Patients with some risk factors are likely to already have a high endoscopic activity (i.e., many residual lesions) imme- diately after surgery. These patients are considered to require careful observation following surgery. A high rate of residual lesions may lead to overestimation of the risk of postoperative clinical recurrence [17]. How - ever, there are so far no available data regarding the course of residual lesions. Thus, we also followed clinical courses prospectively. As a result, postoperative clinical recurrence was observed in 20% at about 10months following surgery.

Clinical characteristics and postoperative medical treatments did not a ect clinical recurrence. There was also no signicant association between the endoscopic severity as classied by the LS and postoperative clinical recurrence. However, when grouped according to the highest tertile score, the cumulative clinical recurrence rate was signicantly higher in the group with the highest third tertile score. In addition, when grouped according to the presence of the parameters (villous edema and ulcers) which compose the tertile score, the cumulative recurrence rate was signicantly higher in the group with ulcers in the third tertile. Residual lesions, especially in the distal small intestine, were associated with clinical recurrence.

The location as well as the presence of residual lesions imme- diately after surgery was associated with postoperative clinical recurrence. Of course, CE is accompanied by some risk of retention and expensive cost in follow-up study. Thus, ileoco- lonoscopy or close monitoring of biomarkers (treat to target approach) may be a better alternative [20].

We acknowledge that there are several limitations in the present study. First, the small number of patients and the short observation period might have inuenced the afore- mentioned outcomes. Second, we did not show any data about repeated CEs. Up to now, there are no available data regarding the optimal timing to detect endoscopic recur - rence. Therefore, we conducted the present study as the basic data to detect recurrent lesions. With a larger number of patients and a longer observation period, further studies performing CE repeatedly are required. Third, we could not show what the inammation in the rst or second tertile is associated with. Some factors such as non-steroidal anti- inammatory drugs (NSAIDs) or proton pump inhibitors (PPIs) may have been related to the inammation in these sites. NSAIDs are known to have a strong potential to induce inammation in the upper small intestine, especially when used with PPIs [21, 22]. However, there was no signicant association between the endoscopic activity in the upper small intestine and concurrent use of NSAIDs and/or PPIs in the present study (data not shown). In conclusion, many cases with CD have endoscopic activity despite having undergone surgery. These residual lesions, especially in the distal small intestine, were asso- ciated with postoperative clinical recurrence. Optimizing medical treatments based on the assessment of both resid- ual lesions and recurrent lesions may improve the long-term prognosis. With a larger number of patients and a longer observation period, further studies are required. Author’s contribution Hisashi Shiga had the original idea for this study and was involved in writing the original study protocol, data collection, and writing manuscript. Jun Kusaka was involved in data collection and writing manuscript. Masatake Kuroha, Tomoya Kimura, Yoichi Kakuta, Katsuya Endo, Yoshitaka Kinouchi, and Tooru Shimosegawa contributed to discussions and reviewed manuscript.

Compliance with ethical standards Conflict of interest All authors have no conict of interest with respect to the present study.

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