Prophylactic clip application for large pedunculated polyps before snare polypectomy may decrease immediate postpolypectomy bleeding.

BACKGROUND: Although prophylactic clip application before polypectomy may prevent postpolypectomy bleeding (PPB), the usefulness of prophylactic clipping in the treatment of large pedunculated polyps is controversial in some prospective randomized studies. This study was conducted to evaluate the efficacy of prophylactic clip application and to investigate the predictors of PPB in large pedunculated colorectal polyps. METHODS: A total of 137 pedunculated polyps (size ≥1 cm) in 116 patients were prospectively included and randomized into group A (with clipping) and group B (without clipping), and resected. The occurrences of immediate PPB (graded 1-4) and delayed PPB were compared. RESULTS: Sixty-seven polyps were allocated in group A and 70 polyps in group B. In both groups, the median polyp diameter was 15 mm (P = 0.173) and the median stalk diameter was 3 mm (P = 0.362). Twenty-eight (20.4%) immediate PPB episodes in 137 polyps occurred, 6 (9.0%) in group A and 22 (31.4%) in group B (P = 0.001). However, the occurrence of delayed PPB was not different between the groups (P = 0.943). Prophylactic clip application decreased the occurrence of immediate PPB (odds ratio 0.215, 95% confidence interval 0.081-0.571). Moreover, polyp size ≥20 mm and stalk diameter ≥ 4 mm increased the risk of immediate PPB. CONCLUSIONS: Clip application before polypectomy of ≥1 cm pedunculated polyps is effective in decreasing the occurrence of immediate PPB. Thus, clip application should be considered before performing snare polypectomy, especially for large polyps with a thick stalk. TRIAL REGISTRATION: This research was studied a prospective maneuver and enrolled in a registry of clinical trials run by United States National Library of Medicine at the National Institutes of Health (ClinicalTrials.gov Protocol Registration and Results system ID: NCT01437631). This study was registered on September 19, 2011.

Clinical outcomes of colorectal endoscopic submucosal dissection and risk factors associated with piecemeal resection.

BACKGROUND/AIMS: We aimed to investigate the factors associated with piecemeal resection of colorectal neoplasia (CRN), in spite of endoscopic submucosal dissection (ESD). MATERIALS AND METHODS: We analyzed the retrospective data for colorectal ESD cases from January 2005 to April 2014. We also reviewed the piecemeal endoscopic mucosal resection (EMR) for CRNs ≥20 mm, performed over the same period. RESULTS: En bloc resection was possible in 648 (85.7%) of 756 lesions in 740 patients. Multivariate analysis showed that hybrid ESD (odds ratio (OR), 29.07; 95% confidence interval (CI), 15.46-54.65; p<0.01) and mild or severe submucosal fibrosis (OR, 3.62; 95% CI, 1.94-6.76; p<0.01) were independently associated with piecemeal ESD. The en bloc ESD group showed higher histologic complete resection rate than the piecemeal ESD group (80.4% vs. 56.5%; p<0.01), and the piecemeal ESD group showed higher recurrence rate than in the en bloc ESD group (5.6% [4/72] vs. 0.7% [3/450]; p<0.01). Overall recurrence rate was 1.3% (7/522). CONCLUSION: Hybrid ESD and submucosal fibrosis are independently associated with piecemeal ESD. Piecemeal ESD cases recurred more frequently than en bloc ESD cases.

Risankizumab in patients with moderate to severe Crohn's disease: an open-label extension study.

BACKGROUND: Risankizumab, an anti-interleukin 23 antibody, was superior to placebo in achieving clinical and endoscopic remission at week 12 in a randomised, phase 2 induction study in patients with moderately to severely active Crohn's disease. Here we aimed to assess the efficacy and safety of extended intravenous induction and subcutaneous maintenance therapy with risankizumab. METHODS: All patients who completed the 12-week induction phase of the double-blind phase 2 induction study were included in this open-label extension study. Patients who did not achieve deep remission, defined as clinical remission (Crohn's Disease Activity Index [CDAI] <150) and endoscopic remission (Crohn's Disease Endoscopic Index of Severity [CDEIS] ≤4, or ≤2 for patients with isolated ileitis), at week 12 received open-label intravenous therapy with 600 mg risankizumab every 4 weeks for 12 weeks; patients in deep remission at week 12 entered a 12-week washout phase. Patients in clinical remission at week 26 were invited to participate in the maintenance phase of the study, in which they received open-label subcutaneous risankizumab (180 mg) every 8 weeks for 26 weeks. 26-week efficacy endpoints were the proportion of patients in clinical remission (CDAI <150), and the proportion of patients who achieved clinical response (either CDAI of <150 or a reduction from baseline of at least 100 points). 52-week efficacy endpoints were the proportion of patients achieving: clinical remission; clinical response; endoscopic response (>50% CDEIS reduction from baseline); endoscopic remission, as defined previously; mucosal healing; and deep remission. Safety was assessed in patients who received at least one dose of the study drug during the open-label phases of the study. This study is registered with ClinicalTrials.gov, number NCT02031276. FINDINGS: Of the 108 patients who completed the 12-week double-blind induction trial, six patients were in deep remission and entered the 12-week washout phase. 102 patients were not in deep remission, 101 of whom received 12 weeks of 600 mg risankizumab (33 from the original placebo group, 34 from the 200 mg risankizumab group, and 34 from the 600 mg risankizumab group); the other patient declined to continue the study. At week 26, 54 (53%) of 101 patients treated with 600 mg rizankizumab were in clinical remission. Among patients included in the open-label extension trial, clinical remission rates at week 26 versus week 12 were: 18 (55%) versus six (18%) of 33 patients in the original placebo group; 20 (59%) versus seven (21%) of 34 patients in the original 200 mg risankizumab group; and 16 (47%) versus nine (26%) of 34 patients in the original 600 mg risankizumab group. 62 patients received risankizumab maintenance treatment, including the 54 patients who achieved clinical remission at week 26, the six patients who had achieved deep remission at week 12, and one patient because of a protocol violation. At week 52, clinical remission was maintained in 44 (71%) patients; 50 (81%) patients had a clinical response, 22 (35%) patients were in endoscopic remission, and 34 (55%) patients had an endoscopic response. 15 (24%) patients had mucosal healing and 18 (29%) patients achieved deep remission at week 52. Risankizumab was well tolerated with no new safety signals noted. The most frequent treatment-emergent adverse events were arthralgia (25 [22%] of 115 patients), headache (23 [20%]), abdominal pain (21 [18%]), nasopharyngitis (18 [16%]), nausea (18 [16%]), and pyrexia (15 [13%]). Most adverse events were mild or moderate and considered to be unrelated to study treatment. There were no treatment-related deaths. INTERPRETATION: Extended induction treatment with open-label intravenous risankizumab was effective in increasing clinical response and remission rates at week 26. Open-label subcutaneous risankizumab maintained remission until week 52 in most patients who were in clinical remission at week 26. Selective blockade of interleukin 23 warrants further investigation as a treatment for Crohn's disease. FUNDING: Boehringer Ingelheim.

Comparison of Concomitant Mesalamine and Immunomodulator Therapy and Immunomodulator Monotherapy for Crohn's Disease.

BACKGROUND: Although immunomodulators are increasingly used in Crohn's disease (CD), a significant number of gastroenterologists still use 5-aminosalicylate (5-ASA) in combination with azathioprine (AZA) or 6-mercaptopurine (6-MP); there is limited evidence regarding the benefit of concomitant 5-ASA with AZA/6-MP compared with AZA/6-MP monotherapy for the treatment of CD. STUDY DESIGN: A total of 106 patients who received AZA/6-MP for more than 3 months between January 1991 and May 2014 were identified retrospectively. Each patient was matched with 3 randomly selected controls who were treated with concomitant therapy during the same period. RESULTS: The cumulative probabilities of steroid use at 5 and 10 years were 24.9% and 75.8% in the 5-ASA + AZA/6-MP group and 31.2% and 87.8% in the AZA/6-MP group, respectively (P = 0.187). The cumulative probabilities of anti-TNF use, resectional surgery, and disease-related hospitalization were comparable between the groups. The younger age and the use of lower doses of immunomodulators were associated with higher requirement of rescue therapy. CONCLUSIONS: This study did not demonstrate that the concomitant use of 5-ASA with AZA/6-MP showed the proof or effect in terms of steroid requirements, anti-TNF use, resectional surgery, or disease-related hospitalization compared with that of AZA/6-MP alone.

Assessment of factors associated with smoking cessation at diagnosis or during follow-up of Crohn's disease.

BACKGROUND AND AIM: Smoking cessation is known to improve the course of Crohn's disease (CD). However, the factors associated with smoking cessation after CD diagnosis have not been well established. METHODS: Clinical characteristics and change in smoking status were evaluated in 445 current smokers at the time of CD diagnosis. Patients were classified into three subgroups based on their final smoking status and time of smoking cessation: non-quitters, quitters at diagnosis, and quitters during follow-up. RESULTS: The overall smoking cessation rate was 55.7% (248 of 445 patients). The diagnosis of CD was the main reason for quitting (41.5%, 103 of 248 patients). Smoking cessation at the time of CD diagnosis was associated with intestinal resection within 3 months from CD diagnosis (odds ratio [OR] 2.355, 95% confidence interval [CI] 1.348-4.116, P = 0.003), light smoking (OR 2.041, 95% CI 1.157-3.602, P = 0.014), and initiation of smoking before 18 years of age (OR 0.570, 95% CI 0.327-0.994, P = 0.047). Light smoking (OR 1.762, 95% CI 1.019-3.144, P = 0.043) and initiation of smoking before 18 years (OR 0.588, 95% CI 0.381-0.908, P = 0.017) were also associated with overall smoking cessation. CONCLUSION: Quitters after CD diagnosis, including quitters at diagnosis and quitters during follow-up, had features distinct from those of non-quitters. Given the motivation at CD diagnosis, a detailed history of smoking habits should be taken and all current smokers should be encouraged to quit smoking at the time of CD diagnosis.

Local recurrence and subsequent endoscopic treatment after endoscopic piecemeal mucosal resection with or without precutting in the colorectum.

BACKGROUND/AIMS: Precutting before endoscopic piecemeal mucosal resection (EPMR) may increase colorectal polyp resection effectiveness. We aimed to identify risk factors for recurrence after conventional EPMR (CEPMR) and precut EPMR (PEPMR) and investigated endoscopic treatment outcomes for recurrent cases. METHODS: The medical records of patients with colorectal polyps treated by EPMR were analyzed. Patients without follow-up surveillance colonoscopies were excluded. RESULTS: Among 359 lesions, the local recurrence rate on the first surveillance colonoscopy was 5.8% (18/312) and 6.4% (3/47) after CEPMR and PEPMR, respectively. Among lesions without recurrence at the first surveillance colonoscopy, the rates of late recurrence on subsequent surveillance colonoscopy were 3.9% (6/152) and 0% after CEPMR and PEPMR, respectively. Larger tumor size was the only independent risk factor for recurrence (odds ratio, 7.93; 95% confidence interval, 1.95-32.30; P<0.001). Endoscopic treatment was performed for all 27 recurrences. A combination of ≥2 endoscopic treatment modalities was used in 19 of 27 recurrences (70.4%). Surveillance colonoscopies were performed in 20 of 27 recurrences after endoscopic treatment. One (5.0%) had a re-recurrence and was treated by surgical resection because recurrence occurred at the appendiceal orifice. Nineteen of 20 lesions (95.0%) could be cured endoscopically, although 3 of the 19 showed second or third recurrences and were treated by repeat endoscopic resection. CONCLUSIONS: The local recurrence rates after CEPMR and PEPMR were similar. Larger tumor size was an independent risk factor for local recurrence after EPMR. Endoscopic treatment of recurrences resulted in high cure rates, although combination methods were necessary in many cases.

Fecal calprotectin predicts complete mucosal healing and better correlates with the ulcerative colitis endoscopic index of severity than with the Mayo endoscopic subscore in patients with ulcerative colitis.

BACKGROUND: We aimed to evaluate the role of fecal calprotectin (FC) as a noninvasive marker for the disease activity of ulcerative colitis (UC) in a Korean cohort. METHODS: A total of 181 fecal samples were collected from 181 consecutive UC patients between April 2015 and September 2016. FC levels were measured using the Quantum Blue® Calprotectin rapid test. The laboratory test results, partial Mayo Score (pMS), and colonoscopic imaging findings at FC level measurement were retrospectively reviewed. The Mayo endoscopic subscore (MES) and UC endoscopic index of severity (UCEIS) were graded by 2 certified endoscopists after training with 50 other cases. RESULTS: The FC levels were significantly correlated with pMS (Spearman correlation coefficient r = 0.428, p < 0.001), MES (r = 0.304, p < 0.001), UCEIS (r = 0.430, p < 0.001), and CRP (r = 0.379, p < 0.001). FC levels exhibited a significantly better correlation with UCEIS than with MES (Meng's z = - 2.457, p = 0.01). The FC cut-off level of 187.0 mg/kg indicated complete mucosal healing (MES = 0; UCEIS =0) with a sensitivity and specificity of 0.857 and 0.891, respectively (area under the curve, 0.883; 95% confidence interval, 0.772-1.000). CONCLUSION: The FC level is significantly correlated with the clinical disease activity index, endoscopic indices, and serum inflammatory biomarkers in a Korean UC cohort. FC is highly predictive of complete mucosal healing in UC. UCEIS exhibits a stronger correlation with the FC level, as compared to MES. Thus, FC could be used as a reliable noninvasive indicator for evaluating disease activity and mucosal healing in UC.

Temporal trends in the misdiagnosis rates between Crohn's disease and intestinal tuberculosis.

AIM: To investigate the temporal trends in the misdiagnosis rate between Crohn's disease (CD) and intestinal tuberculosis (ITB) in South Korea. METHODS: We retrospectively reviewed the medical records of patients managed for CD or ITB at Asan Medical Center, a tertiary referral hospital, Seoul, Korea between 1996 and 2014. The temporal trends in the misdiagnosis rates between the two diseases were analyzed. The demographic and clinical characteristics were compared between CD patients who were initially misdiagnosed as ITB (final CD group) and vice versa (final ITB group). Final diagnostic criteria for ITB and medication for CD before definite diagnosis of TB were also analyzed in final ITB group. RESULTS: In total, 2760 patients were managed for CD and 772 patients for ITB between 1996 and 2014. As well, 494 of the 2760 CD patients (17.9%) were initially misdiagnosed as ITB and 83 of the 772 ITB patients (10.8%) as CD. The temporal trend in misdiagnosing CD as ITB showed a decrease (OR = 0.89, 95%CI: 0.87-0.91, P < 0.001), whereas the temporal trend in misdiagnosing ITB as CD showed an increase (OR = 1.06, 95%CI: 1.01-1.11, P = 0.013). Age at diagnosis, presenting symptoms, and proportion of patients with active/past perianal fistula and active/inactive pulmonary tuberculosis (TB) were significantly different between final CD group and final ITB group. Forty patients (48.2%) in final ITB group were diagnosed by favorable response to empirical anti-TB treatment. Seventeen patients (20.5%) in final ITB group had inappropriately received corticosteroids and/or thiopurines due to misdiagnosis as CD. However, there were no mortalities in both groups. CONCLUSION: Cases of CD misdiagnosed as ITB have been decreasing, whereas cases of ITB misdiagnosed as CD have been increasing over the past two decades.

Long-Term Outcomes of Adalimumab Treatment in 254 Patients with Crohn's Disease: A Hospital-Based Cohort Study from Korea.

BACKGROUND AND AIMS: Large-scale studies regarding the long-term outcomes of adalimumab (ADA) treatment in Asian patients with Crohn's disease (CD) are still scarce. METHODS: We retrospectively analyzed the long-term outcomes of ADA treatment in Korean CD patients who commenced on scheduled ADA treatment at Asan Medical Center between November 2008 and July 2016. Clinical response was defined as maintaining ADA treatment without dose intensification (DI) and/or major abdominal surgery (MAS). RESULTS: Of the 254 patients who received at least two doses of ADA at 2-week intervals as induction therapy, 250 patients (98.4%) showed an initial favorable response by week 4. Among responders, 243 patients were followed up for longer than 4 weeks and were included for further analysis. The median duration of ADA maintenance therapy was 19.4 months. At the last follow-up, 45 patients (18.5%) required DI after a median of 16.8 months and 31 (12.8%) required MAS after a median of 8.9 months. Finally, 161 patients (66.3%) were still receiving ADA without DI and/or MAS. The cumulative probability of maintaining ADA without DI and/or MAS was 81.1% at 1 year, and 36.5% at 5 years. Secondary loss of response to previous infliximab (P = 0.001) and elevated baseline C-reactive protein at starting ADA treatment (P = 0.008) were identified as independent predictors of a poor response to ADA treatment using multivariate regression analysis. CONCLUSIONS: The long-term outcome of ADA treatment in a real-life cohort of Korean patients with CD appears to be comparable to that reported in previously published Western studies.

Development and Validation of a Novel Prediction Model for Differential Diagnosis Between Crohn's Disease and Intestinal Tuberculosis.

BACKGROUND: Although colonoscopy is useful for differentiating between Crohn's disease (CD) and intestinal tuberculosis (ITB), the technique has limitations. We developed a practical prediction model for differentiating between CD and ITB using laboratory and radiologic parameters and colonoscopic characteristics. METHODS: We prospectively enrolled 80 patients newly diagnosed with CD (n = 40) and ITB (n = 40). We developed a new prediction score by integrating colonoscopic, laboratory, and radiologic parameters. The score's predictive ability was validated on an additional 37 patients. RESULTS: The accuracy of colonoscopic scoring for differentiation was 81.2% (65/80), with 65.0% sensitivity for CD and 97.5% for ITB. In multivariate analysis, positive IgA and/or IgG anti-Saccharomyces cerevisiae antibody and involvement of the proximal intestine were the independent laboratory and radiologic parameters for CD, and positive QuantiFERON-TB Gold In-Tube Test and typical pulmonary TB findings were the parameters for ITB. A new prediction scoring combining colonoscopic, laboratory, and radiologic factors increased the accuracy of diagnosis from 81.2% to 96.3% (77/80). The CD prediction score (from -2 to 2) estimated the likelihood of CD, from 0.3% for patients scoring -2 to 100% for patients scoring 2. The area under the receiver operating characteristic curve of the score was 0.990 in the development group and 0.981 in the validation group. CONCLUSIONS: The new prediction model using a CD prediction score can be useful for calculating the probability of either CD or ITB at initial evaluation (NCT01392365).

Elevated C-reactive protein level during clinical remission can predict poor outcomes in patients with Crohn's disease.

Intestinal inflammation and mucosal damage in Crohn's disease (CD) are believed to progress even during clinical remission. We investigated the long-term prognosis of CD patients in clinical remission according to serum C-reactive protein (CRP) levels. This study included 339 CD patients in clinical remission (Crohn's disease activity index < 150) for more than 6 months between January 2008 and December 2010. Clinical outcomes were compared between patients with normal and elevated CRP levels during clinical remission. During clinical remission, 150 patients had normal CRP consistently and 189 had elevated CRP at least once. During follow-up (median, 7.9 years [interquartile range, 6.8-8.0]), the Kaplan-Meier analysis with the log-rank test showed that normal CRP group had a longer CD-related hospitalization-free survival (P = 0.007) and a longer CD-related intestinal resection-free survival (P = 0.046) than elevated CRP group. In multivariate analysis, elevated CRP was significantly and independently associated with an increased risk of subsequent CD-related hospitalization (adjusted hazard ratio [aHR] 1.787, 95% confidence interval [CI]: 1.245-2.565, P = 0.002) and of subsequent CD-related intestinal resection (aHR 1.726, 95% CI: 1.003-2.969, P = 0.049). The most common reason for CD-related hospitalization was penetrating complications (35.6%). Even when CD patients are in clinical remission, elevated CRP is significantly associated with subsequent CD-related hospitalization and CD-related intestinal resection during follow-up. CD patients in clinical remission but elevated CRP should receive more careful attention and timely interventions to improve long-term outcomes.

Early anti-TNF/immunomodulator therapy is associated with better long-term clinical outcomes in Asian patients with Crohn's disease with poor prognostic factors.

Although early treatment of Crohn's disease (CD) patients with anti-tumor necrosis factor (TNF) agents or immunomodulators (IMs) may improve long-term outcomes, especially those with poor prognostic factors, their effectiveness in Asians remains unclear. In this study, Korean patients with CD naïve to both intestinal surgery and intestinal complications, and with at least two risk factors for progression (diagnosis at age <40 years, systemic corticosteroid treatment <3 months after diagnosis, and perianal fistula at diagnosis) were retrospectively analyzed. Patients were classified into those who started anti-TNFs, or IMs but not anti-TNFs, within 2 years of diagnosis, and those who started anti-TNFs and/or IMs later. Their probabilities of intestinal surgery and intestinal complications were compared. A total of 670 patients were enrolled, 79 in the early anti-TNF, 286 in the early IM, and 305 in the late treatment group. Kaplan-Meier analysis with the log-rank test showed that from starting anti-TNFs/IMs, times to intestinal surgery (P < 0.001), stricturing complications (P = 0.002), and penetrating complications (P < 0.001) were significantly longer in the early anti-TNF/IM groups than in the late treatment group. Multivariate Cox regression analysis showed that, from starting anti-TNFs/IMs, late anti-TNF/IM treatment was independently associated with higher risks of intestinal surgery (adjusted hazard ratio [aHR] 2.321, 95% confidence interval [CI] 1.503-3.584, P < 0.001), behavioral progression (aHR 2.001, 95% CI 1.449-2.763, P < 0.001), stricturing complications (aHR 1.736, 95% CI 1.209-2.493, P = 0.003), and penetrating complications (aHR 3.315, 95% CI 2.094-5.249, P < 0.001) than early treatment. In conclusion, treatment of Asian CD patients having poor prognostic factors with anti-TNFs/IMs within 2 years of diagnosis is associated with better clinical outcomes than later treatment.

Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn's disease: a randomised, double-blind, placebo-controlled phase 2 study.

BACKGROUND: The interleukin-23 pathway is implicated genetically and biologically in the pathogenesis of Crohn's disease. We aimed to assess the efficacy and safety of risankizumab (BI 655066, Boehringer Ingelheim, Ingelheim, Germany), a humanised monoclonal antibody targeting the p19 subunit of interleukin-23, in patients with moderately-to-severely active Crohn's disease. METHODS: In this randomised, double-blind, placebo-controlled phase 2 study, we enrolled patients at 36 referral sites in North America, Europe, and southeast Asia. Eligible patients were aged 18-75 years, with a diagnosis of Crohn's disease for at least 3 months, assessed as moderate-to-severe Crohn's disease at screening, defined as a Crohn's Disease Activity Index (CDAI) of 220-450, with mucosal ulcers in the ileum or colon, or both, and a Crohn's Disease Endoscopic Index of Severity (CDEIS) of at least 7 (≥4 for patients with isolated ileitis) on ileocolonoscopy scored by a masked central reader. Patients were randomised 1:1:1 using an interactive response system to a double-blind investigational product, and stratified by previous exposure to TNF antagonists (yes vs no). Patients received intravenous 200 mg risankizumab, 600 mg risankizumab, or placebo, at weeks 0, 4, and 8. The primary outcome was clinical remission (CDAI <150) at week 12 (intention-to-treat population). Safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02031276. FINDINGS: Between March, 2014, and September, 2015, 213 patients were screened, and 121 patients randomised. At baseline, 113 patients (93%) had been previously treated with at least one tumour necrosis factor (TNF) antagonist (which had failed in 96 [79%]). At week 12, 25 (31%) of 82 risankizumab patients (pooled 41 patients in 200 mg and 41 patients in 600 mg arms) had clinical remission versus six (15%) of 39 placebo patients (difference vs placebo 15·0%, 95% CI 0·1 to 30·1; p=0·0489). Ten (24%) of 41 patients who received 200 mg risankizumab had clinical remission (9·0%, -8·3 to 26·2; p=0·31) and 15 (37%) of 41 who received the 600 mg dose (20·9%, 2·6 to 39·2; p=0·0252). 95 (79%) patients had adverse events (32 in the placebo group, 32 randomised to 200 mg risankizumab, 31 randomised to 600 mg risankizumab); 18 had severe adverse events (nine, six, three); 12 discontinued (six, five, one); 24 had serious adverse events (12, nine, three). The most common adverse event was nausea and most common serious adverse event was worsening of underlying Crohn's disease. No deaths occurred. INTERPRETATION: In this short-term study, risankizumab was more effective than placebo for inducing clinical remission in patients with active Crohn's disease. Therefore, selective blockade of interleukin-23 via inhibition of p19 might be a viable therapeutic approach in Crohn's disease. FUNDING: Boehringer Ingelheim.

X Chromosome-wide Association Study Identifies a Susceptibility Locus for Inflammatory Bowel Disease in Koreans.

BACKGROUND AND AIMS: Genome-wide association studies of inflammatory bowel disease identified > 200 susceptibility loci only in autosomes. This study aimed to identify inflammatory bowel disease susceptibility loci on the X chromosome. METHODS: We performed an X chromosome-wide association study in Korean patients with inflammatory bowel disease. We analysed X chromosome data from our recent genome-wide association studies, including 1505 cases [922 Crohn's disease and 583 ulcerative colitis] and 4041 controls during the discovery phase, followed by replication in additional 1989 cases [993 Crohn's disease, 996 ulcerative colitis] and 3491 controls. Sex-related differential effects of single nucleotide polymorphisms on disease were also evaluated. RESULTS: We confirmed a significant association of a previously reported inflammatory bowel disease susceptibility locus at chromosome Xq26.3 [CD40LG-ARHGEF6; odds ratio, 1.22; 95% confidence interval, 1.16-1.28; combined p = 3.79 × 10-15]. This locus accounted for 0.18% and 0.12% of genetic variance in Crohn's disease and ulcerative colitis, respectively, and increased the total autosomal chromosome genetic variance from 6.65% to 6.83% and from 5.47% to 5.59% for Crohn's disease and ulcerative colitis risk, respectively, in the Korean population. Sex-stratified analyses did not reveal sex-related differences in effect sizes. CONCLUSIONS: We confirmed the association of rs2427870 at the CD40LG-ARHGEF6 locus with an inflammatory bowel disease through an X chromosome-wide association study in a Korean population. Our data suggest that the CD40LG-ARHGEF6 locus on the X chromosome might play a role in inflammatory bowel disease pathogenesis in the Korean population.

Incidence of and Risk Factors for Free Bowel Perforation in Patients with Crohn's Disease.

BACKGROUND: Incidence of and risk factors for intestinal free perforation (FP) in patients with Crohn's disease (CD) are not established. AIM: To establish rate of and risk factors for FP in a large cohort of CD patients. METHODS: Medical records of CD patients who visited Asan Medical Center from June 1989 to December 2012 were reviewed. After matching the FP patients to controls (1:4) by gender, year, and age at CD diagnosis, and disease location, their clinical characteristics were compared using conditional logistic regression analysis. RESULTS: Among 2043 patients who were included in our study cohort, 44 patients (2.15%) developed FP over a median follow-up period of 79.8 months (interquartile range 37.3-124.6), with an incidence of 3.18 per 1000 person-years [95% confidence interval (CI) 2.37-4.28]. All 44 patients underwent emergency surgery, and eight patients underwent reoperation within 12 months (8/44, 18.2%). Multivariable-adjusted analysis revealed that anti-TNF therapy [odds ratio (OR), 3.73; 95% CI 1.19-11.69; p = 0.024] was associated with an increased risk of FP. CONCLUSIONS: The incidence of FP in a large cohort of Korean CD patients was 2.15%, which was similar to that in Western reports. Anti-TNF therapy could be risk factors for FP.

MR Enterography Assessment of Bowel Inflammation Severity in Crohn Disease Using the MR Index of Activity Score: Modifying Roles of DWI and Effects of Contrast Phases.

OBJECTIVE: The purpose of this article is to appraise the use of the MR index of activity (MaRIA) score in evaluating Crohn disease (CD) on present-day MR enterography images, with an emphasis on determining the modifying roles of DWI and the effects of different contrast enhancement phases. SUBJECTS AND METHODS: Fifty patients prospectively underwent MR enterography, including DWI and enteric and portal phase scans, and ileocolonoscopy with segmental CD endoscopic index of severity (CDEIS) scoring within a week. Thirty-nine terminal ilea and 40 right-sided colons (mean [± SD] segmental CDEIS score, 14.3 ± 12.1) from 42 patients with CD (mean age, 27 ± 6.2 years) were finally analyzed by three independent readers. Original and modified (ulcer replaced with DWI grade) MaRIA scores were compared regarding their correlation with segmental CDEIS score, accuracy in diagnosing active (segmental CDEIS score ≥ 3) and severe (segmental CDEIS score ≥ 12) inflammation, and interobserver reproducibility. The primary analysis used portal phase data, and the agreement between portal and enteric phase scores was analyzed. RESULTS: MaRIA and modified MaRIA scores correlated similarly with CDEIS scores (r = 0.737 and 0.742; p = 0.387) and did not significantly differ in terms of AUC values for the diagnosis of active (0.909 and 0.903; p = 0.571) or severe (0.907 and 0.892; p = 0.443) inflammation. The intraclass correlation coefficient was significantly higher for modified MaRIA than for MaRIA (0.845 and 0.701; p < 0.001). The mean difference between portal and enteric phase scores (i.e., portal minus enteric) was 0.33-0.36 score points for individual readers, and the Bland-Altman repeatability coefficient was 0.9-1.42 score points. CONCLUSION: Interobserver reproducibility in evaluating the severity of bowel inflammation in CD using the MaRIA score can be improved by modification with DWI. MaRIA scoring provides steady results across enteric and portal phases.

Pathologic features of colorectal carcinomas associated with Crohn's disease in Korean population.

BACKGROUND: Colorectal cancer (CRC) has been known to complicate Crohn's disease (CD). Several reports in Western population revealed that CRC in CD were characterized by much younger onset and equal distribution of tumors along the entire colon. However, clinicopathologic features of CD-associated CRC in Korean population have not been well documented yet. METHODS: Among 2968 Korean CD patients, 16 patients (0.54%) were found to develop CRC during follow up. We reviewed clinicopathologic features of the 16 CRC patients. RESULTS: The mean age at the time of CRC diagnosis was 39.3 years (range 18-59 years) and 14 of the 16 CRCs (87.5%) occurred in anorectal region. Mucinous adenocarcinoma was strikingly frequent (9/16, 56.3%) and eight cases (8/9) of the mucinous adenocarcinoma cases were located at anorectal area. The other cases consisted of 4 tubular adenocarcinomas, 2 signet ring cell carcinomas and 1 neuroendocrine tumor. Thirteen patients (81.3%) had a history of perianal fistula and 8 of them had a histological association between the CRC and the perianal fistula. CONCLUSIONS: CD-associated CRC was characterized by young age at diagnosis, mucinous histology and association with perianal fistula in Korean patients.

Diffusion-Weighted MR Enterography to Monitor Bowel Inflammation after Medical Therapy in Crohn's Disease: A Prospective Longitudinal Study.

OBJECTIVE: To prospectively evaluate the performance of diffusion-weighted imaging (DWI) to monitor bowel inflammation after medical therapy for Crohn's disease (CD). MATERIALS AND METHODS: Before and following 1-2 years of medical therapy, between October 2012 and May 2015, 18 randomly selected adult CD patients (male:female, 13:5; mean age ± SD, 25.8 ± 7.9 years at the time of enrollment) prospectively underwent MR enterography (MRE) including DWI (b = 900 s/mm2) and ileocolonoscopy. Thirty-seven prospectively defined index lesions (one contiguous endoscopy-confirmed inflamed area chosen from each inflamed anatomical bowel segment; 1-4 index lesions per patient; median, 2 lesions) were assessed on pre- and post-treatment MRE and endoscopy. Visual assessment of treatment responses on DWI in 4 categories including complete remission and reduced, unchanged or increased inflammation, and measurements of changes in apparent diffusion coefficient (ΔADC), i.e., pre-treatment-post-treatment, were performed by 2 independent readers. Endoscopic findings and CD MRI activity index (CDMI) obtained using conventional MRE served as reference standards. RESULTS: ΔADC significantly differed between improved (i.e., complete remission and reduced inflammation) and unimproved (i.e., unchanged or increased inflammation) lesions: mean ± SD (× 10-3 mm2/s) of -0.65 ± 0.58 vs. 0.06 ± 0.15 for reader 1 (p = 0.022) and -0.68 ± 0.56 vs. 0.10 ± 0.26 for reader 2 (p = 0.025). DWI accuracy for diagnosing complete remission or improved inflammation ranged from 76% (28/37) to 84% (31/37). A significant negative correlation was noted between ΔADC and ΔCDMI for both readers with correlation coefficients of -0.438 and -0.461, respectively (p < 0.05). CONCLUSION: DWI is potentially a feasible tool to monitor quantitatively and qualitatively bowel inflammation of CD after medical treatment.

Overall and cause-specific mortality in Korean patients with inflammatory bowel disease: A hospital-based cohort study.

BACKGROUND AND AIM: Limited data are available regarding mortality from inflammatory bowel disease in non-Caucasian populations. Herein, we evaluated overall and cause-specific mortality in a hospital-based cohort of Korean inflammatory bowel disease patients. METHODS: We determined mortality in 2414 Crohn's disease patients and 2798 ulcerative colitis patients diagnosed between 1977 and 2013. Standardized mortality ratios were calculated in several demographic and phenotypic subgroups. RESULTS: During the mean 9-year follow up, 114 patients died: 35 with Crohn's disease and 79 with ulcerative colitis. The overall standardized mortality ratios were 1.40 (95% confidence interval: 0.97-1.94) in Crohn's disease and 0.73 (0.58-0.91) in ulcerative colitis. In Crohn's disease, female sex, age < 30 years at diagnosis, disease duration > 10 years, ileocolonic disease at diagnosis, perianal fistula, intestinal resection, and ever-use of corticosteroids were associated with higher mortality. In ulcerative colitis, male sex, age ≥ 30 years at diagnosis, disease duration ≤ 5 years, proctitis at diagnosis, and no history of colectomy were associated with lower mortality, while primary sclerosing cholangitis was associated with higher mortality. In both Crohn's disease and ulcerative colitis, high mortality rates due to nonmalignant gastrointestinal causes (standardized mortality ratios: 4.59 and 2.32, respectively) and gastrointestinal malignancies (standardized mortality ratios: 16.59 and 3.45, respectively) were observed. Cardiovascular mortality was lower in ulcerative colitis (standardized mortality ratio: 0.47). CONCLUSIONS: The overall mortality tended to be higher in Crohn's disease patients than in the general population; it was slightly lower in ulcerative colitis patients than in the general population.

Underestimation of Smoking Rates in an East Asian Population with Crohn's Disease.

BACKGROUND/AIMS: The reported rates of current smoking at the time of Crohn's disease (CD) diagnosis tend to be low in East Asian studies. However, we hypothesized that East Asian patients may be reluctant to disclose their smoking history, likely because of the influence of the Confucian culture. METHODS: We prospectively re-evaluated the smoking status at diagnosis in 1,437 Korean CD patients whose smoking status had been reported in our previous study. RESULTS: After re-evaluation, the current smokers at diagnosis increased from 388 patients (27.0%) to 445 patients (31.0%), indicating that 12.8% (57 of 445 patients) of the current smokers at diagnosis did not disclose their smoking status at their initial evaluation. The proportion of current smokers at diagnosis who had initially concealed their smoking status was significantly higher among the female patients (29.7%, 11/37) compared with the male patients (11.3%, 46/408) (p<0.005) and among the patients who were ≤18 years old at diagnosis (56.4%, 22/39) compared with the patients >18 years old at diagnosis (8.6%, 35/406) (p<0.001). CONCLUSIONS: Subgroups of Korean CD patients, particularly young patients and female patients, are reluctant to disclose their smoking history. Therefore, the suggestion that smoking is not a risk factor for the development of CD in East Asians should be made with caution.