Artificial intelligence quantifying endoscopic severity of ulcerative colitis in gradation scale.

OBJECTIVES: Existing endoscopic scores for ulcerative colitis (UC) objectively categorize disease severity based on the presence or absence of endoscopic findings; therefore, it may not reflect the range of clinical severity within each category. However, inflammatory bowel disease (IBD) expert endoscopists categorize the severity and diagnose the overall impression of the degree of inflammation. This study aimed to develop an artificial intelligence (AI) system that can accurately represent the assessment of the endoscopic severity of UC by IBD expert endoscopists. METHODS: A ranking-convolutional neural network (ranking-CNN) was trained using comparative information on the UC severity of 13,826 pairs of endoscopic images created by IBD expert endoscopists. Using the trained ranking-CNN, the UC Endoscopic Gradation Scale (UCEGS) was used to express severity. Correlation coefficients were calculated to ensure that there were no inconsistencies in assessments of severity made using UCEGS diagnosed by the AI and the Mayo Endoscopic Subscore, and the correlation coefficients of the mean for test images assessed using UCEGS by four IBD expert endoscopists and the AI. RESULTS: Spearman's correlation coefficient between the UCEGS diagnosed by AI and Mayo Endoscopic Subscore was approximately 0.89. The correlation coefficients between IBD expert endoscopists and the AI of the evaluation results were all higher than 0.95 (P < 0.01). CONCLUSIONS: The AI developed here can diagnose UC severity endoscopically similar to IBD expert endoscopists.

Multicenter epidemiological survey of pneumatosis intestinalis in Japan.

BACKGROUND: Pneumatosis intestinalis (PI) is a rare condition characterized by gas collection in the intestinal wall. We aimed to determine the etiology and affected segments associated with complications, treatment, and outcome. METHODS: We conducted a multicenter epidemiological survey using a standardized data collection sheet in Japan. Complicating PI was defined as strangulation or bowel necrosis, bowel obstruction, adynamic ileus, sepsis, shock, and massive gastrointestinal bleeding requiring blood transfusion. RESULTS: We enrolled 167 patients from 48 facilities. Multivariate analysis revealed that older age (adjusted OR, 1.05 and 95% confidence intervals [CI], 1.02-1.09, P = 0.0053) and chronic kidney disease (adjusted OR, 13.19 and 95% CI 1.04-167.62, P = 0.0468) were independent predictors of the small-bowel-involved type. Complicating PI was associated with the small-bowel-involved combined type (adjusted OR, 27.02 and 95% CI 4.80-152.01, P = 0.0002), the small-bowel-only type (adjusted OR, 3.94 and 95% CI 1.02-15.27, P = 0.0472), and symptomatic PI (adjusted OR, 16.24 and 95% CI 1.82-145.24, P = 0.0126). Oxygen therapy was performed in patients with a past history of bowel obstruction (adjusted OR, 13.77 and 95% CI 1.31-144.56, P = 0.0288) and surgery was performed in patients with complicating PI (adjusted OR, 8.93 and 95% CI 1.10-72.78, P = 0.0408). Antihypertensives (adjusted OR, 12.28 and 95% CI 1.07-140.79, P = 0.0439) and complicating PI (adjusted OR, 11.77 and 95% CI 1.053-131.526; P = 0.0453) were associated with exacerbation of PI. The complicating PI was the only indicator of death (adjusted OR, 14.40 and 95% CI 1.09-189.48, P = 0.0425). DISCUSSION: Small-bowel-involved type and symptomatic PI were associated with complications which were indicators of poor prognosis.

Safety and efficacy of long-term tofacitinib treatment in East Asian patients with ulcerative colitis in OCTAVE Open.

BACKGROUND AND AIM: Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We present safety and efficacy data from patients from East Asia (Japan, Korea, and Taiwan) in OCTAVE Open, an open-label, long-term extension study. METHODS: Patients in remission at OCTAVE Open baseline received tofacitinib 5 mg twice daily (BID); all others received tofacitinib 10 mg BID. Proportions and IRs (unique patients with events/100 patient-years) were calculated for adverse events (AEs) of special interest. Efficacy endpoints were evaluated up to 36 months. RESULTS: In OCTAVE Open, 105/944 patients were from East Asia (tofacitinib 5 mg BID, n = 22; tofacitinib 10 mg BID, n = 83). Overall, 87.6% and 24.8% of patients had AEs and serious AEs, respectively; IRs (95% CI) for AEs of special interest were herpes zoster (HZ; non-serious and serious), 6.07 (3.40-10.02); serious infections, 1.47 (0.40-3.76); opportunistic infections, 1.91 (0.62-4.45); major cardiovascular adverse events, 0.37 (0.01-2.04); malignancies (excluding non-melanoma skin cancer [NMSC]), 0.37 (0.01-2.04); and NMSC, 0.00 (0.00-1.35). No deaths, venous thromboembolic events, or gastrointestinal perforations occurred. At month 36, 68.2% and 54.2% of patients had a clinical response, 68.2% and 53.0% had endoscopic improvement, and 63.6% and 49.4% were in remission with tofacitinib 5 and 10 mg BID, respectively. CONCLUSIONS: The HZ IR in East Asian patients was numerically higher versus the global study population; excluding HZ, tofacitinib safety and efficacy were consistent with the global study population.

Real-World Insurance Claims Analysis of Venous Thromboembolism in Japanese Patients with Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD), which encompasses both ulcerative colitis (UC) and Crohn's disease (CD), is a risk factor for venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). AIM: To investigate the incidence of, and risk factors for, VTE in patients with IBD in Japan. METHODS: This was a retrospective, non-interventional study in patients with IBD from the Japan Medical Data Center claims database. Incidence rates (IRs; unique patients with events per 100 patient-years) were calculated for VTE, DVT, and PE among the IBD, UC, and CD cohorts. Odds ratios of potential risk factors were calculated by univariate and multivariate analyses in a nested case-control design. RESULTS: Overall, 16 273 patients with IBD were included: 13 585 with UC and 3443 with CD. VTE events occurred in 1.3%, 1.2%, and 1.9% of patients with IBD, UC, and CD, respectively. In patients with IBD, UC, and CD, IRs of VTE were 0.45, 0.40, and 0.64, respectively, IRs of DVT were 0.42, 0.38, and 0.61, respectively, and IRs of PE were 0.07, 0.07, and 0.11, respectively. In patients with IBD, treatment history (immunomodulators), cardiovascular risk (hypertension, high-density lipoprotein or diabetes mellitus, and history of coronary artery disease or heart failure), malignancy, and undergoing major surgery were identified as potential risk factors for VTE in the multivariate analysis, with similar risk factors reported for patients with UC and CD. CONCLUSIONS: This large study provides insight into the incidence and risk factors for VTE in patients with IBD from Japan.

Certolizumab pegol for maintenance of medically induced remission in Crohn's disease.

BACKGROUND: Crohn's disease (CD) is a disease with an impaired immune response characterized by chronic, relapsing-remitting, and progressive inflammation mainly affecting the gastrointestinal tract. Certolizumab pegol (CZP) is a biological agent that regulates the impaired immune response by controlling tumour necrosis factor-α (TNFα). However, the efficacy and safety of long-term administration of CZP for people with CD with inflammation under control are not well understood. OBJECTIVES: To assess the efficacy and safety of CZP for maintenance of remission in people with CD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, WHO ICTRP, and conference abstracts from inception to 23 March 2022. We contacted pharmaceutical companies involved with the production of CZP for further relevant information. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing CZP with placebo in adults with CD. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. The main outcomes were failure to maintain clinical remission at week 26, failure to maintain clinical response at week 26, and serious adverse events. We planned to perform meta-analyses including all available studies if similar enough for pooling to be appropriate and calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes and mean differences with 95% CIs for continuous outcomes. We analyzed the number needed to treat for an additional beneficial outcome (NNTB) and the number needed to treat for an additional harmful outcome (NNTH) to indicate the magnitude of treatment effects. The same two review authors independently evaluated the risk of bias by using the Cochrane RoB 2 tool and evaluated the certainty of evidence using the GRADE framework. MAIN RESULTS: We identified one study meeting our prespecified eligibility criteria. The included study enrolled 428 adults with CD who responded to induction therapy with CZP 400 mg at weeks 0, 2, and 4. The study evaluated long-term efficacy and safety of CZP administered subcutaneously every four weeks compared with placebo. The proportion of participants who failed to maintain clinical remission at week 26 was 52.3% (113/216) in the CZP group compared to 71.7% (152/212) in the placebo group. Treatment of CZP probably results in a large reduction in failure to maintain clinical remission at week 26 (RR 0.73, 95% CI 0.63 to 0.85). The NNTB was 5 (95% CI 4 to 9). We judged this outcome at low risk of bias. Using the GRADE assessment, we judged the certainty of evidence as moderate due to the low number of events occurred. The proportion of participants who failed to maintain clinical response at week 26 was 37.5% (81/216) in the CZP group compared to 64.2% (136/212) in the placebo group. Treatment of CZP probably results in a large reduction in failure to maintain clinical response at week 26 (RR 0.58, 95% CI 0.48 to 0.71). The NNTB was 4 (95% CI 3 to 5). We judged this outcome at low risk of bias. Using the GRADE assessment, we judged the certainty of evidence as moderate due to the low number of events occurred. The proportion of participants who developed serious adverse events was 5.6% (12/216) in the CZP group compared to 6.6% (14/212) in the placebo group. Treatment of CZP may lead to no difference in serious adverse events compared to placebo when used as a remission maintenance treatment (RR 0.84, 95% CI 0.40 to 1.78). The NNTB was 95 (95% CI NNTH 19 to NNTB 25). We evaluated the risk of bias for this outcome as low. We evaluated the certainty of evidence as low due to the low number of events occurred and the CIs were not sufficiently narrow. AUTHORS' CONCLUSIONS: CZP probably results in a large reduction in failure to maintain clinical remission and response at week 26 in people with CD. The evidence suggests that CZP may lead to no difference in serious adverse events compared to placebo when used as a remission maintenance treatment. However, the current studies are limited to 26 weeks of follow-up and only included adults. Therefore, these conclusions cannot be used to guide longer term treatment or for treatment in children at present.

Development and Validation of a Deep Neural Network for Accurate Evaluation of Endoscopic Images From Patients With Ulcerative Colitis.

BACKGROUND & AIMS: There are intra- and interobserver variations in endoscopic assessment of ulcerative colitis (UC) and biopsies are often collected for histologic evaluation. We sought to develop a deep neural network system for consistent, objective, and real-time analysis of endoscopic images from patients with UC. METHODS: We constructed the deep neural network for evaluation of UC (DNUC) algorithm using 40,758 images of colonoscopies and 6885 biopsy results from 2012 patients with UC who underwent colonoscopy from January 2014 through March 2018 at a single center in Japan (the training set). We validated the accuracy of the DNUC algorithm in a prospective study of 875 patients with UC who underwent colonoscopy from April 2018 through April 2019, with 4187 endoscopic images and 4104 biopsy specimens. Endoscopic remission was defined as a UC endoscopic index of severity score of 0; histologic remission was defined as a Geboes score of 3 points or less. RESULTS: In the prospective study, the DNUC identified patients with endoscopic remission with 90.1% accuracy (95% confidence interval [CI] 89.2%-90.9%) and a kappa coefficient of 0.798 (95% CI 0.780-0.814), using findings reported by endoscopists as the reference standard. The intraclass correlation coefficient between the DNUC and the endoscopists for UC endoscopic index of severity scoring was 0.917 (95% CI 0.911-0.921). The DNUC identified patients in histologic remission with 92.9% accuracy (95% CI 92.1%-93.7%); the kappa coefficient between the DNUC and the biopsy result was 0.859 (95% CI 0.841-0.875). CONCLUSIONS: We developed a deep neural network for evaluation of endoscopic images from patients with UC that identified those in endoscopic remission with 90.1% accuracy and histologic remission with 92.9% accuracy. The DNUC can therefore identify patients in remission without the need for mucosal biopsy collection and analysis. Trial number: UMIN000031430.

Phase 1 study on the safety and efficacy of E6011, antifractalkine antibody, in patients with Crohn's disease.

BACKGROUND AND AIM: E6011 is a humanized monoclonal antibody targeting fractalkine (FKN), a CX3C chemokine, which regulates leukocyte trafficking during inflammation. We evaluated the safety and pharmacokinetic profile of E6011 in patients with Crohn's disease (CD) and also performed preliminary pharmacodynamic (PD) and efficacy assessments. METHODS: This study included a 12-week multiple ascending dose (MAD) phase (2, 5, 10, and 15 mg/kg intravenously every 2 weeks, n = 6, 8, 7, and 7, respectively) and a 40-week Extension phase (n = 12) at the same dose as the MAD phase. Serum E6011, serum total FKN (free soluble FKN and E6011-FKN complex) as a PD marker and CD activity index were evaluated. The primary outcome was safety assessment in the MAD phase. RESULTS: Twenty-seven (96%) of 28 patients had previously been treated with anti-tumor necrosis factor α agents. During the MAD phase, adverse events (AEs) occurred in 18 (64%). The most common AE was nasopharyngitis (five patients, 18%). No severe AEs occurred. Serious AEs occurred in three patients, progression of CD in two, and anemia in one. Serum E6011 concentrations increased dose-dependently after infusion and reached a plateau around 4-6 weeks. Serum total FKN rose simultaneously. Five (18%) patients developed anti-E6011 antibodies during the study. Overall, clinical response and clinical remission were observed at Week 12 in 40% (10/25) and 16% (4/25) of active CD patients, respectively. CONCLUSION: E6011 was well-tolerated and might be effective in CD patients. These findings need to be clarified in a randomized controlled study.

Concomitant use of an immunomodulator with ustekinumab as an induction therapy for Crohn's disease: A systematic review and meta-analysis.

BACKGROUND AND AIM: Ustekinumab (UST), a fully humanized monoclonal antibody against the p40 subunit of interleukin-12/23, is effective for the treatment of Crohn's disease (CD). The benefit of concomitant use of an immunomodulator (IM) with UST, however, is unclear. This study aimed to provide a systematic review and meta-analysis comparing the efficacy and safety of concomitant use of an IM with UST as an induction therapy for CD patients. METHODS: A systematic literature search was performed using PubMed/MEDLINE, the Cochrane Library, and the Japana Centra Revuo Medicina from inception to October 31, 2019. The main outcome measure was achievement of clinical efficacy (remission, response, and clinical benefit) at 6-12 weeks. The quality of the included studies was assessed using the risk of bias in non-randomized studies of interventions (ROBINS-I) tools. The fixed-effects model was used to calculate the pooled odds ratios. RESULTS: From 189 yielded articles, six including a total of 1507 patients were considered in this meta-analysis. Concomitant use of an IM with UST was significantly effective than UST monotherapy as an induction therapy (pooled odds ratio in the fixed-effects model: 1.35, 95% confidence interval [1.06-1.71], P = 0.015). The heterogeneity among studies was low (I2  = 2.6%). No statistical comparisons of the occurrence of adverse events between UST monotherapy and concomitant use of an IM with UST were performed. CONCLUSION: The efficacy of concomitant use of an IM with UST as an induction therapy for CD was significantly superior to that of monotherapy with UST.

Intestinal cancer in patients with Crohn's disease: A systematic review and meta-analysis.

BACKGROUND AND AIM: Although surveillance colonoscopy is recommended by several guidelines for Crohn's disease (CD), the evidence is insufficient to support the validity of this recommendation. Moreover, the efficacy of surveillance colonoscopy for anorectal cancer remains unclear. Therefore, we performed a systematic review of cancer in patients with CD before considering the proper surveillance methods. METHODS: We conducted a systematic review and meta-analysis examining the incidence of intestinal cancer and a literature review to clarify the characteristic features of cancer in CD. We performed the systematic literature review of studies published up to May 2019. RESULTS: Overall, 7344 patients were included in eight studies. The standardized incidence ratios (95% confidence intervals) of colorectal cancer (CRC) and small bowel cancer (SBC) were 2.08 (1.43-3.02) and 22.01 (9.10-53.25), respectively. The prevalence of CRC and SBC was 57/7344 (0.77%) and 17/7344 (0.23%), respectively, during a median follow-up of 12.55 years. Additionally, 54 studies reporting 208 anorectal cancer cases were identified. In patients with anorectal cancer, the prognosis for survival was 2.1 ± 2.3 years, and advanced cancer greater than stage T3 occurred in 46/74 patients (62.1%). Many more reports of anorectal cancer were published in Asia than in Western countries. CONCLUSION: Although we were unable to state a recommendation for surveillance for SBC, we should perform cancer surveillance for CRC in patients with CD. However, the characteristics of cancer may differ according to geography or race. We must establish proper and effective surveillance methods that are independently suitable to detect these differences.

Does anti-tumor necrosis factor alpha prevent the recurrence of Crohn's disease? Systematic review and meta-analysis.

BACKGROUND AND AIM: Anti-tumor necrosis factor (TNF) α agents are now well known to function as effective treatments for Crohn's disease (CD). Several meta-analyses have revealed the efficacy of anti-TNF therapy for preventing recurrence after surgery; however, the efficacies reported in some prospective studies differed according to the outcomes. Moreover, adverse events (AEs) were not well evaluated. We conducted this systematic review and meta-analysis to evaluate both the efficacy of anti-TNF therapy after stratification by the outcome of interest and the AEs. METHODS: We performed a systematic literature review of studies investigating anti-TNF therapy, CD, and postoperative recurrence. Meta-analyses were performed for endoscopic and clinical recurrence and AEs. RESULTS: A total of 570 participants, including 254 patients in the intervention group and 316 patients in the control group, in eight studies, were analyzed for recurrence. Based on the results of the meta-analysis, the efficacies of anti-TNF therapy at preventing endoscopic and clinical recurrence were as follows: relative risk (RR) 0.34, 95% confidence interval (CI) 0.22-0.53 and RR 0.60, 95% CI 0.36-1.02, respectively. The RR of AEs with anti-TNF therapy was 1.75 (95% CI 0.81-3.79). CONCLUSIONS: Anti-TNF therapy after surgery for CD displays efficacy at preventing endoscopic recurrence for 1-2 years, without increasing the incidence of AEs. However, clinical recurrence was not significantly reduced. The efficacy of postoperative anti-TNF therapy may differ in terms of the outcomes, which include long-term prevention, the avoidance of further surgery, and cost-effectiveness.

Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology practice recommendations for medical management and monitoring of inflammatory bowel disease in Asia.

Inflammatory bowel disease (IBD) has increased in incidence and prevalence in Asian countries since the end of the 20th century. Moreover, differences in the cause, phenotypes, and natural history of IBD between the East and West have been recognized. Therefore, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have established recommendations on medical management of IBD in Asia. Initially, the committee members drafted 40 recommendations, which were then assessed according to Grading of Recommendations Assessment, Development and Evaluation. Eight statements were rejected as this indicated that consensus had not been reached. The recommendations encompass pretreatment evaluation; medical management of active IBD; medical management of IBD in remission; management of IBD during the periconception period and pregnancy; surveillance strategies for colitis-associated cancer; monitoring side effects of thiopurines and methotrexate; and infections in IBD.

Leucine-Rich Alpha-2 Glycoprotein May Be Predictive of the Adalimumab Trough Level and Antidrug Antibody Development for Patients with Inflammatory Bowel Disease: A Sub-Analysis of the PLANET Study.

INTRODUCTION: The aim of this study was to examine whether biomarkers are predictive of the adalimumab (ADA) trough level and antidrug antibody development in patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Using data obtained in a prospective, multicenter, observational study (PLANET), we assessed serial changes in a novel biomarker - leucine-rich alpha-2 glycoprotein (LRG) - during ADA treatment for patients with active CD and UC. We measured serum LRG, C-reactive protein (CRP), and fecal calprotectin (fCAL) at weeks 0, 12, 24, and 52. The ADA trough level and anti-ADA antibody (AAA) were also measured at weeks 12 and 52. Correlations between the ADA trough level, AAA, and biomarkers were examined. RESULTS: In all, 34 patients with CD and 47 patients with UC were enrolled. The ADA trough level at week 12 or at the time of ADA withdrawal was 8.5 ± 3.9 in the AAA-negative group (n = 70) and 2.9 ± 2.7 µg/mL in the AAA-positive group (n = 8) (p < 0.0001). The ADA trough level at week 12 or at the time of ADA withdrawal was associated with pretreatment LRG (p = 0.0437 and r = -0.23). CONCLUSION: LRG, rather than CRP or fCAL, may be a marker for predicting the trough level of ADA for patients with CD and UC treated with ADA.

Expert Opinions on the Current Therapeutic Management of Inflammatory Bowel Disease during the COVID-19 Pandemic: Japan IBD COVID-19 Taskforce, Intractable Diseases, the Health and Labor Sciences Research.

BACKGROUND: The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a dramatic challenge for all healthcare systems worldwide. This outbreak immediately affected gastroenterologists as well as global physicians worldwide because COVID-19 can be associated with not only triggering respiratory inflammation but also gastrointestinal (GI) inflammation based on the mechanism by which SARS-CoV-2 enters cells via its receptor the angiotensin-converting enzyme 2, which is expressed on GI cells. However, the comorbidity spectrum of digestive system in patients with COVID-19 remains unknown. Because the inflammatory bowel disease (IBD) management involves treating uncontrolled inflammation with immune-based therapies, physicians, and patients have great concern about whether IBD patients are more susceptible to SARS-CoV-2 infection and have worsened disease courses. SUMMARY: It is necessary to precisely ascertain the risk of SARS-CoV-2 infection and the COVID-19 severity in IBD patients and to acknowledge the IBD management during the COVID-19 pandemic with clinically reliable information from COVID-19 cohorts and IBD experts' opinions. In this review, we highlight clinical questions regarding IBD management during the COVID-19 pandemic and make comments corresponding to each question based on recent publications. Key Messages: We propose that there is (1) no evidence that IBD itself increases the risk of SARS-CoV-2 infection, (2) to basically prioritize the control of disease activity of IBD, (3) no need for physicians to suddenly discontinue immunomodulatory or biologic therapy in patients with quiescent IBD, and (4) a need for careful observation of elderly (>60 years old) and IBD patients receiving corticosteroid treatment during the COVID-19 pandemic.

Significance of Conducting 2 Types of Fecal Tests in Patients With Ulcerative Colitis.

BACKGROUND & AIMS: We compared the diagnostic accuracy of the fecal calprotectin (FCP) test vs the fecal immunochemical blood test (FIT) in determining the endoscopic severity and predicting outcomes of patients with ulcerative colitis (UC). METHODS: We performed a nationwide study of 879 patients with UC, enrolled at medical centers across Japan, from March 2015 to March 2017. We collected data on fecal biomarkers, endoscopic severities, and other clinical indices from Cohort 1 (n = 427) and assessed the diagnostic accuracy of FCP measurement and FIT results in determining clinical severity, based on Mayo score, and endoscopic remission, based on Mayo endoscopic sub-score (MES) or UC endoscopic index of severity. We also followed 452 patients in clinical remission from UC (Cohort 2) for 12 months and evaluated the associations of FCP levels and FIT results with clinical recurrence. RESULTS: The levels of FCP and FIT each correlated with the MES and UC endoscopic index of severity. There were no significant differences in the areas under the curve of FCP vs FIT in distinguishing patients with MES≤1 from those with MES≥2 (P = .394) or in distinguishing patients with MES=0 from those with MES≥1 (P = .178). Among 405 patients in clinical remission at baseline, 38 (9.4%) had UC recurrences within 3 months and 90 (22.2%) had recurrences within 12 months. FCP≥146 mg/kg (hazard ratio [HR], 4.83; 95% confidence interval [CI], 2.80-8.33) and FIT≥77 ng/mL (HR, 2.92; 95% CI, 1.76-4.83) were independently associated with clinical recurrence within 12 months. UC recurred within 12 months in 69% of patients with levels of FCP≥146 mg/kg and FIT ≥77 ng/mL; this value was significantly higher than the rate of recurrence in patients with levels of FCP≥146 mg/kg and FIT <77 ng/mL (31.5%, P < .001) or patients with levels of FCP<146 mg/kg and FIT ≥77 ng/mL (30.0%, P < .001). CONCLUSION: In a nationwide study of patients with UC in Japan, we found that the level of FCP and FIT could each identify patients with endoscopic markers of disease severity (MES≥2). The combination of FCP and FIT results can identify patients in remission who are at risk for disease recurrence. Clinical Trials Registry no: UMIN000017650 (http://www.umin.ac.jp/ctr/).

Factors contributing to the systemic clearance of infliximab with long-term administration in Japanese patients with Crohn's disease: Analysis using population pharmacokinetics
.

OBJECTIVE: Crohn's disease (CD) is a chronic inflammatory gastrointestinal disease with repeated cycles of exacerbation and remission. Infliximab (IFX), a chimeric anti-TNF-α monoclonal antibody, has been widely used for the treatment of CD. However, no study in Japanese CD patients receiving continuous IFX for more than 1 year has been reported. To avoid therapeutic failure during long-term administration in Japanese CD patients, we evaluated the variable factors of IFX pharmacokinetics and the optimal trough IFX concentration at 8 weeks after administration. MATERIALS AND METHODS: Population pharmacokinetic (PPK) analysis was performed using the nonlinear mixed-effect model based on the IFX serum concentration in 832 samples from 121 patients. A one-compartment model was used to examine interindividual variability in the systemic clearance (CL) of intravenously administered IFX. RESULTS: PPK estimates (estimated value, RSE%) were total clearance (CL: 0.018 L/h, 9.1) and volumes of distribution (Vd: 7.35 L, 12.0). Interindividual variability for CL and Vd of 0.11 and 0.16, respectively, was found. Body weight, antibody to IFX (ATI), and albumin level were factors affecting the IFX CL. IFX CL was greater in the ATI-positive than in the ATI-negative group. CL was also greater in nonremission patients. There was a significant association between the predicted serum IFX trough concentration at 8 weeks and therapeutic response with long-term continuous administration (p < 0.05), with a higher concentration at 8 weeks seen in the remission group. CONCLUSION: Using these variables including body weight, ATI, and albumin level, the IFX dose could be calculated for individual CD patients to achieve the optimal therapeutic range.

Efficacy of Indigo Naturalis in a Multicenter Randomized Controlled Trial of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Indigo naturalis (IN) is a traditional Chinese medicine that contains ligands for the aryl hydrocarbon receptor and promotes regeneration of the mucosa by inducing production of interleukin 22. IN might induce mucosal healing in patients with ulcerative colitis (UC). We performed a randomized controlled trial to investigate the safety and efficacy of IN in patients with UC. METHODS: We performed a multicenter, double-blind trial evaluating the safety of 86 patients in Japan with active UC (Mayo scores of 6 or more), enrolled from March 30 through December 27, 2016. Patients were randomly assigned to groups and given a daily dose of 0.5, 1.0, or 2.0 g IN or placebo (1:1:1:1 ratio) for 8 weeks. The primary endpoint was the rate of clinical response at week 8, defined as a 3-point decrease in the Mayo score and a decrease of at least 30% from baseline, with a decrease of at least 1 point for the rectal bleeding subscore or absolute rectal bleeding score of 0-1. The main secondary endpoint was the rate of clinical remission at week 8, defined as a Mayo score or ≤2 and no subscores with a value >1. Mucosal healing was also assessed at week 8. RESULTS: The trial was terminated because of an external reason: a report of pulmonary arterial hypertension in a patient who used self-purchased IN for 6 months. In the intent-to-treat analysis, we observed a significant, dose-dependent linear trend in proportions of patients with clinical responses (13.6% with a clinical response to placebo; 69.6% to 0.5 g IN; 75.0% to 1.0 g IN; and 81.0% to 2.0 g IN) (Cochran-Armitage trend test P < .0001 compared with placebo). Proportions of patients in clinical remission at week 8 were significantly higher in the 1.0 g IN group (55.0%, P = .0004) and the 2.0 g IN group (38.1%, (P = .0093) than in the placebo group (4.5%). Proportions of patients with mucosal healing were 13.6% in the placebo group, 56.5% in the 0.5 g IN group, 60.0% in the 1.0 g IN group, and 47.6% in the 2.0 g IN group (P = .0278 compared with placebo). Although mild liver dysfunction was observed in 10 patients who received IN, no serious adverse events were observed. CONCLUSIONS: In a randomized, placebo-controlled trial, we found 8 weeks of IN (0.5-2.0 g per day) to be effective in inducing a clinical response in patients with UC. However, IN should not yet be used because of the potential for adverse effects, including pulmonary arterial hypertension. Clinical Trials Registry no: UMIN000021439 (http://www.umin.ac.jp/ctr/).

Predictors of mucosal healing during induction therapy in patients with acute moderate-to-severe ulcerative colitis.

BACKGROUND AND AIM: The treat-to-target strategy has emerged in ulcerative colitis management. Mucosal healing is the best target, albeit not in induction therapy of acute diseases as clinical conditions vary over a short duration. To determine the targets during induction therapy for acute ulcerative colitis, we identified markers to predict mucosal healing at 3 and 12 months of initiating the induction therapy. METHODS: This single-center prospective observational study enrolling 61 adult patients hospitalized for disease exacerbation collected the partial Mayo scores, ulcerative colitis endoscopic index of severity, fecal markers, and laboratory data (0 day, 2 weeks, and 3 and 12 months) of initiating induction therapy. RESULTS: At 2 weeks, patients with mucosal healing at 3 months had had lower partial Mayo and ulcerative colitis endoscopic index of severity scores and higher white blood cell count and total cholesterol than those without mucosal healing. At 3 months, patients with mucosal healing at 12 months had had lower partial Mayo and ulcerative colitis endoscopic index of severity scores than those without mucosal healing. A kinetic analysis demonstrated a difference in the partial Mayo scores and total cholesterol and albumin levels at 2 weeks and in the ulcerative colitis endoscopic index of severity, fecal calprotectin, and fecal immunochemical tests at 3 months between patients who achieved mucosal healing at 12 months and those who did not. CONCLUSIONS: Partial Mayo scores and total cholesterol levels act as short-term therapeutic targets during induction therapy in patients with acute ulcerative colitis. Mucosal healing at 3 months correlates to longer time mucosal healing.

Long-term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine.

BACKGROUND AND AIM: A missense variant of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene (R139C) predisposes Asian patients with inflammatory bowel disease (IBD) to thiopurine-induced leukopenia. This study evaluates the long-term effect of NUDT15 R139C heterozygosity on hematological parameters during thiopurine administration. METHODS: We enrolled 83 Japanese IBD patients who were on anti-tumor necrosis factor-α agents and had used thiopurine. NUDT15 R139C was genotyped by polymerase chain reaction. We retrospectively reviewed patient clinical charts to collect data on white blood cell (WBC) count, mean corpuscular volume (MCV), hemoglobin, and platelet count during the 24 months following thiopurine initiation. RESULTS: The included patients had either Crohn's disease (54; 65.1%) or ulcerative colitis (29; 34.9%). Genotyping of NUDT15 R139C identified 62 patients (74.7%) of genotype C/C and 21 (25.3%) of genotype C/T. The median dose of thiopurine was lower in the C/T group than in the C/C group after starting thiopurine. At 6 months, the mean WBC count of the C/T group became significantly lower than that of the C/C group (P = 0.008) and remained lower through the 24 months. The C/T group developed grade 2-4 leukopenia by 6 months, which persisted through 12-24 months. The mean MCV in the C/T group became higher than that of the C/C group after 3 months. CONCLUSIONS: NUDT15 R139C heterozygosity affected the WBC count and MCV for 24 months after thiopurine administration. Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15 R139C.

Certolizumab pegol for induction of remission in Crohn's disease.

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract, and immune response modulation is the main treatment strategy to induce remission in active CD. Certolizumab pegol (CZP) is a tumor necrosis factor-alfa (TNF-α) inhibitor which regulates impaired immune response. OBJECTIVES: The primary objectives were to evaluate the efficacy and safety of CZP for the induction of remission in CD. SEARCH METHODS: We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD group specialized register, trials registers and other sources from inception to 28 January 2019. Moreover, we contacted the pharmaceutical company that manufactures CZP. SELECTION CRITERIA: We included randomized controlled trials comparing CZP with placebo or no treatment in active CD patients. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. The main outcomes selected for GRADE analysis were clinical remission at week 8 (Crohn's Disease Activity Index [CDAI] ≤150), clinical response at week 8 (CDAI reduction ≥ 100 or clinical remission), and serious adverse events. The Mantel-Haenszel random-effects method was applied for the statistical analyses. For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI). MAIN RESULTS: Four studies involving 1485 participants with moderate to severe CD met the inclusion criteria and were used in the meta-analyses. All studies included active CD patients with CDAI ranging from 220 to 450. Most patients were adults over 18 years of age. One study was identified as high risk of bias due to a non-identical placebo while the other studies were judged to be at low risk of bias.CZP (100 mg to 400 mg every 2 to 4 weeks) was shown to be superior to placebo for achieving clinical remission at week 8 (RR 1.36, 95% CI 1.11 to 1.66; moderate certainty evidence). The raw numbers of participants achieving clinical remission at week 8 were 26.9% (225/835) and 19.8% (129/650) in the CZP and the placebo groups, respectively.CZP was shown to be superior to placebo for achieving clinical response at week 8 (RR 1.29, 95% CI 1.09 to 1.53; moderate certainty evidence). In raw numbers, clinical response at week 8 was achieved in 40.2% (336/835) and 30.9% (201/650) of participants in the CZP and the placebo groups, respectively.In raw numbers, serious adverse events were observed in 8.7% (73/835) and 6.2% (40/650) of participants in the CZP and the placebo groups, respectively (RR 1.35, 95% CI 0.93 to 1.97; moderate certainty evidence). Serious adverse events included worsening Crohn's disease, infections, and malignancy. AUTHORS' CONCLUSIONS: Moderate certainty evidence suggests that CZP is effective for induction of clinical remission and clinical response in participants with active CD patients. It is uncertain whether the risk of serious adverse events differs between CZP and placebo as the 95% CI includes the possibility of a small decrease or doubling of events. Future studies are needed to evaluate the long-term efficacy and safety of CZP in CD patients.

Gastrointestinal function in dementia with Lewy bodies: a comparison with Parkinson disease.

PURPOSE: To investigate gastrointestinal function in dementia with Lewy bodies and Parkinson disease. METHODS: We examined gastric emptying and colonic transit time in 19 dementia with Lewy bodies and 46 Parkinson disease patients. RESULTS: Gastric emptying was longer in dementia with Lewy bodies than in Parkinson disease (p = 0.014). Colonic transit time tended to be longer in dementia with Lewy bodies than in Parkinson disease. There was no relationship between gastric emptying and colonic transit time, nor between gastric emptying, colonic transit time and age. CONCLUSION: Gastric emptying was prolonged in dementia with Lewy bodies compared to Parkinson disease.