Azathioprine Is Useful for Maintaining Long-term Remission Induced by Tacrolimus for the Treatment of Ulcerative Colitis: An Inverse Probability of a Treatment Weighing Analysis.

Objective The need for and efficacy of immunomodulators for maintaining remission after tacrolimus therapy have not been sufficiently defined. This study evaluated the efficacy of immunomodulators for maintaining remission in patients with ulcerative colitis after tacrolimus therapy. Methods Patients with active ulcerative colitis who started oral tacrolimus between January 2009 and September 2017 and were responsive were retrospectively evaluated. Long-term outcomes were compared using Cox proportional hazard regression with inverse probability of treatment weighting. Results Among the 63 patients in the study, 45 received immunomodulators. During the follow-up, 30 patients (47.6%) experienced a relapse. The relapse-free survival rate was significantly worse in the group that did not receive immunomodulators than in those that did (p=0.01, log-rank test); the 2-year relapse-free rates were 22.5% and 63.6% in the non-immunomodulator and immunomodulator groups, respectively. A multivariate analysis showed immunomodulator treatment to be an independent protective factor for clinical relapse (adjusted hazard ratio: 0.35, 95% confidence interval: 0.16-0.78, p=0.01). A Cox regression analysis using inverse probability of treatment weighting also showed that immunomodulator maintenance therapy was correlated with a longer relapse-free survival (hazard ratio: 0.31, 95% confidence interval: 0.15-0.64, p<0.01), A similar response was also observed in non-steroid-dependent patients (hazard ratio: 0.36, 95% confidence interval: 0.14-0.99, p=0.047). No serious adverse events occurred due to tacrolimus or immunomodulator, and immunomodulator use did not increase the incidence of adverse events caused by tacrolimus. Conclusion Our data suggest that the use of immunomodulators to maintain remission after tacrolimus therapy is beneficial for patients with ulcerative colitis.

Pretreatment neutrophil-to-lymphocyte ratio predicts clinical relapse of ulcerative colitis after tacrolimus induction.

OBJECTIVES: Although tacrolimus is useful as an induction therapy in patients with ulcerative colitis (UC), information regarding the long-term outcome after tacrolimus therapy is insufficient. The aim of this study was to evaluate the clinical significance of the pretreatment neutrophil-to-lymphocyte ratio (NLR) as a prognostic factor in patients with UC receiving tacrolimus, to aid treatment selection. MATERIALS AND METHODS: Patients with moderate-to-severe active UC who received oral tacrolimus induction therapy and subsequent immunomodulatory maintenance therapy at our hospital between 2009 and 2017 and who showed clinical response at week 12, were retrospectively enrolled. Cox regression analysis was conducted to study the prognostic role of the pretreatment NLR. The combined impact of the NLR and other known prognostic factors was investigated with multivariate regression. RESULTS: Among 45 patients included in this study, 21 patients experienced relapse during a median follow-up period of 16.6 months. Multivariate Cox regression analysis identified the pretreatment NLR (hazard ratio [HR]: 0.82, 95% confidence interval [CI]: 0.72-0.94, P < 0.01) and the use of immunomodulators at the start of tacrolimus treatment (HR: 0.18, 95% CI: 0.05-0.66, P = 0.01) as independent predictors of clinical relapse. CONCLUSIONS: The pretreatment NLR is an independent prognostic factor in patients with UC treated with tacrolimus.

Combined Infection of Human Herpes Viruses: A Risk Factor for Subsequent Colectomy in Ulcerative Colitis.

Background: Little is known about the prevalence and pathogenicity of human herpes viruses except for cytomegalovirus (CMV) in patients with inflammatory bowel disease (IBD). The aim of this study was to determine the prevalence of human herpes viruses on colonic mucosa in patients with IBD and assess the long-term outcomes in these patients. Methods: We examined the colonic mucosal specimens from 66 patients with ulcerative colitis (UC), 54 patients with Crohn's disease (CD), and 29 healthy patients to identify the 6 most common types of human herpes virus, using multiplex polymerase chain reaction (PCR) technique. Results: Herpes simplex virus (HSV)-1/2 and varicella-zoster virus (VZV) were not detected in any of the groups. There was a higher prevalence of Epstein-Barr virus (EBV) (21.2%) and CMV (15.1%) in patients with UC than in patients with CD (EBV 9.3%, CMV 0%) and patents in the healthy control group (EBV 0%, CMV 3.4%). The prevalence of human herpes virus (HHV)-6A/B and HHV-7 was not statistically different among the groups. Five UC patients with inflammation had coexisting CMV and EBV or HHV-6. The combined infection of CMV with EBV or HHV-6 was a significant and independent prognostic factor for subsequent colectomy in patients with UC. Conclusions: The increased prevalence of CMV coexisting with EBV/HHV-6 infection was associated with the clinical course in patients with UC. 10.1093/ibd/izy005_video1izy005_Video_15786489376001.

Serum interleukin-6 level is associated with response to infliximab in ulcerative colitis.

OBJECTIVES: Infliximab is effective in patients with ulcerative colitis (UC); however, one-third of patients do not respond and require additional therapies such as other biologic agents. Therefore, the aim of this study was to analyze the association between pro-inflammatory molecules and clinical efficacy to elucidate possible mechanisms for the non-response to infliximab to aid in treatment selection. MATERIALS AND METHOD: Patients with moderate-to-severe active UC receiving infliximab in our hospital between 2010 and 2016 for whom pre-treatment serum samples were available were retrospectively evaluated. We analyzed the association between serum interleukin (IL)-6, tumor necrosis factor-α (TNF-α) and soluble mucosal vascular addressin cell adhesion molecule-1 (sMAdCAM-1) and the clinical efficacy of infliximab. The primary endpoint was clinical response at the end of the induction period. RESULTS: Forty-one patients were included in this study. After induction therapy, 27 patients (65.9%) showed a clinical response. Serum IL-6 levels were significantly lower in responders than in non-responders (p = .012), whereas no significant differences were noted in other factors including sMAdCAM-1 and TNF-α. Multivariate analysis identified that serum IL-6 level (odds ratio = 0.72; 95% confidence interval, 0.54-0.96; p = .027) was independently associated with response to infliximab. CONCLUSIONS: Serum IL-6 level is associated with response to infliximab in UC. Elevated concentrations of IL-6 may provide insight to the mechanism of non-response to infliximab.

Sepsis Markers Soluble IL-2 Receptor and Soluble CD14 Subtype as Potential Biomarkers for Complete Mucosal Healing in Patients With Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Novel noninvasive biomarkers with high diagnostic accuracy are required to assess mucosal healing, which is associated with sustained clinical remission, in inflammatory bowel disease. This study aimed to explore sepsis markers as potential biomarkers for mucosal healing. METHODS: Patients with ulcerative colitis [UC] or Crohn's disease [CD], who underwent blood tests for C-reactive protein [CRP], serum procalcitonin [PCT], soluble interleukin-2 receptor [sIL-2R], and plasma soluble CD14 subtype [sCD14-ST] within 2 weeks of endoscopy, were retrospectively recruited; and we assessed the relationship between marker levels and clinical features. Complete mucosal healing [cMH] was defined as a Mayo endoscopic subscore [MES] of 0 for UC and a simple endoscopic score for Crohn's disease [SES-CD] of 0 for CD. RESULTS: In all, 68 UC patients and 33 CD patients were included in this study. In patients with UC, the sIL-2R level was significantly higher in patients without cMH than in those with cMH. The sIL-2R level had the highest diagnostic value for identifying cMH in UC. In patients with CD, CRP and sCD14-ST levels were significantly higher in patients without cMH than in those with cMH, and both CRP and sCD14-ST had good diagnostic values for identifying cMH. The sCD14-ST level had a high diagnostic value for identifying cMH even among CD patients with complete clinical remission, defined as a Harvey-Bradshaw index of 0. CONCLUSIONS: The sIL-2R and sCD14-ST levels in patients with UC and CD, respectively, can be useful surrogate markers for identifying mucosal healing in inflammatory bowel disease.

Efficacy of a concomitant elemental diet to reduce the loss of response to adalimumab in patients with intractable Crohn's disease.

BACKGROUND AND AIM: Secondary loss of response to adalimumab (ADA-LOR) commonly occurs in patients with Crohn's disease (CD) treated with adalimumab (ADA). We evaluated the efficacy of concomitant elemental diet (ED) therapy to reduce ADA-LOR in adult CD patients. METHODS: Patients were divided into either an ED (≥900 kcal/day) or a non-ED group (<900 kcal/day). Cumulative non-ADA-LOR rates were compared between groups. The effects of ED intake to reduce ADA-LOR were also assessed in antitumor necrosis factor-alpha (TNF-α)-naïve and infliximab (IFX)-intolerant or refractory CD patients. Serum ADA and TNF-α levels were measured. RESULTS: We enrolled 117 CD patients into the ED (n = 25) or non-ED (n = 92) groups. Although the cumulative non-ADA-LOR rate was higher in the ED group than in the non-ED group, ED intake was not an independent reducing factor for ADA-LOR (adjusted hazard ratio = 0.725; 95% confidence interval: 0.448-1.180; P = 0.196) in all patients. ED intake was significantly more effective in reducing ADA-LOR in IFX-intolerant or refractory patients than in anti-TNF-α-naïve patients in a dose-related manner (P for interaction <0.20). Serum ADA levels did not differ between the groups. Serum TNF-α levels were significantly lower in the ED group than in the non-ED group at week 28 (P = 0.044) and week 52 (P = 0.043). CONCLUSIONS: Concomitant ED therapy reduced ADA-LOR in IFX-intolerant or refractory patients in a dose-related manner. Reductions in the TNF-α levels by concomitant ED intake may contribute to reduce ADA-LOR in CD patients.

Analysis of the Risk Factors of Surgery after Endoscopic Balloon Dilation for Small Intestinal Strictures in Crohn's Disease Using Double-balloon Endoscopy.

Objective Balloon-assisted endoscopy enables access to and treatment of strictures in the small intestine using endoscopic balloon dilation (EBD); however, the long-term outcomes of EBD have not been sufficiently evaluated. This study evaluated the long-term outcomes of EBD in Crohn's disease to identify the risk factors associated with the need for subsequent surgical intervention. Methods We retrospectively analyzed patients with Crohn's disease who had undergone EBD with double-balloon endoscopy (DBE) for small intestinal strictures at a single center between 2006 and 2015. The long-term outcomes were assessed based on the cumulative surgery-free rate following initial EBD. Results Seventy-two EBD with DBE sessions and 112 procedures were performed for 37 patients during this period. Eighteen patients (48.6%) required surgery during follow-up. Significant factors associated with the need for surgery in a multivariate analysis were multiple strictures (adjusted hazard ratio, 14.94; 95% confidence interval, 1.91-117.12; p=0.010). One patient (6.7%) required surgery among 15 who had single strictures compared to 17 (77.3%) among 22 patients with multiple strictures. Conclusion In a multivariate analysis, the presence of multiple strictures was a significant risk factor associated with the need for surgery; therefore, a single stricture might be a good indication for EBD using DBE for small intestinal strictures in Crohn's disease patients.

A comparison of short-term therapeutic efficacy between infliximab and tacrolimus for moderate to severe ulcerative colitis.

INTRODUCTION: Both infliximab (IFX) and tacrolimus (Tac) are effective for inducing clinical remission in patients with ulcerative colitis (UC). However, no randomized study has addressed the relative efficacies of IFX and Tac for patients with moderate to severe UC. This study aimed to conduct a retrospective study on the relative efficacy of IFX and Tac in patients with moderate to severe UC, using an inverse probability of treatment weighting (IPTW) technique to adjust background factors statistically. METHODS: Between July 2009 and March 2016, data obtained from 122 patients with moderate to severe UC who were treated with either IFX (n = 58) or Tac (n = 64) were analyzed retrospectively. We compared the short-term therapeutic efficacy between the IFX group and Tac group using IPTW technique. RESULTS: The clinical remission rate at 14 weeks after treatment was 37.9% (22/58) in the IFX group and 50% (32/64) in the Tac group, respectively. The efficacy of IFX and Tac for clinical remission rate was not different according to univariate (Odds ratio [OR] 1.64, 95% confidence interval [CI] 0.80-3.37 P = 0.18) and multivariate analyses (OR 2.19, 95% CI 0.85-5.61, P = 0.10). After the background and confounders factors were adjusted by using IPTW based on propensity score, the efficacy of IFX and Tac for clinical remission rate was not differed statistically (OR, 1.483; 95% CI, 0.581-3.785; P = 0.409) Conclusion. IFX and Tac have equivalent short-term efficacies for induction in patients with moderate to severe UC.

Neutrophil-to-Lymphocyte Ratio for Predicting Loss of Response to Infliximab in Ulcerative Colitis.

OBJECTIVES: Neutrophil-to-lymphocyte ratio (NLR) has been used to determine the outcome in malignancies and coronary heart disease. Some reports considered the value of NLR as a predictor of response to infliximab in patients with Crohn's disease or rheumatoid arthritis; however, no similar studies have been reported for ulcerative colitis (UC). This study aimed to evaluate the clinical significance of the baseline NLR in patients with UC treated by infliximab. MATERIALS AND METHODS: Patients with moderate-to-severe active UC who received the first infliximab infusion in our hospital between 2010 and 2015, who showed clinical response during the induction period, were retrospectively evaluated for long-term outcomes and risk factors for loss of response (LOR) during infliximab maintenance therapy. Baseline inflammatory markers including NLR were measured within one week before the initiation of infliximab. RESULTS: Fifty-nine patients with moderate-to-severe active UC started treatment with infliximab and 37 patients (62.7%) experienced clinical response after induction therapy. Fourteen of 37 patients on maintenance therapy lost the response during follow-up. Baseline NLR of patients with LOR was significantly higher than in patients with sustained response. The NLR cut-off value of 4.488 was predictive of LOR, using receiver operating characteristic analysis (sensitivity: 78.6%, specificity: 78.3%). A univariate analysis revealed a significant relationship between relapse-free survival and the NLR (P = 0.018). Multivariate analysis indicated the NLR as an independent prognostic factor for LOR (hazard ratio = 3.86, 95% confidence interval: 1.20-12.4, P = 0.023). CONCLUSIONS: Baseline NLR is a useful prognostic marker in patients with moderate-to-severe active UC treated with infliximab, and may contribute to appropriate use of infliximab.

Efficacy of concomitant elemental diet therapy in scheduled infliximab therapy in patients with Crohn's disease to prevent loss of response.

BACKGROUND: Loss of response (LOR) to infliximab (IFX) has become an important clinical issue for patients with Crohn's disease (CD). Elemental diet (ED) therapy has been established as a nutrition therapy for CD in Japan. ED therapy can reduce antigen exposure and is both efficacious and safe. AIM: To evaluate the efficacy of concomitant ED therapy in maintaining regular IFX infusion in patients with CD. METHODS: We retrospectively studied 125 patients with luminal CD treated with scheduled IFX maintenance therapy with a regular dosage. Patients were classified into two groups: the ED group with intake ≥ 900 kcal/day and the non-ED group with intake <900 kcal/day. When clinical LOR was detected on the basis of disease activity, laboratory parameters, or endoscopic findings, the physician discontinued the infusion schedule of IFX. We investigated the efficacy of ED therapy for sustaining the scheduled IFX maintenance therapy. RESULTS: With the exception of ED intake, no significant differences were found in patient characteristics between the ED group and the non-ED group. The ED group was significantly superior to the non-ED group (p = 0.049) in sustaining scheduled IFX maintenance therapy. It is well known that ED therapy is more effective for small bowel lesions than colonic lesions in CD. When comparing ileitis and ileocolitis patients with CD, the ED group was significantly superior to the non-ED group (p = 0.015). CONCLUSIONS: Concomitant ED therapy is effective in maintaining scheduled IFX maintenance therapy in patients with luminal CD in order to prevent LOR.

The preventive effects of low-dose enteric-coated aspirin tablets on the development of colorectal tumours in Asian patients: a randomised trial.

OBJECTIVE: To evaluate the influence of low-dose, enteric-coated aspirin tablets (100 mg/day for 2 years) on colorectal tumour recurrence in Asian patients with single/multiple colorectal tumours excised by endoscopy. DESIGN: A double-blinded, randomised, placebo-controlled multicentre clinical trial was conducted. PARTICIPANTS: 311 subjects with single/multiple colorectal adenomas and adenocarcinomas excised by endoscopy were enrolled in the study (152 patients in the aspirin group and 159 patients in the placebo group). Enrolment began at the hospitals (n=19) in 2007 and was completed in 2009. RESULTS: The subjects treated with aspirin displayed reduced colorectal tumourigenesis and primary endpoints with an adjusted OR of 0.60 (95% CI 0.36 to 0.98) compared with the subjects in the placebo group. Subgroup analysis revealed that subjects who were non-smokers, defined as those who had smoked in the past or who had never smoked, had a marked reduction in the number of recurrent tumours in the aspirin-treated group. The adjusted OR for aspirin treatment in non-smokers was 0.37 (CI 0.21 to 0.68, p<0.05). Interestingly, the use of aspirin in smokers resulted in an increased risk, with an OR of 3.44. In addition, no severe adverse effects were observed in either group. CONCLUSIONS: Low-dose, enteric-coated aspirin tablets reduced colorectal tumour recurrence in an Asian population. The results are consistent with those obtained from other randomised controlled trials in Western countries. THE CLINICAL TRIAL REGISTRY WEBSITE AND THE CLINICAL TRIAL NUMBER: http://www.umin.ac.jp (number UMIN000000697).

Differential expression of vasoactive intestinal peptide receptor 1 expression in inflammatory bowel disease.

There is conflicting evidence regarding the significance of vasoactive intestinal peptide (VIP) in inflammatory bowel disease (IBD). Involvement of the VIP receptor in IBD has not been reported. We examined the expression and localization of the VIP receptor in IBD. We determined the location of VIP receptor 1 (VIPR1) immunohistologically in surgically resected intestinal samples from 10 controls, 15 patients with ulcerative colitis, and 10 patients with Crohn's disease. A fluorescein-linked immunohistological study was performed using anti-VIPR1 antibody, with double-staining with antibodies to CD3, CD19, and CD68. Correlations with interleukin (IL)-4 and TNF-alpha expression were also investigated. Results showed that the number of VIPR1-positive cells was significantly increased in the inflammatory mucosa. VIPR1 was expressed in CD3-, CD19-, and CD68-positive cells. The proportion of VIPR1-positive cells among CD3-positive cells was significantly higher in the lamina propria of patients with ulcerative colitis than in those with Crohn's disease and the controls. The proportion of VIPR1-positive cells among CD68-positive cells was significantly higher in patients with ulcerative colitis and Crohn's disease than in the controls. A correlation between the numbers of VIPR1- and IL-4-positive cells was found in patients with ulcerative colitis, and between the numbers of VIPR1- and TNF-alpha-positive cells in patients with Crohn's disease. In conclusion, VIPR1 was widely expressed in infiltrating inflammatory cells, especially CD3- and CD68-positive cells in ulcerative colitis mucosa and CD68-positive cells in Crohn's disease mucosa. The differential expression of VIPR1 in ulcerative colitis and Crohn's disease mucosa suggests that the VIP system plays different roles in the pathogenesis of IBD.

Mucosa-associated lymphoid tissue lymphoma of the duodenum: report of a case resistant to Helicobacter pylori eradication.

We present a case of mucosa-associated lymphoid tissue (MALT) lymphoma of the duodenum treated with surgical resection. A 64-year-old woman underwent upper gastrointestinal endoscopy because of melena. Examinations revealed an ulcer-forming lesion at the second portion of the duodenum that was diagnosed histologically as low-grade MALT lymphoma. We attempted Helicobacter pylori eradication therapy, although all the tests revealed negative results for its infection. No sign of remission was observed and we performed surgical resection. The patient has shown no sign of recurrence at present, 39 months after the operation. Duodenal MALT lymphoma is a rare entity. Only 17 cases have been reported in the English literature. We summarized the characteristics of the disease and tried to figure out differences in comparison with those in the stomach, including the involvement of the Helicobacter pylori infection.