Malnutrition and inflammation status in nonobese patients with inflammatory bowel disease are associated with nonalcoholic fatty liver disease: a retrospective study.

BACKGROUND/AIMS: The frequency and details of nonalcoholic fatty liver disease (NAFLD) complications in patients with inflammatory bowel disease (IBD) remain unclear. This study aimed to clarify characteristics of NAFLD in patients with IBD. METHODS: We retrospectively identified and enrolled patients with IBD diagnosed with or without NAFLD by undergoing abdominal computed tomography (CT) at our institution between 2005 and 2020. The primary endpoint was the complication rate of NAFLD in patients with IBD. Secondary endpoints were the clinical characteristics of nonobese patients with IBD and comorbid NAFLD and their association with nutritional and inflammatory parameters. RESULTS: Twenty-one (21.9%) of 96 eligible patients with IBD also had NAFLD. In nonobese patients (defined as patients with a body mass index <25 kg/m2), C-reactive protein (CRP; P<0.001) and alanine aminotransferase (P=0.018) levels were higher and the albumin level (P=0.005) and prognostic nutritional index (PNI; P=0.002) values were lower in patients with NAFLD than in those without NAFLD. The PNI value was positively correlated (P<0.001) and the CRP level was negatively correlated (P=0.001) with the hepatosplenic ratio. However, in the NAFLD combined group, PNI (P<0.05) and CRP values (P<0.001) were improved over time after CT imaging by continuing IBD treatment. CONCLUSIONS: Worsening nutritional and inflammatory status in IBD patients is associated with complications of NAFLD. Diagnosis of NAFLD in IBD patients using CT imaging might be useful not only for early detection of NAFLD but also in assessing the need for therapeutic intervention for IBD.

A novel self-assembling peptide hemostatic gel as an option for initial hemostasis in endoscopic sphincterotomy-related hemorrhage: a case series.

Endoscopic sphincterotomy (EST) is a fundamental procedure of therapeutic endoscopic retrograde cholangiopancreatography, with post-EST bleeding as a serious adverse event. Although there are various hemostatic methods for post-EST bleeding, there is no consensus regarding the treatment choice. PuraStat is a novel self-assembling peptide developed as a hemostatic agent. We report six cases of EST-related hemorrhage with initial hemostasis achieved using PuraStat. The cases were observed in four men and two women, with an average age of 77.8 years. EST was performed for biliary drainage in four cases and for stone removal in two cases. Bleeding occurred during the same session as EST in five of six cases, with the remaining case showing bleeding 4 days after EST. As all patients with EST-related hemorrhage presented oozing with stable vital signs, we selected PuraStat as first-line hemostasis in each case. We applied PuraStat using a dedicated catheter with the tip pressed against the bleeding point. Hemostasis was confirmed without additional procedure in all cases. No adverse events were noted after the procedures. As PuraStat hemostasis is effective, feasible, and safe for EST-related hemorrhage, PuraStat may be an option for initial hemostasis, although it is limited to oozing.

Adrenomedullin for biologic-resistant Crohn's disease: A randomized, double-blind, placebo-controlled phase 2a clinical trial.

BACKGROUND AND AIM: Adrenomedullin is a bioactive peptide with many pleiotropic effects, including mucosal healing and immunomodulation. Adrenomedullin has shown beneficial effects in rodent models of inflammatory bowel disease and, more importantly, in clinical trials including patients with ulcerative colitis. We performed a successive clinical trial to investigate the efficacy and safety of adrenomedullin in patients with Crohn's disease (CD). METHODS: This was a multicenter, double-blind, placebo-controlled phase 2a trial that evaluated 24 patients with biologic-resistant CD in Japan. Patients were randomly assigned to three groups and were given an infusion of 10 or 15 ng/kg/min of adrenomedullin or placebo for 8 h per day for 7 days. The primary endpoint was the change in the CD activity index (CDAI) at 8 weeks. The main secondary endpoints included changes in CDAI from week 4 to week 24. RESULTS: No differences in the primary or secondary endpoints were observed between the three groups by the 8th week. Changes in CDAI in the placebo group gradually decreased and disappeared at 24 weeks, but those in the adrenomedullin-treated groups (10 or 15 ng/kg/min group) remained at steady levels for 24 weeks. Therefore, a significant difference was observed between the placebo and adrenomedullin-treated groups at 24 weeks (P = 0.043) in the mixed-effects model. We noted mild adverse events caused by the vasodilatory effect of adrenomedullin. CONCLUSION: In this trial, we observed a long-lasting (24 weeks) decrease in CDAI in the adrenomedullin-treated groups. Adrenomedullin might be beneficial for biologic-resistant CD, but further research is needed.

Adrenomedullin: A Novel Therapeutic for the Treatment of Inflammatory Bowel Disease.

Adrenomedullin (AM) is a bioactive peptide with various physiological functions, including vasodilation, angiogenesis, anti-inflammation, organ protection, and tissue repair. AM suppresses inflammatory cytokine production in the intestinal mucosa, improves vascular and lymphatic regeneration and function, mucosal epithelial repair, and immune function in the intestinal bacteria of animal models with intestinal inflammation. We have been promoting translational research to develop novel therapeutic agents for inflammatory bowel disease (IBD) using AM and have started clinical research for IBD patients since 2010. A multicenter clinical trial is currently underway in Japan for patients with refractory ulcerative colitis and Crohn's disease. Moreover, since current AM administration is limited to continuous intravenous infusion, the development of a subcutaneous formulation using long-acting AM is underway for outpatient treatment.

Development of a novel human adrenomedullin derivative: human serum albumin-conjugated adrenomedullin.

Adrenomedullin is a biologically active peptide with multiple functions. Here, we have developed a novel human serum albumin-adrenomedullin (HSA-AM) conjugate, which was synthesized by the covalent attachment of a maleimide derivative of adrenomedullin to the 34th cysteine residue of HSA via a linker. Denaturing gel electrophoresis and western blotting for HSA-AM yielded a single band with adrenomedullin immunoreactivity at the position corresponding to a molecular weight (MW) of 73 kDa. Following gel-filtration chromatography, the purified HSA-AM showed a single main peak corresponding with an MW of 73 kDa, indicating that HSA-AM is a monomer. Both adrenomedullin and HSA-AM stimulated the intracellular accumulation of cyclic AMP (cAMP) in HEK-293 cells stably expressing the adrenomedullin 1 receptor. The pEC50 values for adrenomedullin and HSA-AM were 8.660 and 7.208 (equivalent to 2.19 and 61.9 nM as EC50), respectively. The bioavailability of HSA-AM compared with that of adrenomedullin was much improved after subcutaneous administration in the rat, which was probably due to the superior resistance of HSA-AM towards endogenous proteases and its reduced clearance from the blood. HSA-AM may be a promising drug candidate for clinical application.

Refractory Duodenal Bleeding Ulcers Successfully Treated with Factor XIII Transfusion.

A 67-year-old woman with a history of autoimmune hepatitis was admitted for fever, acute hepatic dysfunction, and acute kidney injury. She was diagnosed with multiple duodenal ulcers. Despite the administration of proton pump inhibitor and red blood cells, her black stool and anemia progressed, and she was therefore transferred to our hospital. Despite hemostatic treatments, she continued to bleed. On the 21st day of admission, an endoscopic examination showed the oozing of blood from the duodenal mucosa. A low factor XIII (FXIII) activity level was detected, and she was administered FXIII concentrate. The bleeding stopped and she was thereafter discharged.

A nationwide, multi-center, retrospective study of symptomatic small bowel stricture in patients with Crohn's disease.

BACKGROUND: Small bowel stricture is one of the most common complications in patients with Crohn's disease (CD). Endoscopic balloon dilatation (EBD) is a minimally invasive treatment intended to avoid surgery; however, whether EBD prevents subsequent surgery remains unclear. We aimed to reveal the factors contributing to surgery in patients with small bowel stricture and the factors associated with subsequent surgery after initial EBD. METHODS: Data were retrospectively collected from surgically untreated CD patients who developed symptomatic small bowel stricture after 2008 when the use of balloon-assisted enteroscopy and maintenance therapy with anti-tumor necrosis factor (TNF) became available. RESULTS: A total of 305 cases from 32 tertiary referral centers were enrolled. Cumulative surgery-free survival was 74.0% at 1 year, 54.4% at 5 years, and 44.3% at 10 years. The factors associated with avoiding surgery were non-stricturing, non-penetrating disease at onset, mild severity of symptoms, successful EBD, stricture length < 2 cm, and immunomodulator or anti-TNF added after onset of obstructive symptoms. In 95 cases with successful initial EBD, longer EBD interval was associated with lower risk of surgery. Receiver operating characteristic analysis revealed that an EBD interval of ≤ 446 days predicted subsequent surgery, and the proportion of smokers was significantly high in patients who required frequent dilatation. CONCLUSIONS: In CD patients with symptomatic small bowel stricture, addition of immunomodulator or anti-TNF and smoking cessation may improve the outcome of symptomatic small bowel stricture, by avoiding frequent EBD and subsequent surgery after initial EBD.

Single Rectal Neuroendocrine Tumor Associated with Multiple Endocrine Cell Micronests.

Although a few reports of neuroendocrine tumor (NET) in the stomach or appendix with surrounding micronests have been published, cases of rectal NET are rare. We herein report a unique case of a patient with single rectal NET treated endoscopically. A pathological examination revealed multiple endocrine cell micronests (ECMs) in the submucosal layer around the main NET lesion. Neither lymph node metastasis nor distant metastasis in computed tomography was observed six years after the treatment. Because case reports of multiple ECM are very rare, the significance of malignancy is unclear. It therefore appears to be necessary to accumulate similar cases.

Risk Factors for Mortality in Pneumocystis jirovecii Pneumonia in Patients with Inflammatory Bowel Disease.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is highly fatal once infection is established. In this study, we investigated the risk of PJP mortality in patients with inflammatory bowel disease (IBD). METHODS: We conducted a retrospective observational study of case data from IBD patients who developed PJP, compiled from 17 collaborating institutions. Parameters such as age, sex, medications used, and blood test results were analyzed to identify risk factors for mortality. RESULTS: The mortality rate among the 28 IBD patients who developed PJP was 17.9%. A low serum albumin level at the start of IBD treatment was identified as a risk factor for mortality and showed the following association with probability of death (P): P = 1/[1 + exp(-5.5 + 2.4 × Alb). The probability of death exceeded 0.5 when serum albumin was 2.2 g/dL or lower. CONCLUSION: Patients with IBD who develop PJP have a high mortality rate and often cannot continue treatment with medication alone. Therefore, it is necessary to pay attention to albumin levels at the start of immunosuppressive therapy when creating a treatment plan.

Adrenomedullin: A Novel Therapy for Intractable Crohn's Disease with a Loss of Response to Infliximab.

A 35-year-old man with refractory Crohn's disease showed a loss of response to infliximab after requiring treatment with infliximab at 10 mg/kg together with steroid to maintain remission. His symptoms recurred, and colonoscopy showed extensive active ulcers in the colon. Adrenomedullin therapy was started in addition to the conventional infliximab therapy. A few days after, his symptoms went into remission. Endoscopy at 2 and 7 weeks revealed significant mucosal remission without steroid therapy. Adrenomedullin promoted mucosal healing and led to the re-induction of remission in Crohn's disease in a patient with a loss of response to infliximab.

Effect of a concomitant elemental diet with maintenance anti-tumor necrosis factor-α antibody therapy in patients with Crohn's disease: A multicenter, prospective cohort study.

BACKGROUND AND AIM: The aim of this study was to clarify the additional effect of a concomitant elemental diet (ED) for patients with Crohn's disease on maintenance anti-tumor necrosis factor-α antibody (anti-TNF). METHODS: Crohn's disease patients who received anti-TNF induction therapy were enrolled. Patients who achieved clinical response (defined as delta Crohn's disease activity index [CDAI] > 70 and CDAI < 200) at 10-14 weeks after the start of infliximab or adalimumab were included. Eligible patients took a tolerability test of ED (900 kcal/day) for 3 days. Then, patients who preferred concomitant ED and whose ED tolerance was confirmed were allocated to the ED group and given Elental 900 kcal/day or more. Other patients were allocated to the non-ED group. The primary endpoint was the cumulative remission rate at 2 years after baseline. Clinical relapse was defined as CDAI > 200 and/or need for additional treatment. Adherence to the ED was confirmed at each visit. RESULTS: Seventy-two patients were included. Thirty-seven were allocated to the ED group, and 35 were allocated to the non-ED group. The cumulative remission rate at 2 years was not significantly different between the two groups (60.9% vs 56.7%, P = 0.98). Adherence to the ED in the ED group was relatively low, and only 11 patients were maintained on an ED of 900 kcal/day. CONCLUSIONS: The addition of ED for Crohn's disease patients who responded to initial anti-TNF induction therapy was not found to improve outcomes. The efficacy of concomitant ED in other clinical settings, such as loss of response, needs to be clarified in the future (UMIN000009789).

Capsule endoscopy findings for the diagnosis of Crohn's disease: a nationwide case-control study.

BACKGROUND: Capsule endoscopy can be used to identify the early stage of small bowel Crohn's disease (CD). We evaluated significant small bowel capsule endoscopy (SBCE) findings that can lead to early diagnosis of CD. METHODS: We retrospectively accumulated clinical and SBCE data of 108 patients (63 with and 45 without CD). Types of small bowel mucosal injuries, including erosion, ulceration, and cobblestone appearance, and the alignment of diminutive lesions were compared between patients with and without CD. Inter- and intra-observer agreement in the determination of lesions was assessed in 25 pairs of SBCE from the two groups. RESULTS: Under SBCE, cobblestone appearance (33% vs. 2%, p < 0.0001), longitudinal ulcers (78% vs. 20%, p < 0.0001), and irregular ulcers (84% vs. 60%, p < 0.01) were more frequently found in patients with CD. Linear erosion (90% vs. 38%, p < 0.0001) and irregular erosion (89% vs. 64%, p < 0.005) were also more frequent in patients with CD. Furthermore, circumferential (75% vs. 9%, p < 0.0001) and longitudinal (56% vs. 7%, p < 0.0001) alignment of diminutive lesions, mainly observed in the 1st tertile of the small bowel, was more frequent in patients with CD. Good intra-observer agreement was found for ulcers, cobblestone appearance, and lesion alignment. However, inter-observer agreement of SBCE findings differed among observers. CONCLUSIONS: Circumferential or longitudinal alignment of diminutive lesions, especially in the upper small bowel, may be a diagnostic clue for CD under SBCE, while inter-observer variations should be cautiously considered when using SBCE.

Subcutaneously administered adrenomedullin exerts a potent therapeutic effect in a murine model of ulcerative colitis.

Adrenomedullin (AM) exerts a potent anti-inflammatory effect. Intrarectal or consecutive intravenous administrations of AM reduce pathological manifestations in rodent colitis models. However, in clinical applications, a safer administration route that provides stronger alleviation of patient burden is preferred. We investigated whether subcutaneously administered AM is effective against dextran sulfate sodium (DSS)-induced colitis. C57BL/6J mice were administered 1% DSS in drinking water and received AM at 8, 40 or 80 nmol/kg subcutaneously once a day for 7 consecutive days. Subcutaneously administered AM significantly and dose-dependently ameliorated body weight loss, diarrhea, and histological severity of colonic inflammation in DSS-treated mice. The AM therapeutic effect was associated with the upregulation of the production of autocrine AM, and expression of cAMP, c-fos, KLF4, and downregulation of STAT3 and NF-κB p65 phosphorylation, as well as a decrease in proinflammatory cytokine expression in the colon. Subcutaneous AM treatment potently attenuated DSS-induced colitis, which suggests that AM administered subcutaneously in ulcerative colitis (UC) patients may decrease diseases burden and improve quality of life.

Real-world Experience of Anti-tumor Necrosis Factor Therapy for Internal Fistulas in Crohn's Disease: A Retrospective Multicenter Cohort Study.

BACKGROUND: Internal fistula in Crohn's disease is a condition likely to require surgery, although few reports showed successful medical treatments such as anti-tumor necrosis factor (TNF) therapy. We performed a multicenter retrospective cohort study to investigate the outcome of anti-TNF therapy for internal fistula in Crohn's disease. METHODS: Data were retrospectively collected from patients with Crohn's disease diagnosed with internal fistula treated with anti-TNF agents (infliximab or adalimumab) between January 2002 and November 2015. Need for surgery and fistula closure were assessed as primary and secondary endpoints. Cumulative rate of surgery was evaluated by the Kaplan-Meier analysis. Prognostic factors for the outcomes were also assessed by univariate and multivariate analyses. RESULTS: A total of 93 Crohn's disease cases were included in the study with a mean follow-up period of 1452.8 days. Fistula locations were entero-entero/colonic (n = 72, 77.4%), enterovesical (n = 16, 17.2%), or enterovaginal (n = 5, 5.4%). Cumulative surgery rate was 47.2%, and fistula closure rate was 27.0% at 5 years from the induction of anti-TNF agents. Lower Crohn's Disease Activity Index and shorter duration from the diagnosis of fistula were independently associated with the lower risk of surgery (P = 0.017 and 0.048, respectively). Single fistula was associated with the successful fistula closure. Second-line surgical treatments were mostly successful for anti-TNF failures. CONCLUSIONS: In the present retrospective cohort study, approximately half of patients with internal fistulas avoided surgery for long periods. It may be reasonable to treat quiescent single internal fistulas with anti-TNF agents soon after the diagnosis of internal fistulas.

Nursing care management of photodynamic therapy in digestive tract carcinomas at a single cancer center.

The primary goal of nursing care in cases of endoscopic photodynamic therapy (PDT) for digestive tract carcinoma is to prevent phototoxicity by the intravenous administration of photosensitizers. The adequate protocol and management of patients should be conducted under the instruction of expert physicians. Our experiences of administering porfimer sodium and talaporfin sodium during clinical PDT provide insight regarding the specific management protocol of each photosensitizer during an in-hospital stay. We herein report our nursing protocol based on 15 years of experience. Under adequate management, PDT can be safely performed.

Adrenomedullin Therapy in Patients with Refractory Ulcerative Colitis: A Case Series.

BACKGROUND AND AIMS: Adrenomedullin (AM) is a multifunctional biologically active peptide that has an ameliorative effect against inflammatory bowel disease in several experimental models. We reported the first case where AM infusion dramatically improved symptoms and colonoscopy findings in patients with refractory ulcerative colitis (UC). To confirm the reproducibility of the efficacy and safety of AM infusion, this pilot study evaluated the clinical feasibility of intravenous administration of AM in patients with refractory UC. METHODS: Seven patients with active refractory UC participated and received intravenous infusion of AM (1.5 pmol/kg/min) for 8 h daily for 14 days, and their Disease Activity Index (DAI) were evaluated before and 2 and 12 weeks after beginning AM administration. RESULTS: DAI were improved in all patients after AM administration. Within 2 weeks, marked declines in DAI (≥ 3 points and ≥ 30%) were observed in six patients (85.7%), while a more modest decline was observed in one patient (14.3%). Overall mean DAI improved from 9.3 ± 0.6 at baseline to 4.6 ± 0.8 at 2 weeks, and then to 1.2 ± 0.5 at 12 weeks. Endoscopic examination revealed substantial amelioration of ulcers, with mucosal healing and scarring. Four patients remained in clinical remission 12 months after AM treatment. AM administration produced significant increases in plasma AM concentrations (approximately 2.5-fold) that had a mild effect on blood pressure and heart rate, but with no serious adverse effects. CONCLUSION: AM is a potentially useful agent that acts via a novel mechanism to safely induce mucosal healing and clinical remission in patients with refractory UC.