Recent trends in diagnostic techniques for inflammatory bowel disease

Makoto Naganuma,Naoki Hosoe,Takanori Kanai,Haruhiko Ogata 대한내과학회 2015 The Korean Journal of Internal Medicine Vol.30 No.3

Although ileocolonoscopy is the gold standard for diagnosis of inflammatory bowel disease and is useful for assessing the disease severity in the colon and terminal ileum, several alternative diagnostic techniques have been developed recently. For ulcerative colitis (UC), magnification colonoscopy, endocytoscopy, and confocal laser endomicroscopy enable assessment of histological inflammation without the need for biopsy. Capsule endoscopy is useful for detection of small intestinal and colonic lesions in both female and male patients. For UC, capsule endoscopy may be useful for evaluating colonic inflammation in patients with a previous poor colonoscopy experience, while it should be used only in Crohn’s disease (CD) patients with unexplained symptoms when other examinations are negative. Magnetic resonance enterography (MRE) is particularly useful for detecting transmural inflammation, stenosis, and extraintestinal lesions, including abscesses and fistulas. MRE is also useful when evaluating small and large intestinal lesions, even in cases with severe strictures in which full evaluation of the small bowel would be virtually impossible using other devices. Therefore, the appropriate diagnostic devices for detecting CD lesions in the small and large intestine should be used.

Current new challenges in the management of ulcerative colitis

Tomohiro Fukuda,Makoto Naganuma,Takanori Kanai 대한장연구학회 2019 Intestinal Research Vol.17 No.1

Ulcerative colitis (UC) is a chronic inflammatory condition of the gastrointestinal tract. Although the cause of UC is postulatedto be multifactorial in nature, including genetic predisposition, epithelial barrier defects, dysregulation of immune responses,and environmental factors, the specific pathogenesis of UC is still incompletely understood. In the treatment of UC so far, amethod of suppressing immunity and treating it has been mainstream. Immunosuppressant drugs, including thiopurines(azathioprine or 6-mercaptopurine), anti-tumor necrosis factor-α (anti-TNF-α) antibody (infliximab and adalimumab), andcalcineurin inhibitor, can be used in treat patients with corticosteroid-dependent and/or corticosteroid-refractory moderateto-severe UC. Recently, in addition to such a conventional therapeutic agent, golimumab, which is the first transgenic humanmonoclonal anti-TNF-α antibody to be fabricated, anti α-4/β-7 integrin antibody, and Janus kinase inhibitor have been reportedto novel immunosuppressant therapy. Furthermore, other treatments with unique mechanisms different from immunosuppression,have also been suggested, including fecal microbiota transplantation and Indigo naturalis, which is a Chinese herbalmedicine. We compared the features and efficacy of these new treatments. In this issue, the features and treatment options forthese new treatments is reviewed. (Intest Res 2019;17:36-44)

Predictive factors for achievement of mucosal healing by budesonide 2-mg foam in ulcerative colitis: a pooled analysis of data from two clinical trials

( Toshifumi Hibi ),( Makoto Naganuma ),( Eisei Oda ),( Yoji Yamada ),( Yoshitomo Chujoh ),( Ryoichi Yoshihara ),( Mamoru Watanabe ) 대한장연구학회 2020 Intestinal Research Vol.18 No.1

Background/Aims: Mucosal healing (MH) of distal lesions in ulcerative colitis (UC) has recently been confirmed with budesonide 2-mg foam (BF) treatment in 2 clinical trials; however, few studies have investigated the predictive factors for complete MH. Methods: We conducted a post hoc analysis using pooled data from phase II and III clinical trials evaluating the efficacy and safety of BF for UC. Additionally, we analyzed the relationships between complete MH and baseline factors and clinical symptoms from baseline to week 6. Results: Among the 291 Japanese patients from the 2 pooled clinical studies, 119 patients in the BF twice a day group and 117 in the placebo group were included in the full analysis set. The proportion of patients with a rectal bleeding (RB) subscore of 0 was significantly higher in the BF group than in the placebo group after a 5-day treatment (P<0.05). After a 2-day treatment, significantly more patients in the BF group had a stool frequency (SF) subscore of 0 than patients in the placebo group (P<0.05). Multivariate analysis showed that complete MH at week 6 was influenced by baseline SF subscore and 5-aminosalicylic acid (5-ASA) enema or suppository use (P=0.0086 and P=0.0015, respectively). The relationship between complete MH at week 6 and RB subscore after week 2 was also confirmed. Conclusions: Normal SF at baseline, history of 5-ASA topical product use, and elimination of RB after week 2 are suggested predictors of complete MH at week 6 with twice-daily BF treatment. (Intest Res 2020;18:56-68)

β-(1,3)-Glucan derived from Candida albicans induces inflammatory cytokines from macrophages and lamina propria mononuclear cells derived from patients with Crohn’s disease

( Kiyoto Mori ),( Makoto Naganuma ),( Shinta Mizuno ),( Hiroaki Suzuki ),( Mina T. Kitazume ),( Katsuyoshi Shimamura ),( Sayako Chiba ),( Akira Sugita ),( Katsuyoshi Matsuoka ),( Tadakazu Hisamatsu ) 대한장연구학회 2018 Intestinal Research Vol.16 No.3

Background/Aims: Recent research has highlighted the importance of interactions between commensal fungi and intestinal inflammation. However, there are few studies investigating whether commensal fungi contribute to inflammation in patients with Crohn’s disease (CD). The aim of this study is to investigate reveal interactions between commensal fungi and host immune cells in CD. Methods: CD14-positive monocytes were isolated from peripheral blood mononuclear cells from healthy human volunteers and then differentiated in the presence of macrophage colony-stimulating factor (M-CSF) (referred to as M-macrophages, M-Mφs) or M-CSF and interferon-γ (IFN-γ) (referred to as M-gamma macrophages, Mγ-Mφs). Cytokine production by these in vitro differentiated macrophages in response to β-(1,3)-glucan was analyzed by flow cytometry. Expression of Dectin-1 was examined using flow cytometry, western blotting, and quantitative reverse transcription-polymerase chain reaction. Cytokine production by in vitro differentiated macrophages in response to β-(1,3)-glucan was measured in the presence of an anti-Dectin-1 receptor antagonist, anti-Syr, or an anti-Fas-1 antibody. Cytokine production by lamina propria mononuclear cells (LPMCs) derived from CD patients in response to β-(1,3)-glucan was also analyzed. Results: Mγ-Mφs produced a large amount of tumor necrosis factor-α (TNF-α) and interleukin-6 in response to β-(1,3)-glucan. Dectin-1 expression was significantly higher in Mγ-Mφs than in M-Mφs. The increase in TNF-α production by Mγ-Mφs stimulated with glucan was reversed by blocking Dectin-1, Syr or Fas-1. LPMCs derived from CD patients stimulated with β-(1,3)-glucan produced significantly higher amount of TNF-α than LPMCs derived from UC patients. Conclusions: These results suggest that commensal fungal microbiota may contribute to the pathogenesis of CD by inducing macrophages-derived pro-inflammatory cytokines. (Intest Res 2018;16:384-392)

REVIEW : Diet, microbiota, and inflammatory bowel disease: Lessons from Japanese foods

( Takanori Kanai ),( Katsuyoshi Matsuoka ),( Makoto Naganuma ),( Atsushi Hayashi ),( Tadakazu Hisamatsu ) 대한내과학회 2014 The Korean Journal of Internal Medicine Vol.29 No.4

The incidence and prevalence of inflammatory bowel diseases (IBDs) including ulcerative colitis and Crohn disease are rapidly increasing in Western countries and in developed Asian countries. Although biologic agents targeting the immune system have been effective in patients with IBD, cessation of treatment leads to relapse in the majority of patients, suggesting that intrinsic immune dysregulation is an effect, not a cause, of IBD. Dramatic changes in the environment, resulting in the dysregulated composition of intestinal microbiota or dysbiosis, may be associated with the fundamental causes of IBD. Japan now has upgraded water supply and sewerage systems, as well as dietary habits and antibiotic overuse that are similar to such features found in developed Western countries. The purpose of this review article was to describe the association of diet, particularly Japanese food and microbiota, with IBD.

Long-term safety and efficacy of adalimumab for intestinal Behcet`s disease in the open label study following a phase 3 clinical trial

( Nagamu Inoue ),( Kiyonori Kobayashi ),( Makoto Naganuma ),( Fumihito Hirai ),( Morio Ozawa ),( Dilek Arikan ),( Bidan Huang ),( Anne M. Robinson ),( Roopal B. Thakkar ),( Toshifumi Hibi ) 대한장연구학회 2017 Intestinal Research Vol.15 No.3

Background/Aims: Intestinal Behcet`s disease (BD) is an immune-mediated inflammatory disorder. We followed up the patients and evaluated safety profile and effectiveness of adalimumab for the treatment of intestinal BD through 100 weeks rolled over from the 52 week clinical trial (NCT01243671). Methods: Patients initiated adalimumab therapy at 160 mg at week 0, followed by 80 mg at week 2, followed by 40 mg every other week until the end of the study. Long-term safety and all adverse events (AEs) were examined. The efficacy was assessed on the basis of marked improvement (MI) and complete remission (CR) using a composite efficacy index, which combined global gastrointestinal symptoms and endoscopic assessments. Re-sults: Twenty patients were enrolled in this study; 15 patients received adalimumab treatment until study completion. The incidence of AEs through week 100 was 544.4 events/100 person-years, which was comparable to the incidence through week 52 (560.4 events/100 person-years). No unexpected trend was observed and adalimumab was well tolerated. At weeks 52 and 100, 60.0% and 40.0% of patients showed MI, respectively, and 20.0% and 15.0% of patients showed CR, respectively. Conclusions: This report demonstrates 2 years safety and effectiveness of adalimumab in intestinal BD patients. Patients with intestinal BD refractory to conventional treatment receiving up to 2 years of adalimumab treatment demonstrated safety outcomes consistent with the known profile of adalimumab, and the treatment led to sustained reduction of clinical and endoscopic disease activity. (Intest Res 2017;15:395-401)

5-Aminosalicylic acid aggravates colitis mimicking exacerbation of ulcerative colitis

( Jun Miyoshi ),( Katsuyoshi Matsuoka ),( Atsushi Yoshida ),( Makoto Naganuma ),( Tadakazu Hisamatsu ),( Tomoharu Yajima ),( Nagamu Inoue ),( Susumu Okamoto ),( Yasushi Iwao ),( Haruhiko Ogata ),( Fum 대한장연구학회 2018 Intestinal Research Vol.16 No.4

Ulcerative colitis (UC) is one of the major clinical phenotypes of inflammatory bowel diseases. Although 5-aminosalicylic acid (5-ASA) is widely used for UC and its efficacy and safety have been demonstrated, a few patients paradoxically develop a severe exacerbation of colitis by 5-ASA administration. It is crucial to know clinical features including endoscopic findings in this condition for making a correct diagnosis and a prompt decision to withdraw the medication. Here, we report case series with UC exacerbated by 5-ASA. Medical records of 8 UC patients experiencing an exacerbation of colitis after induction of 5-ASA that was improved by the withdrawal of 5-ASA but also re-aggravated by dose increase or re-administration of 5-ASA were reviewed. The patients were newly diagnosed with UC, started 5-ASA and developed an exacerbation in approximately 2 to 3 weeks. They did not appear to have systemic allergic reactions. Seven of the 8 patients had a high fever. Three of 5 patients who undertook total colonoscopy showed right-side-dominant colitis. These findings suggest clinical characteristics in this condition. Further assessment of clinical and endoscopic features in more cases is necessary for establishing diagnostic criteria and understanding underlying mechanisms in those cases where 5-ASA aggravates the colitis. (Intest Res 2018;16:635-640)

5-Aminosalicylic acid intolerance is associated with a risk of adverse clinical outcomes and dysbiosis in patients with ulcerative colitis

( Shinta Mizuno ),( Keiko Ono ),( Yohei Mikami ),( Makoto Naganuma ),( Tomohiro Fukuda ),( Kazuhiro Minami ),( Tatsuhiro Masaoka ),( Soichiro Terada ),( Takeshi Yoshida ),( Keiichiro Saigusa ),( Norim 대한장연구학회 2020 Intestinal Research Vol.18 No.1

Background/Aims: 5-Aminosalicylic acid (ASA) causes intolerance reactions in some patients. This study was performed to examine the prognosis of patients with ulcerative colitis (UC) and 5-ASA intolerance, and to evaluate the potential interaction between 5-ASA intolerance and the intestinal microbiota. Methods: We performed a retrospective cohort study of patients with UC who visited participating hospitals. The primary endpoint was to compare the incidence of hospitalization within 12 months between the 5-ASA intolerance group and the 5-ASA tolerance group. The secondary endpoint was to compare the risk of adverse clinical outcomes after the start of biologics between the 2 groups. We also assessed the correlation between 5-ASA intolerance and microbial change in an independently recruited cohort of patients with UC. Results: Of 793 patients, 59 (7.4%) were assigned to the 5-ASA intolerance group and 734 (92.5%) were assigned to the 5-ASA tolerance group. The admission rate and incidence of corticosteroid use were significantly higher in the intolerance than tolerance group (P<0.001). In 108 patients undergoing treatment with anti-tumor necrosis factor biologics, 5-ASA intolerance increased the incidence of additional induction therapy after starting biologics (P<0.001). The 5-ASA intolerance group had a greater abundance of bacteria in the genera Faecalibacterium, Streptococcus, and Clostridium than the 5-ASA tolerance group (P<0.05). Conclusions: In patients with UC, 5-ASA intolerance is associated with a risk of adverse clinical outcomes and dysbiosis. Bacterial therapeutic optimization of 5-ASA administration may be important for improving the prognosis of patients with UC. (Intest Res 2020;18:69-78)

Effects of the Oral Administration of Mosapride Citrate on Capsule Endoscopy Completion Rate

( Yosuke Ida ),( Naoki Hosoe ),( Hiroyuki Imaeda ),( Rieko Bessho ),( Riko Ichikawa ),( Makoto Naganuma ),( Takanori Kanai ),( Toshifumi Hibi ),( Haruhiko Ogata ) 대한소화기학회 2012 Gut and Liver Vol.6 No.3

Background/Aims: In capsule endoscopy (CE), the capsule does not always reach the cecum within its battery life, which may reduce its diagnostic yield. We evaluated the effect of mosapride citrate, a 5-hydroxytryptamine-4 agonist that increases gastrointestinal motility, on CE completion. Meth-ods: In a retrospective study, we performed univariate and multivariate analyses for 232 CE procedures performed at our hospital. To identify factors that affect CE completion, the following data were systematically collected: gender, age, gastric transit time (GTT), nonsteroidal anti-inflammatory drug administration, previous abdominal surgery, hospitaliza-tion, use of a polyethylene glycol solution, use of mosapride citrate (10 mg), body mass index (BMI), and total recording time. Results: The univariate analysis showed that oral mo-sapride citrate, GTT, and BMI were associated with improved CE completion. Multivariate analyses showed that oral mo-sapride citrate (odds ratio [OR], 1.99; 95% confidence inter-val [CI], 1.01 to 3.91) and GTT (OR, 2.34; 95% CI, 1.13 to 4.87) were significant factors for improving the CE completion. Oral mosapride citrate significantly shortened the GTT and small bowel transit time (SBTT). Conclusions: Oral mosapride ci-trate reduced the GTT and SBTT during CE and improved the CE completion rate. (Gut Liver 2012;6:339-343)

Evaluation of a new method, “non-injection resection using bipolar soft coagulation mode (NIRBS)”, for colonic adenomatous lesions

Mitsuo Tokuhara,Masaaki Shimatani,Kazunari Tominaga,Hiroko Nakahira,Takuya Ohtsu,Katsuyasu Kouda,Makoto Naganuma 대한소화기내시경학회 2023 Clinical Endoscopy Vol.56 No.5

Background/Aims: Endoscopic resection of all colorectal adenomatous lesions with a low complication rate, simplicity, and negativeresiduals is challenging. Hence, we developed a new method called “non-injection resection using bipolar soft coagulation mode(NIRBS)” method, adapted for colorectal lesions. In addition, we evaluated the effectiveness of this method. Methods: We performed NIRBS throughout a 12-month period for all colorectal lesions which snare resection was acceptable withoutcancerous lesions infiltrating deeper than the submucosal layer. Results: A total of 746 resected lesions were included in the study, with a 4.5 mm mean size (range, 1–35 mm). The major pathologicalbreakdowns were as follows: 64.3% (480/746) were adenomas, and 5.0% (37/746) were intraepithelial adenocarcinomas (Tis lesions). Noresiduals were observed in any of the 37 Tis lesions (mean size, 15.3 mm). Adverse events included bleeding (0.4%) but no perforation. Conclusions: NIRBS allowed the resection of multiple lesions with simplicity because of the non-injection and without perforating dueto the minimal burn effect of the bipolar snare set in the soft coagulation mode. Therefore, NIRBS can be used to resect adenomatouslesions easily, including Tis lesions, from small to large lesions without leaving residuals.