Comparison of efficacy of once daily multimatrix mesalazine 2.4 g/day and 4.8 g/day with other 5-aminosalicylic acid preparation in active ulcerative colitis: a randomized, double-blind study

( Haruhiko Ogata ),( Tadashi Yokoyama ),( Seiichi Mizushima ),( Atsushi Hagino ),( Toshifumi Hibi ) 대한장연구학회 2018 Intestinal Research Vol.16 No.2

Background/Aims: This study compared the efficacy of multimatrix mesalazine 2.4 g/day and 4.8 g/day with controlled-release mesalazine 2.25 g/day. Methods: In this multicenter, randomized, double-blind study, 251 patients with mildly to moderately active ulcerative colitis received multimatrix mesalazine 2.4 g/day once daily (Multimatrix-2.4), 4.8 g/day once daily (Multimatrix-4.8), or controlled-release (time-dependent) mesalazine 2.25 g/day 3 times daily (Time-2.25) for 8 weeks. The primary efficacy endpoint was the change in the ulcerative colitis-disease activity index (UC-DAI) score. Results: The mean change in the UC-DAI score and standard deviation in the per protocol set was -1.9±2.5 for Multimatrix-2.4 and -2.4±2.8 for Time-2.25. The difference between Multimatrix-2.4 and Time-2.25 was 0.3 (two-sided 95% confidence interval [CI], -0.5 to 1.1), thus non-inferiority was not demonstrated based on the pre-defined non-inferiority margin (1.0). In the full analysis set, the difference between Multimatrix-4.8 and Time-2.25 was -1.2 (two-sided 95% CI, -2.0 to -0.5), and the mean change in UC-DAI score in the FAS was -3.3 (two-sided 95% CI, -3.9 to -2.8) for Multimatrix-4.8 and -1.9 (two-sided 95% CI, -2.5 to -1.3) for Multimatrix-2.4, indicating that Multimatrix-4.8 was more effective than Time-2.25 and Multimatrix-2.4. There was no difference among the treatment groups in terms of safety. Conclusions: This study showed that the efficacy of multimatrix mesalazine 2.4 g/day was comparable to controlled release mesalazine 2.25 g/day, although non-inferiority was not demonstrated. Importantly, this was the first study to indicate that multimatrix mesalazine 4.8 g/day was more effective than 2.4g/day with no associated safety concerns. (Intest Res 2018;16:255-266)

Safety and effectiveness of adalimumab in the treatment of ulcerative colitis: results from a large-scale, prospective, multicenter, observational study

( Haruhiko Ogata ),( Takashi Hagiwara ),( Takeshi Kawaberi ),( Mariko Kobayashi ),( Toshifumi Hibi ) 대한장연구학회 2021 Intestinal Research Vol.19 No.4

Background/Aims: Adalimumab has been shown to induce and maintain clinical remission in patients with moderate to se-vere ulcerative colitis (UC). However, no large-scale population-based studies have been performed in Japan. This study was conducted to evaluate the safety and effectiveness of adalimumab in clinical practice in Japanese patients with UC. Methods: In this 52-week, prospective, multicenter, single-cohort, noninterventional, observational, postmarketing surveillance study, patients with moderate to severe UC received an initial subcutaneous injection of adalimumab 160 mg, followed by 80 mg at 2 weeks, and then 40 mg every other week. Safety assessments were the incidence of adverse drug reactions (ADRs) and seri-ous ADRs. Effectiveness assessments were clinical remission, corticosteroid-free remission, mucosal healing, and change in C-reactive protein (CRP) levels from baseline. Results: Of 1,593 registered patients, 1,523 (male, 57.6%; mean age, 41.8 years) and 1,241 patients were included in the safety and effectiveness populations, respectively. ADRs were reported in 18.1% and serious ADRs in 4.9% of patients. Clinical remission was achieved in 49.7% of patients at week 4, increasing to 74.4% at week 52. Corticosteroid-free remission rates increased over time, from 10.4% at week 4 to 53.1% at week 52. More than 60% of patients demonstrated mucosal healing at weeks 24 and 52. Mean CRP levels (mg/dL) decreased from 1.2 at baseline to 0.6 at week 4 and 0.3 at week 52. Conclusions: This large real-world study confirmed the safety and effectiveness of adalimumab in patients with UC in Japan. No new safety concerns were identified. (Intest Res 2021;19:419-429)

Comparison of efficacy of multimatrix mesalazine 4.8 g/ day once-daily with other high-dose mesalazine in active ulcerative colitis: a randomized, double-blind study

( Haruhiko Ogata ),( Nobuo Aoyama ),( Seiichi Mizushima ),( Atsushi Hagino ),( Toshifumi Hibi ) 대한장연구학회 2017 Intestinal Research Vol.15 No.3

Background/Aims: This study assessed the efficacy and safety of high-dose multimatrix mesalazine once-daily (QD) compared to another form of high-dose mesalazine. Methods: In this multicenter, randomized, double-blind study, 280 patients with mildly to moderately active ulcerative colitis (UC) received multimatrix mesalazine 4.8 g/day QD or pH-dependentrelease mesalazine 3.6 g/day three times daily for 8 weeks. The primary endpoint was the change in the UC-Disease Activity Index (UC-DAI) at the end of the treatment period. Results: The change in the UC-DAI (mean±standard deviation) in the perprotocol set was -2.6±2.47 in the multimatrix mesalazine 4.8 g/day group (n=134) and -1.8±2.64 in the pH-dependent-release mesalazine 3.6 g/day group (n=129). The difference in the mean change between the 2 groups was -0.7 (two-sided 95% confidence interval, -1.3 to -0.1). The noninferiority of multimatrix mesalazine 4.8 g/day to pH-dependent-release mesalazine 3.6 g/ day was verified within the noninferiority margin (1.1). The superiority of multimatrix mesalazine 4.8 g/day to pH-dependentrelease mesalazine 3.6 g/day was also investigated and confirmed in the full analysis set, according to the study protocol. In subgroup analyses, the effectiveness of multimatrix mesalazine 4.8 g/day was consistent in all subgroups. There was no difference in safety between the 2 treatment groups. Conclusions: Multimatrix mesalazine 4.8 g/day has higher efficacy and shows no difference in safety in mildly to moderately active UC, in comparison with pH-dependent-release mesalazine 3.6 g/day. (Intest Res 2017;15:368-379)

Comparison of efficacies of once-daily dose multimatrix mesalazine and multiple-dose mesalazine for the maintenance of remission in ulcerative colitis: a randomized, double-blind study

( Haruhiko Ogata ),( Akihiro Ohori ),( Haruo Nishino ),( Seiichi Mizushima ),( Atsushi Hagino ),( Toshifumi Hibi ) 대한장연구학회 2017 Intestinal Research Vol.15 No.3

Background/Aims: This study compared the efficacy of once-daily administration of multimatrix mesalazine 2.4 g/day with multiple-dose mesalazine for the maintenance of remission. Methods: In this multicenter, randomized, double-blind study, 203 patients with ulcerative colitis in remission received multimatrix mesalazine 2.4 g/day once-daily or time-dependent (controlled- release) mesalazine 2.25 g/day 3 times-daily for 48 weeks. The primary efficacy endpoint was the proportion of patients without rectal bleeding. Results: The proportion of patients without rectal bleeding during the 48-week treatment period in the per protocol set was 84.8% (84/99) in the multimatrix mesalazine 2.4 g/day group and 78.0% (78/100) in the controlled-release mesalazine 2.25 g/day group. The difference between the 2 treatment groups was 6.8% (two-sided 95% confidence interval, -3.9% to 17.6%). The noninferiority margin of -10% was met in the comparison of multimatrix mesalazine 2.4 g/day once-daily with controlled-release mesalazine 2.25 g/day. Multimatrix mesalazine 2.4 g/day once-daily demonstrated consistent efficacy in all subgroups. There was no difference between the 2 treatment groups with regard to safety. Conclusions: A once-daily dose of 2 multimatrix mesalazine tablets (2.4 g) was not inferior to controlled-release mesalazine 2.25 g/day 3 times-daily in maintaining absence of rectal bleeding in ulcerative colitis. (Intest Res 2017;15:358-367)

Application and Efficacy of Super-Magnifying Endoscopy for the Lower Intestinal Tract

Naoki Hosoe,Haruhiko Ogata 대한소화기내시경학회 2016 Clinical Endoscopy Vol.49 No.1

Endoscopy plays a significant role in the diagnosis, management, and surveillance of colorectal cancer (CRC) and inflammatory bowel diseases (IBDs). Moreover, magnifying endoscopy and image-enhanced endoscopy has a crucial role in the clinical setting. Recently, a super-magnifying endoscope has been developed, and two devices, confocal laser endomicroscopy (CLE) and an endocytoscopy system (ECS), which allow in vivo microscopic inspection of the microstructural mucosal features of the gastrointestinal tract, are currently available. Studies on the use of ECS in CRC were reported by a Japanese group. Additionally, a few studies on the use of ECS in IBD have been reported. CLE has been shown to be reliable in assessing the activity of the disease in IBDs in both ulcerative colitis and Crohn’s disease. Various published studies evaluated the use of CLE during colonoscopy to distinguish colorectal polyp pathology and neoplasia. However, these studies are heterogeneous, and further evidence is necessary to confirm the efficacy of CLE.

Colon Capsule Endoscopy for Inflammatory Bowel Disease

Naoki Hosoe,Yukie Hayashi,Haruhiko Ogata 대한소화기내시경학회 2020 Clinical Endoscopy Vol.53 No.5

Colon capsule endoscopy was initially introduced in 2006. Since the results of a prospective study to evaluate first-generation coloncapsule endoscopy efficacy for the detection of colonic neoplasia were unsatisfactory, second-generation colon capsule endoscopywas developed and reported in 2009. In this review article, we provide an overview of the current state of colon capsule endoscopyfor evaluation of inflammatory bowel disease in a clinical setting and describe our clinical experience with this technology and itsapplication. Among the various types of inflammatory bowel diseases, ulcerative colitis is the primary target for application of coloncapsule endoscopy. Nevertheless, the initial results of studies using first-generation colon capsule endoscopy to evaluate inflammationwere unclear. More recently, second-generation colon capsule endoscopy has provided higher accuracy for assessment of inflammationin patients with ulcerative colitis. Colon capsule endoscopy enables noninvasive observation (with reduced volume preparation) ofmucosal inflammation severity in patients with ulcerative colitis.

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.

Predicting outcomes to optimize disease management in inflammatory bowel disease in Japan: their differences and similarities to Western countries

( Taku Kobayashi ),( Tadakazu Hisamatsu ),( Yasuo Suzuki ),( Haruhiko Ogata ),( Akira Andoh ),( Toshimitsu Araki ),( Ryota Hokari ),( Hideki Iijima ),( Hiroki Ikeuchi ),( Yoh Ishiguro ),( Shingo Kato 대한장연구학회 2018 Intestinal Research Vol.16 No.2

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease of the gastrointestinal tract, with increasing prevalence worldwide. IBD Ahead is an international educational program that aims to explore questions commonly raised by clinicians about various areas of IBD care and to consolidate available published evidence and expert opinion into a consensus for the optimization of IBD management. Given differences in the epidemiology, clinical and genetic characteristics, management, and prognosis of IBD between patients in Japan and the rest of the world, this statement was formulated as the result of literature reviews and discussions among Japanese experts as part of the IBD Ahead program to consolidate statements of factors for disease prognosis in IBD. Evidence levels were assigned to summary statements in the following categories: disease progression in CD and UC; surgery, hospitalization, intestinal failure, and permanent stoma in CD; acute severe UC; colectomy in UC; and colorectal carcinoma and dysplasia in IBD. The goal is that this statement can aid in the optimization of the treatment strategy for Japanese patients with IBD and help identify high-risk patients that require early intervention, to provide a better long-term prognosis in these patients. (Intest Res 2018;16:168-177)

Long-term safety and effectiveness of adalimumab in Japanese patients with Crohn’s disease: 3-year results from a real-world study

( Tadakazu Hisamatsu ),( Yasuo Suzuki ),( Mariko Kobayashi ),( Takashi Hagiwara ),( Takeshi Kawaberi ),( Haruhiko Ogata ),( Toshiyuki Matsui ),( Mamoru Watanabe ),( Toshifumi Hibi ) 대한장연구학회 2021 Intestinal Research Vol.19 No.4

Background/Aims: Crohn’s disease is a chronic disorder; therefore, it is essential to investigate long-term safety and efficacy of treatments. This study assessed the safety and effectiveness of adalimumab for up to 3 years in Japanese patients with Crohn’s disease in real-world settings. Methods: This was a multicenter, single-cohort, observational study of patients with Crohn’s disease. Safety assessments included incidence of adverse drug reactions. Effectiveness assessments included clinical remis-sion, mucosal healing, and Work Productivity and Activity Impairment (WPAI). Results: The safety and effectiveness analysis populations comprised 389 and 310 patients, respectively. Mean (standard deviation) exposure to adalimumab in the safety analysis population was 793.4 (402.8) days, with a 58.1% retention rate. A total of 105 patients (27.0%) and 43 patients (11.1%) experienced adverse drug reactions and serious adverse drug reactions, respectively, with no patient reporting tuberculosis or hepatitis B. Infections and serious infections were reported in 37 patients (9.5%) and 17 patients (4.4%), respectively. Malig-nancy was reported as an adverse drug reaction in 2 patients (0.5%). Remission rate increased from 37.8% (98/259) at baseline to 73.9% (167/226) at week 4 and remained >70% over 3 years. Proportion of patients without mucosal ulcerations increased from 2.7% (2/73) at baseline to 42.3% (11/26) between years >2 to ≤3. WPAI improvement started at 4 weeks, with the overall work impairment score improving from 42.7 (n=102) at baseline to 26.9 (n=84) at 4 weeks. Conclusions: Results from this study confirm the long-term safety and effectiveness of adalimumab treatment in Japanese patients with Crohn’s disease in the real-world setting. (Intest Res 2021;19:408-418)

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)