FOCUSED REVIEW: INFECTION AND IBD : Diagnosis and Treatment of Ulcerative Colitis with Cytomegalovirus Infection: Importance of Controlling Mucosal Inflammation to Prevent Cytomegalovirus Reactivation

( Hiroshi Nakase ),( Yusuke Honzawa ),( Takahiko Toyonaga ),( Satoshi Yamada ),( Naoki Minami ),( Takuya Yoshino ),( Minoru Matsuura ) 대한장연구학회 2014 Intestinal Research Vol.12 No.1

Human cytomegalovirus (HCMV) is a member of the herpesvirus family. HCMV infection persists throughout the host lifespan in a latent state following primary infection. The ability of HCMV to escape control by the host immune system and its resulting reactivation suggests the importance of ongoing immune surveillance in the prevention of HCMV reactivation. HCMV is a common cause of opportunistic infection that causes severe and fatal disease in immune-compromised individuals. In inflammatory bowel disease patients, particularly those with ulcerative colitis (UC), HCMV is often reactivated because these patients are frequently treated with immunosuppressive agents. This reactivation exacerbates colitis. Additionally, HCMV infection can induce severe colitis, even in patients with UC who have never been treated with immunosuppressive agents. However, the role of HCMV in colonic inflammation in patients with UC remains unclear. Here, we present previous and current clinical data on the diagnosis and treatment of HCMV infection in UC. Additionally, our experimental data from a newly established mouse model mimicking UC with concomitant CMV infection clearly demonstrate that inflammation could result in the exacerbation of UC disease activity with induction of HCMV reactivation. In summary, optimal control of colonic inflammation should be achieved in UC patients who are refractory to conventional immunosuppressive therapies and are positive for HCMV. (Intest Res 2014;12:5-11)

Individualized treatment based on CYP3A5 single-nucleotide polymorphisms with tacrolimus in ulcerative colitis

Shinji Okabayashi,Taku Kobayashi,Eiko Saito,Takahiko Toyonaga,Ryo Ozaki,Shintaro Sagami,Masaru Nakano,Junichi Tanaka,Keiji Yagisawa,Satoshi Kuronuma,Osamu Takeuchi,Toshifumi Hibi 대한장연구학회 2019 Intestinal Research Vol.17 No.2

Background/Aims: The pharmacokinetics of tacrolimus (TAC) is known to be largely influenced by single-nucleotide polymorphisms (SNPs) in CYP3A5. Patients starting TAC require careful dose adjustment, owing to the wide range of optimal dosages, depending on their CYP3A5 expression status. Here, we evaluated whether individualization of TAC dosages based on CYP3A5 SNPs would improve its therapeutic efficacy in ulcerative colitis. Methods: Twenty-one patients were prospectively treated, with their initial dosage adjusted according to their CYP3A5 status (0.1, 0.15, and 0.2 mg/kg/day for CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1, respectively). Their clinical outcomes were compared with those of patients treated with a fixed dose (0.1 mg/kg/day). Results: The first blood trough level of CYP3A5 expressors, CYP3A5*1/*3 or CYP3A5*1/*1, and the overall rate in achieving the target blood trough level within a week in the individualized-dose group were significantly higher than those in the fixed-dose group (5.15±2.33 ng/mL vs. 9.63±0.79 ng/mL, P=0.035 and 12.5% vs. 66.7%, P=0.01). The remission rate at 2 weeks in the expressors was as high as that in the nonexpressors, CYP3A5*3/*3, in the individualized-dose group. Conclusions: Individualized TAC treatment is effective against ulcerative colitis regardless of the CYP3A5 genotype. (Intest Res 2019;17:218-226)

Efficacy and Safety of Long-Term Thiopurine Maintenance Treatment in Japanese Patients With Ulcerative Colitis

( Satoshi Yamada ),( Takuya Yoshino ),( Minoru Matsuura ),( Masamichi Kimura ),( Yorimitsu Koshikawa ),( Naoki Minami ),( Takahiko Toyonaga ),( Yusuke Honzawa ),( Hiroshi Nakase ) 대한장연구학회 2015 Intestinal Research Vol.13 No.3

Background/Aims: The long-term clinical outcomes of patients with bio-naive ulcerative colitis (UC) who maintain remission with thiopurine are unclear. The aim of this study was to assess the long-term efficacy and safety of maintenance treatment with thiopurine in UC patients. Methods: This was a retrospective observational cohort analysis conducted at a single center. Between December 1998 and August 2013, 59 of 87 patients with bio-naive UC who achieved remission after induction with treatments other than biologics were enrolled. Remission maintenance with thiopurine was defined as no concomitant treatment needed other than 5-aminosalicylate without relapse. We assessed the remissionmaintenance rate, mucosal healing rate, colectomy-free rate, and treatment safety in UC patients who received thiopurineas maintenance treatment. Results: The 84-month cumulative remission-maintenance and colectomy-free survival rates in the UC patients who were receiving maintenance treatment with thiopurine and 5-aminosalicylate were 43.9% and 88.0%, respectively. Of the 38 patients who underwent colonoscopy during thiopurine maintenance treatment, 23 (60.5%) achieved mucosal healing. Of the 59 patients who achieved clinical remission with thiopurine, 6 patients (10.2%) discontinued the thiopurine therapy because of adverse events. Conclusions: Our study demonstrates the long-term efficacy and safety of thiopurine treatment in patients with bio-naive UC. (Intest Res 2015;13:250-258)

Steroid-refractory extensive enteritis complicated by ulcerative colitis successfully treated with adalimumab

( Shinji Okabayashi ),( Taku Kobayashi ),( Tomohisa Sujino ),( Ryo Ozaki ),( Satoko Umeda ),( Takahiko Toyonaga ),( Eiko Saito ),( Masaru Nakano ),( Maria Carla Tablante ),( Shojiroh Morinaga ),( Tosh 대한장연구학회 2017 Intestinal Research Vol.15 No.4

Extracolonic involvement of the gastrointestinal tract is extremely uncommon in ulcerative colitis (UC) and rarely found in the upper gastrointestinal tract or in postoperative cases since it typically responds to steroids. Here we report a case of UC complicated by extensive ileal inflammation that was refractory to steroids. A 20-year-old man was diagnosed with UC of typical pancolitis without ileal involvement and started treatment with pH-dependent mesalazine and oral prednisolone. Although his symptoms transiently resolved, the condition flared when the steroid dose was tapered down. Computed tomography revealed marked thickening of the ileal wall, and capsule endoscopy and balloon-assisted enteroscopy found diffuse mucosal inflammation with ulcers in the ileum. On the contrary, the inflammation in the colon and rectum was improving. Since the response to the second steroid course was inadequate, treatment with adalimumab and 6-mercaptopurine was initiated and finally achieved clinical and endoscopic remission. The investigation of small intestinal lesions is necessary in patients with UC whose clinical deterioration cannot be explained by colonic lesions. (Intest Res 2017;15:535-539)

Randomized, crossover questionnaire survey of acceptabilities of controlled-release mesalazine tablets and granules in ulcerative colitis patients

Keiji Yagisawa,Taku Kobayashi,Ryo Ozaki,Shinji Okabayashi,Takahiko Toyonaga,Miki Miura,Mari Hayashida,Eiko Saito,Masaru Nakano,Hajime Matsubara,Tadakazu Hisamatsu,Toshifumi Hibi 대한장연구학회 2019 Intestinal Research Vol.17 No.1

Background/Aims: Oral mesalazine is an important treatment for ulcerative colitis (UC), and non-adherence to mesalazineincreases the risk of relapse. Controlled-release (CR) mesalazine has 2 formulations: tablets and granules. The relative acceptabilitiesof these formulations may influence patient adherence; however, they have not been compared to date. This studyaimed to evaluate the acceptabilities of the 2 formulations of CR mesalazine in relation to patient adherence using a crossoverquestionnaire survey. Methods: UC patients were randomly assigned to 2 groups in a 1:1 ratio. Patients in each group tookeither 4 g of CR mesalazine tablets or granules for 6 to 9 weeks, and then switched to 4 g of the other formulation for a further 6to 9 weeks. The acceptability and efficacy were evaluated by questionnaires, and adherence was assessed using a visual analogscale. The difference in acceptabilities between the 2 formulations and its impact on adherence were assessed. Results: A totalof 49 patients were prospectively enrolled and 33 patients were included in the analysis. Significantly more patients found thetablets to be less acceptable than the granules (76% vs. 33%, P=0.0005). The granules were preferable to the tablets when the 2formulations were compared directly (73% vs. 21%, P=0.004), for their portability, size, and numbers of pills. The adherence ratewas slightly better among patients taking the granules (94% vs. 91%) during the observation period, but the difference was notsignificant (P=0.139). Conclusion: CR mesalazine granules are more acceptable than tablets, and may therefore be a better optionfor long-term medication. (Intest Res 2019;17:87-93)

Efficacy of Thiopurines in Biologic-Naive Japanese Patients With Crohn`s Disease: A Single-Center Experience

( Takuya Yoshino ),( Minoru Matsuura ),( Naoki Minami ),( Satoshi Yamada ),( Yusuke Honzawa ),( Masamichi Kimura ),( Yorimitsu Koshikawa ),( Ali Madian ),( Takahiko Toyonaga ),( Hiroshi Nakase ) 대한장연구학회 2015 Intestinal Research Vol.13 No.3

Background/Aims: Early use of biologics in patients with Crohn`s disease (CD) improves quality of life. However, the effects of the early use of immunomodulators on long-term outcomes remain unclear. This study aimed to evaluate the effects of immunomodulatorsin patients with CD. Methods: Between January 2004 and December 2011, 47 biologic-naive CD patients treated with thiopurines alone for remission maintenance were analyzed. The patients were classified into 2 groups depending on the presence or absence of digestive complications. We evaluated the efficacy of and predictive factors for thiopurine use for remission maintenance. Results: The cumulative relapse rates at 24 and 60 months were 13.7% and 35.4%, respectively. Regarding patient characteristics, there was a significant difference in patient history of surgery between the non-relapse and relapse groups (P =0.021). The cumulative relapse rate was lower in patients without a history of surgery than in those with such a history (27.2% and 52.9% at 60.0 months, respectively). Multivariate analysis suggested that the prevalence of stricturing and penetrating complications is an independent factor for relapse. The cumulative relapse rate in patients without a history ofsurgery was significantly lower in the non-stricturing and non-penetrating group than in the stricturing and penetrating group (11.8% at 85.0 months vs. 58.5% at 69.0 months; P =0.036). Conclusions: Thiopurine use might be beneficial for the long-term maintenance of remission in biologic-naive Crohn`s disease patients without digestive complications and a history of surgery. (Intest Res 2015;13:266-273)