Masaki Iimuro

Scheduled infliximab monotherapy to prevent recurrence of Crohn's disease following ileocolic or ileal resection: A 3-year prospective randomized open trial

Background: Infliximab (IFX) is effective for remission induction and maintenance of Crohns disease (CD). This trial assessed the efficacy of scheduled maintenance IFX monotherapy to prevent postoperative CD recurrence. Methods: Thirty‐one CD patients who had ileocolic resection within the past 4 weeks were randomly assigned to scheduled IFX at 5 mg/kg intravenously every 8 weeks for 36 months (n = 15) or without IFX (control, n = 16). All patients were treated without immunomodulator or corticosteroid following surgery. The primary and secondary endpoints were remission rates at 12 and 36 months, defined as CD Activity Index (CDAI) ≤150, an International Organization for the Study of Inflammatory Bowel Disease (IOIBD) score <2, and C‐reactive protein (CRP) <0.3 mg/dL. Additionally, endoscopic recurrences at 12 and 36 months were evaluated. Results: At 12 and 36 months, 100%, and 93.3% of patients in the IFX group were in remission (IOIBD <2), respectively vs. 68.8% and 56.3% in the control arm (P < 0.03). Similarly, 86.7% and 86.7% of patients in the IFX group maintained serological remission (CRP <0.3 mg/dL) vs. 37.5% and 37.5% in the control arm (P < 0.02). Further, the IFX group achieved higher endoscopic remission at 12 months, 78.6% vs. 18.8% (P = 0.004). However, in the Kaplan–Meier survival analysis the CDAI scores between the two arms were not significantly different either at 12 or at 36 months. No adverse event (AE) was observed. Conclusions: An early intervention with IFX monotherapy should prevent clinical, serological, and endoscopic CD recurrence following ileocolic resection. Thiopurine naivety and eliminating the initial loading dose of IFX might minimize serious AEs. (Inflamm Bowel Dis 2012)

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).

Placebo controlled evaluation of Xilei San, a herbal preparation in patients with intractable ulcerative proctitis

Background and Aim:  Topical mesalamine or corticosteroid has shown efficacy in patients with ulcerative proctitis, but patients often become refractory to these interventions. Xilei San is a herbal preparation with evidence of anti‐inflammatory effects. We evaluated the efficacy of topical Xilei San in ulcerative proctitis patients.

The CD4+CD28null and the regulatory CD4+CD25High T-cell phenotypes in patients with ulcerative colitis during active and quiescent disease, and following colectomy

The CD4+CD25High T-cell phenotype has an essential immunoregulatory role, while the CD4+CD28null T-cell reflects immune pathology. We investigated the profiles of the CD4+CD25High and the CD4+CD28null T-cell phenotypes in patients with ulcerative colitis (UC) during active and quiescent phases as well as following colectomy. Fifty-nine UC patients, 34 active (UCa) and 25 quiescent (UCq) together with 19 healthy controls (HC) were included. Ten of 34 UCa patients underwent colectomy due to unremitting UC (UCo). Immunohistochemical phenotypic of the peripheral blood lymphocytes bearing CD4, CD25 or CD28 was done for analyzes by a multiparameter fluorescence activated cell sorting technique. The expression of the CD4+CD25High phenotype was higher in UCq (P<0.01) or UCo (P<0.01) group vs UCa group. Further, the expression of the CD4+CD28null phenotype in UCa or UCo group was higher than in the HC group (P<0.05). However, the expression of the CD4+CD28null phenotype up to 12 months after colectomy was not significantly different from the levels in the same patients during acute phase. Our impression is that a high CD4+CD25High T-cell reflects alleviation of inflammation, while the expression of the CD4+CD28null T-cell phenotype is an etiologic feature in UC patients, and is maintained after removing the affected colon.

Looking for predictive factors of clinical response to adsorptive granulocyte and monocyte apheresis in patients with ulcerative colitis: markers of response to GMA

BackgroundAdsorptive granulocyte and monocyte apheresis (GMA) with an Adacolumn in patients with ulcerative colitis (UC) has been applied as a non-pharmacological treatment strategy, but the efficacy has been encouraging as well as discouraging, depending on patients’ demography at entry. In this study, we looked for predictive factors for clinical response to GMA in patients with UC.MethodsIn a retrospective setting, 43 outpatients who had been treated with GMA for active UC were evaluated. Patients were divided into remission group and non-remission group based on Lichtiger’s clinical activity index (CAI) before and after 10, once a week GMA sessions. The efficacy was analysed in relation to patients’ demographic variables. To determine predictive factors that closely related to the response to GMA, receiver operating characteristic (ROC) curve, and multiple logistic regression analyses were applied.ResultsAfter 10 GMA sessions, the overall clinical remission rate (CAI < 4) was 53.5%. Multiple logistic regression and ROC analyses showed that the interval between relapse and the first GMA session was a significant and independent predictive factor for clinical response to GMA (P = 0.016); the clinical response was better in patients who received GMA immediately after a relapse and vice versa. Likewise, univariate analyses showed that, the duration of UC (P = 0.036) and the cumulative prednisolone (PSL) dose (P = 0.006) before the first GMA session were significantly greater in the GMA non-responder group as compared with the responder group. Additionally, a lower white blood cell (WBC) count at first GMA session was related to clinical response to GMA (P = 0.032).ConclusionsIn this study, patients with a short duration of UC and low cumulative PSL dose seemed to respond well to GMA. However, we found that the best responders were patients who received GMA immediately after a clinical relapse. Additionally, GMA was effective in patients with low WBC count at the first GMA session. The findings of this study should spare medical cost and reduce morbidity time for many patients, relevant for decision making in clinical settings.

Evaluation of discomfort during colonoscopy with conventional and ultrathin colonoscopes in ulcerative colitis patients

In patients with ulcerative colitis (UC), colonoscopy is an essential procedure for evaluating mucosal damage, and treatment outcomes. A new flexible ultrathin colonoscope (PCF‐PQ260) has been developed to readily pass through tortuous and narrow lesions of the colon and cause minimum patient discomfort. The objective of the present study was to evaluate the comfort and performance of this new type of scope in UC patients who underwent colonoscopy for estimation of mucosal inflammation, basically without sedation.

NUDT15, FTO, and RUNX1 genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases.

Background/Aims Recent genome-wide analyses have provided strong evidence concerning adverse events caused by thiopurine drugs such as azathioprine (AZA) and 6-mercaptopurine. The strong associations identified between NUDT15 p.Arg139Cys and thiopurine-induced leukopenia and severe hair loss have been studied and confirmed over the last 2 years. However, other coding variants, including NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, and FTO p.Ala134Thr, and a noncoding variation in RUNX1 (rs2834826) remain to be examined in detail in this respect. Therefore, we investigated the correlation between these adverse events and the 5 recently identified variants mentioned above among Japanese patients with inflammatory bowel diseases (IBD). Methods One hundred sixty thiopurine-treated patients with IBD were enrolled. Genotyping was performed using TaqMan SNP Genotyping Assays or Sanger sequencing. Results None of the 5 variants were associated with gastrointestinal intolerance to AZA. However, NUDT15 p.Arg139Cys was significantly associated with the interval between initiation and discontinuation of AZA among patients with gastrointestinal intolerance. This variant was strongly associated with early (<8 weeks) and late (≥8 weeks) leukopenia and severe hair loss. Moreover, it correlated with the interval between initiation of thiopurine therapy and leukopenia occurrence, and average thiopurine dose. NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, FTO p.Ala134Thr, and RUNX1 rs2834826 exhibited no significant relationship with the adverse events examined. Conclusions Of the 5 variants investigated, NUDT15 p.Arg139Cys had the strongest impact on thiopurine-induced leukopenia and severe hair loss; therefore, its genotyping should be prioritized over that of other variants in efforts to predict these adverse events in Japanese patients with IBD.

Cytapheresis in Patients with Severe Ulcerative Colitis after Failure of Intravenous Corticosteroid: A Long-Term Retrospective Cohort Study

BACKGROUND/AIMS Cytapheresis (CAP) is a novel strategy for ulcerative colitis (UC). However, there is insufficient data on the long-term outcome of UC patients who achieve remission by CAP. This study involved patients with severe UC who refracted to intravenous (iv) corticosteroid. METHODS Forty-seven UC patients who had received CAP therapy for the first time within 1 year after UC diagnosis were followed for 36 months. One of the inclusion criteria was a clinical activity index (CAI) of >/=7 points at the end of a 2-week iv course of corticosteroid therapy. CAP therapy consisted of ten sessions over 10 weeks. RESULTS CAP induced clinical remission (CAI</=4) in 70.2% patients (33/47). The number of submissions for colectomy was higher for severe UC at entry (CAI>/=12, n=25) than for moderately severe UC at entry (7</=CAI<12, p=15; p<0.02). The cumulative rates of avoiding surgery and relapse were 54.5% and 24.2%, respectively, at 36 months in patients who responded to CAP therapy. This was similar to that of iv cyclosporine reported recently. CONCLUSIONS This study suggest that CAP is an effective therapy in patients who are refractory to conventional medications including iv corticosteroid. Increased remission rates should be expected in refractory patients with moderately severe UC.

Optimal apheresis treatment volume for the efficacy and safety of leukocytapheresis with Cellsorba in patients with active ulcerative colitis.

Background: Leukocytapheresis (LCAP) is used as an adjunct therapy for patients with active ulcerative colitis (UC). Although, LCAP is routinely performed at 3,000 mL per session, we were interested to see that if this can be replaced with bodyweight (BW) adjusted volume. Methods: In an open label prospective trial, the clinical response to BW adjusted LCAP (BWA‐LCAP) was evaluated in 14 patients with active UC. Fourteen demography matched UC patients who had been treated with the routine 3,000 mL LCAP were randomly sampled from our database as a control group. All patients were given 10 weekly LCAP sessions. In the BWA‐LCAP group, the processed blood volume (PBV) was set at 30 mL/kg × BW/session. Baseline demographic measures were not significantly different between the two groups. Results: The average PBV in the BWA‐LCAP group was 1971.0 ± 330.0 mL, range 1,020–2,460. In both groups, the average UC clinical disease activity index, the endoscopic index, and the concomitant prednisolone dosage were significantly and equally reduced during the course of 10 LCAP. Accordingly, at the end of the trial, no significant difference was seen in any outcome measure between the two groups. However, a significantly higher incidence of adverse event (AE) was observed in the routine 3,000 mL LCAP group as compared with the BWA‐LCAP group (P < 0.01). Conclusions: The outcomes of this investigation showed that the therapeutic efficacy of LCAP based on 30 mL/kg × BW is similar to the routine 3,000 mL per session LCAP. However, BWA‐LCAP should be favored if one is to see the full potential of LCAP without AE.

Does discontinuation of antithrombotics affect the diagnostic yield of small bowel capsule endoscopy in patients demonstrating obscure gastrointestinal bleeding

A large proportion of patients demonstrating obscure gastrointestinal bleeding (OGIB) are antithrombotic users and need to undergo small bowel capsule endoscopy (SBCE). We examined the effect of discontinuation of antithrombotics on the diagnostic yield of SBCE. Additionally, we assessed predictive factors associated with positive SBCE findings. Our study included 130 patients using antithrombotics who underwent SBCE for overt OGIB. The primary endpoint was the difference in the rate of positive SBCE findings between patients who continued and those who discontinued antithrombotics. Secondary endpoints were to investigate the effect of discontinuation of antithrombotics using a propensity score analysis, and to assess predictive factors associated with a positive SBCE. Among the 73 patients who continued use of antithrombotics, 36 (49.3%) patients demonstrated positive findings, while among the 57 patients who discontinued antithrombotics, 35 (61.4%) patients showed positive findings. Rates of positive SBCE findings didn’t differ between the two groups. After we performed propensity score matching, discontinuation didn’t affect the rate of positive SBCE findings. The lowest hemoglobin level was the only independent predictive factor associated with positive SBCE findings. In conclusion, discontinuation of antithrombotic therapy didn’t affect the diagnostic yield of SBCE in patients presenting with overt OGIB.