[show abstract][hide abstract] ABSTRACT: Despite numerous studies, the best postoperative therapy for Crohn's disease is still undefined. We retrospectively evaluated the effects of postoperative maintenance therapy with daikenchuto, a traditional Japanese Kampo medicine, on the reoperation rate at 3 years in patients with Crohn's disease.
A total of 258 patients who underwent surgery for Crohn's disease were identified for the study. For the prevention of postoperative recurrence, patients were stratified to receive 5-aminosalicylic acid, azathioprine or daikenchuto, and their effects on preventing reoperation at 3 years were evaluated.
Of the 258 patients, 44 required reoperation with intestinal resection within 3 years due to disease recurrence. The 3-year reoperation rate was significantly lower in the postoperative daikenchuto group than in the non-daikenchuto group (11.3 vs. 24.5 %, P = 0.01), and was similarly significantly lower in the postoperative 5-aminosalicylic acid group than in the non-5-aminosalicylic acid group (14.8 vs. 29.6 %, P = 0.0049). A multivariate Cox analysis showed that postoperative daikenchuto (P = 0.035) and postoperative 5-aminosalicylic acid (P = 0.022) were significantly and independently associated with the rate of reoperation at 3 years in patients with Crohn's disease.
We propose that continuous daikenchuto therapy is a clinically useful and feasible maintenance therapy for the prevention of postoperative reoperation in patients with Crohn's disease.
[show abstract][hide abstract] ABSTRACT: There are substantial differences in inflammatory bowel disease (IBD) genetics depending on the populations examined. We aimed to identify Japanese population-specific or true culprit susceptibility genes through a meta-analysis of past genetic studies of Japanese IBD.
For this study, we reviewed 2,703 articles. The review process consisted of three screening stages: we initially searched for relevant studies and then relevant single nucleotide polymorphisms (SNPs). Finally, we adjusted them for the meta-analysis. To maximize our chances of analysis, we introduced proxy SNPs during the first stage. To minimize publication bias, no significant SNPs and solitary SNPs without pairs were combined to be reconsidered during the third stage. Additionally, two SNPs were newly genotyped. Finally, we conducted a meta-analysis of 37 published studies in 50 SNPs located at 22 loci corresponding to the total number of 4,853 Crohn's disease (CD), 5,612 ulcerative colitis (UC) patients, and 14,239 healthy controls.
We confirmed that the NKX2-3 polymorphism is associated with common susceptibility to IBD and that HLA-DRB1*0450 alleles increase susceptibility to CD but reduce risk for UC while HLA-DRB1*1502 alleles increase susceptibility to UC but reduce CD risk. Moreover, we found individual disease risk loci: TNFSF15 and TNFα to CD and HLA-B*5201, and NFKBIL1 to UC. The genetic risk of HLA was substantially high (odds ratios ranged from 1.54 to 2.69) while that of common susceptibility loci to IBD was modest (odds ratio ranged from 1.13 to 1.24).
Results indicate that Japanese IBD susceptibility loci identified by the meta-analysis are closely associated with the HLA regions.
Journal of Gastroenterology 08/2013; · 3.79 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: The ability of serum infliximab level to predict clinical outcome in infliximab therapy in Crohn's disease is unclear. Here, we aimed to clarify the correlation between the timing of loss of response (LOR) to treatment and a decrease in serum infliximab level, and, in addition, to identify an indicator of infliximab level. METHODS: The study used data from a previous clinical study of infliximab for Crohn's disease, in which infliximab was initially given at 0, 2, 6 weeks at 5 mg/kg, and then at 8-week intervals to 62 week-10 responders. Of these 62, here we analysed data from 57 in whom Crohn's disease activity index and serum infliximab level were evaluated at week 14. RESULTS: Twelve patients showed a clinical response despite an infliximab level <1 μg/mL at week 14; of these, 8 (67 %) experienced LOR by week 54. A decrease in infliximab level preceded LOR in 6 (75 %). In receiver operating characteristic curve analysis, C-reactive protein (CRP) showed better performance in detecting an infliximab level <1 μg/mL. Infliximab level was <1 μg/mL in 60-80 % of patients with CRP >0.5 mg/dL. Time to LOR (median: 22.0 weeks) was significantly longer than that to a decrease in infliximab level to <1 μg/mL (14.0 weeks, p < 0.05) or to an increase in CRP to >0.5 mg/dL (14.0 weeks, p < 0.01). CONCLUSIONS: A decrease in serum infliximab level preceded LOR, and was easily detected by an increase in CRP. The CRP may be an indicator of serum infliximab level in predicting LOR.
Journal of Gastroenterology 04/2013; · 3.79 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND:: A large-scale meta-analysis of a series of European genome-wide association studies revealed 71 susceptibility loci for Crohn's disease (CD). However, it is not clear whether these susceptibility loci are also shared with Japanese populations. METHODS:: We genotyped 71 single-nucleotide polymorphisms (SNPs) comprising 1311 CD cases and 6585 controls of Japanese descent, and their associations with CD were evaluated using the Cochran-Armitage trend test. In addition, genotype-phenotype analyses were conducted on the SNPs showing associations with Japanese CD based on the Montreal classification. RESULTS:: Twenty-seven SNPs showed at least nominal association (P < 0.05) and 11 of them remained significant even after Bonferroni correction (P < 0.0007). Despite high statistical power, we could not find any association in 17 loci. Moreover, SNPs in 9 loci were rare or absent in the Japanese population. Genetic variations involved in the innate immune system (NOD2, ATG16L1, and IRGM) showed no association with CD susceptibility in the Japanese population. Genotype-phenotype analyses showed that rs3810936, a marker of TNFSF15, correlated with severe CD phenotypes. CONCLUSIONS:: Our study suggests that there is a differential genetic background of CD susceptibility between Japanese and European populations.
[show abstract][hide abstract] ABSTRACT: INTRODUCTION: A liver abscess in Crohn's disease is a rare but important entity that is associated with a poor prognosis and high mortality when treatment is delayed. We report a case of successful liver segmentectomy for a methicillin-resistant Staphylococcus aureus liver abscess in a patient with Crohn's disease under infliximab treatment. CASE PRESENTATION: A 31-year-old Japanese man, who had been treated with infliximab infusions for Crohn's disease, was referred to our hospital presenting with an abrupt onset of high fever and an elevated white blood cell count and serum C-reactive protein level. Computed tomography revealed a liver abscess occupying segment 8. The limited effect of percutaneous transhepatic abscess drainage and antibiotics led us to perform radical resection of the abscess. The patient recovered quickly after surgery and the postoperative course was uneventful. CONCLUSION: The present case suggests that surgical removal of an abscess should be considered for patients under immunosuppression or refractory to conventional treatment.
[show abstract][hide abstract] ABSTRACT: BACKGROUND & AIMS: Crohn's disease is an inflammatory bowel disease induced by multiple genetic and environmental factors. Genome-wide association studies have identified genetic factors that affect risk for Crohn's disease in European populations, but information from other ethnic groups is scarce. We therefore investigated genetic factors associated with Crohn's disease in the Japanese population. METHODS: We performed a genome-wide association study with 372 individuals with Crohn's disease (cases) and 3389 controls, all from the Japanese population. To confirm identified associations, we performed a replication study with an independent panel of 1151 Crohn's disease cases and 15,800 controls. We also performed an association analysis using genome-wide genotype imputation in the discovery cohort. RESULTS: We confirmed associations of Crohn's disease with variants inMHC (rs7765379,P = 2.11 x 10(-59)),TNFSF15 (rs6478106,P = 3.87 x 10(-45)), andSTAT3 (rs9891119,P = 2.24 x 10(-14)). We identified 2 new susceptibility loci, on chromosome 4p14 (rs1487630,P = 2.40 x 10(-11), odds ratio = 1.33) and in theSLC25A15-ELF1-WBP4region on 13q14 (rs7329174 in ELF1,P = 5.12 x 10(-9), odds ratio = 1.27). CONCLUSIONS: In a genome-wide association study, we identified 2 new susceptibility loci for Crohn's disease in a Japanese population. These findings could increase our understanding of the pathogenesis of Crohn's disease.
[show abstract][hide abstract] ABSTRACT: BACKGROUND: In 2009, influenza A (H1N1) infections spread worldwide. Because the use of immunomodulators is associated with an increased risk of infection, inflammatory bowel disease (IBD) patients who are on immunomodulators might be concerned about H1N1 influenza infections. The aim of this study was to investigate the age distribution and risk factors associated with H1N1 influenza of IBD patients in 2009-2010. METHODS: A multicenter, prospective study was conducted, and 570 IBD patients were enrolled. Patients were followed up for 10months to identify any new infections. The incidence and age distribution of the H1N1 influenza infections were analyzed. IBD patients with H1N1 influenza infections and 2 matched, noninfected IBD patients were selected to assess the effect of specifying the medication on the incidence of infections. RESULTS: A total of 38 patients (6.7%) developed H1N1 influenza infections. The incidence of H1N1 influenza infections in patients aged less than 20years was significantly higher than that among patients in other age groups (p<0.01). The age distribution for H1N1 influenza infections in IBD patients was comparable to those in the general population. No patients needed hospitalization due to influenza infection. A total of 29 patients (76%) recovered from the H1N1 influenza symptoms within 7days and 20 patients (53%) received antiviral treatment. The percentage of patients who used steroids or thiopurine was comparable between the cases of H1N1 influenza infection and the control group. CONCLUSION: Our prospective study showed that younger IBD patients were frequently infected with the influenza A (H1N1) virus as well as general population. Admission and fatal cases due to H1N1 influenza infections were not observed.
Journal of Crohn s and Colitis 07/2012; · 3.39 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND AND AIMS: Current treatments for Japanese patients with active Crohn's disease have not proved optimal, and new treatment options are required. The present study therefore evaluated the efficacy and tolerability of oral budesonide in Japanese patients with mild-to-moderate active Crohn's disease. METHODS: In this multicentre, double-blind, randomized, parallel-group, Phase II study, patients (18-65years) with baseline Crohn's Disease Activity Index (CDAI) score≥200 were randomized to once-daily (od) oral budesonide 9mg or 15mg, or matching placebo, for 8weeks. Concomitant therapy with sulfasalazine or 5-aminosalicylic acid, and nutritional therapy, was allowed. The rate of remission (defined as CDAI score≤150) after 8weeks' treatment (primary variable), health-related quality of life (assessed using the Inflammatory Bowel Disease Questionnaire [IBDQ]), and tolerability were assessed. RESULTS: 77 patients were randomized and 63 completed the study. The proportion of budesonide-treated patients with remission after 8weeks' treatment was higher compared with placebo (23.1%, 28.0%, and 11.5% for budesonide 9mg, 15mg, and placebo, respectively; no significant difference). The mean change from baseline to week 8 in CDAI total score (-48.0, -58.2, and -27.2, respectively) and IBDQ total score (10.8, 23.2, and 6.5, respectively) was greater for budesonide-treated patients than placebo recipients. While budesonide 9mg and 15mg demonstrated similar efficacy, budesonide 9mg caused fewer drug- and glucocorticosteroid-related adverse events and less adrenal suppression. CONCLUSIONS: Oral budesonide 9mg od (for up to 8weeks) may offer a new treatment option for Japanese patients with mild-to-moderate active Crohn's disease.
Journal of Crohn s and Colitis 07/2012; · 3.39 Impact Factor
[show abstract][hide abstract] ABSTRACT: Infliximab has shown beneficial effects in the treatment of Crohn's disease (CD). The aim of this study was to assess 1) the clinical efficacy of shortening the infusion interval from 8 to 4 weeks when patients had shown loss of response during maintenance therapy, and 2) the association between the serum trough level and clinical efficacy.
This was an open-label prospective multicenter study. Infliximab was administered at 5 mg/kg to patients with active CD at weeks 0, 2, and 6. Week 10 responders received infliximab every 8 weeks thereafter. In those with loss of response after week 14 the interval was switched to every 4 weeks. Co-primary endpoints were the rate of patients achieving clinical response and remission at week 54. Serum level of infliximab was measured at each visit.
Fifty-seven patients who responded to induction treatment received maintenance therapy after week 14. Thirty-seven patients continued at the 8-week interval and 20 patients were switched to a 4-week interval. The overall clinical response and remission rates at week 54 were 82.5% and 61.4%, respectively. For those with loss of response, treatment at the 4-week interval resulted in clinical response and remission rates of 83.3% (15/18) and 55.6% (10/18), respectively, at week 54. A correlation between clinical efficacy and serum trough level was found (P < 0.01, overall).
A treatment strategy with an option of shortening the dosing interval of infliximab retrieves its trough level and may be useful for maintaining its efficacy.
[show abstract][hide abstract] ABSTRACT: Hitherto, therapeutic depletion of granulocytes and monocytes by adsorption (GMA) has been associated with significant and insignificant efficacy in patients with ulcerative colitis (UC). Further, the processed blood volume in one GMA session has been fixed at 30 mL/min × 60 min, regardless of patients' body weight (BW). We were interested to see the efficacy and safety of GMA when administered in relation to patients' BW.
Sixty patients were randomly assigned to the routine GMA (n = 30) and to GMA adjusted to patients' BW, 60 mL/kg (n = 30). GMA was done with the Adacolumn, up to 10 sessions over 10 weeks. At entry and 1 week post last GMA, patients were clinically and endoscopically evaluated. Remission was defined as clinical activity index (CAI) ≤4, whereas mucosal remission was defined as endoscopic index (EI) ≤3.
In the BW group, the processed volume/session was 3,260 ± 581 versus 1,800 mL in the routine group (P < 0.001). In the BW group, 25 of 30 patients (83.3%) achieved remission versus 19 of 30 patients (63.3%) in the routine group. The average CAI in the BW group fell from 9.6 ± 2.6 to 2.3 ± 2.1 versus from 9.1 ± 2.4 to 4.0 ± 2.1 (P < 0.05) in the routine group. Similarly, the EI in the BW group fell from 9.4 ± 1.3 to 2.1 ± 2.1 versus from 9.2 ± 1.8 to 4.5 ± 2.3 (P < 0.01).
GMA adjusted to patients' BW and at a vastly greater processed volume produces significantly higher efficacy as compared with the routine GMA protocol. Further, in this study, up to twofold higher processed volume caused no safety concern.
Journal of Gastroenterology 09/2011; 47(1):49-55. · 3.79 Impact Factor
[show abstract][hide abstract] ABSTRACT: Neither conceptions and pregnancy outcomes nor the safety of medications for childbearing inflammatory bowel disease (IBD) patients has been investigated in Asia. The aim of this study is to analyse conception and pregnancy outcomes of Japanese female IBD patients.
We conducted a retrospective cohort study of pregnant IBD patients at 6 institutions. The incidences of abortion, Caesarean delivery, low birth weight (LBW) (<2500g), and congenital malformation were analysed in these patients. Risk factors associated with adverse outcomes in IBD patients were also assessed.
A total of 325 patients experienced 534 conceptions. Among these, 303 conceptions (57%) were observed during/after disease onset. Although conceptions and pregnancy outcomes after disease onset were comparable to the observed levels prior to disease onset in UC patients, the incidences of spontaneous abortion (OR 5.3; 95%CI 1.1-25.0) and Caesarean delivery (OR 4.8; 95%CI 1.5-15.0) were significantly higher in Crohn's disease (CD) patients whose conceptions occurred after disease onset compared to CD patients whose conceptions occurred before disease onset. The incidences of spontaneous abortion, LBW, and Caesarean delivery were higher in CD patients who had a history of surgery for perianal lesions than in those who did not have perianal lesions or who had ulcerative colitis (UC). In the IBD patients studied after disease onset, independent risk factors for spontaneous abortions included a history of previous treatment for sterility (OR 2.9; 95%CI 1.2-7.0). Independent risk factors for Caesarean operation (OR 4.1, 95% CI: 1.7-10.1) and LBW (OR 3.5, 95% CI: 1.3-9.1) included a history of bowel resection for the treatment of IBD. Congenital malformation was not associated with the factors of type of disease, smoking, and previous surgery.
In Japanese UC patients, conception and pregnancy outcomes after disease onset were comparable to the outcomes observed prior to disease onset, whereas CD appeared to be associated with adverse outcomes. Caesarean operation and LBW were more frequently observed in CD patients who had a history of surgery for perianal lesions and bowel resection.
Journal of Crohn s and Colitis 09/2011; 5(4):317-23. · 3.39 Impact Factor
[show abstract][hide abstract] ABSTRACT: There are many genetic factors that are associated with both ulcerative colitis (UC) and Crohn's disease (CD). However, genetic factors that have distinct effects on UC and CD have not been examined.
We performed a comparative genome-wide association study (GWAS) and a replication study using data from 748 patients with UC and 979 with CD, selected from a Japanese population. We conducted high-resolution (4-digit) genotyping of human leukocyte antigen (HLA) alleles in patients with UC and CD and additional 905 healthy individuals (controls). We performed haplotype-based analysis using data from the GWAS and HLA alleles to associate them with UC or CD.
The comparative GWAS and the replication study identified significant associations in the major histocompatibility complex region at 6p21 with UC and CD (rs9271366, P = 1.6 × 10⁻⁷⁰; odds ratio [OR] = 4.44). Haplotype-based analysis in the major histocompatibility complex region showed that HLA-Cw*1202-B*5201-DRB1*1502 haplotype was significantly associated with increased risk of UC compared with CD (P = 1.1 × 10⁻³³; OR = 6.58), accounting for most of the associations observed in the GWAS. Compared with the controls, this HLA haplotype significantly increases susceptibility to UC (P = 4.0 × 10⁻²¹; OR = 2.65), but reduces risk for CD (P = 1.1 × 10⁻⁷; OR = 0.40). Distinct effects of this HLA haplotype on UC and CD were independent of other HLA alleles and haplotypes (P = 2.0 × 10⁻¹⁹ and P = 7.2 × 10⁻⁵, respectively).
The HLA-Cw*1202-B*5201-DRB1*1502 haplotype increases susceptibility to UC but reduces risk for CD, based on a GWAS of a Japanese population.
[show abstract][hide abstract] ABSTRACT: A 23-year-old female was diagnosed as having simultaneous ulcerative colitis (UC) relapse and hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL) without FIP1L1-platelet-derived growth factor receptor alpha (PDGFRA) (F/P) fusion gene. Pathological findings of colon specimens were compatible with UC, however, focal severe infiltration of eosinophils was observed in the rectum, which is unusual in UC, suggesting eosinophil-mediated organ damage. Although imatinib mesylate (IM) is usually ineffective for the treatment of HES/CEL with negative-F/P fusion gene, in the present case it led to the remission of HES/CEL and UC at a higher drug dosage level (400 mg/day). That suggested the presence of unknown tyrosine kinase abnormalities not yet categorized.
Internal Medicine 01/2011; 50(16):1741-5. · 0.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: Crohn's disease is a chronic inflammatory bowel disease characterized by discontinuous chronic inflammation that may affect virtually all organs, including the head and neck. Laryngeal involvement in Crohn's disease is very rare, and only 9 cases have been reported. All 9 patients complained of difficulty in breathing due to edema and ulceration from the larynx to the hypopharynx. The present patient was a 31-year-old woman who had experienced the intestinal symptoms of Crohn's disease starting 20 months earlier and complained of hoarseness, sore throat, and odynophagia. The hoarseness worsened gradually because of limited ulceration of the vocal fold without edema. We describe the first case in which limited ulceration occurred on the vocal fold without airway involvement.
The Annals of otology, rhinology, and laryngology 08/2009; 118(7):532-5. · 1.21 Impact Factor
[show abstract][hide abstract] ABSTRACT: To investigate the application of free-breathing diffusion-weighted MR imaging (DWI) to the assessment of disease activity in Crohn's disease.
Thirty-one patients with Crohn's disease were investigated using free-breathing DWI without special patient preparation or IV or intraluminal contrast agent. The bowel was divided into seven segments, and disease activity was assessed visually on DWI. For quantitative analysis, the apparent diffusion coefficient (ADC) was measured in each segment. The findings of a conventional barium study or surgery were regarded as the gold standard for evaluating the diagnostic ability of DWI to assess disease activity.
Upon visual assessment, the sensitivity, specificity, and accuracy for the detection of disease-active segments were 86.0, 81.4, and 82.4%, respectively. In the quantitative assessment, the ADC value in the disease-active area was lower than that in disease-inactive area in small and large bowels (1.61 +/- 0.44 x 10(-3) mm(2)/s versus 2.56 +/- 0.51 x 10(-3) mm(2)/s in small bowel and 1.52 +/- 0.43 x 10(-3) mm(2)/s versus 2.31 +/- 0.59 x 10(-3) mm(2)/s in large bowel, respectively, P<0.001).
Free-breathing DWI is useful in the assessment of Crohn's disease. The accuracy of DWI is high in evaluating disease activity, especially in the small bowel, and the ADC may facilitate quantitative analysis of disease activity.
Journal of Magnetic Resonance Imaging 05/2009; 29(4):880-6. · 2.57 Impact Factor
[show abstract][hide abstract] ABSTRACT: We describe a 42-year-old-man with HIV infection who developed ulcerative colitis. Ulcerative colitis was diagnosed on the basis of clinical symptoms, and the findings of colonoscopy, pathology and culture. Although remission of ulcerative colitis was induced by PSL and SASP, HIV infection progressed. Treatment with highly active antiretroviral therapy (HAART) was started. HIV viral load decreased to less than 50copies/ml and CD4 counts increased to over 400/microl. After discontinuance of PSL and SASP, he is still in good condition. This is the first report of HIV infection associated with ulcerative colitis in Japan. A relationship between immune disorder in advanced HIV infection and inflammatory bowel disease was suggested. Ulcerative colitis might be an important complication in HIV infection.
Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology 05/2009; 106(4):536-41.
[show abstract][hide abstract] ABSTRACT: We aimed to assess the tolerability, pharmacokinetics, safety, and efficacy of sargramostim in Japanese patients with active Crohn's disease (CD).
Patients with moderately to severely active CD were enrolled. Step 1 was an open-label, phase 1 study of 2 microg/kg per day sargramostim administered subcutaneously (SC) for 4 weeks, with an optional 8-week extension with 6 microg/kg per day. Step 2 was an open-label, phase 1-2 study of the tolerability and pharmacokinetics of SC sargramostim 6 microg/kg per day over 4 weeks and of 8-week efficacy and safety. Efficacy variables were the proportion of patients achieving a clinical response [> or =100-point decrease from baseline in the CD activity index (CDAI)] and the proportion achieving clinical remission (CDAI < or = 150 points).
Six patients participated in Step 1; five in Step 2. Serum concentrations of sargramostim peaked within 1 h of administration; mean terminal half-life was 2 h. Maximal serum concentrations increased with the dose. Mean accumulation ratios were 0.998 in Step 1 and 0.673 in Step 2. One of the six patients in the Step-1 extension and none of the five in Step 2 achieved a clinical response. Clinical remission was reported in one patient in each step. A notable decrease in median CDAI scores was observed in the extension and Step 2. In responders, improvement tended to be maintained through the 30-day follow-up. Drug-related adverse events included injection-site reaction, pyrexia, back pain, and bone pain.
The systemic exposure of sargramostim increased dose-dependently. No accumulation in systemic exposure was associated with the repeated once-daily administration. SC sargramostim at 6 microg/kg per day improved median CDAI scores. A minority of patients experienced clinical remission or clinical response.
Journal of Gastroenterology 04/2009; 44(6):535-43. · 3.79 Impact Factor