Reiko Kunisaki

The 2nd edition of consensus statements for the diagnosis and management of intestinal Behçet’s disease: indication of anti-TNFα monoclonal antibodies

BackgroundClinical evidence regarding intestinal Behçet’s disease (BD) management is lacking and intestinal lesions are a poor prognostic factor. In 2007, the Japan consensus statement for diagnosis and management of intestinal BD was developed. Recently, the efficacy of anti-tumor necrosis factor (TNF)α monoclonal antibodies (mAbs), and infliximab (IFX) was reported and adalimumab (ADA) was approved for intestinal BD in Japan. This study renewed consensus-based practice guidelines for diagnosis and treatment of intestinal BD focusing on the indication of anti-TNFα mAbs.MethodsAn expert panel of Japanese gastroenterology and rheumatology specialists was involved. Clinical statements for ratings were extracted from the literature, a professional group survey, and by an expert panel discussion, which rated clinical statements on a nine-point scale. After the first round of ratings, a panelist meeting discussed areas of disagreement and clarified areas of uncertainty. The list of clinical statements was revised after the panelist meeting and a second round of ratings was conducted.ResultsFifteen relevant articles were selected. Based on the first edition consensus statement, improved clinical statements regarding indications for anti-TNFα mAbs use were developed. After a two-round modified Delphi approach, the second edition of consensus statements was finalized.ConclusionsIn addition to standard therapies in the first edition, anti-TNFα mAbs (ADA and IFX) should be considered as a standard therapy for intestinal BD. Colchicines, thalidomide, other pharmacological therapy, endoscopic therapy, and leukocytapheresis were deemed experimental therapies.

Differential diagnosis of gallbladder diseases with contrast-enhanced harmonic gray scale ultrasonography

We evaluated the usefulness of contrast‐enhanced harmonic gray scale ultrasonographic findings for differential diagnosis of gallbladder diseases.

Conception and pregnancy outcome in women with inflammatory bowel disease: A multicentre study from Japan

BACKGROUND 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. METHODS 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. RESULTS 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 Crohns 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. CONCLUSION 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.

Clostridium difficile infection in patients with ulcerative colitis: investigations of risk factors and efficacy of antibiotics for steroid refractory patients.

BACKGROUND AND OBJECTIVE The incidence of Clostridium difficile infection (CDI) has increased throughout the world and patients with ulcerative colitis (UC) are at a high risk for CDI. Potentially, CDI can exacerbate UC. Therefore, knowledge on the prevalence of CDI should contribute to better management of UC patients. METHODS The presence of toxin A antigen was defined as CDI, and the outcome of the test in patients with active UC during 2006-2009 was reviewed for identifying patients with CDI. Demographic data (disease profile, clinical response to medications and the need for colectomy) in UC patients with CDI were compared with the data from CDI free UC patients. RESULTS Fifty-five of 137 patients (40.1%) were CDI positive. Univariate and multivariate analyses revealed that CDI was not associated with any demographic factor. Intensive antibiotic therapy spared five of 17 (29.4%) steroid refractory patients with CDI from steroids. CDI was not a predictor of colectomy although this could be an outcome of efficient eradication strategy. CONCLUSION CDI was not associated with any demographic factor or colectomy rate. However, CDI eradication therapy allowed some refractory patients to withdraw from steroids. Patients with active UC benefit from regular CDI test and eradication treatment for CDI.

Use of color Doppler ultrasonography for evaluating vascularity of small intestinal lesions in Crohn's disease: correlation with endoscopic and surgical macroscopic findings

Abstract Objective. Ultrasonography (US) is a simple, inexpensive and minimally invasive method. We evaluated the vascularity of small intestinal lesions in Crohns disease using color Doppler US (CD-US) and retrospectively compared them with endoscopic and surgical macroscopic findings. Material and methods. In order to compare CD-US and endoscopic findings, 108 Crohns disease patients who underwent examination of the terminal ileum by both colonoscopy and CD-US were included in the study. Vascularity was evaluated in CD-US using a semiquantitative method, the Limberg score. We analyzed correlations between Limberg score and simple endoscopic score for Crohns disease (SES-CD), an index reflecting endoscopic activity. Scores of SES-CD 3 and higher were defined as endoscopically active. For comparison with surgical macroscopic findings, 22 Crohns disease patients who received CD-US and subsequent iliectomies were included. Lesions with apparent open ulcers were defined as active, and those without as non-active. These findings were compared with the Limberg score. Results. A substantial positive correlation was observed between Limberg scores and SES-CD (ρ = 0.709 [p < 0.001]). Notably, all 27 cases with a Limberg score of 3 or 4 were classified as endoscopically active. Compared to surgical macroscopic activity, Limberg scores of active lesions were significantly higher than those of non-active lesions (p = 0.005). In particular, all 11 cases with a Limberg score of 3 or 4 were classified as active lesions. Conclusion. Vascularity of small intestinal lesions of Crohns disease evaluated by CD-US with Limberg score is well correlated with endoscopic and surgical macroscopic findings.

Hepatocellular carcinoma occurring in a young Crohn's disease patient

Reported herein is a case of hepatocellular carcinoma (HCC) occurring in a 25‐year‐old Japanese man who was diagnosed with Crohns disease (CD) at 14 years of age; treatment included predonisolone, azathioprine, and infliximab. The tumor was located in right upper lobe and the size was 8 cm in diameter; histology was poorly differentiated HCC with pleomorphic cellular changes. Adjacent normal liver showed no evidence of cirrhosis or viral hepatitis. Until now, only six cases of HCC arising in patients with CD have been reported in the English‐language literature. Most of these patients had early onset of CD and HCC: none had cirrhosis or virus hepatitis. Most patients had a long disease history of CD and were being medicated with several immunosuppressive agents. Some factors associated with CD might indirectly or directly be related to the development of HCC in CD patients, although the possibility that these HCC occurred coincidentally in CD patients, including the present patient, cannot be ruled out. Accumulation of cases is necessary to evaluate the relationship between CD and HCC precisely.

Doppler ultrasound findings correlate with tissue vascularity and inflammation in surgical pathology specimens from patients with small intestinal Crohn's disease

BackgroundCrohn’s disease (CD) is routinely evaluated using clinical symptoms, laboratory variables, and the CD activity index (CDAI). However, clinical parameters are often nonspecific and do not precisely reflect the actual activity of CD small-intestinal lesions. The purposes of this prospective study were to compare color Doppler ultrasound (US) findings with histological findings from surgically resected specimens and confirm the hypothesis that color Doppler US can distinguish tissue inflammation and fibrosis.MethodsAmong 1764 consecutive patients who underwent color Doppler US examinations, 10 patients with CD (12 small-intestinal CD lesions) who underwent US examinations before elective small-intestine resection were evaluated in the present study. Areas of thickened intestinal walls were evaluated in terms of blood flow using color Doppler US imaging. The blood flow was semiquantitatively classified as “hyper-flow” and “hypo-flow” according to the Limberg score. Resected lesions were macroscopically and histopathologically processed. Inflammatory cell infiltration, fibrosis and vascularity were evaluated by myeloperoxidase (granulocytes), CD163 (macrophages), CD79a (B cells), CD3 (T cells), Masson’s trichrome (fibrosis), and factor VIII staining (vascular walls). All histopathological images were entered into virtual slide equipment and quantified using a quantitative microscopy integrated system (TissueMorph™).ResultsThere were no significant differences in disease features or laboratory findings between “hypo-flow” lesions (n = 4) and “hyper-flow” lesions (n = 8). Histopathologically, “hyper-flow” lesions showed significantly greater bowel wall vascularity (factor VIII) (p = 0.047) and inflammatory cell infiltration, including CD163 macrophages (p = 0.008), CD3 T cells, and CD79a B cells (p = 0.043), than did “hypo-flow” lesions. There was no apparent association between the blood flow and CDAI.ConclusionsIn this study, active CD lesions were macroscopically visible in surgical specimens of patients with increased blood flow on preoperative color Doppler US imaging. Additionally, these CD lesions exhibited significantly greater vascularity and numbers of inflammatory leukocytes microscopically. Color Doppler US may predict tissue inflammation and fibrosis in small-intenstinal CD lesions.

Pregnancy outcome in women with inflammatory bowel disease treated with anti-tumor necrosis factor and/or thiopurine therapy: a multicenter study from Japan

Background/Aims Anti-tumor necrosis factor drugs (anti-TNF) and thiopurines are important treatment options in patients with inflammatory bowel disease (IBD), including during pregnancy. However, there are limited data on the benefit/risk profile of anti-TNF and thiopurines during pregnancy in Asia. The aim of this study was to analyze pregnancy outcomes of female Japanese IBD patients treated with anti-TNF and/or thiopurines. Methods This cross-sectional study assessed pregnancy outcomes in 72 women with IBD. Pregnancy outcomes were compared among 31 pregnancies without exposure to infliximab (IFX), adalimumab (ADA), or thiopurines; 24 pregnancies with exposure to anti-TNF treatment (23 IFX, 1 ADA); 7 pregnancies with exposure to thiopurines alone; and 10 pregnancies with exposure to both IFX and thiopurines. Results Thirty-five of the 41 pregnancies (85.3%) that were exposed to anti-TNF treatment and/or thiopurines resulted in live births after a median gestational period of 38 weeks. Of the 35 live births, 3 involved premature deliveries; 7, low birth weight; and 1, a congenital abnormality. There were 6 spontaneous abortions in pregnancies that were exposed to anti-TNF treatment (17.7%). Pregnancy outcomes among the 4 groups were similar, except for the rate of spontaneous abortions (P =0.037). Conclusions Exposure to anti-TNF treatment or thiopurines during pregnancy was not related to a higher incidence of adverse pregnancy outcomes in Japanese IBD patients except for spontaneous abortion.

Hematopoietic Stem Cell Transplantation for XIAP Deficiency in Japan

BackgroundX-linked inhibitor of apoptosis protein (XIAP) deficiency is a rare immunodeficiency that is characterized by recurrent hemophagocytic lymphohistiocytosis (HLH) and splenomegaly and sometimes associated with refractory inflammatory bowel disease (IBD). Although hematopoietic stem cell transplantation (HSCT) is the only curative therapy, the outcomes of HSCT for XIAP deficiency remain unsatisfactory compared with those for SLAM-associated protein deficiency and familial HLH.AimTo investigate the outcomes and adverse events of HSCT for patients with XIAP deficiency, a national survey was conducted.MethodsA spreadsheet questionnaire was sent to physicians who had provided HSCT treatment for patients with XIAP deficiency in Japan.ResultsUp to the end of September 2016, 10 patients with XIAP deficiency had undergone HSCT in Japan, 9 of whom (90%) had survived. All surviving patients had received a fludarabine-based reduced intensity conditioning (RIC) regimen. Although 5 patients developed post-HSCT HLH, 4 of them survived after etoposide administration. In addition, the IBD associated with XIAP deficiency improved remarkably after HSCT in all affected cases.ConclusionThe RIC regimen and HLH control might be important factors for successful HSCT outcomes, with improved IBD, in patients with XIAP deficiency.

Evidence-based clinical practice guidelines for inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic disorder involving mainly the intestinal tract, but possibly other gastrointestinal and extraintestinal organs. Although etiology is still uncertain, recent knowledge in pathogenesis has accumulated, and novel diagnostic and therapeutic modalities have become available for clinical use. Therefore, the previous guidelines were urged to be updated. In 2016, the Japanese Society of Gastroenterology revised the previous versions of evidence-based clinical practice guidelines for ulcerative colitis (UC) and Crohn’s disease (CD) in Japanese. A total of 59 clinical questions for 9 categories (1. clinical features of IBD; 2. diagnosis; 3. general consideration in treatment; 4. therapeutic interventions for IBD; 5. treatment of UC; 6. treatment of CD; 7. extraintestinal complications; 8. cancer surveillance; 9. IBD in special situation) were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases. The guidelines were developed with the basic concept of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Recommendations were made using Delphi rounds. This English version was produced and edited based on the existing updated guidelines in Japanese.