Haruhiko Ogata

A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis

Background and aims: Immunosuppressive therapy with intravenous ciclosporin is an alternative treatment option to total colectomy for patients with ulcerative colitis (UC), while the benefits of oral administration of tacrolimus are not well defined and are based on reports of several uncontrolled studies. Methods: Patients with refractory active UC were randomly assigned to a high trough concentration (10–15 ng/ml) group (HT group) (n = 21), low trough concentration (5–10 ng/ml) group (LT group) (n = 22), or placebo group (n = 20). Patients received an initial oral dose of 0.05 mg/kg tacrolimus or placebo twice daily. Efficacy was evaluated in 60 patients based on a disease activity index (DAI) score. Fifty eight patients had additional treatment with tacrolimus and were evaluated for efficacy in a 10 week open label extension. Results: An improvement in DAI score (⩾4 points, all categories improved) was observed for 68.4% of cases in the HT group compared with 10.0% in the placebo group (p<0.001). In the HT group, 20.0% of patients had clinical remission and 78.9% had mucosal healing. In the open label extension, 55.2% of all patients had an improved DAI score at week 10. Mean dose of prednisolone was reduced from 19.7 mg/day at study entry to 7.8 mg/day at week 10. The incidence of side effects in the HT group was significantly higher than that of the placebo group (p = 0.043). The most common event was mild finger tremor. Conclusions: Our findings demonstrate dose dependent efficacy and safety of oral tacrolimus for remission-induction therapy of refractory UC. The optimal target range appears to be 10–15 ng/ml in terms of efficacy with two week therapy.

Cytomegalovirus is frequently reactivated and disappears without antiviral agents in ulcerative colitis patients

OBJECTIVE: The clinical significance of cytomegalovirus (CMV) reactivation complicating ulcerative colitis (UC) patients has been uncertain. It has therefore remained undetermined whether or not CMV reactivation should be treated in UC patients under immunosuppression. The aim of the study was to clarify the natural history of CMV reactivation in UC patients.METHODS: Sixty-nine UC patients with moderate to severe activity were enrolled in the study. All of the patients were treated with prednisolone, and/or immunosuppressants such as cyclosporine A. We sequentially monitored CMV reactivation every 2 wk up until 8 wk using the CMV antigenemia (Ag) assay and plasma quantitative real-time polymerase chain reaction (PCR) assay for CMV.RESULTS: Immunoglobulin (Ig) G for CMV was positive in 48 patients (69.6%) and negative in 21 patients (30.4%). CMV was reactivated in 25 patients out of the 48 seropositive patients (52.1%) during the study period. The CMV Ag and PCR values were low and none of the patients showed any evidence of CMV infection on biopsy specimens by hematoxylin and eosin staining. While gancylovir (GCV) was not used except in two patients, clinical outcomes including rates of remission and colectomy were not significantly different among the CMV reactivation-positive, -negative, and CMV IgG negative groups. Furthermore, CMV disappeared without GCV in most of the CMV reactivation-positive patients.CONCLUSIONS: CMV is frequently reactivated in active UC patients; however, it disappears without antiviral agents. Therefore, antiviral therapies should not be necessary for most UC patients with only CMV reactivation as long as CMV Ag values are low.

T-bet upregulation and subsequent interleukin 12 stimulation are essential for induction of Th1 mediated immunopathology in Crohn’s disease

Background and aims: Many lines of evidence suggest that T helper cell type 1 (Th1) immune responses predominate in Crohn’s disease (CD). Recently, a novel transcription factor T-box expressed in T cells (T-bet) has been reported as the master regulator of Th1 development. This study was designed to investigate the role of T-bet and proinflammatory cytokines in Th1 mediated immunopathology in CD. Materials: CD4+ lamina propria mononuclear cells (LPMCs) were isolated from surgically resected specimens (CD, n = 10; ulcerative colitis (UC), n = 10; normal controls (NL), n = 5). Methods: (1) T-bet expression of CD4+ LPMCs was examined by quantitative real time polymerase chain reaction and western blotting. (2) T-bet expression of LPMCs stimulated by interleukin (IL)-12/IL-18 was analysed by western blotting. (3) Interferon γ (IFN-γ) production and T-bet expression of CD4+ peripheral blood mononuclear cells (PBMCs) were examined with or without stimulation by anti-CD3/CD28 monoclonal antibodies and/or IL-12. Results: (1) T-bet expression of CD4+ LPMCs was increased in CD compared with UC and NL. (2) Synergistically, augmentation of IFN-γ production by IL-12/IL-18 was independent of T-bet expression in LPMCs. (3) T-bet was induced by T cell receptor stimulation in CD4+ PBMCs. T-bet induction correlated with IFN-γ production and with augmentation of surface expressed IL-12 receptor β2. Conclusions: T-bet induction by antigenic stimulation and subsequent stimulation by macrophage derived IL-12/IL-18 are important for establishing Th1 mediated immunopathology in CD.

Double‐blind, placebo‐controlled trial of oral tacrolimus (FK506) in the management of hospitalized patients with steroid‐refractory ulcerative colitis

Background: We report a multicenter study of oral tacrolimus (FK506) therapy in steroid‐refractory ulcerative colitis (UC). Methods: In a placebo‐controlled, double‐blind study, 62 patients with steroid‐refractory, moderate‐to‐severe UC were randomized into either a tacrolimus group or a placebo for 2 weeks. Patients were evaluated using the Disease Activity Index (DAI). As an entry criterion, patients had to have a total DAI score of 6 or more as well as a mucosal appearance subscore of 2 or 3. Clinical response was defined as improvement in all DAI subscores. Mucosal healing was defined as mucosal appearance subscore of 0 or 1. Clinical remission was defined as a total DAI score ≤2 with an individual subscore of 0 or 1. Results: The mean total DAI score at study entry was 9.8 ± 1.61 in the tacrolimus group and 9.1 ± 1.05 in the placebo group. At week 2 the clinical response rate was 50.0% (16/32) in the tacrolimus group and 13.3% (4/30) in the placebo group (P = 0.003). The rate of mucosal healing observed was 43.8% (14/32) in the tacrolimus group and 13.3% (4/30) in the placebo group (P = 0.012) and the rate of clinical remission observed was 9.4% (3/32) in the tacrolimus group and 0.0% (0/30) in the placebo group (P = 0.238). The therapies in this study were well tolerated, with only minor side effects. Conclusions: Oral tacrolimus therapy in patients with steroid‐refractory UC shortened the acute phase and induced rapid mucosal healing. These results suggest that tacrolimus therapy is useful as an alternative therapy for steroid‐refractory UC. (Inflamm Bowel Dis 2011;)

Granulocytapheresis is useful as an alternative therapy in patients with steroid-refractory or -dependent ulcerative colitis

Background:Recently, granulocyte and monocyte adsorption apheresis (GCAP) has been shown to be safe and effective for active ulcerative colitis (UC). We analyzed the safety and efficacy of GCAP (G-1 Adacolumn) in patients with steroid-refractory and -dependent UC. G-1 Adacolumn is filled with cellulose acetate carriers that selectively adsorb granulocytes and monocytes/macrophages. Methods:Forty-four patients with UC were treated with GCAP. These patients received 5 apheresis sessions over 4 weeks. Twenty patients had steroid-refractory UC (group 1) and 10 had steroid-dependent UC (group 2). Fourteen patients who did not want re-administration of steroids were treated with GCAP at the time of relapse, just after discontinuation of steroid therapy (group 3). Results:Of 44 patients treated with GCAP, 24 (55%) obtained remission (CAI ≤ 4), 9 (20%) showed a clinical response, and 11 (25%) remained unchanged. Only 2 of 10 patients (20%) with severe steroid-refractory UC (CAI ≥ 12) achieved remission, whereas 7 of 10 patients (70%) with moderate steroid-refractory UC achieved remission (p < 0.05). The dose of corticosteroids was tapered in 9 of 10 (90%) patients with steroid-dependent UC after GCAP therapy. Twelve (86%) of 14 patients in group 3 showed an improvement in symptoms and could avoid re-administration of steroids after GCAP. No severe adverse effects occurred. Conclusions:The findings of this study suggest that GCAP may be a useful alternative therapy for patients with moderate steroid-refractory or -dependent UC, although cyclosporin A or colectomy is necessary in patients with severe UC. GCAP may also be useful for avoiding re-administration of steroids at the time of relapse. Randomized, controlled clinical trials are needed to confirm these findings.

Novel pathophysiological concepts of inflammatory bowel disease

It is very clear that genetic factors play an important role in the pathogenesis of IBD and in both Crohn’s disease (CD) and ulcerative colitis (UC). Epidemiological studies in monozygotic and dizygotic twins, as well as family studies, have indicated that genetic factors may be more important in CD than in UC. The search for susceptibility genes had its first success in 1996, when the first susceptibility locus for CD was identified in the pericentromeric region of chromosome 16, which was called IBD1. In 2001 a caspase recruitment domain-containing protein, CARD15/NOD2, was found to be mutated in 20%–30% of CD patients, establishing a proof of principle for the “genetic concept” of IBD pathophysiology. Multiple mutations in the CARD15/NOD2 gene have been identified (Fig. 3), three of which have been shown to be independently associated with CD (arg702trp, gly908arg, and leu1007fsinsC).8 These three variants confer a 15%– 20% attributable population risk among cases of familial CD. The relevance of CARD15/NOD2 for the etiology of CD was confirmed in a number of subsequent studies.9,10 CARD15/NOD2 mutations are associated with ileal disease, earlier age of disease onset, and stricturing disease.11 In contrast, a few articles support data that CARD15/NOD2 mutations do not play a role in the etiology of CD in Asia12 (see Fig. 3). However, there are several abnormalities in genetic factors of Japanese IBD patients, including the HLA-DR regions.13,14 Interestingly, most of these abnormalities are not found in Western countries. In addition, healthy homozygous carriers of the 3020insC frameshift mutation have been described,15 indicating that CARD15/ NOD2 mutations are not the sole determinant of CD and that environmental factors also play an important role. Although epidemiological data concerning CARD15/NOD2 are rather clear and have been con

Feasibility of stomach exploration with a guided capsule endoscope.

BACKGROUND AND STUDY AIMS Video capsule endoscopy has been established in diagnosis of small-bowel disease and has been evaluated for esophageal pathology and recently for colorectal diagnostics. Gastric capsule endoscopy has not hitherto been feasible due to the stomachs large surface area and volume. We present the first application of a magnetically navigated capsule in the human stomach. PATIENTS AND METHODS 29 volunteers and 24 patients (men 42, women 11; mean age 47.5 years) were included in a feasibility study. Low-level magnetic fields were used to maneuver the double-sensor video capsule within the human stomach with an air-water interface provided by ingestion of 1300 ml water within 1 hour before examination. Visualization of all parts of the stomach was attempted; time for visualization was recorded, and a subjective assessment of completeness of visualization was documented. RESULTS There was technical failure in one individual; thus technical success rate was 98 %. In the 52 remaining cases, examiners assessed that the antrum, body, fundus, and cardia were fully visualized in 98 %, 96 %, 73 % and 75 %, respectively. Mean duration of examinations was 30 minutes (range 8 - 50), with a longer time (mean 37 minutes) for volunteers for study reasons. In total, 30 findings were identified: 14 were detected by both gastroscopy and capsule, 10 lesions were identified by guided capsule examination only, 6 by gastroscopy only. No significant capsule-related adverse events occurred. CONCLUSION Magnetically navigated video capsule endoscopy appears to be feasible and sufficiently accurate for gastric examination. It may permit endoscopic examinations that are more patient-friendly and without sedation. Comparative studies are under way.

Cytokine and anti-cytokine therapies for inflammatory bowel disease

Although the pathogenesis of inflammatory bowel disease (IBD) remains elusive, it appears that there is chronic activation of the immune and inflammatory cascade in genetically susceptible individuals. Current disease management guidelines have therefore focused on the use of anti-inflammatory agents, aminosalicylates and corticosteroids. These conventional therapies continue to be a first choice in the management of IBD. Immunomodulators, such as azathioprine, 6-mercaptopurine, methotrexate or cyclosporin, are demonstrating increasing importance against steroid-resistant and steroid-dependent patients. However, some patients are still refractory to these therapies. Recent advances in the understanding of the pathophysiological conditions of IBD have provided new immune system modulators as therapeutic tools. Other immunosuppressive agents including FK506 and thalidomide have expanded the choice of medical therapies available for certain subgroups of patients. Furthermore, biological therapies have begun to assume a prominent role. Studies with chimeric monoclonal anti-TNF-alpha antibody treatment have been reported with dramatic successes. However, observations in larger numbers of treated patients are needed to explicate fully the safety of or risks posed by this agent such as developing lymphoma, or other malignancies. Another anti-inflammatory cytokine-therapy includes anti anti-IL-6R, anti-IL-12 or toxin-conjugated anti IL-7R, recombinant cytokines (IL-10 or IL-11). Given the diversity of proinflammatory products under its control, NF-kappaB may be viewed as a master switch in lymphocytes and macrophages, regulating inflammation and immunity. Although some of them still need more confirmatory studies, those immune therapies will provide new insights into cell-based and gene-based treatment against IBD in near future.

Animal models of inflammatory bowel disease.

models are adoptive transfer models and genetically engineered models of chronic intestinal inflammation, with many of these models resulting from the availability of gene targeting/transgenic technologies in mice, and a better understanding of the pathogenic role of certain cell populations with a pathogenic function. It became clear that, by inducing systemic immune disorders in these models, inflammation would occur in the intestine and this provided new insights into the pathogenic mechanisms and development of new therapies for inflammatory bowel disease (IBD). Some of these models, including those reported recently, are discussed in this review.

Reactivation of hepatitis B in a patient with Crohn’s disease treated using infliximab

We encountered a case of reactivation of hepatitis B virus after administration of infliximab for Crohn’s disease. The use of infliximab was considered because the patient displayed abdominal symptoms and perianal lesions. Transaminases were normal, and hepatitis B virus (HBV) DNA was undetectable before treatment, so no antiviral treatment was used, and infliximab and low-dose 6-mercaptopurine were administered. This treatment was effective, but liver dysfunction and reactivation of HBV were observed after the fourth injection of infliximab. This is the first report of Crohn’s disease for which infliximab use was continued even after reactivation of HBV was observed. However, liver dysfunction was not improved by lamivudine. Antiviral treatment should be considered before administration of infliximab for patients with HBV.