Abstract: BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. (Inflamm Bowel Dis 2011;).
Abstract: The treatment options for inflammatory bowel disease have expanded with the introduction of biological therapies. Recently published controlled clinical trials were searched and those that impact the clinical management of ulcerative colitis (UC) are discussed in this review. In the management of mild to moderate UC, mesalamine still remains the first choice of drug. The newly developed once daily formulations have shown equal efficacy to divided doses and possibly portend better compliance owing to a simplified regimen. In outpatients with moderate to severe UC, recent data indicate that infliximab induced and maintained remission leads to decreased colectomy rates and fewer hospitalizations. An alternative anti-tumor necrosis factor (TNF) agent, adalimumab, was also recently shown to be effective for induction of remission in moderate to severe UC. The use of immunosuppressives, such as azathioprine and mercaptopurine, is associated with decreased colectomy rates and thioguanine was shown to be effective in maintaining clinical remission in those who are intolerant to azathioprine/mercaptopurine. In hospitalized patients with steroid resistant severe UC, infliximab and tacrolimus may be alternatives to cyclosporine in those who are otherwise candidates for colectomy. Adequate long-term maintenance therapy with immunosuppressives or anti-TNF therapy is required after rescue therapy for a sustained benefit. Future research is needed to position the available anti-TNF agents and combined immunosuppressive therapy in the treatment of UC to achieve and maintain steroid free remission.
Abstract: The aim of this study was to elucidate the molecular mechanisms responsible for the therapeutic effects of granulocyte and monocyte adsorption apheresis (GMA). We investigated the alterations in circulating monocyte subsets and monocyte-derived dendritic cell (moDC) function after GMA therapy in ulcerative colitis (UC) patients. Eighteen patients with UC were enrolled: 14 patients were responders, and 4 patients were non-responders. Peripheral venous blood was obtained within 5 min before and 5 min after GMA therapy. Flow cytometric analysis for monocyte markers (CD14/CD16) was then performed. Monocyte-derived dendritic cells were obtained and alterations in their phenotype were analyzed by flow cytometry. Their function was also analyzed in a mixed lymphocyte reaction assay between allo-naïve T lymphocytes. Flow cytometric analysis for intracellular interferon (IFN)-gamma (T-helper 1 cells) and interleukin (IL)-4 (T-helper 2 cells) was then performed for the stimulated T lymphocytes. In patients who responded to GMA, the average numbers of monocytes, especially CD16(+) monocytes, were significantly decreased after therapy (P < 0.05). In responders, post-GMA moDCs expressed significantly lower CD80 and B7-DC, which are one of the stimulation and maturation markers of dendritic cells, compared to pre-GMA moDCs. CD83, CD86 and human leukocyte antigen-DR also showed a tendency to decrease. In responders, naïve T lymphocytes stimulated with post-GMA moDCs produced significantly less IFN-gamma and IL-4 compared to those stimulated with pre-GMA moDCs. The results of our study show that some of the immunosuppressive effects of GMA therapy may be associated with the modulation of monocyte subsets and moDC function.
Abstract: Granulocyte and monocyte adsorptive apheresis (GMA) has shown efficacy in patients with active ulcerative colitis (UC). However, with routine weekly treatment, it may take several weeks to achieve remission, and to date, the efficacy of a more frequent treatment schedule remains unknown. The aim of this study was to assess the clinical efficacy and safety of intensive GMA treatment in patients with active UC.
Abstract: Dendritic cells (DCs) possess the most potent ability to induce acquired immunity. However, their involvement in the pathogenesis of Crohn's disease (CD) has not yet been determined. We aimed to establish the immune status of mesenteric lymph nodes, the major gut-associated lymphoid tissue, and isolated DCs and determine their involvement in the pathogenesis of CD.
Abstract: Intestinal Behçet disease (BD) is characterized by intestinal inflammation with round and oval ulcers associated with gastrointestinal symptoms. Although several cases have been reported that infliximab is effective for induction of remission, the efficacy of infliximab for maintaining remission is unknown.
Abstract: Recently, granulocyte and monocyte adsorption apheresis (GMA) has been shown to be effective for active ulcerative colitis (UC). Its original weekly treatment schedule is effective in about 70% of active UC. However, it takes about 3-4 weeks to achieve remission, and the efficacy of a more frequent treatment schedule has not been elucidated yet. We performed a pilot open-labeled prospective, randomized, controlled study comparing weekly and an intensive treatment schedule with three treatment sessions per week in the first 2 weeks.
Abstract: Since genetically engineered animal models of inflammatory bowel disease (IBD) do not develop colitis under germ-free conditions, the intestinal microflora is thought to be one of the most important environmental factors associated with IBD. To understand the involvement of intestinal microflora in the pathogenesis of IBD, we analyzed the constituents of intestinal microflora in IBD. Faecal samples from 73 patients with ulcerative colitis (UC) and 23 patients with Crohn's disease (CD) were analyzed by quantitative PCR using 16S rRNA gene-targeted group-specific primers for Bacteroides fragilis group, Bifidobacterium, Clostridium coccoides groups, Clostridium leptum subgroup, Atopobium cluster, and seven species of Bacteroides. We analyzed the distribution of the predominant microflora by fluorescence in situ hybridization (FISH) using group-specific probes. We also examined the concentration of faecal organic acids produced by intestinal microflora. Contrary to previous reports, we found that the B. fragilis group was significantly decreased in the faeces of patients with IBD. Moreover, B. vulgatus was the predominant microflora in healthy controls and relatively decreased among IBD patients. Most of the microflora adhering to the colonic mucosa surrounding the mucus layer comprised C. coccoides group and Bifidobacterium. B. fragilis group mainly inhabited the faeces, but did not adhere to or invade the mucosa. The concentrations of propionic and butyric acids in the faeces were significantly decreased in patients with IBD. These findings indicate that IBD is not caused by a specific intestinal bacterial cluster or species and that disordered intestinal microflora could be involved in the pathogenesis of IBD.
Abstract: Intestinal macrophages play a central role in regulation of immune responses against commensal bacteria. In general, intestinal macrophages lack the expression of innate-immune receptor CD14 and do not produce proinflammatory cytokines against commensal bacteria. In this study, we identified what we believe to be a unique macrophage subset in human intestine. This subset expressed both macrophage (CD14, CD33, CD68) and DC markers (CD205, CD209) and produced larger amounts of proinflammatory cytokines, such as IL-23, TNF-alpha, and IL-6, than typical intestinal resident macrophages (CD14-CD33+ macrophages). In patients with Crohn disease (CD), the number of these CD14+ macrophages were significantly increased compared with normal control subjects. In addition to increased numbers of cells, these cells also produced larger amounts of IL-23 and TNF-alpha compared with those in normal controls or patients with ulcerative colitis. In addition, the CD14+ macrophages contributed to IFN-gamma production rather than IL-17 production by lamina propria mononuclear cells (LPMCs) dependent on IL-23 and TNF-alpha. Furthermore, the IFN-gamma produced by LPMCs triggered further abnormal macrophage differentiation with an IL-23-hyperproducing phenotype. Collectively, these data suggest that this IL-23/IFN-gamma-positive feedback loop induced by abnormal intestinal macrophages contributes to the pathogenesis of chronic intestinal inflammation in patients with CD.
Abstract: 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.
Abstract: The pathogenesis of Crohn's disease (CD), a chronic inflammatory bowel disease characterised by a Th1 immune response, remains unclear. Osteopontin (OPN) is a phosphoprotein known as an adhesive bone matrix protein. Recent studies have shown that OPN plays an important role in lymphocyte migration, granuloma formation, and interleukin 12 (IL-12) production. The present study investigated expression and the pathophysiological role of OPN in CD.
Abstract: To investigate the role of inducible costimulator (ICOS), a new member of the CD28 family involved in regulation of T-cell activation and chronic intestinal inflammation, we assessed its expression and functional role in patients with inflammatory bowel disease (IBD).
Abstract: 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.
Abstract: 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.
