Jochen Maul

Combination immunomodulator and antibiotic treatment in patients with inflammatory bowel disease and clostridium difficile infection.

BACKGROUND & AIMS Management of Clostridium difficile infection in patients with flaring inflammatory bowel disease (IBD) has not been optimized. We investigated the effects of combination therapy with antibiotics and immunomodulators in patients with IBD and C difficile infection. METHODS We analyzed data from 155 patients (59% with ulcerative colitis [UC]) from a retrospective, European Crohns and Colitis organization, multi-center study comparing outcome of hospitalized IBD patients with C difficile infection who were treated with antibiotics (n = 51) or antibiotics and immunomodulators (n = 104). The primary composite outcome was death or colectomy within 3 months of admission, in-hospital megacolon, bowel perforation, hemodynamic shock, or respiratory failure. RESULTS The primary outcome occurred in 12% of patients given the combination treatment vs none of the patients given antibiotics alone (P = .01). UC, abdominal tenderness, or severe bloody diarrhea was more common among patients that received the combined therapy. However, multivariate analysis revealed that only the combination therapy maintained a trend for an independent association with the primary outcome (likelihood ratio = 11.9; CI, 0.9-157; P = .06). Treatment with 2 or 3 immunomodulators was correlated with the primary outcome, independent of disease severity at presentation (odds ratio [OR] = 17; CI, 3.2-91; P < .01). Acid-suppressing medications increased the risk of C difficile relapse (OR = 3.8; CI, 1.1-12.9; P = .03), whereas recent hospitalization correlated with increased rate of C difficile persistence (OR = 8; CI, 2.1-29; P = .002). CONCLUSIONS Patients with IBD that also have C difficile infection are frequently treated with a combination of antibiotics and immunomodulators. However, this combination tends to associate with a worse outcome than antibiotic therapy alone. Prospective controlled trials are urgently needed to optimize the management of these challenging patients.

Vedolizumab provides clinical benefit over 1 year in patients with active inflammatory bowel disease – a prospective multicenter observational study

Vedolizumab, a monoclonal antibody targeting the α4β7‐integrin, is effective in inducing and maintaining clinical remission in Crohns disease and ulcerative colitis according to randomised clinical trials.

H1N1 vaccines in a large observational cohort of patients with inflammatory bowel disease treated with immunomodulators and biological therapy

Background Safety data are lacking on influenza vaccination in general and on A (H1N1)v vaccination in particular in patients with inflammatory bowel disease (IBD) receiving immmunomodulators and/or biological therapy. Aims and methods The authors conducted a multicentre observational cohort study to evaluate symptoms associated with influenza H1N1 adjuvanted (Pandemrix, Focetria, FluvalP) and non-adjuvanted (Celvapan) vaccines and to assess the risk of flare of IBD after vaccination. Patients with stable IBD treated with immunomodulators and/or biological therapy were recruited from November 2009 until March 2010 in 12 European countries. Harvey–Bradshaw Index and Partial Mayo Score were used to assess disease activity before and 4 weeks after vaccination in Crohns disease (CD) and ulcerative colitis (UC). Vaccination-related events up to 7 days after vaccination were recorded. Results Of 575 patients enrolled (407 CD, 159 UC and nine indeterminate colitis; 53.9% female; mean age 40.3 years, SD 13.9), local and systemic symptoms were reported by 34.6% and 15.5% of patients, respectively. The most common local and systemic reactions were pain in 32.8% and fatigue in 6.1% of subjects. Local symptoms were more common with adjuvanted (39.3%) than non-adjuvanted (3.9%) vaccines (p<0.0001), whereas rates of systemic symptoms were similar with both types (15.0% vs 18.4%, p=0.44). Among the adjuvanted group, Pandemrix more often induced local reactions than FluvalP and Focetria (51.2% vs 27.6% and 15.4%, p<0.0001). Solicited adverse events were not associated with any patient characteristics, specific immunomodulatory treatment, or biological therapy. Four weeks after vaccination, absence of flare was observed in 377 patients with CD (96.7%) and 151 with UC (95.6%). Conclusion Influenza A (H1N1)v vaccines are well tolerated in patients with IBD. Non-adjuvanted vaccines are associated with fewer local reactions. The risk of IBD flare is probably not increased after H1N1 vaccination.

Autoimmunity, Intestinal Lymphoid Hyperplasia, and Defects in Mucosal B-Cell Homeostasis in Patients With PTEN Hamartoma Tumor Syndrome

The Phosphatase And Tensin Homolog Deleted On Chromosome 10 (PTEN) regulates the phosphoinositol-3-kinase (PI3K)-AKT signaling pathway. In a series of 34 patients with PTEN mutations, we described gastrointestinal lymphoid hyperplasia, extensive hyperplastic tonsils, thymus hyperplasia, autoimmune lymphocytic thyroiditis, autoimmune hemolytic anemia, and colitis. Functional analysis of the gastrointestinal mucosa-associated lymphoid tissue revealed increased signaling via the PI3K-AKT pathway, including phosphorylation of S6 and increased cell proliferation, but also reduced apoptosis of CD20(+)CD10(+) B cells. Reduced activity of PTEN therefore affects homeostasis of human germinal center B cells by increasing PI3K-AKT signaling via mammalian target of rapamycin as well as antiapoptotic signals.

Ulcerative colitis: immune function, tissue fibrosis and current therapeutic considerations

BackgroundUlcerative colitis (UC) is a complex disease in which the interaction of genetic, environmental and microbial factors drives chronic intestinal inflammation that finally leads to extensive tissue fibrosis.DiscussionThe present review discusses the current knowledge on genetic susceptibility, especially of the IL-12/IL-23 pathway, the pathophysiologic role of the involved cytokines (e.g. IL-13, IL-23, TGFβ1) and immune cells (e.g. T cells, epithelial cells, fibroblasts) in UC followed by an overview on actual therapeutic considerations. These future therapies will target selectively the involved cell types by blocking their activation and its downstream signalling, by inhibiting their migration to the inflamed site and by anti-cytokine strategies. This may avoid–when initiated in time–the perpetuation of the inflammatory mechanisms thus preventing fibrosis. With respect to animal models that have guided the most productive efforts for understanding human inflammatory bowel disease, these will be shortly discussed in the respective context.

Modulation of systemic antigen-specific immune responses by oral antigen in humans.

Oral antigen uptake can induce systemic immune responses ranging from tolerance to immunity. However, the underlying mechanisms are poorly understood, especially in humans. Here, keyhole limpet hemocyanin (KLH), a neoantigen which has been used in earlier studies of oral tolerance, was fed in a repeated low‐dose and a single high‐dose protocol to healthy volunteers. KLH‐specific CD4+ T‐cell proliferation and cytokine production, as well as KLH‐specific serum Ab and the effects of oral KLH on a subsequent parenterally induced systemic immune response, were analyzed. Repeated low‐dose oral KLH alone induced antigen‐specific CD4+ T cells positive predominantly for the gut‐homing receptor integrin β7 and the cytokines IL‐2 and TNF‐α; some CD4+ T cells also produced IL‐4. Oral feeding of KLH accelerated a subsequent parenterally induced systemic CD4+ T‐cell response. The cytokine pattern of KLH‐specific CD4+ T cells shifted toward more IL‐4‐ and IL‐10‐ and less IFN‐γ‐, IL‐2‐ and TNF‐α‐producing cells. The parenterally induced systemic KLH‐specific B‐cell response was accelerated and amplified by oral KLH. The impact of single high‐dose oral KLH on antigen‐specific immune responses was less pronounced compared with repeated low‐dose oral KLH. These findings suggest that oral antigen can effectively modulate subsequently induced systemic antigen‐specific immune responses. Immunomodulation by oral antigen may offer new therapeutic strategies for Th type1‐mediated inflammatory diseases and for the development of vaccination strategies.

Colesevelam for the treatment of bile acid malabsorption-associated diarrhea in patients with Crohn's disease: A randomized, double-blind, placebo-controlled study

BACKGROUND AND AIMS Bile acid malabsorption (BAM)-associated diarrhea is an important clinical issue in patients with Crohns disease (CD). We analyzed the efficacy and safety of the bile acid sequestrant colesevelam for treatment of BAM-associated diarrhea in CD patients in a randomized, double-blind, placebo-controlled study. METHODS The primary endpoint was the proportion of patients with >30% reduction of liquid stools/day from baseline to termination visit at week 4. Secondary endpoints were reduction of the number of liquid stools/day, improvement of stool consistency and quality of life. RESULTS 26 patients were analyzed in the intention-to-treat (ITT) analysis. The primary endpoint was reached by 10 patients (69.7%) in the colesevelam group compared to 3 patients (27.3%) in the placebo group (risk difference RD=.394, 95%CI:[-0.012; 0.706]; P=.0566). In the per-protocol analysis (n=22), the risk difference was statistically significant (RD=.470, 95%CI:[0.018; 0.788], P(H0: RD=0)=0.0364; 95% CI:[1.3;54.7]). Regarding secondary endpoints, in the ITT population colesevelam-treated patients had a significant reduction of liquid stools/day at week 4 (median 5.0 to 2.0; P=0.01), while patients treated with placebo had no significant reduction (median 4.0 to 3.0; P=0.42). Significantly more patients in the colesevelam group had improvement of stool consistency of at least one level in the Bristol stool chart, as compared to the placebo group (P=0.003). CONCLUSIONS We found significant differences in favor for colesevelam treatment compared to placebo treatment for CD patients with BAM regarding the reduction of the number of liquid stools/day and stool consistency. ClinicalTrials.gov number: NCT01203254.

Use of Intestinal Ultrasound to Monitor Crohn’s Disease Activity

BACKGROUND & AIMS We performed a multicenter study to determine whether transabdominal bowel wall ultrasonography, a noninvasive procedure that does not require radiation, can be used to monitor progression of Crohn’s disease (CD). METHODS We performed a 12‐month prospective, noninterventional study at 47 sites in Germany, from December 2010 through September 2014. Our study included 234 adult patients with CD who experienced a flare, defined as Harvey‐Bradshaw index score of ≥7. All patients received treatment intensification, most with tumor necrosis factor antagonists. Ultrasound parameters and clinical data were assessed at baseline and then after 3, 6, and 12 months. The primary endpoint was the change in ultrasound parameters within 12 months of study enrollment. RESULTS All patients included had bowel wall alterations either within the terminal ileum and/or segments of the colon. After 3 and 12 months, ultrasonographic examination showed significant improvements of nearly all ultrasound parameters, including reductions in bowel wall thickening or stratification, decreased fibrofatty proliferation, and increased signals in color Doppler ultrasound (P < .01 for all parameters at months 3 and 12). Median Harvey‐Bradshaw index scores decreased from 10 at baseline to 2 after 12 months. Improvement in bowel wall thickness correlated with reduced levels of C‐reactive protein after 3 months (P ≤ .001). CONCLUSIONS In a multicenter prospective study, we found that ultrasonographic examination can be used to monitor disease activity in patients with active CD. Bowel ultrasonography seems to be an ideal follow‐up method to evaluate early transmural changes in disease activity, in response to medical treatment. German Clinical Trials Register: drks.de/DRKS00010805.

EndoClot Polysaccharide Hemostatic System in Nonvariceal Gastrointestinal Bleeding: Results of a Prospective Multicenter Observational Pilot Study.

Background and Study Aims: Hemostatic powders have been introduced to improve the management of gastrointestinal (GI) bleeding and to extend the variety of tools available for emergency endoscopy. The aim of the present pilot study was to evaluate the indication profiles and the short-term outcome of EndoClot. Patients, Materials and Methods: In a prospective observational pilot study patients with acute nonvariceal GI bleeding were included. Primary or secondary application of EndoClot was assessed. Hemoglobin, prothrombine time and platelets were documented before and after hemostasis. The efficacy of EndoClot was assessed 72 hours and 1 week after application. Results: Seventy patients with acute GI bleeding were recruited into the study. Eighty-three percent (58/70) of the patients had upper and 17% (12/70) had lower GI bleeding. In the upper GI tract treatment success was achieved in 64% (30/47, 95% confidence interval, 50%-76%) after primary use and in all patients, when used after established techniques had failed (95% confidence interval, 70%-100%). In lower GI bleeding hemostasis was achieved in 83% of cases (10/12, 95% confidence interval 54%-97%). Rebleeding occurred in 11% (8/70), in 10% EndoClot served as a bridge to surgery (7/70). Conclusions: EndoClot expanded the therapeutic options in the management of GI bleeding. It was applicable as a monotherapy or in combination with other techniques from oozing bleeding type or lower. It was most effective in diffuse or extensive bleeding activity or when access to the bleeding vessel was difficult. EndoClot can be applied as a bridge to surgery when classical methods of hemostasis have failed.

To the Editor – Eur. J. Immunol. 1/2006

We read with great interest the recent article by Roncador et al. [1]. These authors report on the characterization of seven generated anti-FOXP3 monoclonal antibodies and the distribution of FOXP3 expressing CD4CD25 cells in vivo. In addition, a commercially available goat polyclonal FOXP3 Ab (Abcam, ab2481) was evaluated and described to label human FOXP3 protein only in frozen tissue. In contrast to Roncador et al., we were able to successfully apply the Abcam goat polyclonal FOXP3 Ab to routinely fixed paraffin-embedded tissues. In a study on peripheral and intestinal regulatory CD4 CD25 T cells in inflammatory bowel disease, we used an amplification method combining a secondary rabbit anti-goat Ab followed by the EnVision peroxidase kit (DakoCytomation) for the detection of FOXP3 protein [2]. We have confirmed the immunophenotype of the regulatory T cells by double-labeling FOXP3/CD3 and FOXP3/CD25. In line with Roncador et al., we also observed scattered FOXP3 cells within the interfollicular area of tonsils serving as controls (Fig. 1) and few positive cells