Welmoed K. van Deen

MicroRNA214 Is Associated With Progression of Ulcerative Colitis, and Inhibition Reduces Development of Colitis and Colitis-Associated Cancer in Mice

BACKGROUND & AIMS Persistent activation of the inflammatory response contributes to the development of inflammatory bowel diseases, which increase the risk of colorectal cancer. We aimed to identify microRNAs that regulate inflammation during the development of ulcerative colitis (UC) and progression to colitis-associated colon cancer (CAC). METHODS We performed a quantitative polymerase chain reaction analysis to measure microRNAs in 401 colon specimens from patients with UC, Crohns disease, irritable bowel syndrome, sporadic colorectal cancer, or CAC, as well as subjects without these disorders (controls); levels were correlated with clinical features and disease activity of patients. Colitis was induced in mice by administration of dextran sodium sulfate (DSS), and carcinogenesis was induced by addition of azoxymethane; some mice also were given an inhibitor of microRNA214 (miR214). RESULTS A high-throughput functional screen of the human microRNAome found that miR214 regulated the activity of nuclear factor-κB. Higher levels of miR214 were detected in colon tissues from patients with active UC or CAC than from patients with other disorders or controls and correlated with disease progression. Bioinformatic and genome-wide profile analyses showed that miR214 activates an inflammatory response and is amplified through a feedback loop circuit mediated by phosphatase and tensin homolog (PTEN) and PDZ and LIM domain 2 (PDLIM2). Interleukin-6 induced signal transducer and activator of transcription 3 (STAT3)-mediated transcription of miR214. A miR214 chemical inhibitor blocked this circuit and reduced the severity of DSS-induced colitis in mice, as well as the number and size of tumors that formed in mice given azoxymethane and DSS. In fresh colonic biopsy specimens from patients with active UC, the miR214 inhibitor reduced inflammation by increasing levels of PDLIM2 and PTEN. CONCLUSIONS Interleukin-6 up-regulates STAT3-mediated transcription of miR214 in colon tissues, which reduces levels of PDLIM2 and PTEN, increases phosphorylation of AKT, and activates nuclear factor-κB. The activity of this circuit correlates with disease activity in patients with UC and progression to colorectal cancer.

Optimization of human mesenchymal stem cell manufacturing: the effects of animal/xeno-free media

Due to their immunosuppressive properties, mesenchymal stem cells (MSC) have been evaluated for the treatment of immunological diseases. However, the animal-derived growth supplements utilized for MSC manufacturing may lead to clinical complications. Characterization of alternative media formulations is imperative for MSC therapeutic application. Human BMMSC and AdMSC were expanded in media supplemented with either human platelet lysates (HPL), serum-free media/xeno-free FDA-approved culture medium (SFM/XF), or fetal bovine serum (FBS) and the effects on their properties were investigated. The immunophenotype of resting and IFN-γ primed BMMSC and AdMSC remained unaltered in all media. Both HPL and SFM/XF increased the proliferation of BMMSC and AdMSC. Expansion of BMMSC and AdMSC in HPL increased their differentiation, compared to SFM/XF and FBS. Resting BMMSC and AdMSC, expanded in FBS or SFM/XF, demonstrated potent immunosuppressive properties in both non-primed and IFN-γ primed conditions, whereas HPL-expanded MSC exhibited diminished immunosuppressive properties. Finally, IFN-γ primed BMMSC and AdMSC expanded in SFM/XF and HPL expressed attenuated levels of IDO-1 compared to FBS. Herein, we provide strong evidence supporting the use of the FDA-approved SFM/XF medium, in contrast to the HPL medium, for the expansion of MSC towards therapeutic applications.

A nationwide 2010-2012 analysis of U.S. health care utilization in inflammatory bowel diseases.

Background:Implementation of the 2010 Affordable Care Act (ACA) calls for a collaborative effort to transform the U.S. health care system toward patient-centered and value-based care. To identify how specialty care can be improved, we mapped current U.S. health care utilization in patients with inflammatory bowel diseases (IBD) using a national insurance claims database. Methods:We performed a cross-sectional study analyzing U.S. health care utilization in 964,633 patients with IBD between 2010 and 2012 using insurance claims data, including pharmacy and medical claims. Frequency of IBD-related care utilization (medication, tests, and treatments) and their charges were evaluated. Subsequently, outcomes were put into the framework of current U.S. guidelines to identify areas of improvement. Results:A disproportionate usage of aminosalicylates in Crohns disease (42%), frequent corticosteroid use (46%, with 9% long-term users), and low rates of corticosteroid-sparing drugs (thiopurines 15%; methotrexate 2.7%) were observed. Markers for inflammatory activity, such as C-reactive protein or fecal calprotectin were not commonly used (8.8% and 0.13%, respectively). Although infrequently used (11%), anti-TNF antibody therapy represents a major part of observed IBD charges. Conclusions:This analysis shows 2010–2012 utilization and medication patterns of IBD health care in the United States and suggests that improvement can be obtained through enhanced guidelines adherence.

The impact of value-based healthcare for inflammatory bowel diseases on healthcare utilization: a pilot study.

Background and objectives Value-based healthcare (VBHC) is considered to be the solution that will improve quality and decrease costs in healthcare. Many hospitals are implementing programs on the basis of this strategy, but rigorous scientific reports are still lacking. In this pilot study, we present the first-year outcomes of a VBHC program for inflammatory bowel disease (IBD) management that focuses on highly coordinated care, task differentiation of providers, and continuous home monitoring. Methods IBD patients treated within the VBHC program were identified in an administrative claims database from a commercial insurer allowing comparisons to matched controls. Only patients for whom data were available the year before and after starting the program were included. Healthcare utilization including visits, hospitalizations, laboratory and imaging tests, and medications were compared between groups. Results In total, 60 IBD patients treated at the VBHC Center were identified and were matched to 177 controls. Significantly fewer upper endoscopies were performed (−10%, P=0.012), and numerically fewer surgeries (−25%, P=0.49), hospitalizations (−28%, 0=0.71), emergency department visits (-37%, P=0.44), and imaging studies (−25 to −86%) were observed. In addition, 65% fewer patients (P=0.16) used steroids long term. IBD-related costs were 16% (

Presenteeism in Inflammatory Bowel Diseases: A Hidden Problem with Significant Economic Impact

771) lower than expected (P=0.24). Conclusion These are the first results of a successfully implemented VBHC program for IBD. Encouraging trends toward fewer emergency department visits, hospitalizations, and long-term corticosteroid use were observed. These results will need to be confirmed in a larger sample with more follow-up.

Anti-TNF Antibodies in Inflammatory Bowel Disease: Do We Finally Know How it Works?

Background:Indirect costs associated with impaired productivity at work (presenteeism) due to inflammatory bowel disease (IBD) are a major contributor to health expenditures. Studies estimating indirect costs in the United States did not take presenteeism into account. We aimed to quantify work limitations and presenteeism and its associated costs in an IBD population to generate recommendations to reduce presenteeism and decrease indirect costs. Methods:We performed a prospective study at a tertiary IBD center. During clinic visits, work productivity, work-related problems and adjustments, quality of life, and disease activity were assessed in patients with IBD. Work productivity and impairment were assessed in a control population as well. Indirect costs associated with lost work hours (absenteeism) and presenteeism were estimated, as well as the effect of disease activity on those costs. Results:Of the 440 included patients with IBD, 35.6% were unemployed. Significantly more presenteeism was detected in patients with IBD (62.9%) compared with controls (27.3%) (P = 0.004), with no significant differences in absenteeism. Patients in remission experienced significantly more presenteeism than controls (54.7% versus 27.3%, respectively, P < 0.01), and indirect costs were significantly higher for remissive patients versus controls (

Immunomodulatory Effects of Mesenchymal Stromal Cells in Crohn’s Disease

17,766 per yr versus

Value-based health care for inflammatory bowel diseases.

9179 per yr, respectively, P < 0.03). Only 34.3% had made adjustments to battle work-related problems such as fatigue, irritability, and decreased motivation. Conclusions:Patients with IBD in clinical remission still cope with significantly more presenteeism and work limitations than controls; this translates in higher indirect costs and decreased quality of life. The majority have not made any adjustments to battle these problems.

Developing a Standard Set of Patient-Centred Outcomes for Inflammatory Bowel Disease-an International, Cross-disciplinary Consensus

Tumor necrosis factor (TNF) is a central pro-inflammatory cytokine that regulates the expression of numerous signaling pathways implicated in the progression of the immunological reaction. Unraveling the importance of TNF on the pathogenesis of inflammatory bowel disease (IBD) promoted anti-TNF antibodies as novel therapeutic agents. Initially, the main hypothesis behind the clinical application of anti-TNF antagonists in the clinic was that they exert their effects solely through neutralization of TNF. Anti-TNF antibodies induce and maintain clinical remission in patients with minimal side-effects. However, the cellular and molecular mechanisms of actions of the anti-TNF antibodies remain unknown. Various mechanisms of action have been proposed such as activation of transmembrane TNF mediated reverse signaling, induction of apoptosis, pro-inflammatory cytokine down-regulation, complement dependent cytotoxicity, antibodydependent cell-mediated cytotoxicity, and finally activation of regulatory immune cells via interactions with the Fc receptors. The observed discrepancies in the clinical efficacies as well as the differences in the structure of the various TNF antagonists nourish the investigation for additional modes of function.

Value redefined for inflammatory bowel disease patients: a choice-based conjoint analysis of patients’ preferences

The ability of mesenchymal stromal cells (MSCs) to suppress immune responses combined with their potential to actively participate in tissue repair provides a strong rationale for the use of MSCs as a new treatment option in diseases characterized by inflammation and severe tissue damage, such as Crohns disease (CD) and perianal fistulas. Multiple studies have shown that MSCs suppress a range of immune cells, such as dendritic cells (DC), naïve and effector T cells, and natural killer (NK) cells. Recently published papers attribute the immunosuppressive capacity of MSCs to soluble factors produced by MSCs, such as prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), and indoleamine 2,3-dioxygenase (IDO). Promising results are obtained from phase I and II clinical trials with autologous and allogeneic MSCs as treatment for refractory CD and perianal fistulas; however the question remains: what are the molecular mechanisms underlying the immunomodulating properties of MSCs? This paper highlights the present knowledge on the immunosuppressive effects of MSCs and its complexity in relation to CD and perianal fistulas.