Yun Qiu

Systematic review with meta-analysis: magnetic resonance enterography vs. computed tomography enterography for evaluating disease activity in small bowel Crohn's disease.

Magnetic resonance enterography (MRE) has been proposed as a non‐ionising alternative method to computed tomography enterography (CTE). Some studies have directly compared CTE and MRE in patients with small bowel Crohns disease (CD) with variable results.

Fecal calprotectin for evaluating postoperative recurrence of Crohn's disease: a meta-analysis of prospective studies.

Background:Fecal calprotectin (FC) levels have been extensively reported to correlate with clinical and endoscopic activities in Crohns disease (CD); however, the utility of FC levels in the postoperative setting remains to be determined. Using meta-analysis, we aimed to evaluate the utility of FC as a noninvasive marker of recurrence in patients with CD who had undergone previous surgical resection. Methods:An electronic search using keywords related to CD and FC was performed in multiple electronic resources from 1966 to March 2014. The extracted data were pooled using a hierarchical summary receiver operating curve model. Results:Ten articles met the inclusion criteria, and methodological quality was determined in detail for each study. The 10 studies presented FC levels in 613 postoperative CD patients. The pooled sensitivity and specificity values for assessing suspected endoscopic recurrence were 0.82 (95% confidence interval (CI), 0.73–0.89, 8 studies, n = 391) and 0.61 (95% CI, 0.51–0.71), respectively. The overall positive and negative likelihood ratios were 2.11 (95% CI, 1.68–2.66) and 0.29 (95% CI, 0.197–0.44), respectively. The pooled sensitivity and specificity values for evaluating clinical relapse were 0.59 (95% CI, 0.47–0.71; 3 studies, n = 183) and 0.88 (95% CI, 0.80–0.93), respectively. The overall positive and negative likelihood ratios were 5.10 and 0.47, respectively. Conclusions:As a simple and noninvasive marker, FC is useful in evaluating recurrence of postoperative patients with CD.

Upregulation of miR-665 promotes apoptosis and colitis in inflammatory bowel disease by repressing the endoplasmic reticulum stress components XBP1 and ORMDL3

MicroRNAs are critical post-transcriptional regulators of gene expression and key mediators of pathophysiology of inflammatory bowel disease (IBD). This study is aimed to study the role of miR-665 in the progression of IBD. Real-time PCR analysis was used to determine miR-665 expression in 89 freshly isolated IBD samples and dextran sulfate sodium (DSS)-induced colonic mucosal tissues. The role of miR-665 in inducing apoptosis and colitis were examined by Annexin V, TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) staining, colony formation in vitro and DSS-induced colitis mice model in vivo. Moreover, luciferase reporter assay, western blot analysis and microribonucleoprotein immunoprecipitation were performed to determine that miR-665 directly repressed XBP1 (X-box-binding protein-1) and ORMDL3 expression. Herein, our results revealed that miR-665 was markedly upregulated in active colitis. Gain-of-function and loss-of-function studies showed that ectopic expression of miR-665 promoted apoptosis under different inflammatory stimuli. Importantly, delivery of miR-665 mimic promoted, while injection of antagomiR-665 markedly impaired DSS-induced colitis in vivo. Mechanistically, we demonstrated that miR-665 induced apoptosis by inhibiting XBP1 and ORMDL3. Taken together, our findings reveal a new regulatory mechanism for ER stress signaling and suggest that miR-665 might be a potential target in IBD therapy.

Systematic review with meta-analysis: loss of response and requirement of anti-TNFα dose intensification in Crohn’s disease

BackgroundTo review the frequency with which anti-TNF-α loses its effect and dose “intensification” is required for Crohn’s disease (CD) treatment.MethodsElectronic databases were searched for eligible studies. Raw data from studies meeting inclusion criteria were pooled for effect estimates. Subgroup analyses were performed for exploration of heterogeneity regarding all outcomes.ResultsEighty-six eligible studies were included. Estimates of loss of response (LOR) incidence ranged from 8 to 71%. The random effects pooled incidence of LOR with a median follow-up of 1-year was 33% (95% CI 29–38, 55 studies, n = 6135). The effect estimate based on data from patients with infliximab was 33% (95% CI 27-40), 30% (95% CI 22–39) for adalimumab, and 41% (95% CI 30–53) for certolizumabpegol. Overall, the mean percentage of patients’ LOR to anti-TNFs was 38.5%. The annual risk for LOR was 20.9% per patient-year. The random-effects pooled rate of need for dose intensification with a median follow-up of 1 year was 34% (95% CI 28–41, 38 studies, n = 10,690). The effect estimate for infliximab was 38% (95% CI 28–50), 36% (95% CI 30–43) for adalimumab, and 2% (95% CI 2–3) for certolizumab-pegol. The mean percentage of patients who needed an anti-TNF dose escalation was 23% with an annual risk of 18.5% per patient-year. There was no evidence of publication bias for incidence of LOR but not for the dose intensification (p = 0.001).ConclusionsOverall, around one-third of CD patients experience a LOR and required dose intensification in primary anti-TNF-α responders.

Effects of Combination Therapy With Immunomodulators on Trough Levels and Antibodies Against Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Disease: A Meta-analysis

BACKGROUND & AIMS: It is not clear whether combination therapy with immunomodulators affects the immunogenicity of tumor necrosis factor (TNF) antagonists in patients with inflammatory bowel disease. We performed a meta‐analysis to quantify the effects of combined immunomodulator therapy on the presence of antibodies against TNF antagonists (antidrug antibodies [ADAs]) and trough levels of anti‐TNF agents. METHODS: We systematically searched publication databases for studies that reported prevalence of ADAs in patients who received anti‐TNF agents. Raw data from studies that met the inclusion criteria were pooled to determine effect estimates. We performed subgroup and metaregression analyses to determine the level of heterogeneity among study outcomes. RESULTS: We analyzed findings from 35 studies that met inclusion criteria (results reported from 6790 patients with inflammatory bowel disease). The pooled risk ratio for formation of ADAs in patients receiving combined therapy with immunomodulators, versus that of patients receiving anti‐TNF monotherapy, was 0.49 (95% confidence interval, 0.41–0.59; P < .001). However, the pooled analysis did not demonstrate a significant difference in trough levels of anti‐TNF agents between patients with versus without concurrent use of immunomodulators (standardized mean difference, 0.11; 95% confidence interval, 0.19–0.41; P = .47). Subgroup analyses of patients treated with different TNF antagonists revealed no difference in the formation of ADAs (P = .50 for interaction); the protective effect of immunomodulators did not differ with type of drug patients were given (methotrexate vs thiopurines), or assay for ADA. We observed heterogeneity only among studies of patients with ulcerative colitis (I2 = 76%). Funnel plot and Egger test analyses indicated publication bias in the studies (P = .001). CONCLUSIONS: In a meta‐analysis of published studies, we associated combined treatment with immunomodulators with reduced risk of formation of antibodies against TNF antagonists in patients with inflammatory bowel disease.

Human umbilical cord-derived mesenchymal stem cells protect against experimental colitis via CD5 + B regulatory cells

BackgroundTo clarify the effect of human umbilical cord-derived mesenchymal stem cell (hUC-MSCs) treatment on colitis and to explore the role of CD5+ B cells in MSC therapy.MethodsThe trinitrobenzenesulfonic acid (TNBS)-induced colitis mouse model was used. HUC-MSCs were transferred peritoneally. Survival rates, colitis symptoms, and macroscopic and histologic scores were evaluated. CD4+ T helper (Th) cell subgroups and CD5+ regulatory B cell (Bregs) in lymphocytes were quantitated by flow cytometry. Cytokine levels were detected by ELISA and Bio-plex. CD5+ B cells were isolated for in vitro co-culture and adaptive transfer.ResultsHUC-MSC treatment alleviated TNBS-induced colitis by increasing survival rates, relieving symptoms, and improving macroscopic and histologic scores. Labeled hUC-MSCs were located in the inflamed areas of colitis mice. Increases in regulatory T cells (Tregs) and CD5+ B cells and decreases in Th1 cells, Th17 cells, and several pro-inflammatory cytokines were observed with hUC-MSC treatment. After adaptive transfer, CD5+ B cells, which were located mainly in the peritoneal lavage fluid, improved TNBS-induced colitis by correcting Treg/Th1/Th17 imbalances. CD5+ B cells also inhibited T-cell proliferation and produced interleukin (IL)-10.ConclusionsHUC-MSCs protected against experimental colitis by boosting the numbers of CD5+ B cells and IL-10-producing CD5+ Bregs, and correcting Treg/Th17/Th1 imbalances.

Systematic Review with Meta-analysis of Prospective Studies: Anti-tumour Necrosis Factor for Prevention of Postoperative Crohn’s Disease Recurrence

BACKGROUND AND AIM Although promising, the evidence supporting the use of anti-tumour necrosis factor agents [anti-TNFs] in postoperative Crohns disease [CD] is still based on limited experience. We aimed to conduct a meta-analysis of prospective studies evaluating the efficacy and safety of anti-TNFs for prevention of postoperative recurrence [POR] in CD. METHODS MEDLINE, EMBASE, Web of Science, the Cochrane database and conference proceeding abstracts were searched. The primary outcome measure was the number of patients who developed POR as defined by the primary studies. RESULTS Six prospective studies were included. The rate of endoscopic recurrence [ER] was significantly lower using anti-TNFs [9.2%, 7/76] compared with the non-biologicals group [61.5%, 83/135] (odds ratio [OR] 0.05, 95% confidence interval [CI] 0.02-0.13; p < 0.001]. The rate of severe ER was also lower in the anti-TNFs group [1.6%, 1/64] than that in the non-biologicals group [32.7%, 18/55, OR 0.10; p = 0.04]. A significantly lower proportion of patients in the anti-TNFs group developed clinical recurrence [3.4%, 2/59] compared with the non-biologicals arm [41.1%, 49/119, OR 0.1; p < 0.001]. More anti-TNFs-treated patients [86.5%, 45/52] were maintained in clinical remission compared with the non-biologicals group [58.1%, 43/74, OR 4.05, 95% CI 1.60-10.29; p < 0.01]. The adverse events were similar between the two groups [anti-TNFs 44.9% [22/49] vs control 52.5% [42/80]; p = 0.69]. CONCLUSIONS Anti-TNFs are superior to non-biological agents in preventing endoscopic and clinical recurrence of CD without causing more adverse events.

Safety Profile of Thiopurines in Crohn Disease: Analysis of 893 Patient-Years Follow-Up in a Southern China Cohort.

AbstractThiopurines have been associated with both clinical improvement and mucosal healing in treating Crohn disease (CD). Unfortunately, the high rate of adverse events (AEs) leading to drug withdrawal represents a major limitation in the use of these drugs.To evaluate the safety of thiopurines in patients with CD. To identify predictive factors associated with the development of thiopurine-induced AEs and withdrawal.This longitudinal cohort study examined patients from a university-based IBD referral center. Time-to-event analysis was performed with the Kaplan–Meier curve. Cox regression analysis was performed to identify potential predictive factors of AEs.Two hundred sixty-seven CD patients on thiopurines were included. A total of 143 AEs occurred at a median of 7.4 months (interquartile range, 3.7–15.3 months) after starting treatment. The cumulative incidence of AEs was 26%, with an annual risk of 4.3% per patient-year of treatment. The most frequent was leucopenia (41/267, 15.36%), followed by infections (29/267, 10.86%). Independent factors predictive of leucopenia were lower baseline hemoglobin (hazard ratio (HR), 0.34; 95% confidence interval (CI) 0.18–0.67) and the concomitant use of 5-aminosalicylic acid (HR, 3.05; 95% CI 1.44–8.76). Of the 28.44% (76/267) CD patients discontinued therapy, 14.61% due to AEs. A lower body mass index, the presence of extraintestinal manifestation, and the incidence of leucopenia independently predicted thiopurine withdrawal. In total, 37.5% of these patients restarted thiopurines and 52.3% of them had AEs again.About a quarter of patients on thiopurine therapy had AEs during follow-up and 1 of 7 patients had to discontinue thiopurines due to AEs.

Serum Interleukin 9 Levels Predict Disease Severity and the Clinical Efficacy of Infliximab in Patients with Crohnʼs Disease

Background: Interleukin (IL)-9 drives gut inflammation, but its role in Crohns disease (CD) is unclear. We aimed to analyze correlations between serum IL-9 levels and disease severity and to evaluate their predictive value in relation to the clinical efficacy of infliximab (IFX) in patients with CD. Methods: Between January 2013 and December 2015, 100 consecutive patients with active CD and 50 age- and sex-matched control individuals were recruited from a tertiary center. Their serum IL-9 levels were measured using an enzyme-linked immunosorbent assay. Correlations between the serum IL-9 levels and disease severity were examined. The serum IL-9 level was explored as a predictor of clinical remission and mucosal healing at week 30 in 50 patients for whom IFX therapy was administered. Results: The serum IL-9 levels were significantly higher in the patients with active CD (22.0 pg/mL) than in the control individuals (6.3 pg/mL) (P < 0.001); they differed according to disease severity (moderate-to-severe CD: 29.1 pg/mL versus mild CD: 12.9 pg/mL) (P < 0.001), and they correlated well with the clinical activity of CD. IFX lowered the serum IL-9 level in patients who achieved efficacy at week 30. The areas under the curves for the IL-9 levels at weeks 14 and 30 that could predict clinical remission and mucosal healing at week 30 were 0.803 and 0.752 and 0.746 and 0.781, respectively. Conclusions: Serum IL-9 levels correlate with disease severity and the clinical efficacy of IFX in patients with CD, and IL-9 may be a promising novel biomarker for CD monitoring.

Over-reaching beyond disease activity: the influence of anxiety and medical economic burden on health-related quality of life in patients with inflammatory bowel disease.

Purpose Many patients with inflammatory bowel disease (IBD) have impaired health-related quality of life (HRQOL). The influence of psychological and economic factors on HRQOL has not been fully elucidated in IBD. Therefore, we aimed to identify the predictors of HRQOL in an IBD cohort. Patients and methods This was a cross-sectional cohort study of patients presenting to our tertiary IBD center. HRQOL was measured using the 36-item Short Form Health Survey (SF-36) and the Inflammatory Bowel Disease Questionnaire (IBDQ). Anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HADS). Perceived stress and perceived social support were also assessed by standardized scales. Demographic, socioeconomic and clinical data were obtained from a prespecified questionnaire and patients’ medical records. Univariate analyses and multiple regression analysis were performed to identify predictors of HRQOL. Results A total of 242 IBD patients were recruited, and the questionnaire return rate was 90.5% (219/242). The prevalence rates of anxiety and depression were 24.7% and 17.4%, respectively. In all, 30.6% of the patients spent over half of their income to cover medical costs. Multivariate analysis revealed that anxiety symptoms (P<0.001), active disease (P<0.001) and higher medical expenditures (P=0.001) were strong and independent predictors of reduced HRQOL. Conclusion Psychological factors and costs of medical care strongly impair HRQOL in IBD, independent of the disease activity. Psychological counseling and socioeconomic support programs should be considered for integration into the management of IBD patients.