Ren Mao

Fecal calprotectin in predicting relapse of inflammatory bowel diseases: a meta-analysis of prospective studies.

Background: Fecal calprotectin (FC) is a relatively new marker of intestinal inflammation. Recently, many studies have extended its role in predicting relapse of quiescent inflammatory bowel disease (IBD), but the reported results have been inconsistent. We aimed to perform a meta‐analysis of the predictive capacity of FC in IBD relapse. Methods: We systematically searched the Medline, Web of Science, Cochrane Library, and EMBASE databases for prospective studies that used FC concentrations at remission in predicting relapse of Crohns disease (CD) and ulcerative colitis (UC). Pooled sensitivity, specificity, and other diagnostic indices were evaluated. Results: A total of 672 IBD patients (318 UC and 354 CD) from six different studies were analyzed. The pooled sensitivity and specificity of FC to predict relapse of quiescent IBD was 78% (95% confidence interval [CI]: 72–83) and 73% (95% CI: 68–77), respectively. The area under the summary receiver‐operating characteristic (sROC) curve was 0.83 and the diagnostic odds ratio was 10.31 (95% CI: 5.05–21.06). The capacity of FC to predict relapse was comparable between UC and CD. In CD patients the predictive value of FC in isolated small bowel CD was not assessed due to insufficiency of available data. Compared with all enrolled CD patients, FC appeared to be more accurate in ileocolonic and colonic CD. Conclusions: As a simple and noninvasive marker, FC is useful to predict relapse in quiescent IBD patients. (Inflamm Bowel Dis 2012)

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.

Computed tomographic enterography adds value to colonoscopy in differentiating Crohn’s disease from intestinal tuberculosis: a potential diagnostic algorithm

BACKGROUND Crohns disease and intestinal tuberculosis (ITB) are chronic granulomatous disorders that are difficult to distinguish. Computed tomographic enterography (CTE) yields striking findings for Crohns disease in the small bowel but its role in differentiating Crohns from ITB is undefined. This prospective study aimed to investigate the value of CTE for differential diagnosis between Crohns disease and ITB. PATIENTS AND METHODS 105 consecutive patients (67 Crohns, 38 ITB) who underwent CTE and colonoscopy were enrolled. CTE findings and colonoscopic parameters were compared between Crohns disease and ITB by blinded reviewers. Based on univariate and multiple logistic regression analyses, a diagnostic algorithm combining colonoscopy and CTE was formulated. and its performance validated on 60 new patients (40 Crohns, 20 ITB). RESULTS On univariate analysis of CTE findings, proximal small-bowel involvement, asymmetrical mural thickening, segmental small-bowel lesions, mural stratification, the comb sign, and mesentery fibrofatty proliferation were significantly more common in Crohns disease, whereas mesenteric lymph node change (calcification or central necrosis) and focal ileocecal lesions were more common in ITB. On multivariate analysis, segmental small-bowel involvement (odds ratio [OR] 0.104, 95 % confidence interval [95 %CI] 0.022 - 0.50), and comb sign (OR 0.02, 95 %CI 0.003 - 0.26) were independent predictors of Crohns. Combining CTE and colonoscopic findings increased the accuracy of diagnosing either Crohns disease or ITB from 66.7 % (70/105) to 95.2 % (100/105) in the development set (P < 0.001). Sensitivity, specificity, and area under the curve for receiver-operating characteristic (ROC) in the validation dataset were 92.5 %, 80 %, and 0.862 (95 %CI 0.75 - 0.98), respectively. CONCLUSIONS CTE adds unique information to colonoscopy in differential diagnosis between Crohns disease and ITB, allowing correct diagnosis in most patients.

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.

Assessment of Activity of Crohn Disease by Diffusion-Weighted Magnetic Resonance Imaging.

AbstractTo assess the diagnostic efficacy of diffusion-weighted MR imaging (DWI) for evaluating inflammatory activity in patients with Crohns disease (CD). A total of 47 CD patients underwent MR enterography (MRE) and DWI using 3 b values of 50, 400, and 800 s/mm.2 Apparent diffusion coefficients (ADCs) of inflamed and normal bowel wall were calculated. The conventional MRE findings and DWI signal intensities were qualitatively scored from 0 to 3. The correlation between Crohn disease activity index (CDAI) and both ADCs and magnetic resonance imaging scores was analyzed. Receiver-operating characteristic curve analysis was used to determine the diagnostic accuracy of CD activity. Of the 47 patients, 25 were active CD (CDAI≥150) and 22 were inactive (CDAI<150). Diffusion-weighted MR imaging and MRE + DWI scores of active CD were significantly higher than that of inactive CD (both P < 0.001). Apparent diffusion coefficients in inflamed segments of active CD were lower than that of inactive CD (P < 0.001). The DWI scores (r = 0.74, P < 0.001), ADCs (r = −0.71, P < 0.001), MRE scores (r = 0.54, P < 0.001), and MRE + DWI scores (r = 0.66, P < 0.001) were all correlated with CDAI. The areas under the receiver-operating characteristics curves for ADCs, DWI scores, MRE scores, and MRE + DWI scores ranged from 0.83 to 0.98. The threshold ADC value of 1.17 × 10−3 mm2/s allowed differentiation of active from inactive CD with 100% sensitivity and 88% specificity. Diffusion-weighted MR imaging and ADC correlated with CD activity, and had excellent diagnostic accuracy for differentiating active from inactive CD.

Association of Vedolizumab Level, Anti-Drug Antibodies, and α4β7 Occupancy With Response in Patients With Inflammatory Bowel Diseases

Background & Aims: There are few data available on the real‐life pharmacokinetic and pharmacodynamics features of vedolizumab, a monoclonal antibody against integrin &agr;4&bgr;7. We performed a prospective study of patients with inflammatory bowel diseases (IBDs) treated with vedolizumab to determine serum drug concentrations, formation of antivedolizumab antibodies (AVAs), and integrin &agr;4&bgr;7 saturation. Methods: We performed a prospective study of 106 patients with IBD (67 with Crohn’s disease and 39 with ulcerative colitis) treated with vedolizumab from September 2014 through March 2017 at 2 tertiary medical centers in Israel. Clinical data and serum samples were collected before and during induction and maintenance therapy. Clinical remission was defined as Harvey–Bradshaw index scores below 5 or as Simple Clinical Colitis Activity Index scores of 3 or less. We measured serum levels of vedolizumab, AVAs, and markers of inflammation. Peripheral blood mononuclear cells were obtained from some patients at designated trough time points and CD3+ CD45RO+ T cells were isolated from 36 samples. Cells were incubated with fluorescent‐conjugated vedolizumab and flow cytometry was used to quantify &agr;4&bgr;7 integrin saturation. We also performed flow cytometry analyses of CD3+ CD45RO+ lamina propria T cells isolated from intestinal mucosa of patients without IBD (non‐IBD controls, n = 6), patients with IBD not treated with vedolizumab (untreated IBD controls, n = 8), and patients with IBD treated with vedolizumab (n = 15). Results: Clinical remission was achieved by 48 of 106 patients (45%) by week 6 and 50 of 106 patients (48%) by week 14 of treatment. The median level of vedolizumab at week 6 was higher in patients in clinical remission (40.2 &mgr;g/mL) than in patients with active disease (29.7 &mgr;g/mL; P =.05). The median serum level of vedolizumab was significantly higher in patients with a normal level of C‐reactive protein (21.8 &mgr;g/mL vedolizumab) vs the level in those with a high level of C‐reactive protein (11.9 &mgr;g/mL vedolizumab) during maintenance treatment (P =.0006). The other clinical outcomes measured were not associated with median serum level of vedolizumab at any time point examined. AVAs were detected in 17% of patients during induction therapy and 3% of patients during maintenance therapy, but did not correlate with clinical outcomes. Flow‐cytometry analysis of peripheral blood memory T cells (n = 36) showed near‐complete occupancy of &agr;4&bgr;7 integrin at weeks 2 and 14 and during the maintenance phase, regardless of response status or drug levels. Most intestinal CD3+CD45RO+ memory T cells of healthy and IBD controls expressed &agr;4&bgr;7 (72%; interquartile range, 56%–81%). In contrast, free &agr;4&bgr;7 was detectable on only 5.6% of intestinal memory cells (interquartile range, 4.4%–11.2%) (P <.0001) from vedolizumab‐treated patients, regardless of response. Conclusions: In a prospective study of real‐life patients with IBD, we associated vedolizumab drug levels with remission and inflammatory marker level. Integrin &agr;4&bgr;7 was blocked in almost all T cells from patients treated with vedolizumab, regardless of serum level of the drug or response to treatment. These findings indicate a need to explore alternative mechanisms that prevent response to vedolizumab.

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.

Optimizing biologic treatment in IBD: objective measures, but when, how and how often?

BackgroundThe advent of biologic agents for the treatment of inflammatory bowel disease (IBD) was accompanied in parallel with emerging understanding of persisting underlying inflammation and ensuing bowel damage that can occur even in patients with seeming clinical remission. This lead to the concepts of mucosal healing and deep remission gaining acceptance as the more desired goals for therapy within an ambitious disease-control therapeutic approach, namely, treat-to-target strategy. However, how to practically monitor IBD patients, which objective measures to follow, at what time-points and whether to act upon results in asymptomatic patients are all questions that remain disputed.Methods and resultIn this concise review we aim to provide an overview of objective measures for monitoring of IBD patients, focusing on the challenging group of patients treated by infliximab, adalimumab, vedolizumab and other biologics. These objective measures are discussed in the context of the different common clinical scenarios wherein the clinician may contemplate their use. Specifically, we will delineate the role of objective parameters to be monitored during induction phase of treatment, during maintenance therapy, at loss of response and after elective cessation of therapy in patients in remission.ConclusionCoupled with the non-negligible costs of therapy, and the over-all worse prognosis of moderate-severe patients who are the usual recipients of biologic therapies, this challenging patients seem to be the first candidates for this more proactive strategy combining inflammatory and pharmacokinetic monitoring of objective inflammatory and pharmacokinetic measures. More data is still desirable to better define the exact parameters to be followed and their optimal thresholds, and to delineate the optimal cost-effective interventions for these patients.