Mucosal healing(MH)is vital in maintaining homeostasis within the gut and protecting against injury and infections.Multiple factors and signaling pathways contribute in a dynamic and coordinated manner to maintain int...Mucosal healing(MH)is vital in maintaining homeostasis within the gut and protecting against injury and infections.Multiple factors and signaling pathways contribute in a dynamic and coordinated manner to maintain intestinal homeostasis and mucosal regeneration/repair.However,when intestinal homeostasis becomes chronically disturbed and an inflammatory immune response is constitutively active due to impairment of the intestinal epithelial barrier autoimmune disease results,particularly inflammatory bowel disease(IBD).Many proteins and signaling pathways become dysregulated or impaired during these pathological conditions,with the mechanisms of regulation just beginning to be understood.Consequently,there remains a relative lack of broadly effective therapeutics that can restore MH due to the complexity of both the disease and healing processes,so tissue damage in the gastrointestinal tract of patients,even those in clinical remission,persists.With increased understanding of the molecular mechanisms of IBD and MH,tissue damage from autoimmune disease may in the future be ameliorated by developing therapeutics that enhance the body’s own healing response.In this review,we introduce the concept of mucosal healing and its relevance in IBD as well as discuss the mechanisms of IBD and potential strategies for altering these processes and inducing MH.展开更多
AIM To evaluate the utility of fecal calprotectin(FC) in predicting relapse and endoscopic activity during follow-up in an inflammatory bowel disease(IBD) cohort.METHODS All FC measurements that were obtained during a...AIM To evaluate the utility of fecal calprotectin(FC) in predicting relapse and endoscopic activity during follow-up in an inflammatory bowel disease(IBD) cohort.METHODS All FC measurements that were obtained during a 3-year period from patients with inflammatory bowel disease in clinical remission were identified. Data regarding the short-term(6 mo) course of the disease were extracted from the medical files. Exclusion criteria were defined as:(1) An established flare of the disease at the time of FC measurement,(2) Loss to follow up within 6 mo from baseline FC measurement, and,(3) Insufficient data on file. Statistical analysis was performed to evaluate whether baseline FC measurement could predict the short term clinical relapse and/or the presence of mucosal healing.RESULTS We included 149 [Crohn's disease(CD) = 113, Ulcerative colitis(UC) = 36, male = 77] IBD patients in our study. Within the determined 6-month period post-FC measurement, 47(31.5%) had a disease flare. Among 76 patients who underwent endoscopy, 39(51.3%) had mucosal healing. Baseline FC concentrations were significantly higher in those who had clinical relapse compared to those who remained in remission during follow up(481.0 μg/g, 286.0-600.0 vs 89.0, 36.0-180.8, P < 0.001). The significant predictive value of baseline median with IQR FC for clinical relapse was confirmed by multivariate Cox analysis [HR for 100μg/g: 1.75(95%CI: 1.28-2.39), P = 0.001]. Furthermore, lower FC baseline values significantly correlated to the presence of mucosal healing in endoscopy(69.0 μg/g, 30.0-128.0 vs 481.0, 278.0-600.0, in those with mucosal inflammation, median with IQR, P < 0.001). We were able to extract cut-off values for FC concentration with a high sensitivity and specificity for predicting clinical relapse(261 μg/g with AUC = 0.901, sensitivity 87.2%, specificity 85.3%, P < 0.001) or mucosal healing(174 μg/g with AUC = 0.956, sensitivity 91.9%, specificity 87.2%, P < 0.001). FC was better than CRP in predicting either outcome; nevertheless, having a pathological CRP(> 5 mg/L) in addition to the cutoffs for FC, significantly enhanced the specificity for predicting clinical relapse(95.1% from 85.3%) or endoscopic activity(100% from 87.2%). CONCLUSION Serial FC measurements may be useful in monitoring IBD patients in remission, as FC appears to be a reliable predictor of short-term relapse and endoscopic activity.展开更多
Mucosal healing(MH)has emerged as a key therapeutic target in inflammatory bowel disease(IBD),and achievement of this goal is documented by endoscopy with biopsy.However,colonoscopy is burdensome and invasive,and subs...Mucosal healing(MH)has emerged as a key therapeutic target in inflammatory bowel disease(IBD),and achievement of this goal is documented by endoscopy with biopsy.However,colonoscopy is burdensome and invasive,and substitution with an accurate noninvasive biomarker is desirable.AIM To summarize published data regarding the performance of noninvasive biomarkers in assessing MH in IBD patients.METHODS We conducted a systematic review of studies that reported the performance of biomarkers in diagnosing MH in patients with IBD.The main outcome measure was to review the diagnostic accuracy of serum and fecal markers that showed promising utility in assessing MH.RESULTS We screened 1301 articles,retrieved 46 manuscripts and included 23 articles for full-text analysis.The majority of the included manuscripts referred to fecal markers(12/23),followed by circulatory markers(8/23);only 3/23 of the included manuscripts investigated combined markers(serum and/or fecal markers).Fecal calprotectin(FC)was the most investigated fecal marker for assessing MH.In ulcerative colitis,for cutoff levels ranging between 58 mcg/g and 490 mcg/g,the sensitivity was 89.7%-100%and the specificity was 62%-93.3%.For Crohn’s disease,the cutoff levels of FC ranged from 71 mcg/g to 918 mcg/g(sensitivity 50%-95.9%and specificity 52.3%-100%).The best performance for a serum marker was observed for the endoscopic healing index,which showed a comparable accuracy to the measurement of FC and a higher accuracy than the measurement of serum C-reactive protein.CONCLUSION Several promising biomarkers of MH are emerging but cannot yet substitute for endoscopy with biopsy due to issues with reproducibility and standardization assessing MH.In ulcerative colitis,for cutoff levels ranging between 58 mcg/g and 490 mcg/g,the sensitivity was 89.7%-100%and the specificity was 62%-93.3%.For Crohn’s disease,the cutoff levels of FC ranged from 71 mcg/g to 918 mcg/g(sensitivity 50%-95.9%and specificity 52.3%-100%).The best performance for a serum marker was observed for the endoscopic healing index,which showed a comparable accuracy to the measurement of FC and a higher accuracy than the measurement of serum C-reactive protein.CONCLUSION Several promising biomarkers of MH are emerging but cannot yet substitute for endoscopy with biopsy due to issues with reproducibility and standardization.展开更多
AIM:To determine the difference in clinical outcome between ulcerative colitis(UC)patients with Mayo endoscopic subscore(MES)0 and those with MES 1.METHODS:UC patients with sustained clinical remission of 6 mo or more...AIM:To determine the difference in clinical outcome between ulcerative colitis(UC)patients with Mayo endoscopic subscore(MES)0 and those with MES 1.METHODS:UC patients with sustained clinical remission of 6 mo or more at the time of colonoscopy were examined for clinical outcomes and the hazard ratios of clinical relapse according to MES.Parameters,including blood tests,to identify predictive factors for MES 0and slight endoscopic recurrence in clinically stablepatients were assessed.Moreover,a receiver operating characteristic curve was generated,and the area under the curve was calculated to indicate the utility of the parameters for the division between complete and partial mucosal healing.All P values were two-sided and considered significant when less than 0.05.RESULTS:A total of 183 patients with clinical remission were examined.Patients with MES 0(complete mucosal healing:n=80,44%)were much less likely to relapse than those with MES 1(partial mucosal healing:n=89,48%)(P<0.0001,log-rank test),and the hazard ratio of risk of relapse in patients with MES 1 vs MES0 was 8.17(95%CI:4.19-17.96,P<0.0001).The platelet count(PLT)<26×104/μL was an independent predictive factor for complete mucosal healing(OR=4.1,95%CI:2.15-7.99).Among patients with MES 0 at the initial colonoscopy,patients of whom colonoscopy findings shifted to MES 1 showed significant increases in PLT compared to those who maintained MES 0(3.8×104/μL vs-0.6×104/μL,P<0.0001).CONCLUSION:The relapse rate differed greatly between patients with complete and partial mucosal healing.A shift from complete to partial healing in clinically stable UC patients can be predicted by monitoring PLT.展开更多
AIM: To review the published literature concerning the accuracy of faecal inflammatory markers for identifying mucosal healing. METHODS: Bibliographical searches were performed in MEDLINE electronic database up to Feb...AIM: To review the published literature concerning the accuracy of faecal inflammatory markers for identifying mucosal healing. METHODS: Bibliographical searches were performed in MEDLINE electronic database up to February 2015,using the following terms: "inflammatory bowel disease","Crohn′s disease","ulcerative colitis","faecal markers","calprotectin","lactoferrin","S100A12","endoscop*","mucosal healing","remission". In addition,relevant references from these studies were also included. Data were extracted from the published papers including odds ratios with 95%CI,P values and correlation coefficients. Data were grouped together according to each faecal marker,Crohn's disease or ulcerative colitis,and paediatric compared with adult study populations. Studies included in this review assessed mucosal inflammation by endoscopic and/or histological means and compared these findings to faecal marker concentrations in inflammatory bowel diseases(IBD) patient cohorts. Articles had to be published between 1990 and February 2015 and written in English. Papers excluded from the review were those where the faecal biomarker concentration was compared between patients with IBD and controls or other disease groups,those where serum biomarkers were used,those with a heterogeneous study population and those only assessing post-operative disease. RESULTS: The available studies show that faecal markers,such as calprotectin and lactoferrin,are promising non-invasive indicators of mucosal healing. However,due to wide variability in study design,especially with regard to the definition of mucosal healing and evaluation of marker cut offs,the available data do not yet indicate the optimal roles of these markers. Thirty-six studies published between 1990 and 2014 were included. Studies comprised variable numbers of study participants,considered CD(15-164 participants) or UC(12-152 participants) separately or as a combined group(11-252 participants). Eight reports included paediatric patients. Several indices were used to document mucosal inflammation,encompassing elevenendoscopic and eight histologic grading systems. The majority of the available reports focused on faecal calprotectin(33 studies),whilst others assessed faecal lactoferrin(13 studies) and one study assessed S100A12. Across all of the biomarkers,there is a wide range of correlation describing the association between faecal markers and endoscopic disease activity(r values ranging from 0.32 to 0.87,P values ranging from < 0.0001 to 0.7815). Correlation coefficients are described in almost all studies and are used more commonly than outcome measures such as sensitivity,specificity,PPV and/or NPV. Overall,the studies that have evaluated faecal calprotectin and/or faecal lactoferrin and their relationship with endoscopic disease activity show inconsistent results. CONCLUSION: Future studies should report the results of faecal inflammatory markers in the context of mucosal healing with clear validated cut offs.展开更多
Ulcerative colitis(UC), a chronic, relapsing, remitting disease of the colon and rectum, is characterized by inflammatory ulceration of the mucosa. Current UC therapy relies on controlling acute episodes and preventin...Ulcerative colitis(UC), a chronic, relapsing, remitting disease of the colon and rectum, is characterized by inflammatory ulceration of the mucosa. Current UC therapy relies on controlling acute episodes and preventing relapse. To predict modifications in the natural course of UC, mucosal healing(MH) has emerged as a major treatment goal. Endoscopic evaluation is considered the gold standard for assessing MH, which can be achieved by conventional drugs and biologics in many, but not all, patients. Consequently, interest is focusing on the development of new substances for UC therapy, and new oral agents are in the pipeline. This review will focus on the ability of newly developed oral drugs to induce and maintain MH in UC patients.展开更多
The use of specific terms under different meanings and varying definitions has always been a source of confusion in science.When we point our efforts towards an evidence based medicine for inflammatory bowel diseases(...The use of specific terms under different meanings and varying definitions has always been a source of confusion in science.When we point our efforts towards an evidence based medicine for inflammatory bowel diseases(IBD)the same is true:Terms such as"mucosal healing"or"deep remission"as endpoints in clinical trials or treatment goals in daily patient care may contribute to misconceptions if meanings change over time or definitions are altered.It appears to be useful to first have a look at the development of terms and their definitions,to assess their intrinsic and context-independent problems and then to analyze the different relevance in present-day clinical studies and trials.The purpose of such an attempt would be to gain clearer insights into the true impact of the clinical findings behind the terms.It may also lead to a better defined use of those terms for future studies.The terms"mucosal healing"and"deep remission"have been introduced in recent years as new therapeutic targets in the treatment of IBD patients.Several clinical trials,cohort studies or inception cohorts provided data that the long term disease course is better,when mucosal healing is achieved.However,it is still unclear whether continued or increased therapeutic measures will aid or improve mucosal healing for patients in clinical remission.Clinical trials are under way to answer this question.Attention should be paid to clearly address what levels of IBD activity are looked at.In the present review article authors aim to summarize the current evidence available on mucosal healing and deep remission and try to highlight their value and position in the everyday decision making for gastroenterologists.展开更多
In the past decade, thanks to the introduction of biologic therapies, a new therapeutic goal, mucosal healing(MH), has been introduced. MH is the expression of an arrest of disease progression, resulting in minor hosp...In the past decade, thanks to the introduction of biologic therapies, a new therapeutic goal, mucosal healing(MH), has been introduced. MH is the expression of an arrest of disease progression, resulting in minor hospitalizations, surgeries, and prolonged clinical remission. MH may be achieved with several therapeutic strategies reaching success rates up to 80% for both, ulcerative colitis(UC) and Crohn's disease(CD). Various scoring systems for UC and for the transmural CD, have been proposed to standardize the definition of MH. Several attempts have been undertaken to de-escalate therapy once MH is achieved, thus, reducing the risk of adverse events. In this review, we analysed the available studies regarding the achievement of MH and the subsequent treatment de-escalation according to disease type and administered therapy, together with non-invasive markers proposed as predictors for relapse. The available data are not encouraging since de-escalation after the achievement of MH is followed by a high number of clinical relapses reaching up to 50% within one year. Unclear is also another question, in case of combination therapies, which drug is more appropriate to stop, in order to guarantee a durable remission. Predictors of unfavourable outcome such as disease extension, perianal disease, or early onset disease appear to be inadequate to foresee behaviour of disease. Further studies are warranted to investigate the role of histologic healing for the further course of disease.展开更多
AIM: To assess the risk of relapse in ulcerative colitis(UC) patients in clinical remission using mucosal status and fecal immunochemical test(FIT) results. METHODS: The clinical outcomes of 194 UC patients in clinica...AIM: To assess the risk of relapse in ulcerative colitis(UC) patients in clinical remission using mucosal status and fecal immunochemical test(FIT) results. METHODS: The clinical outcomes of 194 UC patients in clinical remission who underwent colonoscopy were based on evaluations of Mayo endoscopic subscores(MESs) and FIT results.RESULTS: Patients with an MES of 0(n = 94, 48%) showed a ten-fold lower risk of relapse than those with an MES of 1-3(n = 100, 52%)(HR = 0.10, 95%CI: 0.05-0.19). A negative FIT result(fecal hemoglobin concentrations ≤ 100 ng/m L) was predictive of patients with an MES of 0, with a sensitivity of 0.94 and a specific of 0.76. Moreover, patients with a negative FIT score had a six-fold lower risk of clinical relapse than those with a positive score(HR = 0.17, 95%CI: 0.10-0.28). Inclusion of the distinguishing parameter, sustaining clinical remission > 12 mo, resulted in an even stronger correlation between negative FIT results and an MES of 0 with respect to the risk of clinical relapse(HR = 0.11, 95%CI: 0.04-0.23).CONCLUSION: Negative FIT results one year or more after remission induction correlate with complete mucosal healing(MES 0) and better prognosis. Performing FIT one year after remission induction may be useful for evaluating relapse risk.展开更多
AIM To evaluate circulating IL9 in inflammatory bowel disease and disease-associated anemia/cachexia and assess its potential as a mucosal healing marker.METHODS Serum IL9 as well as other cytokines(IL1β, IL6, IL13, ...AIM To evaluate circulating IL9 in inflammatory bowel disease and disease-associated anemia/cachexia and assess its potential as a mucosal healing marker.METHODS Serum IL9 as well as other cytokines(IL1β, IL6, IL13, IFNγ, TNFα, and VEGF-A) were determined in 293 individuals: 97 patients with Crohn's disease(CD) and 74 with ulcerative colitis(UC) and in 122 apparently healthy controls. The clinical activity of CD and UC was expressed in terms of the Crohn's Disease Activity Index(CDAI) and the Mayo Scoring System(MDAI), respectively, and the severity of bowel inflammation in UC patients was assessed using Mayo endoscopic score. Cytokine concentrations were measured by a flow cytometry-based method using Luminex x MAP? technology. Highsensitive C-reactive protein concentrations(hs CRP) were determined in CD and UC patients using the enhanced immunoturbidimetric method.RESULTS Systemic IL9 was significantly lower in healthy individuals [9 pg/m L(95%CI: 8.2-10)] than in patients with inflammatory bowel disease(IBD): both inactive [14.3 pg/m L(11.9-19.9)] and active [27.6 pg/m L(24.5-32), P < 0.0001]. Cytokine concentrations were significantly higher in active CD [27.4 pg/m L(23.4-32.2)] and in active UC [32.7 pg/m L(27-38.9)] compared to inactive diseases [15.9 pg/m L(10.8-23.4) in CD and 19.4 pg/m L(13.9-27.1) in UC, P = 0.001]. IL9 correlated weakly with CDAI(ρ = 0.32, P = 0.003) and MDAI(ρ = 0.35, P = 0.002) and strongly with endoscopic inflammation in UC(ρ = 0.74, P < 0.0001). As a negative marker of mucosal healing(MH), IL9 had an accuracy superior to hs CRP and IL6 [97%(P < 0.0001), 67%(P = 0.071), and 55%(P = 0.525), respectively]. IL9 was significantly higher in cachectic IBD patients [30.25 pg/m L(24.4-37.5) vs 21.88 pg/m L(18-26.5), P = 0.026] and negatively correlated with hemoglobin concentrations(ρ =-0.27, P < 0.001). Multiple regression showed IL1β and IL13 to be the independent predictors of circulating IL9 in healthy individuals, IFNγ or IL6 in active and inactive UC, respectively, and IL13 and VEGF-A in both active and inactive CD.CONCLUSION The systemic IL9 level is higher in IBD and corresponds with endoscopic inflammation, suggesting its possible application as a negative marker of mucosal healing in UC.展开更多
AIM:To investigate the effect of mesalazine granules on small intestinal injury induced by naproxen using capsule endoscopy (CE).METHODS:This was a single center,non-randomized,open-label,uncontrolled pilot study,usin...AIM:To investigate the effect of mesalazine granules on small intestinal injury induced by naproxen using capsule endoscopy (CE).METHODS:This was a single center,non-randomized,open-label,uncontrolled pilot study,using the PillCam SB CE system with RAPID 5 software.The Lewis Index Score (LIS) for small bowel injury was investigated to evaluate the severity of mucosal injury.Arthropathy patients with at least one month history of daily naproxen use of 1000 mg and proton pump inhibitor co-therapy were screened.Patients with a minimum LIS of 135 were eligible to enter the 4-wk treatment phase of the study.During this treatment period,3 × 1000 mg/d mesalazine granules were added to ongoing therapies of 1000 mg/d naproxen and 20 mg/d omeprazole.At the end of the 4-wk combined treatment period,a second small bowel CE was performed to re-evaluate the enteropathy according to the LIS results.The primary objective of this study was to assess the mucosal changes after 4 wk of mesalazine treatment.RESULTS:A total of 18 patients (16 females),ranging in age from 46 to 78 years (mean age 60.3 years) were screened,all had been taking 1000 mg/d naproxen for at least one month.Eight patients were excluded from the mesalazine therapeutic phase of the study for the following reasons:the screening CE showed normal small bowel mucosa or only insignificant damages (LIS < 135) in five patients,the screening esophagogastroduodenoscopy revealed gastric ulcer in one patient,capsule technical failure and incomplete CE due to poor small bowel cleanliness in two patients.Ten patients (9 female,mean age 56.2 years) whose initial LIS reached mild and moderate-to-severe enteropathy grades (between 135 and 790 and ≥ 790) entered the 4-wk therapeutic phase and a repeat CE was performed.When comparing the change in LIS from baseline to end of treatment in all patients,a marked decrease was seen (mean LIS:1236.4 ± 821.9 vs 925.2 ± 543.4,P=0.271).Moreover,a significant difference between pre-and post-treatment mean total LIS was detected in 7 patients who had moderate-tosevere enteropathy gradings at the inclusion CE (mean LIS:1615 ± 672vs 1064 ± 424,P=0.033).CONCLUSION:According to the small bowel CE evaluation mesalazine granules significantly attenuated mucosal injuries in patients with moderate-to-severe enteropathies induced by naproxen.展开更多
AIM To evaluate whether repeated serum measurements of trefoil factor-3(TFF-3)can reliably reflect mucosal healing(MH)in Crohn’s disease(CD)patients treated with anti-tumor necrosis factor-α(anti-TNF-α)antibodies.M...AIM To evaluate whether repeated serum measurements of trefoil factor-3(TFF-3)can reliably reflect mucosal healing(MH)in Crohn’s disease(CD)patients treated with anti-tumor necrosis factor-α(anti-TNF-α)antibodies.METHODS Serum TFF-3 was measured before and after antiTNF-αinduction therapy in 30 CD patients.The results were related to clinical,biochemical and endoscopic parameters.MH was defined as a≥50%decrease in Simple Endoscopic Score for Crohn’s disease(SES-CD).RESULTS SES-CD correlated significantly with CD clinical activity and several standard biochemical parameters(albumin,leukocyte and platelet counts,C-reactive protein,erythrocyte sedimentation rate,fibrinogen).In contrast,SES-CD did not correlate with TFF-3(P=0.54).Moreover,TFF-3 levels did not change significantly after therapy irrespectively of whether the patients achieved MH or not.Likewise,TFF-3 did not correlate with changes in fecal calprotectin,which has been proposed as another biochemical marker of mucosal damage in CD.CONCLUSION Serum TFF-3 is not a convenient and reliable surrogate marker of MH during therapy with TNF-αantagonists in CD.展开更多
AIM: To evaluate mucosal healing in patients with small bowel plus colonic Crohn's disease(CD) with a single non-invasive examination, by using PillCam COLON 2.(PCC2).METHODS: Patients with non-stricturing nonpene...AIM: To evaluate mucosal healing in patients with small bowel plus colonic Crohn's disease(CD) with a single non-invasive examination, by using PillCam COLON 2.(PCC2).METHODS: Patients with non-stricturing nonpenetrating small bowel plus colonic CD in sustained corticosteroid-free remission were included. At diagnosis,patients had undergone ileocolonoscopy to identify active CD lesions, such as ulcers and erosions, and small bowel capsule endoscopy to assess the Lewis Score(LS). After ≥ 1 year of follow-up, patients underwent entire gastrointestinal tract evaluation with PCC2. The primary endpoint was assessment of CD mucosal healing, defined as no active colonic CD lesions and LS < 135.RESULTS: Twelve patients were included(7 male;mean age: 32 years), and mean follow-up was 38 mo.The majority of patients(83.3%) received immunosuppressive therapy. Three patients(25%) achieved mucosal healing in both the small bowel and the colon,while disease activity was limited to either the small bowel or the colon in 5 patients(42%). It was possible to observe the entire gastrointestinal tract in 10 of the12 patients(83%) who underwent PCC2.CONCLUSION: Only three patients in sustainedcorticosteroid-free clinical remission achieved mucosal healing in both the small bowel and the colon, highlighting the limitations of clinical assessment when stratifying disease activity, and the need for pan-enteric endoscopy to guide therapeutic modification.展开更多
Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract that is defi ned by relapsing and remitting episodes. Tumor necrosis factor alpha (TNF-α) appears to play a central role in the pat...Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract that is defi ned by relapsing and remitting episodes. Tumor necrosis factor alpha (TNF-α) appears to play a central role in the pathophysiology of the disease. Standard therapies for inflammatory bowel disease fail to induce remission in about 30% of patients. Biological therapies have been associated with an increased incidence of infections, especially infection by Mycobacterium tuberculosis (Mtb). Thalidomide is an oral immunomodulatory agent with anti-TNF-α properties. Recent studies have suggested that thalidomide is effective in refractory luminal and fistulizing Crohn's disease. Thalidomide costimulates T lymphocytes, with greater effect on CD8+ than on CD4+ T cells, which contributes to the protective immune response to Mtb infection. We present a case of Crohn's disease with gastric, ileal, colon and rectum involvement as well as steroid dependency, which progressed with loss of response to infliximabafter three years of therapy. The thorax computed tomography scan demonstrated a pulmonary nodule suspected to be Mtb infection. The patient was started on thalidomide therapy and exhibited an excellent response.展开更多
AIM:To assess the endoscopic activity before and after a one-year period of biological therapy and to evaluate the frequency of relapses and need for retreatment after stopping the biologicals in patients with Crohn’...AIM:To assess the endoscopic activity before and after a one-year period of biological therapy and to evaluate the frequency of relapses and need for retreatment after stopping the biologicals in patients with Crohn’s disease(CD)and ulcerative colitis(UC).METHODS:The data from 41 patients with CD and 22 patients with UC were assessed.Twenty-four CD patients received infliximab,and 17 received adalimumab.The endoscopic severity of CD was quantified with the simplified endoscopic activity score for Crohn’s disease in CD and with the Mayo endoscopic subscore in UC.RESULTS:Mucosal healing was achieved in 23 CD and7 UC patients.Biological therapy had to be restarted in78%of patients achieving complete mucosal healing with CD and in 100%of patients with UC.Neither clinical remission nor mucosal healing was associated with the time to restarting the biological therapy in either CD or UC.CONCLUSION:Mucosal healing did not predict sustained clinical remission in patients in whom the biological therapies had been stopped.展开更多
AIM:To investigate the effects of nilotinib in a rat model of trinitrobenzene sulfonic acid(TNBS)-induced colitis.METHODS:Twenty-one Wistar albino female rats obtained from Dokuz Eylul University Department of Laborat...AIM:To investigate the effects of nilotinib in a rat model of trinitrobenzene sulfonic acid(TNBS)-induced colitis.METHODS:Twenty-one Wistar albino female rats obtained from Dokuz Eylul University Department of Laboratory Animal Science were categorized into a control(n=7),TNBS(n=7)and nilotinib group(n=7).Saline was administered orally for 14 d to the control and the TNBS group.The TNBS group received rectal TNBS on the first day while saline was administered to the control group.The nilotinib group received 20mg/kg nilotinib for 14 d in 2 divided doses,starting the same day as TNBS administration.For 14 d,the rats were fed a standard diet,and their weights were recorded daily.After sacrifice,colon tissue samples from each group were scored for macroscopic and microscopic pathology.Apoptotic indices were determined by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling method.Platelet-derived growth factor receptor(PDGFR)alpha and beta levels were assessed through immunohistochemistry staining scores and compared among the groups.Tissue and serum tumor necrosis factor(TNF)alpha levels were determined by enzyme-linked immunosorbent assay.RESULTS:Between days 1 and 14,the nilotinib group rats lost significantly less weight than the TNBS group rats(-0.7 g vs-14.0 g,P=0.047).The difference in weight between the control and nilotinib groups was also statistically significant(+8.3 gvs-0.7 g,P=0.031).From day 7 to day 14,the weight differences of the control group vs the TNBS group,the TNBS group vs the nilotinib group,and the control group vs the nilotinib group were all statistically significant(+8.0 g vs-11.1 g,P=0.007;-11.1 g vs+2.9 g,P=0.015;+8.0g vs+2.9 g,P=0.042,respectively).Macroscopic and microscopic scores were significantly lower in the nilotinib group than in the TNBS group(0.00±0.00 vs 1.43±0.65,P=0.009;2.86±0.55 vs 7.71±1.48,P=0.030,respectively).However,these scores were similar between the nilotinib and control groups.While no significant difference for the nilotinib vs control groups could be determined for PDGFR alpha and beta scores,PDGFR alpha and beta scores were lower in the nilotinib group than in the TNBS group.Furthermore,the TNF alpha levels in the serum,tissue and apoptosis scores were similar between the nilotinib and TNBS groups.CONCLUSION:Nilotinib prevents weight loss,facilitates mucosal healing by improving the pathological scores without introducing variation into the apoptotic scores or TNF alpha levels.展开更多
AIM To examine whether second generation of colon capsule endoscopy(CCE-2) is acceptable for assessing the severity of mucosal inflammation and evaluating mucosal healing using CCE-2 is able to predict outcome in ulce...AIM To examine whether second generation of colon capsule endoscopy(CCE-2) is acceptable for assessing the severity of mucosal inflammation and evaluating mucosal healing using CCE-2 is able to predict outcome in ulcerative colitis(UC) patients, especially in clinical remission.METHODS A total of 30 consecutive UC patients in clinical remission were enrolled to undergo CCE-2. Clinical remission was defined as clinical activity index(CAI) ≤ 4 according to Rachmilewitz index. The rate of total colon observation and colon cleansing level were evaluated. Severity of mucosal inflammation in UC was assessed according to the Mayo endoscopic subscore(MES) and Ulcerative Colitis Endoscopic Index of Severity(UCEIS). Relapsefree survival was assessed. Acceptability of CCE-2 was assessed using a questionnaire survey.RESULTS The rate of total colon observation within its battery life was 93.3%. The proportion of "excellent" plus "good" cleansing level was 73.3%. The rate of mucosal healing(MES 0, 1) assessed by CCE-2 was 77.0%. The relapse-free survival rate was significantly higher in MES 0, 1 than in MES 2, 3(P = 0.0435), and in UCEIS 0-3 than in UCEIS 4-8(P = 0.0211), whereas there was no significant difference between CAI 0 and CAI 1-4 groups. A questionnaire survey revealed an overall acceptability of CCE.CONCLUSION CCE-2 is acceptable for assessing the severity of mucosal inflammation in UC patients, especially in clinical remission. Evaluating mucosal healing using CCE-2 was able to predict outcome.展开更多
In recent decades,the prominent role of endoscopy in the management of ulcerative colitis(UC)has been translated into the concept of mucosal healing(MH)as a fundamental therapeutic end-point.This is partially the cons...In recent decades,the prominent role of endoscopy in the management of ulcerative colitis(UC)has been translated into the concept of mucosal healing(MH)as a fundamental therapeutic end-point.This is partially the consequence of growing evidence of a positive prognostic role of MH on the disease course and partially due to market cues indicating a higher rate of MH in patients treated by novel potent biologic agents.The aim of the present review is to clarify the current knowledge of MH in UC,analyzing the definition,the putative prognostic role and the association of MH with the current drugs used to treat UC patients.Because solid data about the management of UC patients based solely on the healing of the mucosa are not yet available,a tailored approach for individual patients thatconsiders the natural history of UC and the presence of prognostic indicators of aggressive disease is desirable.Consequently,unnecessary examinations and treatment would be avoided and restricted to UC patients who require the maximum amount of effort to affect the disease course in the short and long term.展开更多
Histiocytes have a pivotal role in wound repair and intestinal epithelial recovery-the most important goal to sustain gut functionality.Yet,an in vivo description of colonic histiocytes by confocal laser endomicroscop...Histiocytes have a pivotal role in wound repair and intestinal epithelial recovery-the most important goal to sustain gut functionality.Yet,an in vivo description of colonic histiocytes by confocal laser endomicroscopy(CLE) is missing.Here,we report the case of a 45-yearsold male patient who was referred to our clinic with weight loss and a history of two consecutive Clostridium difficile colitis episodes,the latter cured 3 wk before present admission.Stool microbiology was negative.Conventional colonoscopy showed atrophy and a light mucosal oedema in the distal colon.During on-going endoscopy,we performed a fluorescein-aided CLE which revealed large polygonal(histiocytes-like) cells with copious cytoplasm and large nuclei in the lamina propria of the sigmoid colon as well as regenerative epithelial changes.Histopathological assessment of biopsies from the same areas confirmed the endomicroscopical findings:Periodic acid-Schiff-and CD68-positive foamy histiocytes in the colonic lamina propria and an advanced epithelial recovery.Since stool microbiology was repeatedly negative and polymerase chain reaction-analysis from colonic biopsies could not detect any mRNA for Thropheryma whippleii and common pathogens,we interpreted this particular setting as a mucosal healing process after consecutive Clostridium difficile infections.In conclusion,by describing these colonic histiocytes,we highlight the clinical usefulness of CLE in describing the entity of histiocytes in vivo and in real-time during the process of post-infectious mucosal healing in the colon.展开更多
Bleeding and altered iron distribution occur in multiple gastrointestinal diseases,but the importance and regulation of these changes remain unclear.We found that hepcidin,the master regulator of systemic iron homeost...Bleeding and altered iron distribution occur in multiple gastrointestinal diseases,but the importance and regulation of these changes remain unclear.We found that hepcidin,the master regulator of systemic iron homeostasis,is required for tissue repair in the mouse intestine after experimental damage.This effect was independent of hepatocyte-derived hepcidin or systemic iron levels.Rather,we identified conventional dendritic cells(cDCs)as a source of hepcidin that is induced by microbial stimulation in mice,prominent in the inflamed intestine of humans,and essential for tissue repair.cDC-derived hepcidin acted on ferroportin-expressing phagocytes to promote local iron sequestration,which regulated the microbiota and consequently facilitated intestinal repair.Collectively,these results identify a pathway whereby cDC-derived hepcidin promotes mucosal healing in the intestine through means of nutritional immunity.展开更多
文摘Mucosal healing(MH)is vital in maintaining homeostasis within the gut and protecting against injury and infections.Multiple factors and signaling pathways contribute in a dynamic and coordinated manner to maintain intestinal homeostasis and mucosal regeneration/repair.However,when intestinal homeostasis becomes chronically disturbed and an inflammatory immune response is constitutively active due to impairment of the intestinal epithelial barrier autoimmune disease results,particularly inflammatory bowel disease(IBD).Many proteins and signaling pathways become dysregulated or impaired during these pathological conditions,with the mechanisms of regulation just beginning to be understood.Consequently,there remains a relative lack of broadly effective therapeutics that can restore MH due to the complexity of both the disease and healing processes,so tissue damage in the gastrointestinal tract of patients,even those in clinical remission,persists.With increased understanding of the molecular mechanisms of IBD and MH,tissue damage from autoimmune disease may in the future be ameliorated by developing therapeutics that enhance the body’s own healing response.In this review,we introduce the concept of mucosal healing and its relevance in IBD as well as discuss the mechanisms of IBD and potential strategies for altering these processes and inducing MH.
文摘AIM To evaluate the utility of fecal calprotectin(FC) in predicting relapse and endoscopic activity during follow-up in an inflammatory bowel disease(IBD) cohort.METHODS All FC measurements that were obtained during a 3-year period from patients with inflammatory bowel disease in clinical remission were identified. Data regarding the short-term(6 mo) course of the disease were extracted from the medical files. Exclusion criteria were defined as:(1) An established flare of the disease at the time of FC measurement,(2) Loss to follow up within 6 mo from baseline FC measurement, and,(3) Insufficient data on file. Statistical analysis was performed to evaluate whether baseline FC measurement could predict the short term clinical relapse and/or the presence of mucosal healing.RESULTS We included 149 [Crohn's disease(CD) = 113, Ulcerative colitis(UC) = 36, male = 77] IBD patients in our study. Within the determined 6-month period post-FC measurement, 47(31.5%) had a disease flare. Among 76 patients who underwent endoscopy, 39(51.3%) had mucosal healing. Baseline FC concentrations were significantly higher in those who had clinical relapse compared to those who remained in remission during follow up(481.0 μg/g, 286.0-600.0 vs 89.0, 36.0-180.8, P < 0.001). The significant predictive value of baseline median with IQR FC for clinical relapse was confirmed by multivariate Cox analysis [HR for 100μg/g: 1.75(95%CI: 1.28-2.39), P = 0.001]. Furthermore, lower FC baseline values significantly correlated to the presence of mucosal healing in endoscopy(69.0 μg/g, 30.0-128.0 vs 481.0, 278.0-600.0, in those with mucosal inflammation, median with IQR, P < 0.001). We were able to extract cut-off values for FC concentration with a high sensitivity and specificity for predicting clinical relapse(261 μg/g with AUC = 0.901, sensitivity 87.2%, specificity 85.3%, P < 0.001) or mucosal healing(174 μg/g with AUC = 0.956, sensitivity 91.9%, specificity 87.2%, P < 0.001). FC was better than CRP in predicting either outcome; nevertheless, having a pathological CRP(> 5 mg/L) in addition to the cutoffs for FC, significantly enhanced the specificity for predicting clinical relapse(95.1% from 85.3%) or endoscopic activity(100% from 87.2%). CONCLUSION Serial FC measurements may be useful in monitoring IBD patients in remission, as FC appears to be a reliable predictor of short-term relapse and endoscopic activity.
文摘Mucosal healing(MH)has emerged as a key therapeutic target in inflammatory bowel disease(IBD),and achievement of this goal is documented by endoscopy with biopsy.However,colonoscopy is burdensome and invasive,and substitution with an accurate noninvasive biomarker is desirable.AIM To summarize published data regarding the performance of noninvasive biomarkers in assessing MH in IBD patients.METHODS We conducted a systematic review of studies that reported the performance of biomarkers in diagnosing MH in patients with IBD.The main outcome measure was to review the diagnostic accuracy of serum and fecal markers that showed promising utility in assessing MH.RESULTS We screened 1301 articles,retrieved 46 manuscripts and included 23 articles for full-text analysis.The majority of the included manuscripts referred to fecal markers(12/23),followed by circulatory markers(8/23);only 3/23 of the included manuscripts investigated combined markers(serum and/or fecal markers).Fecal calprotectin(FC)was the most investigated fecal marker for assessing MH.In ulcerative colitis,for cutoff levels ranging between 58 mcg/g and 490 mcg/g,the sensitivity was 89.7%-100%and the specificity was 62%-93.3%.For Crohn’s disease,the cutoff levels of FC ranged from 71 mcg/g to 918 mcg/g(sensitivity 50%-95.9%and specificity 52.3%-100%).The best performance for a serum marker was observed for the endoscopic healing index,which showed a comparable accuracy to the measurement of FC and a higher accuracy than the measurement of serum C-reactive protein.CONCLUSION Several promising biomarkers of MH are emerging but cannot yet substitute for endoscopy with biopsy due to issues with reproducibility and standardization assessing MH.In ulcerative colitis,for cutoff levels ranging between 58 mcg/g and 490 mcg/g,the sensitivity was 89.7%-100%and the specificity was 62%-93.3%.For Crohn’s disease,the cutoff levels of FC ranged from 71 mcg/g to 918 mcg/g(sensitivity 50%-95.9%and specificity 52.3%-100%).The best performance for a serum marker was observed for the endoscopic healing index,which showed a comparable accuracy to the measurement of FC and a higher accuracy than the measurement of serum C-reactive protein.CONCLUSION Several promising biomarkers of MH are emerging but cannot yet substitute for endoscopy with biopsy due to issues with reproducibility and standardization.
文摘AIM:To determine the difference in clinical outcome between ulcerative colitis(UC)patients with Mayo endoscopic subscore(MES)0 and those with MES 1.METHODS:UC patients with sustained clinical remission of 6 mo or more at the time of colonoscopy were examined for clinical outcomes and the hazard ratios of clinical relapse according to MES.Parameters,including blood tests,to identify predictive factors for MES 0and slight endoscopic recurrence in clinically stablepatients were assessed.Moreover,a receiver operating characteristic curve was generated,and the area under the curve was calculated to indicate the utility of the parameters for the division between complete and partial mucosal healing.All P values were two-sided and considered significant when less than 0.05.RESULTS:A total of 183 patients with clinical remission were examined.Patients with MES 0(complete mucosal healing:n=80,44%)were much less likely to relapse than those with MES 1(partial mucosal healing:n=89,48%)(P<0.0001,log-rank test),and the hazard ratio of risk of relapse in patients with MES 1 vs MES0 was 8.17(95%CI:4.19-17.96,P<0.0001).The platelet count(PLT)<26×104/μL was an independent predictive factor for complete mucosal healing(OR=4.1,95%CI:2.15-7.99).Among patients with MES 0 at the initial colonoscopy,patients of whom colonoscopy findings shifted to MES 1 showed significant increases in PLT compared to those who maintained MES 0(3.8×104/μL vs-0.6×104/μL,P<0.0001).CONCLUSION:The relapse rate differed greatly between patients with complete and partial mucosal healing.A shift from complete to partial healing in clinically stable UC patients can be predicted by monitoring PLT.
文摘AIM: To review the published literature concerning the accuracy of faecal inflammatory markers for identifying mucosal healing. METHODS: Bibliographical searches were performed in MEDLINE electronic database up to February 2015,using the following terms: "inflammatory bowel disease","Crohn′s disease","ulcerative colitis","faecal markers","calprotectin","lactoferrin","S100A12","endoscop*","mucosal healing","remission". In addition,relevant references from these studies were also included. Data were extracted from the published papers including odds ratios with 95%CI,P values and correlation coefficients. Data were grouped together according to each faecal marker,Crohn's disease or ulcerative colitis,and paediatric compared with adult study populations. Studies included in this review assessed mucosal inflammation by endoscopic and/or histological means and compared these findings to faecal marker concentrations in inflammatory bowel diseases(IBD) patient cohorts. Articles had to be published between 1990 and February 2015 and written in English. Papers excluded from the review were those where the faecal biomarker concentration was compared between patients with IBD and controls or other disease groups,those where serum biomarkers were used,those with a heterogeneous study population and those only assessing post-operative disease. RESULTS: The available studies show that faecal markers,such as calprotectin and lactoferrin,are promising non-invasive indicators of mucosal healing. However,due to wide variability in study design,especially with regard to the definition of mucosal healing and evaluation of marker cut offs,the available data do not yet indicate the optimal roles of these markers. Thirty-six studies published between 1990 and 2014 were included. Studies comprised variable numbers of study participants,considered CD(15-164 participants) or UC(12-152 participants) separately or as a combined group(11-252 participants). Eight reports included paediatric patients. Several indices were used to document mucosal inflammation,encompassing elevenendoscopic and eight histologic grading systems. The majority of the available reports focused on faecal calprotectin(33 studies),whilst others assessed faecal lactoferrin(13 studies) and one study assessed S100A12. Across all of the biomarkers,there is a wide range of correlation describing the association between faecal markers and endoscopic disease activity(r values ranging from 0.32 to 0.87,P values ranging from < 0.0001 to 0.7815). Correlation coefficients are described in almost all studies and are used more commonly than outcome measures such as sensitivity,specificity,PPV and/or NPV. Overall,the studies that have evaluated faecal calprotectin and/or faecal lactoferrin and their relationship with endoscopic disease activity show inconsistent results. CONCLUSION: Future studies should report the results of faecal inflammatory markers in the context of mucosal healing with clear validated cut offs.
文摘Ulcerative colitis(UC), a chronic, relapsing, remitting disease of the colon and rectum, is characterized by inflammatory ulceration of the mucosa. Current UC therapy relies on controlling acute episodes and preventing relapse. To predict modifications in the natural course of UC, mucosal healing(MH) has emerged as a major treatment goal. Endoscopic evaluation is considered the gold standard for assessing MH, which can be achieved by conventional drugs and biologics in many, but not all, patients. Consequently, interest is focusing on the development of new substances for UC therapy, and new oral agents are in the pipeline. This review will focus on the ability of newly developed oral drugs to induce and maintain MH in UC patients.
基金Supported by Grants from the Swiss National Science Foundation to Rogler G,Grant No.310030-120312to Schoepfer A,Grant No.32003B_135665/1+1 种基金to Vavricka S,Grant No.320000-114009/3 and 32473B_135694/1to the Swiss IBDCohort,Grant No.33CS30_134274
文摘The use of specific terms under different meanings and varying definitions has always been a source of confusion in science.When we point our efforts towards an evidence based medicine for inflammatory bowel diseases(IBD)the same is true:Terms such as"mucosal healing"or"deep remission"as endpoints in clinical trials or treatment goals in daily patient care may contribute to misconceptions if meanings change over time or definitions are altered.It appears to be useful to first have a look at the development of terms and their definitions,to assess their intrinsic and context-independent problems and then to analyze the different relevance in present-day clinical studies and trials.The purpose of such an attempt would be to gain clearer insights into the true impact of the clinical findings behind the terms.It may also lead to a better defined use of those terms for future studies.The terms"mucosal healing"and"deep remission"have been introduced in recent years as new therapeutic targets in the treatment of IBD patients.Several clinical trials,cohort studies or inception cohorts provided data that the long term disease course is better,when mucosal healing is achieved.However,it is still unclear whether continued or increased therapeutic measures will aid or improve mucosal healing for patients in clinical remission.Clinical trials are under way to answer this question.Attention should be paid to clearly address what levels of IBD activity are looked at.In the present review article authors aim to summarize the current evidence available on mucosal healing and deep remission and try to highlight their value and position in the everyday decision making for gastroenterologists.
文摘In the past decade, thanks to the introduction of biologic therapies, a new therapeutic goal, mucosal healing(MH), has been introduced. MH is the expression of an arrest of disease progression, resulting in minor hospitalizations, surgeries, and prolonged clinical remission. MH may be achieved with several therapeutic strategies reaching success rates up to 80% for both, ulcerative colitis(UC) and Crohn's disease(CD). Various scoring systems for UC and for the transmural CD, have been proposed to standardize the definition of MH. Several attempts have been undertaken to de-escalate therapy once MH is achieved, thus, reducing the risk of adverse events. In this review, we analysed the available studies regarding the achievement of MH and the subsequent treatment de-escalation according to disease type and administered therapy, together with non-invasive markers proposed as predictors for relapse. The available data are not encouraging since de-escalation after the achievement of MH is followed by a high number of clinical relapses reaching up to 50% within one year. Unclear is also another question, in case of combination therapies, which drug is more appropriate to stop, in order to guarantee a durable remission. Predictors of unfavourable outcome such as disease extension, perianal disease, or early onset disease appear to be inadequate to foresee behaviour of disease. Further studies are warranted to investigate the role of histologic healing for the further course of disease.
文摘AIM: To assess the risk of relapse in ulcerative colitis(UC) patients in clinical remission using mucosal status and fecal immunochemical test(FIT) results. METHODS: The clinical outcomes of 194 UC patients in clinical remission who underwent colonoscopy were based on evaluations of Mayo endoscopic subscores(MESs) and FIT results.RESULTS: Patients with an MES of 0(n = 94, 48%) showed a ten-fold lower risk of relapse than those with an MES of 1-3(n = 100, 52%)(HR = 0.10, 95%CI: 0.05-0.19). A negative FIT result(fecal hemoglobin concentrations ≤ 100 ng/m L) was predictive of patients with an MES of 0, with a sensitivity of 0.94 and a specific of 0.76. Moreover, patients with a negative FIT score had a six-fold lower risk of clinical relapse than those with a positive score(HR = 0.17, 95%CI: 0.10-0.28). Inclusion of the distinguishing parameter, sustaining clinical remission > 12 mo, resulted in an even stronger correlation between negative FIT results and an MES of 0 with respect to the risk of clinical relapse(HR = 0.11, 95%CI: 0.04-0.23).CONCLUSION: Negative FIT results one year or more after remission induction correlate with complete mucosal healing(MES 0) and better prognosis. Performing FIT one year after remission induction may be useful for evaluating relapse risk.
基金Supported by National Science Center,No.DEC-2011/01/D/NZ5/02835
文摘AIM To evaluate circulating IL9 in inflammatory bowel disease and disease-associated anemia/cachexia and assess its potential as a mucosal healing marker.METHODS Serum IL9 as well as other cytokines(IL1β, IL6, IL13, IFNγ, TNFα, and VEGF-A) were determined in 293 individuals: 97 patients with Crohn's disease(CD) and 74 with ulcerative colitis(UC) and in 122 apparently healthy controls. The clinical activity of CD and UC was expressed in terms of the Crohn's Disease Activity Index(CDAI) and the Mayo Scoring System(MDAI), respectively, and the severity of bowel inflammation in UC patients was assessed using Mayo endoscopic score. Cytokine concentrations were measured by a flow cytometry-based method using Luminex x MAP? technology. Highsensitive C-reactive protein concentrations(hs CRP) were determined in CD and UC patients using the enhanced immunoturbidimetric method.RESULTS Systemic IL9 was significantly lower in healthy individuals [9 pg/m L(95%CI: 8.2-10)] than in patients with inflammatory bowel disease(IBD): both inactive [14.3 pg/m L(11.9-19.9)] and active [27.6 pg/m L(24.5-32), P < 0.0001]. Cytokine concentrations were significantly higher in active CD [27.4 pg/m L(23.4-32.2)] and in active UC [32.7 pg/m L(27-38.9)] compared to inactive diseases [15.9 pg/m L(10.8-23.4) in CD and 19.4 pg/m L(13.9-27.1) in UC, P = 0.001]. IL9 correlated weakly with CDAI(ρ = 0.32, P = 0.003) and MDAI(ρ = 0.35, P = 0.002) and strongly with endoscopic inflammation in UC(ρ = 0.74, P < 0.0001). As a negative marker of mucosal healing(MH), IL9 had an accuracy superior to hs CRP and IL6 [97%(P < 0.0001), 67%(P = 0.071), and 55%(P = 0.525), respectively]. IL9 was significantly higher in cachectic IBD patients [30.25 pg/m L(24.4-37.5) vs 21.88 pg/m L(18-26.5), P = 0.026] and negatively correlated with hemoglobin concentrations(ρ =-0.27, P < 0.001). Multiple regression showed IL1β and IL13 to be the independent predictors of circulating IL9 in healthy individuals, IFNγ or IL6 in active and inactive UC, respectively, and IL13 and VEGF-A in both active and inactive CD.CONCLUSION The systemic IL9 level is higher in IBD and corresponds with endoscopic inflammation, suggesting its possible application as a negative marker of mucosal healing in UC.
基金Supported by Dr.Falk Pharma GmbH,in part,study code:SAG-43/SBE
文摘AIM:To investigate the effect of mesalazine granules on small intestinal injury induced by naproxen using capsule endoscopy (CE).METHODS:This was a single center,non-randomized,open-label,uncontrolled pilot study,using the PillCam SB CE system with RAPID 5 software.The Lewis Index Score (LIS) for small bowel injury was investigated to evaluate the severity of mucosal injury.Arthropathy patients with at least one month history of daily naproxen use of 1000 mg and proton pump inhibitor co-therapy were screened.Patients with a minimum LIS of 135 were eligible to enter the 4-wk treatment phase of the study.During this treatment period,3 × 1000 mg/d mesalazine granules were added to ongoing therapies of 1000 mg/d naproxen and 20 mg/d omeprazole.At the end of the 4-wk combined treatment period,a second small bowel CE was performed to re-evaluate the enteropathy according to the LIS results.The primary objective of this study was to assess the mucosal changes after 4 wk of mesalazine treatment.RESULTS:A total of 18 patients (16 females),ranging in age from 46 to 78 years (mean age 60.3 years) were screened,all had been taking 1000 mg/d naproxen for at least one month.Eight patients were excluded from the mesalazine therapeutic phase of the study for the following reasons:the screening CE showed normal small bowel mucosa or only insignificant damages (LIS < 135) in five patients,the screening esophagogastroduodenoscopy revealed gastric ulcer in one patient,capsule technical failure and incomplete CE due to poor small bowel cleanliness in two patients.Ten patients (9 female,mean age 56.2 years) whose initial LIS reached mild and moderate-to-severe enteropathy grades (between 135 and 790 and ≥ 790) entered the 4-wk therapeutic phase and a repeat CE was performed.When comparing the change in LIS from baseline to end of treatment in all patients,a marked decrease was seen (mean LIS:1236.4 ± 821.9 vs 925.2 ± 543.4,P=0.271).Moreover,a significant difference between pre-and post-treatment mean total LIS was detected in 7 patients who had moderate-tosevere enteropathy gradings at the inclusion CE (mean LIS:1615 ± 672vs 1064 ± 424,P=0.033).CONCLUSION:According to the small bowel CE evaluation mesalazine granules significantly attenuated mucosal injuries in patients with moderate-to-severe enteropathies induced by naproxen.
基金the Poznan University of Medical Sciences Grant,A helping hand(2014)
文摘AIM To evaluate whether repeated serum measurements of trefoil factor-3(TFF-3)can reliably reflect mucosal healing(MH)in Crohn’s disease(CD)patients treated with anti-tumor necrosis factor-α(anti-TNF-α)antibodies.METHODS Serum TFF-3 was measured before and after antiTNF-αinduction therapy in 30 CD patients.The results were related to clinical,biochemical and endoscopic parameters.MH was defined as a≥50%decrease in Simple Endoscopic Score for Crohn’s disease(SES-CD).RESULTS SES-CD correlated significantly with CD clinical activity and several standard biochemical parameters(albumin,leukocyte and platelet counts,C-reactive protein,erythrocyte sedimentation rate,fibrinogen).In contrast,SES-CD did not correlate with TFF-3(P=0.54).Moreover,TFF-3 levels did not change significantly after therapy irrespectively of whether the patients achieved MH or not.Likewise,TFF-3 did not correlate with changes in fecal calprotectin,which has been proposed as another biochemical marker of mucosal damage in CD.CONCLUSION Serum TFF-3 is not a convenient and reliable surrogate marker of MH during therapy with TNF-αantagonists in CD.
文摘AIM: To evaluate mucosal healing in patients with small bowel plus colonic Crohn's disease(CD) with a single non-invasive examination, by using PillCam COLON 2.(PCC2).METHODS: Patients with non-stricturing nonpenetrating small bowel plus colonic CD in sustained corticosteroid-free remission were included. At diagnosis,patients had undergone ileocolonoscopy to identify active CD lesions, such as ulcers and erosions, and small bowel capsule endoscopy to assess the Lewis Score(LS). After ≥ 1 year of follow-up, patients underwent entire gastrointestinal tract evaluation with PCC2. The primary endpoint was assessment of CD mucosal healing, defined as no active colonic CD lesions and LS < 135.RESULTS: Twelve patients were included(7 male;mean age: 32 years), and mean follow-up was 38 mo.The majority of patients(83.3%) received immunosuppressive therapy. Three patients(25%) achieved mucosal healing in both the small bowel and the colon,while disease activity was limited to either the small bowel or the colon in 5 patients(42%). It was possible to observe the entire gastrointestinal tract in 10 of the12 patients(83%) who underwent PCC2.CONCLUSION: Only three patients in sustainedcorticosteroid-free clinical remission achieved mucosal healing in both the small bowel and the colon, highlighting the limitations of clinical assessment when stratifying disease activity, and the need for pan-enteric endoscopy to guide therapeutic modification.
文摘Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract that is defi ned by relapsing and remitting episodes. Tumor necrosis factor alpha (TNF-α) appears to play a central role in the pathophysiology of the disease. Standard therapies for inflammatory bowel disease fail to induce remission in about 30% of patients. Biological therapies have been associated with an increased incidence of infections, especially infection by Mycobacterium tuberculosis (Mtb). Thalidomide is an oral immunomodulatory agent with anti-TNF-α properties. Recent studies have suggested that thalidomide is effective in refractory luminal and fistulizing Crohn's disease. Thalidomide costimulates T lymphocytes, with greater effect on CD8+ than on CD4+ T cells, which contributes to the protective immune response to Mtb infection. We present a case of Crohn's disease with gastric, ileal, colon and rectum involvement as well as steroid dependency, which progressed with loss of response to infliximabafter three years of therapy. The thorax computed tomography scan demonstrated a pulmonary nodule suspected to be Mtb infection. The patient was started on thalidomide therapy and exhibited an excellent response.
基金Supported by TAMOP-4.2.2.A-11/1/KONV-2012-0035,TA-MOP-4.2.2-A-11/1/KONV-2012-0052 TAMOP-4.2.2.A-11/1/KONV-2012-0073OTKA Research Proposal PD 105948(PI:Klaudia Farkas)
文摘AIM:To assess the endoscopic activity before and after a one-year period of biological therapy and to evaluate the frequency of relapses and need for retreatment after stopping the biologicals in patients with Crohn’s disease(CD)and ulcerative colitis(UC).METHODS:The data from 41 patients with CD and 22 patients with UC were assessed.Twenty-four CD patients received infliximab,and 17 received adalimumab.The endoscopic severity of CD was quantified with the simplified endoscopic activity score for Crohn’s disease in CD and with the Mayo endoscopic subscore in UC.RESULTS:Mucosal healing was achieved in 23 CD and7 UC patients.Biological therapy had to be restarted in78%of patients achieving complete mucosal healing with CD and in 100%of patients with UC.Neither clinical remission nor mucosal healing was associated with the time to restarting the biological therapy in either CD or UC.CONCLUSION:Mucosal healing did not predict sustained clinical remission in patients in whom the biological therapies had been stopped.
基金Supported by Dokuz Eylul University Research Committee,grant number 42/2010
文摘AIM:To investigate the effects of nilotinib in a rat model of trinitrobenzene sulfonic acid(TNBS)-induced colitis.METHODS:Twenty-one Wistar albino female rats obtained from Dokuz Eylul University Department of Laboratory Animal Science were categorized into a control(n=7),TNBS(n=7)and nilotinib group(n=7).Saline was administered orally for 14 d to the control and the TNBS group.The TNBS group received rectal TNBS on the first day while saline was administered to the control group.The nilotinib group received 20mg/kg nilotinib for 14 d in 2 divided doses,starting the same day as TNBS administration.For 14 d,the rats were fed a standard diet,and their weights were recorded daily.After sacrifice,colon tissue samples from each group were scored for macroscopic and microscopic pathology.Apoptotic indices were determined by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling method.Platelet-derived growth factor receptor(PDGFR)alpha and beta levels were assessed through immunohistochemistry staining scores and compared among the groups.Tissue and serum tumor necrosis factor(TNF)alpha levels were determined by enzyme-linked immunosorbent assay.RESULTS:Between days 1 and 14,the nilotinib group rats lost significantly less weight than the TNBS group rats(-0.7 g vs-14.0 g,P=0.047).The difference in weight between the control and nilotinib groups was also statistically significant(+8.3 gvs-0.7 g,P=0.031).From day 7 to day 14,the weight differences of the control group vs the TNBS group,the TNBS group vs the nilotinib group,and the control group vs the nilotinib group were all statistically significant(+8.0 g vs-11.1 g,P=0.007;-11.1 g vs+2.9 g,P=0.015;+8.0g vs+2.9 g,P=0.042,respectively).Macroscopic and microscopic scores were significantly lower in the nilotinib group than in the TNBS group(0.00±0.00 vs 1.43±0.65,P=0.009;2.86±0.55 vs 7.71±1.48,P=0.030,respectively).However,these scores were similar between the nilotinib and control groups.While no significant difference for the nilotinib vs control groups could be determined for PDGFR alpha and beta scores,PDGFR alpha and beta scores were lower in the nilotinib group than in the TNBS group.Furthermore,the TNF alpha levels in the serum,tissue and apoptosis scores were similar between the nilotinib and TNBS groups.CONCLUSION:Nilotinib prevents weight loss,facilitates mucosal healing by improving the pathological scores without introducing variation into the apoptotic scores or TNF alpha levels.
文摘AIM To examine whether second generation of colon capsule endoscopy(CCE-2) is acceptable for assessing the severity of mucosal inflammation and evaluating mucosal healing using CCE-2 is able to predict outcome in ulcerative colitis(UC) patients, especially in clinical remission.METHODS A total of 30 consecutive UC patients in clinical remission were enrolled to undergo CCE-2. Clinical remission was defined as clinical activity index(CAI) ≤ 4 according to Rachmilewitz index. The rate of total colon observation and colon cleansing level were evaluated. Severity of mucosal inflammation in UC was assessed according to the Mayo endoscopic subscore(MES) and Ulcerative Colitis Endoscopic Index of Severity(UCEIS). Relapsefree survival was assessed. Acceptability of CCE-2 was assessed using a questionnaire survey.RESULTS The rate of total colon observation within its battery life was 93.3%. The proportion of "excellent" plus "good" cleansing level was 73.3%. The rate of mucosal healing(MES 0, 1) assessed by CCE-2 was 77.0%. The relapse-free survival rate was significantly higher in MES 0, 1 than in MES 2, 3(P = 0.0435), and in UCEIS 0-3 than in UCEIS 4-8(P = 0.0211), whereas there was no significant difference between CAI 0 and CAI 1-4 groups. A questionnaire survey revealed an overall acceptability of CCE.CONCLUSION CCE-2 is acceptable for assessing the severity of mucosal inflammation in UC patients, especially in clinical remission. Evaluating mucosal healing using CCE-2 was able to predict outcome.
文摘In recent decades,the prominent role of endoscopy in the management of ulcerative colitis(UC)has been translated into the concept of mucosal healing(MH)as a fundamental therapeutic end-point.This is partially the consequence of growing evidence of a positive prognostic role of MH on the disease course and partially due to market cues indicating a higher rate of MH in patients treated by novel potent biologic agents.The aim of the present review is to clarify the current knowledge of MH in UC,analyzing the definition,the putative prognostic role and the association of MH with the current drugs used to treat UC patients.Because solid data about the management of UC patients based solely on the healing of the mucosa are not yet available,a tailored approach for individual patients thatconsiders the natural history of UC and the presence of prognostic indicators of aggressive disease is desirable.Consequently,unnecessary examinations and treatment would be avoided and restricted to UC patients who require the maximum amount of effort to affect the disease course in the short and long term.
文摘Histiocytes have a pivotal role in wound repair and intestinal epithelial recovery-the most important goal to sustain gut functionality.Yet,an in vivo description of colonic histiocytes by confocal laser endomicroscopy(CLE) is missing.Here,we report the case of a 45-yearsold male patient who was referred to our clinic with weight loss and a history of two consecutive Clostridium difficile colitis episodes,the latter cured 3 wk before present admission.Stool microbiology was negative.Conventional colonoscopy showed atrophy and a light mucosal oedema in the distal colon.During on-going endoscopy,we performed a fluorescein-aided CLE which revealed large polygonal(histiocytes-like) cells with copious cytoplasm and large nuclei in the lamina propria of the sigmoid colon as well as regenerative epithelial changes.Histopathological assessment of biopsies from the same areas confirmed the endomicroscopical findings:Periodic acid-Schiff-and CD68-positive foamy histiocytes in the colonic lamina propria and an advanced epithelial recovery.Since stool microbiology was repeatedly negative and polymerase chain reaction-analysis from colonic biopsies could not detect any mRNA for Thropheryma whippleii and common pathogens,we interpreted this particular setting as a mucosal healing process after consecutive Clostridium difficile infections.In conclusion,by describing these colonic histiocytes,we highlight the clinical usefulness of CLE in describing the entity of histiocytes in vivo and in real-time during the process of post-infectious mucosal healing in the colon.
文摘Bleeding and altered iron distribution occur in multiple gastrointestinal diseases,but the importance and regulation of these changes remain unclear.We found that hepcidin,the master regulator of systemic iron homeostasis,is required for tissue repair in the mouse intestine after experimental damage.This effect was independent of hepatocyte-derived hepcidin or systemic iron levels.Rather,we identified conventional dendritic cells(cDCs)as a source of hepcidin that is induced by microbial stimulation in mice,prominent in the inflamed intestine of humans,and essential for tissue repair.cDC-derived hepcidin acted on ferroportin-expressing phagocytes to promote local iron sequestration,which regulated the microbiota and consequently facilitated intestinal repair.Collectively,these results identify a pathway whereby cDC-derived hepcidin promotes mucosal healing in the intestine through means of nutritional immunity.
