Mucosal Healing of Ulcerative Colitis Based on Endoscopic Diagnosis, Histopathology, and Mucosal Inflammatory Mediators

Ulcerative colitis (UC) is a chronic inflammatory disease of unknown cause, for which no curative treatments have been developed. Cytokines play an important role in the pathogenesis of UC, and therapies targeting specific cytokines have been successful in treating refractory UC. The purpose of this study was to measure mucosal cytokines in UC and identify those that contribute to nonrelapsing mucosal healing (MH) diagnosed by endoscopy. This prospective, observational study included 163 patients with UC. The mucosa was evaluated by the Mayo Endoscopic Subscore (MES) and linked color imaging (LCI) at the time of endoscopy, and cytokine mRNA expression in biopsy tissue taken from the same site was quantified by real-time PCR and compared with endoscopic findings. The relationship between cytokine mRNA expression and endoscopic findings was investigated. Cytokines such as IFNγ, IL-1β, IL-8, IL-17A, and IL-23 were significantly elevated in proportion to endoscopic severity of MES and LCI classification. Interestingly, we found differences in the expression of cytokines (eg, IL-22 and IL-33) between MES and LCI classification according to disease severity. Additionally, pathway analysis based on RNA sequencing comparing LCI-A and LCI-B in patients diagnosed as MES 0 revealed that IL-5 and IL-6 are involved in the finer differences in endoscopic mucosal redness. This study is the first to report the correlation between mucosal cytokine expression and the pathogenesis of MH in UC and supports the contribution of specific cytokines as molecular markers of MH or in the pathogenesis of MH in UC.

PiCaSSO: a predictive score for endoscopic findings in ulcerative colitis that sounds like art but is all science

Background: Ulcerative Colitis (UC) is a chronic inflam-matory disorder of the colorectum that is characterized by a remission and relapse course. Mucosal healing has been considered the goal of treatment in UC because it reduces the risk of relapse and colectomy. Fecal biomarkers have emerged as an important easy, rapid and non-invasive tool for assessing and monitoring mucosal healing in patients with UC.Aim of the Study: To determine if the q-FIT can evaluate the mucosal healing in UC patients.Patients and Methods: The study was conducted on 60 UC patients who underwent colonoscopy in the Endoscopy Unit, Internal Medicine Department in Tanta University Hospital. FIT was examined in stool samples from all the patients. Mucosal status was assessed using the Mayo Endo-scopic Subscore (MES).Data were collected from all study patients including; clinical, demographic and laboratory data. Statistical analysis was carried out for all collected data and statistical significance was determined at a p-value <0.05.Results: A total of 60 UC patients were evaluated with FIT results in conjunction with colonoscopies. The sensitivity and specificity of the FIT values (<100ng/ml) for predicting MH (MES 0 alone) were 0.93 and 0.80, respectively. The sensitivity and specificity when MH was defined as (MES 0 or 1) were 0.75 and 0.91, respectively. A significant correlations between FIT levels and the MES was observed (r=0.858, p-value=0.001 *).Conclusion: Quantitative FIT can be a non-invasive and effectivebiomarker for evaluation of mucosal healing in UC.

We previously showed that a quantitative fecal immunochemical test (FIT) can predict mucosal healing (MH) in ulcerative colitis (UC). Fecal calprotectin (Fcal) has also been reported as an important biomarker of UC activity. The aim of this study was to compare the predictive ability of these two fecal markers for MH in UC. FIT and Fcal were examined in stool samples from consecutive UC patients who underwent colonoscopy. Mucosal status was assessed via the Mayo endoscopic subscore (MES). In total, 105 colonoscopies in 92 UC patients were evaluated in conjunction with the FIT and Fcal results. Both FIT and Fcal results were significantly correlated with MES (Spearman's rank correlation coefficient: 0.61 and 0.58, respectively). The sensitivity and specificity of the FIT values (<100 ng/ml) for predicting MH (MES 0 alone) were 0.95 and 0.62, respectively, whereas those of Fcal (<250 μg/g) were 0.82 and 0.62, respectively. The sensitivities became similar when MH was defined as MES 0 or 1 (0.86 vs. 0.86). Although the predictability of MH evaluated by the area under the receiver operating characteristics curve was similar for the two fecal markers (FIT 0.83 vs. Fcal 0.82 for MES 0 alone), the FIT results were relatively robust regardless of the cutoff value selected. Both FIT and Fcal can efficiently predict MH in UC, but FIT appears to be more sensitive than Fcal for predicting MES 0 alone.

The Mayo Endoscopic Subscore (MES) and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) are used to assess endoscopic mucosal healing in patients suffering from ulcerative colitis. Although mucosal healing is defined by MES 0, relapse of ulcerative colitis is often observed. Over a 48-month period, this study investigated the efficacy of linked color imaging (LCI) in predicting the long-term prognosis of ulcerative colitis patients diagnosed with MES 0. Overall, 26 patients in ulcerative colitis remission, diagnosed with MES 0, were enrolled. Using a LASEREO endoscopic system (Fujifilm Co., Tokyo, Japan), endoscopic colonic images were assessed with linked color imaging and the colitis endoscopic index of severity. Endoscopic LCI images were separated into three subgroups (A, no redness; B, redness with visible vessels; and C, redness without visible vessels). The Geboes score was used to evaluate histology; active mucosa was defined as GS>2B.1. Linked color imaging classification subdivided colonic mucosa, which had been diagnosed with MES 0, into two classes. The LCI-A group did not relapse, and the non-relapse rate was significantly higher (P=0.018) than that in the LCI-B group. No difference in relapse rates was observed between patients with a colitis endoscopic index of severity of 0 and 1 (P=0.655). There was no statistical difference between the composition of LCI-A group and the relapse rate between active and inactive mucosa diagnosed by Geboes score. This methodology can be used to evaluate mucosal healing and predict long-term outcomes in ulcerative colitis patients.

Background Endoscopic mucosal healing is considered as an important therapeutic goal in ulcerative colitis (UC) patients, and several endoscopic evaluations for colonic mucosa such as Mayo endoscopic subscore (MES) and Colitis Endoscopic Index of Severity (UCEIS) are used in clinical practice. Though the strict mucosal healing is defined as MES 0, the relapse of UC has been shown in the patients diagnosed as MES 0. In the present study, we aimed to investigate the efficacy of Linked Color Imaging (LCI), a novel endoscopic enhancement system, to predict long-term prognosis in UC patients diagnosed with MES 0. Methods Twenty-six patients with UC in clinical remission and diagnosed with MES 0 were enrolled. Endoscopic colonic images were assessed by LCI and UCEIS, using a LASEREO endoscopic system (FUJIFILM Co., Tokyo, Japan). Endoscopic LCI images were classified into three subgroups by LCI classification as previously reported. Briefly, LCI patterns were classified as A, no redness; B, redness with visible vessels; and C, redness without visible vessels. Forty months was defined as the time interval between endoscopic diagnosis and relapse of UC. Histological activity was scored according to the Geboes’ score (GS) and the active mucosa was defined by GS&amp;gt;2B.1. Results LCI classification can further subdivide the colonic mucosa diagnosed as MES 0. The patients with LCI-A showed no relapse and the non-relapse rates compared with the patients with LCI-B showed significantly higher (p = 0.033), while the relapse rates of the patients with UCEIS 0 showed no difference compared with UCEIS 1 (p = 0.148). There was no statistical difference in the composition of LCI-A and relapse rate between active and inactive mucosa diagnosed by GS score. Conclusion Endoscopic LCI classification can further subdivide samples diagnosed MES 0. LCI can be a novel and surpassing approach to evaluate mucosal healing and predict the outcome in UC patients.

INTRODUCTION: Mucosal healing is a widely accepted target for ulcerative colitis (UC) treatment. Linked color imaging (LCI) is a novel endoscopic enhancement system that utilizes Light Emitting Diode (LED) sources to spectrally enhance subtle erythema and mucosal surface patterns which may improve endoscopic classification of IBD associated inflammation. We aimed to assess the accuracy of LCI in classifying UC-associated mucosal healing compared to a validated histological reference standard (Geboes score). METHODS: 22 patients with ulcerative colitis were prospectively enrolled and evaluated by LCI colonoscopy using the Fujifilm’s digital video Processor VP-7000 and LED light source BL-7000 (Fujifilm, Tokyo Japan). Interobserver agreement was reported as kappa values. Geboes score was reported as score range of 0 to 5.4. A Geboes score of ≥3.1 (presence of surface intraepithelial neutrophils or &lt; 5% crypts) was used to define histologic activity and a score of &lt; 2B (no increase in neutrophils in the lamina propria) was used to define histologic remission. Geboes score has been previously validated to predict clinical recurrence. We calculated the overall accuracy, positive predictive value (PPV) and negative predictive value (NPV) of the LCI classification identifying mucosal healing against the Geboes score using the Fisher’s exact test. RESULTS: Total of 62 endoscopic images were obtained for different parts of the colon, 43 of which were matched to a corresponding biopsy. Endoscopic images were scored by 2 endoscopists into LCI-A (no redness), LCI-B (redness with visible vessels) and LCI-C (redness without visible vessels). A final LCI score was given for images with discrepant scores based on a consensus vote from both endoscopists. The interobserver agreement between the two endoscopists was 81%, kappa of 0.71 (95% confidence interval [CI] 0.57- 0.86). Among regions scored ≥3.1 on Geboes score, 9.5%, 28.6% and 61.9 % were classified as LCI-A, LCI-B and LCI-C, respectively (P &lt; 0.0001). Among images scored &lt; 2B on Geboes score, 81.8%, 13.6% and 4.6% were classified as LCI-A, LCI-B and LCI-C, respectively (P &lt; 0.0001). Analyzing data against histology with LCI-A representing mucosal healing and LCI-B and C representing active mucosal disease, the overall accuracy becomes 86%, with NPV of 82.6% and PPV of 90% for identifying UC patients with histological and endoscopic evidence of mucosal healing. CONCLUSION: LCI technology has a potential role in assessing mucosal healing in UC.

Mucosal healing is an important therapeutic endpoint in the management of Crohn's disease (CD) and ulcerative colitis (UC). Limited data exist regarding the comparative efficacy of various therapies in achieving this outcome. To perform a systematic review and meta-analysis of biologics for induction and maintenance of mucosal healing in Crohn's disease and ulcerative colitis. We performed a systematic review and meta-analysis of randomised controlled trials (RCT) examining mucosal healing as an endpoint of immunosuppressives, anti-tumour necrosis factor α (anti-TNF) or anti-integrin monoclonal antibody therapy for moderate-to-severe CD or UC. Pooled effect sizes for induction and maintenance of mucosal healing were calculated and pairwise treatment comparisons evaluated using a Bayesian network meta-analysis. A total of 12 RCTs were included in the meta-analysis (CD - 2 induction, 4 maintenance; UC - 8 induction, 5 maintenance). Duration of follow-up was 6-12weeks for induction and 32-54weeks for maintenance trials. In CD, anti-TNFs were more effective than placebo for maintaining mucosal healing [28% vs. 1%, Odds ratio (OR) 19.71, 95% confidence interval (CI) 3.51-110.84]. In UC, anti-TNFs and anti-integrins were more effective than placebo for inducing (45% vs. 30%) and maintaining mucosal healing (33% vs. 18%). In network analysis, adalimumab therapy was inferior to infliximab [OR 0.45, 95% credible interval (CrI) 0.25-0.82] and combination infliximab-azathioprine (OR 0.32, 95% CrI 0.12-0.84) for inducing mucosal healing in UC. There was no statistically significant pairwise difference between vedolizumab and anti-TNF agents in UC. Anti-TNF and anti-integrin biological agents are effective in inducing mucosal healing in UC, with adalimumab being inferior to infliximab or combination therapy. Infliximab and adalimumab were similar in CD.

CT-P13 is the first biosimilar to infliximab that has been approved for the same indications as its originator infliximab. No data are available on the effect of infliximab biosimilar on mucosal healing. The aim of this study was to evaluate the efficacy of CT-P13 induction therapy on mucosal healing in patients with ulcerative colitis [UC]. UC patients, who received CT-P13 therapy from its local introduction at three Hungarian and one Czech inflammatory bowel disease centres, were prospectively enrolled. Sigmoidoscopy was performed after the end of the induction therapy at week 14. Mucosal healing was defined as Mayo endoscopic subscore 0 or 1. Complete mucosal healing was defined as Mayo endoscopic subscore 0. Trough level of CT-P13 was measured at week 14. Sixty-three UC patients who underwent CT-P13 induction therapy were enrolled in the study. Indication for the therapy was acute, severe flare up and chronic, refractory activity in 24 and 39 patients, respectively. Cumulative clinical response and steroid-free remission at week 14 were achieved in 82.5% and 47.6% of the patients, respectively. Sigmoidoscopy revealed steroid-free mucosal healing in 47.6% of the patients, and complete mucosal healing was present in 27%. Mayo endoscopic subscore decreased significantly at week 14 compared to baseline. Trough levels of infliximab correlated with mucosal healing. This is, to our knowledge, the first study examining the efficacy of CT-P13 induction therapy on mucosal healing in UC. The results indicate that mucosal healing is achieved in two-thirds of UC patients by the end of the induction treatment with CT-P13.

Mucosal healing (MH) with thiopurines has been poorly investigated in ulcerative colitis (UC). We aimed to assess MH rate in UC patients treated with thiopurine monotherapy. We retrospectively collected all UC patients treated with thiopurines more than 6months who have undergone colonoscopy at baseline and after at least 6months of treatment. Patients were recruited from January 2005 to May 2015 through a personal database and/or standardized hospital inpatient diagnostic dataset. Patients were excluded in case of any use of other immunomodulator or biological agent. MH was defined as a Mayo endoscopic subscore ≤1 and UCEIS≤2. Histological healing (HH) was defined by the absence of epithelial polynuclear infiltrate, cryptic abscesses, or ulcerations. Eighty patients (31 women, median age 43 [IQR 32-58]) were included. Median disease duration was 10.5 [6-16] years. At baseline, median full Mayo score, endoscopic subscore, and UCEIS were 8 [6.8-10], 3 [2-3], and 5 [3-6], respectively. MH was first assessed after a mean follow-up of 38±31months. Median full Mayo score, endoscopic subscore, and UCEIS decreased to 3.5 [1-6], 2 [0-2.2], and 2 [0-4], respectively. MH was achieved in 43.7%, HH in 38%. In multivariate analysis, predictors of MH were thiopurine exposure duration ≥2years [odds ratio (OR) 2.9, CI 95% (1.1-7.6), p=0.03] and a prior acute severe colitis [OR 5.9, CI 95% (1.1-32), p=0.04]. Factors associated with MH during treatment were partial Mayo score ≤2 (NPV=100%), BMI≥25kg/m2 (NPV=75%), and MCV≥95fL (NPV=73%). In UC, thiopurine monotherapy is associated with MH in 43.7% and HH in 38%.

Defining Endpoints and Biomarkers in Inflammatory Bowel Disease: Moving the Needle Through Clinical Trial Design

BackgroundMucosal healing is the therapeutic target for ulcerative colitis (UC). While amino acids (AAs) and the gut microbiota are known to be involved in the pathogenesis of UC, their specific roles in mucosal healing have not been fully defined.ObjectivesTo longitudinally assess the changes in AA concentrations and the gut microbiota composition in the context of mucosal healing in UC patients, with the aim of identifying new biomarkers with predictive value for mucosal healing in UC patients and providing a new theoretical basis for dietary therapy.MethodsA total of 15 UC patients with infliximab-induced mucosal healing were enrolled. Serum and fecal AA concentrations before and after mucosal healing were determined via targeted metabolomics. A receiver operating characteristic (ROC) curve was plotted to evaluate the value of different AAs in predicting mucosal healing in UC patients. The changes in the composition of the fecal gut microbiota were analyzed via metagenomics, and bioinformatics was used to analyze the functional genes and metabolic pathways associated with different bacterial species. Spearman correlation analyses of fecal AAs with significantly different concentrations and the differentially abundant bacterial species before and after mucosal healing were performed.Results1. The fecal concentrations of alanine, aspartic acid, glutamic acid, glutamine, glycine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine were significantly decreased after mucosal healing. The serum concentrations of alanine, cysteine and valine significantly increased, whereas that of aspartic acid significantly decreased. Glutamic acid, leucine, lysine, methionine and threonine could accurately predict mucosal healing in UC patients, and the area under the curve (AUC) was > 0.9. After combining the 5 amino acids, the AUC reached 0.96. 2. There were significant differences in the gut microbiota composition before and after mucosal healing in UC, characterized by an increase in the abundance of beneficial microbiota (Faecalibacterium prausnitzii and Bacteroides fragilis) and a decrease in the abundance of harmful microbiota (Enterococcus faecalis). LEfSe analysis identified 57 species that could predict mucosal healing, and the AUC was 0.7846. 3. Amino acid metabolic pathways were enriched in samples after mucosal healing, was associated with the abundance of multiple species, such as Faecalibacterium prausnitzi, Bacteroides fragilis, Bacteroides vulgatus and Alistipes putredinis. 4. The fecal concentrations of several AAs were negatively correlated with the abundance of a variety of beneficial strains, such as Bacteroides fragilis, uncultured Clostridium sp., Firmicutes bacterium CAG:103, Adlercreutzia equolifaciens, Coprococcus comes and positively correlated with the abundance of several harmful strains, such as Citrobacter freundii, Enterococcus faecalis, Klebsiella aerogenes, Salmonella enterica.ConclusionAltered concentrations of amino acids and their associations with the gut microbiota are implicated in the mucosal healing of UC patients and can serve as noninvasive diagnostic biomarkers.

Shining a Light on Barrier Function

BackgroundWe aimed to evaluate the role of fecal calprotectin (FC) as a noninvasive marker for the disease activity of ulcerative colitis (UC) in a Korean cohort.MethodsA total of 181 fecal samples were collected from 181 consecutive UC patients between April 2015 and September 2016. FC levels were measured using the Quantum Blue® Calprotectin rapid test. The laboratory test results, partial Mayo Score (pMS), and colonoscopic imaging findings at FC level measurement were retrospectively reviewed. The Mayo endoscopic subscore (MES) and UC endoscopic index of severity (UCEIS) were graded by 2 certified endoscopists after training with 50 other cases.ResultsThe FC levels were significantly correlated with pMS (Spearman correlation coefficient r = 0.428, p < 0.001), MES (r = 0.304, p < 0.001), UCEIS (r = 0.430, p < 0.001), and CRP (r = 0.379, p < 0.001). FC levels exhibited a significantly better correlation with UCEIS than with MES (Meng’s z = − 2.457, p = 0.01). The FC cut-off level of 187.0 mg/kg indicated complete mucosal healing (MES = 0; UCEIS =0) with a sensitivity and specificity of 0.857 and 0.891, respectively (area under the curve, 0.883; 95% confidence interval, 0.772–1.000).ConclusionThe FC level is significantly correlated with the clinical disease activity index, endoscopic indices, and serum inflammatory biomarkers in a Korean UC cohort. FC is highly predictive of complete mucosal healing in UC. UCEIS exhibits a stronger correlation with the FC level, as compared to MES. Thus, FC could be used as a reliable noninvasive indicator for evaluating disease activity and mucosal healing in UC.

Data regarding the correlation of histologic and endoscopic healing with fecal calprotectin (FC) are conflicting. We examined how FC levels correlate with histological and endoscopic remission in colonic inflammatory bowel disease. Fifty-eight patients (23 with colonic Crohn's disease [CD] and 35 with ulcerative colitis [UC]) were included. Clinical activity was assessed by Harvey-Bradshaw index (CD) and Mayo score (UC). Inflammatory activity was assessed by ileocolonoscopy, C-reactive protein, and FC. Clinical remission was defined as Harvey-Bradshaw index ≤ 4 or Mayo score ≤ 2 and mucosal healing as Mayo endoscopic subscore = 0 (UC), and Simple Endoscopic Score-CD <3 (CD). Histologic activity was assessed in 27 patients (15 CD, 12 UC). Histological remission was defined as absence of active inflammation (Geboes score <3.1) and absence of basal plasmacytosis. In UC, FC correlated with clinical Mayo score (r = 0.63, P < 0.0001). This correlation was strengthened by adding the endoscopic subscore (r = 0.90, P < 0.0001). The endoscopic subscore also independently correlated with FC (r = 0.96, P < 0.0001). In Crohn's colitis, endoscopic activity correlated with FC (r = 0.61, P < 0.001). FC levels were lower overall for patients with endoscopic remission compared with active endoscopic disease (median 100 versus 1180 μg/g, P < 0.0001). FC also correlated with histological remission (Geboes score < 3.1) and absence of basal plasmacytosis in CD (r = 0.77, r = 0.80, respectively; P < 0.01). Area under the curve for FC as a predictor of histological remission (Geboes score <3.1) was 0.95 (95% CI, 0.82-1). Low FC correlates well with histological remission and mucosal healing in colonic inflammatory bowel disease and is thus a clinically useful surrogate for inflammatory activity.