Inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC) are lifelong chronic, relapsing, and remitting conditions that culminate in disease progression in many patients. Effective management of CD and UC requires consideration of both short- and long-term treatment outcomes. Historically, short-term outcomes such as clinical and endoscopic remission and symptom relief have been evaluated in clinical trials. With the expansion of treatments targeting underlying disease pathophysiology, there is the opportunity to develop management strategies that improve disease control and patients' lives in both the short and the long term. Researchers have been examining novel outcomes for assessing the efficacy of CD and UC treatments that are important to patients, and also those that go beyond symptomatic improvements or clinical remission. These include new patient-reported outcomes for symptoms, as well as transmural/histological healing and disease clearance that can be more reflective of deeper remission states and disease modification. This review analyses published clinical studies involving patients with UC and CD treated with biologics or small molecule therapies. It highlights novel IBD endpoints employed in published clinical trials and discusses their likely value for assessing disease activity and disease modification, and as predictors of reduced risk of complications and morbidities.

Achieving deep remission, encompassing clinical, endoscopic, and biological remission, is the goal in managing Crohn's disease (CD). The role of histological remission (HR) remains unclear. This study aimed to examine the impact of histological inflammation on clinical relapse risk in CD and explore the relationship between histology, endoscopic scores, and biomarkers.

Patients from the prospective STORI (Stable Remission on Combined Therapy with Immunosuppressors) cohort underwent ileocolonoscopy with Crohn's Disease Endoscopic Index of Severity calculation and 2 biopsies from the most inflamed or previously inflamed areas. Histological scores (Robarts, Geboes, modified Geboes, Nancy, and IBD-DCA) were determined by 2 independent pathologists in a central reading process. Histological remission was defined by specific score thresholds. Clinical relapse, defined by Crohn's Disease Activity Index (CDAI) > 250 or a CDAI increase of 70 points over 2 weeks, was monitored for at least 1 year.

Out of 115 patients included in STORI, 160 biopsies (44 ileal and 116 colonic) from 76 patients were analyzed. Histological remission rates were 46% (Nancy), 55% (Robarts), 61% (Geboes), and 41% (IBD-DCA). During follow-up, 35 patients (46%) experienced a clinical relapse: 37% with HR and 56% without, based on the Nancy score. Among the mucosal healing subgroup (45 patients), 34% with HR, and 44% without relapsed (p = 0.18). Histological scores did not predict clinical relapse. Only fecal calprotectin was a significant predictor in multivariate analysis (p = 0.029).

Despite correlations with endoscopy and biomarkers, histological scores did not predict clinical relapse in CD patients in remission. Thus, these scores are not recommended for clinical practice to assess relapse risk in CD.

We aimed to (1) analyze the applicability of the updated Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II) recommendations in real-world clinical practice, (2) identify barriers to their implementation, and (3) propose practical measures to overcome these obstacles.

This qualitative study was based on a survey, a literature review, and expert opinions. Nine inflammatory bowel disease (IBD) experts identified 7 areas likely to be controversial or potential implementation barriers in daily clinical practice: endoscopy, histology, ultrasound, quality of life, biomarkers, symptom control, and patient-reported outcomes (PROs). Based on this, a survey was carried out among educational course participants. The experts discussed the literature review and survey results and proposed several statements and practical actions.

A total of 55 gastroenterologists answered the survey. The reported difficulty level in reaching STRIDE-II treatment goals in clinical practice was high. Only 22% of participants performed clinical remission assessments using clinical indexes and PROs. Seventy percent of responders did not use fecal calprotectin cutoffs and considered changes from the previous levels instead. Mucosal healing as a long-term therapeutic goal was considered necessary to be individualized in specific patient subgroups (eg, elderly/fragile patients, multiple treatment failures, and last-line therapies). Other barriers, like the lack of access to imaging techniques or insufficient knowledge and skills among healthcare professionals, were detected. The experts suggested adding less stringent treatment goals and measurements, patient stratification, local adaptations, educational activities, and research.

STRIDE-II recommendations face various implementation barriers needing careful evaluation in order to enhance their adoption in clinical practice, and ultimately improve outcomes in IBD patients.

Current endoscopic scoring systems for ulcerative colitis (UC) do not consider the extent of mucosal inflammation. The modified Mayo endoscopic score (MMES) was developed to detect segmental endoscopic improvement. We evaluated the ability of the MMES to predict long-term clinical outcomes and compared it to the widely used Mayo endoscopic subscore (MES).

Consecutive patients with moderate to severe UC starting biological therapy were enrolled between January 2014 and September 2017 in this prospective observational study. A clinical and endoscopic evaluation was performed at baseline and at week 8/14. A modified Mayo score was used to grade clinical activity, MES and MMES were used to evaluate endoscopic activity. Patients were divided into 3 groups according to the evolution of endoscopic activity, namely endoscopic improvement (MES ≤ 1), segmental endoscopic response only (MES > 1, but decrease in MMES ≥ 30%) or no endoscopic response (all others). Over the follow-up period clinical relapse-, discontinuation- and colectomy-free survival were assessed.

A total of 150 patients were included (48% female, median age 42 years, median disease duration 7 years) with a median follow-up of 61 months. We identified 69 patients with endoscopic improvement, 27 with segmental endoscopic response and 54 without endoscopic response. Patients with segmental endoscopic response showed intermediate long-term clinical outcomes as compared to the other two groups (log rank p = 0.003 for clinical relapse-, and p < 0.001 for both discontinuation- and colectomy-free survival).

The MMES exhibited a benefit in predicting long-term outcome in UC even though endoscopic improvement remains the strongest predictor.

Ulcerative colitis (UC) is a chronic and recurrent inflammatory bowel disease (IBD) characterized by continuous inflammation in the colonic mucosa. Extraintestinal manifestations (EIM) occur due to the disruption of the intestinal barrier and increased permeability caused by redox imbalance, dysbiosis, and inflammation originating from the intestine and contribute to morbidity and mortality. The aim of this study is to investigate the effects of oral N-acetylcysteine (NAC) on colonic, hepatic, and renal tissues in mice with colitis induced by dextran sulfate sodium (DSS). Male Swiss mice received NAC (150 mg/kg/day) in the drinking water for 30 days before and during (DSS 5% v/v; for 7 days) colitis induction. On the 38th day, colon, liver, and kidney were collected and adequately prepared for the analysis of oxidative stress (superoxide dismutase (SOD), catalase (CAT), glutathione reduced (GSH), glutathione oxidized (GSSG), malondialdehyde (MDA), and hydrogen peroxide (H2O2)) and inflammatory biomarkers (myeloperoxidase (MPO) -, tumor necrosis factor alpha - (TNF-α, and interleukin-10 (IL-10)). In colon, NAC protected the histological architecture. However, NAC did not level up SOD, in contrast, it increased MDA and pro-inflammatory effect (increased of TNF-α and decreased of IL-10). In liver, colitis caused both oxidative (MDA, SOD, and GSH) and inflammatory damage (IL-10). NAC was able only to increase GSH and GSH/GSSG ratio. Kidney was not affected by colitis; however, NAC despite increasing CAT, GSH, and GSH/GSSG ratio promoted lipid peroxidation (increased MDA) and pro-inflammatory action (decreased IL-10). Despite some beneficial antioxidant effects of NAC, the negative outcomes concerning irreversible oxidative and inflammatory damage in the colon, liver, and kidney confirm the nonsafety of the prophylactic use of this antioxidant in models of induced colitis, suggesting that additional studies are needed, and its use in humans not yet recommended for the therapeutic routine of this disease.

The breakdown of the intestinal mucosal barrier is thought to underlie the progression to Crohn disease (CD), whereby numerous risk factors contribute. For example, a genetic polymorphism of the autophagy gene ATG16L1, associated with an increased risk of developing CD, contributes to the perturbation of the intestinal epithelium. We examined the role of Atg16l1 in protecting the murine small intestinal epithelium from T-cell-mediated damage using the anti-CD3 model of enteropathy. Our work showed that mice specifically deleted for Atg16l1 in intestinal epithelial cells (IECs) (Atg16l1^ΔIEC) had exacerbated intestinal damage, characterized by crypt epithelial cell death, heightened inflammation, and decreased survival. Moreover, Atg16l1 deficiency delayed the recovery of the intestinal epithelium, and Atg16l1-deficient IECs were impaired in their proliferative response. Pathology was largely driven by interferon (IFN)-γ signaling in Atg16l1^ΔIEC mice. Mechanistically, although survival was rescued by blocking tumor necrosis factor or IFN-γ independently, only anti-IFN-γ treatment abrogated IEC death in Atg16l1^ΔIEC mice, thereby decoupling IEC death and survival. In summary, our findings suggest differential roles for IFN-γ and tumor necrosis factor in acute enteropathy and IEC death in the context of autophagy deficiency and suggest that IFN-γ-targeted therapy may be appropriate for patients with CD with variants in ATG16L1.

Inflammatory bowel diseases, namely ulcerative colitis and Crohn's disease, are chronic and relapsing conditions that pose a growing burden on healthcare systems worldwide. Because of their complex and partly unknown etiology and pathogenesis, the management of ulcerative colitis and Crohn's disease can prove challenging not only from a clinical point of view but also for resource optimization. Artificial intelligence, an umbrella term that encompasses any cognitive function developed by machines for learning or problem solving, and its subsets machine learning and deep learning are becoming ever more essential tools with a plethora of applications in most medical specialties. In this regard gastroenterology is no exception, and due to the importance of endoscopy and imaging numerous clinical studies have been gradually highlighting the relevant role that artificial intelligence has in inflammatory bowel diseases as well. The aim of this review was to summarize the most recent evidence on the use of artificial intelligence in inflammatory bowel diseases in various contexts such as diagnosis, follow-up, treatment, prognosis, cancer surveillance, data collection, and analysis. Moreover, insights into the potential further developments in this field and their effects on future clinical practice were discussed.

Although histological healing is raising interest in ulcerative colitis to predict recurrence, its meaning in Crohn's disease (CD) remains unknown. We aimed to study the performances of different histological indices to predict recurrence of CD patients with mucosal healing.

Crohn's disease patients with mucosal healing diagnosed between 2010 and 2018 were included if there was available clinical and endoscopical data. Nancy Histological index (NHI), Geboes score (GS), Robarts Histopathology index (RHI), Global Histological Disease Activity Score (GHAS), and Inflammatory Bowel Disease-Distribution Chronicity Activity score (IBD-DCA) were independently assessed by 3 pathologists.

Eighty-eight patients were included, of which 28 relapsed (32%) within 30.5 months. All 4 histological indices were associated with recurrence, with significant relapse risk (NHI, odds ratio [OR], 1.67; GHAS, OR, 2.33; RHI, OR, 1.19; GS, OR, 2.09; and IBD-DCA, OR, 2.14). Microscopic activity was significantly associated with relapse only with the IBD-DCA score. Predicting performances of all these scores were poor. Calibration curves indicate that the GHAS and IBD-DCA are the closest to the ideal predicted probability curve and thus could better predict recurrence than the other scores. Interobserver agreement varied from poor for GHAS (k = .39) to good for RHI (k = .68).

Histological scores are valuable indicators to predict recurrence. Histological assessment of activity seems insufficient to predict CD course with most of the score evaluated, highlighting the need for new indices or adaptation of actual scores to CD specificities.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) affecting the colon and the rectum characterized by a remitting-relapsing course. To detect mucosal inflammation associated with UC, histology is considered the most stringent criteria. In turn, histologic remission (HR) correlates with improved clinical outcomes and has been recently recognized as a desirable treatment target. The leading biomarker for assessing histologic remission is the presence or absence of neutrophils. Therefore, the finding of this cell in specific colon structures indicates that the patient has UC activity. However, no previous studies based on deep learning have been developed to identify UC based on neutrophils detection using whole-slide images (WSI).

The methodological core of this work is a novel multiple instance learning (MIL) framework with location constraints able to determine the presence of UC activity using WSI. In particular, we put forward an effective way to introduce constraints about positive instances to effectively explore additional weakly supervised information that is easy to obtain and enjoy a significant boost to the learning process. In addition, we propose a new weighted embedding to enlarge the relevance of the positive instances.

Extensive experiments on a multi-center dataset of colon and rectum WSIs, PICASSO-MIL, demonstrate that using the location information we can improve considerably the results at WSI-level. In comparison with prior MIL settings, our method allows for 10% improvements in bag-level accuracy.

Our model, which introduces a new form of constraints, surpass the results achieved from current state-of-the-art methods that focus on the MIL paradigm. Our method can be applied to other histological concerns where the morphological features determining a positive WSI are tiny and similar to others in the image.

In inflammatory bowel disease [IBD], mucosal healing is a major therapeutic target and a reliable predictor of clinical course. However, endoscopic mucosal healing is not synonymous with histological healing, and the additional benefits of including histological remission as a target are unclear. In Crohn´s disease [CD], there are few studies highlighting the value of histological remission as a therapeutic target. Histological activity can persist in CD patients who are in endoscopic remission, and the absence of histological activity may be associated with lower relapse rates. Therefore, standardisation of procedures to evaluate CD histological activity is desirable. Topics that would benefit from standardisation and harmonisation include biopsy procedures, biopsy processing techniques, the content of histological scores, and the definitions of histological remission, histological response, and histological activity. In line with these needs, the European Crohn's and Colitis Organisation [ECCO] assembled a consensus group with the objective of developing position statements on CD histology based on published evidence and expert consensus. There was agreement that definitions of histological remission should include absence of erosion, ulceration, and mucosal neutrophils; that the absence of neutrophilic inflammation is an appropriate histological target in CD; that CD histological scores, such as the Global Histological Disease Activity Score, lack formal validation; and that histological scoring systems for ulcerative colitis, including the Geboes Score, Robarts Histopathology Index, and Nancy Histological Index, can be used for scoring intestinal biopsies in CD patients.

Histological remission is evolving as an important treatment target in UC. We aimed to develop a simple histological index, aligned to endoscopy, correlated with clinical outcomes, and suited to apply to an artificial intelligence (AI) system to evaluate inflammatory activity.

Using a set of 614 biopsies from 307 patients with UC enrolled into a prospective multicentre study, we developed the Paddington International virtual ChromoendoScopy ScOre (PICaSSO) Histologic Remission Index (PHRI). Agreement with multiple other histological indices and validation for inter-reader reproducibility were assessed. Finally, to implement PHRI into a computer-aided diagnosis system, we trained and tested a novel deep learning strategy based on a CNN architecture to detect neutrophils, calculate PHRI and identify active from quiescent UC using a subset of 138 biopsies.

PHRI is strongly correlated with endoscopic scores (Mayo Endoscopic Score and UC Endoscopic Index of Severity and PICaSSO) and with clinical outcomes (hospitalisation, colectomy and initiation or changes in medical therapy due to UC flare-up). A PHRI score of 1 could accurately stratify patients' risk of adverse outcomes (hospitalisation, colectomy and treatment optimisation due to flare-up) within 12 months. Our inter-reader agreement was high (intraclass correlation 0.84). Our preliminary AI algorithm differentiated active from quiescent UC with 78% sensitivity, 91.7% specificity and 86% accuracy.

PHRI is a simple histological index in UC, and it exhibits the highest correlation with endoscopic activity and clinical outcomes. A PHRI-based AI system was accurate in predicting histological remission.

Crohn's disease [CD] is characterised by a heterogeneous disease course. Patient stratification at diagnosis using clinical, serological, or genetic markers does not predict disease course sufficiently to facilitate clinical decision making. The current study aimed to investigate the additive predictive value of histopathological features to discriminate between a long-term mild and severe disease course.

Diagnostic biopsies from treatment-naïve CD patients with mild or severe disease courses in the first 10 years after diagnosis were reviewed by two gastrointestinal pathologists after developing a standardised form comprising 15 histopathological features. Multivariable logistic regression models were built to identify predictive features and compute receiver operating characteristic [ROC] curves. Models were internally validated using bootstrapping to obtain optimism-corrected performance estimates.

In total, 817 biopsies from 137 patients [64 mild, 73 severe cases] were included. Using clinical baseline characteristics, disease course could only moderately be predicted (area under receiver operating characteristic curve [AUROC]: 0.738 [optimism 0.018], 95% confidence interval [CI] 0.65-0.83, sensitivity 83.6%, specificity 53.1%). When adding histopathological features, in colonic biopsies a combination of [1] basal plasmacytosis, [2] severe lymphocyte infiltration in lamina propria, [3] Paneth cell metaplasia, and [4] absence of ulcers were identified and resulted in significantly better prediction of a severe course (AUROC: 0.883 [optimism 0.033], 95% CI 0.82-0.94, sensitivity 80.4%, specificity 84.2%).

In this first study investigating the additive predictive value of histopathological features in biopsies at CD diagnosis, we found that certain features of chronic inflammation in colonic biopsies contributed to prediction of a severe disease course, thereby presenting a novel approach to improving stratification and facilitating clinical decision making.

Intestinal stenosis is a common complication of Crohn's Disease (CD). Stenosis is associated with alteration of bowel mechanical properties. This study aims to quantitate the mechanical properties of the intestinal stenosis and to explore associations between histology and mechanical remodeling at stenotic intestinal sites in CD patients.

Intestinal segments from stenotic sites were studied in vitro from 19 CD patients. A luminal catheter with a bag was used to stepwise pressurize the intestinal segments from 0-100 cmH₂O with 10 cmH₂O increments. B-mode ultrasound images were obtained at the narrowest part of the stenosis at each pressure level and morphometric parameters were obtained from ultrasound images. The mechanical behavior of the stenotic tissue were characterized by using an isotropic three dimensional strain energy function in Demiray model form, the mechanical constants were obtained by fitting the model to the recorded intraluminal pressure and the inner radius of the stenotic segment of the small bowel. Grading scores were used for histological analysis of inflammation, fibrosis, muscular hypertrophy and adipocyte proliferation in the intestinal layers. The collagen area fraction in intestinal layers was also calculated. Associations between histological and the mechanical constants (stiffness) were analyzed.

Chronic inflammation was mainly located in mucosa whereas fibrosis was found in submucosa. The mechanical remodeling was performed with changed mechanical constants ranged between 0.35-13.68kPa. The mechanical properties changes were associated mainly with chronic inflammation, fibrosis and combination of inflammation and fibrosis (R>0.69, P<0.001). Furthermore, the mechanical properties correlated with the collagen fraction in submucosa and muscular layers (R>0.53, P<0.05).

We quantitated the intestinal stenosis stiffness. Associations were found between bowel mechanical remodeling and histological changes at the stenotic site in CD patients.

Although intestinal ultrasonography, CT and MRI can be used to diagnose Crohn's Disease (CD)-associated bowel strictures, these techniques may not have sufficient accuracy and resolution to differentiate predominantly inflammatory strictures from predominantly fibrotic strictures. The present study aims to quantitate the mechanical remodeling of intestinal stenosis and to explore the associations between histological parameters and mechanical properties at the intestinal stenotic sites in CD patients. For the first time, we quantitatively demonstrated that the mechanical properties of the intestinal wall in CD stenosis are associated with the chronic inflammation, fibrosis and collagen fraction in the intestinal layers. The results of this study may facilitate design and development of artificial biomaterials for gastrointestinal organs. The potential clinical implication of this study is that the histological characteristics in patients with CD can be predicted clinically by means of inflammation and fibrosis assessment in conjunction with tissue stiffness measurement.

Mucosal healing (MH) and histological healing (HH) have been recently proposed as a novel treatment target for inflammatory bowel disease (IBD). The aim of the present study was to evaluate real-life achievement of such outcomes in a cohort of pediatric patients with IBD treated with anti-TNF-alpha (ATA) agents.

A retrospective analysis was performed on patients affected by IBD who received ATA and were followed up at two referral centers. Incidence and cumulative rates for MH and HH for each group were calculated.

Of 170 (105 Crohn's disease [CD] and 65 ulcerative colitis [UC]) patients, 78 with CD and 56 with UC underwent endoscopic re-assessment during the study period. MH was achieved by 32 CD (41%) and 30 UC (53.6%) patients; 26 CD (33.3%) and 22 UC (39.3%) patients achieved HH. MH incidence rate was 19.1/1000 and 47/1000 person-months, whereas HH incidence rate was 15.5/1000 and 34.7/1000 person-months for CD and UC, respectively. Remission at the end of induction was associated with higher MH and HH rates (HR: 2.43, P = 0.049 and HR: 2.94, P = 0.046, respectively) in CD. In UC, adalimumab was associated with lower MH and HH rates (HR: 0.16, P = 0.004 and HR: 0.07, P = 0.003).

We reported a real-life experience arising from a large cohort of pediatric IBD who received ATA scheduled treatment. Less than half of patients with CD and only a little >50% of UC patients achieved MH. Microscopical inflammation was observed in 18.8% CD and 26.7% UC patients who achieved MH. Overall, MH and HH rates appear lower compared to previously published data.

The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) has proposed treatment targets in 2015 for adult patients with inflammatory bowel disease (IBD). We aimed to update the original STRIDE statements for incorporating treatment targets in both adult and pediatric IBD.

Based on a systematic review of the literature and iterative surveys of 89 IOIBD members, recommendations were drafted and modified in 2 surveys and 2 voting rounds. Consensus was reached if ≥75% of participants scored the recommendation as 7 to 10 on a 10-point rating scale.

In the systematic review, 11,278 manuscripts were screened, of which 435 were included. The first IOIBD survey identified the following targets as most important: clinical response and remission, endoscopic healing, and normalization of C-reactive protein/erythrocyte sedimentation rate and calprotectin. Fifteen recommendations were identified, of which 13 were endorsed. STRIDE-II confirmed STRIDE-I long-term targets of clinical remission and endoscopic healing and added absence of disability, restoration of quality of life, and normal growth in children. Symptomatic relief and normalization of serum and fecal markers have been determined as short-term targets. Transmural healing in Crohn's disease and histological healing in ulcerative colitis are not formal targets but should be assessed as measures of the remission depth.

STRIDE-II encompasses evidence- and consensus-based recommendations for treat-to-target strategies in adults and children with IBD. This frameworkshould be adapted to individual patients and local resources to improve outcomes.

The role of histology in inflammatory bowel disease (IBD) has not yet been well defined. Endoscopic mucosal healing has been proposed as a predictor of the clinical course of IBD and it is indeed considered one of the main therapeutic targets. However, it does not necessarily imply histological healing. Histological remission has been reported to be associated with a better clinical outcome than endoscopic remission only in IBD patients. These observations support the view that histology plays a role as a potential therapeutic target in Crohn's disease and ulcerative colitis. Histological scores being able to quantify the degree of microscopic activity are needed for this purpose. In the era of biologics, indication for proper treatment may benefit from the assessment of clinical and endoscopic activity, as well as histological scores. Such scores may allow us to quantify the microscopic mucosal response to treatment and to define complete healing in IBD. A validated histological score in IBD may lead to the definition of microscopic activity in clinical practice, trials and investigational settings. Several attempts to develop such scores have been reported, but few are currently used and none is applied worldwide in clinical practice. The present review summarizes the main histological scores currently used for assessing IBD activity.

Inflammatory bowel diseases (IBD) comprise two major forms: Crohn's disease and ulcerative colitis. The diagnosis of IBD is based on clinical symptoms combined with results found in endoscopic and radiological examinations. In addition, the discovery of biomarkers has significantly improved the diagnosis and management of IBD. Several potential genetic, serological, fecal, microbial, histological and immunological biomarkers have been proposed for IBD, and they have been evaluated for clinical routine and clinical trials. Ileocolonoscopy, especially with biopsy collection, has been considered the standard method to diagnose IBD and to assess clinical activity of the disease, but it is limited to the colon and terminal ileum and is considered invasive. For this reason, non-invasive biomarkers are necessary for this type of chronic inflammatory disease, which affects mostly young individuals, as they are expected to have a long follow-up.

Although achieving histologic remission in ulcerative colitis is established, the incremental benefit of achieving histologic remission in patients with Crohn disease (CD) treated to a target of endoscopic remission is unclear. We evaluated the risk of treatment failure in patients with CD in clinical and endoscopic remission by histologic activity status.

In a single-center retrospective cohort study, we identified adults with active CD who achieved clinical and endoscopic remission through treatment optimization. We evaluated the risk of treatment failure (composite of clinical flare requiring treatment modification, hospitalization, and/or surgery) in patients who achieved histologic remission vs persistent histologic activity through Cox proportional hazard analysis.

Of 470 patients with active CD, 260 (55%) achieved clinical and endoscopic remission with treatment optimization; 215 patients with histology were included (median age, 33 years; 46% males). Overall, 132 patients (61%) achieved histologic remission. No baseline demographic, disease, or treatment factor was associated with achieving histologic remission. Over a 2-year follow-up, patients with CD in clinical and endoscopic remission who achieved histologic remission experienced a 43% lower risk of treatment failure (1-year cumulative risk: 12.9% vs 18.2%; adjusted hazard ratio, 0.57 [95% confidence interval, 0.35-0.94]) as compared with persistent histologic activity.

Approximately 61% of patients with active CD who achieved clinical and endoscopic remission with treatment optimization simultaneously achieved histologic remission, which was associated with a lower risk of treatment failure. Whether histologic remission should be a treatment target in CD requires evaluation in randomized trials.

The relative proportion of inflammation and fibrosis in a stricture is highly relevant in defining the clinical approach for Crohn's disease [CD] patients. Whereas transmural inflammation in CD can be accurately estimated by cross-sectional imaging, evaluating the extent and severity of fibrosis still requires surgical pathology of intestinal resection specimens. This study systematically reviewed all existing transmural histopathological scoring systems developed for the assessment of inflammation and/or fibrosis in CD.

A systematic review of histopathological scoring systems for the assessment of transmural inflammation and/or fibrosis in CD, focusing on originally developed scoring systems. Risk of bias, methodological quality, and operating or psychometric properties [validity, reliability, responsiveness, and feasibility] of each histological scoring system were analysed.

A total of 29 original scoring systems were included in this review. Three scoring systems were highlighted as the most widely reproduced, one aimed at assessing inflammation only and two aimed at assessing inflammation and fibrosis. These scores were more widely reproduced probably due to their ease of application in clinical studies. Two highly comprehensive scores were identified, showing good operating properties and high methodological quality, as well as the lowest risk of bias; these should, therefore, be further validated in clinical research studies.

This study reviewed all existing transmural histopathological scoring systems for the assessment of inflammation and/or fibrosis in CD and identified the most reliable and accurate scores for clinical research and clinical practice settings.

Although treatment of Crohn's disease has improved with development of tumour necrosis factor antagonists, fewer than 50% of patients have sustained benefit. Durable maintenance therapy with orally administered alternative treatments remains an unmet need. We aimed to evaluate the effects of ozanimod, an oral agent selectively targeting sphingosine-1-phosphate receptor subtypes 1 and 5, on endoscopic disease activity in Crohn's disease.

STEPSTONE was a phase 2, uncontrolled, multicentre trial in adults with moderately to severely active Crohn's disease recruited at 28 hospital and community research centres in Canada, the USA, Hungary, Poland, and Ukraine. All patients began treatment with a 7-day dose escalation (4 days on ozanimod 0·25 mg daily followed by 3 days at 0·5 mg daily). Patients then received ozanimod 1·0 mg oral capsule daily for a further 11 weeks, for a 12-week induction period, followed by a 100-week extension. The primary endpoint was change in Simple Endoscopic Score for Crohn's Disease (SES-CD) from baseline to week 12, as determined by a blinded central reader. Data are reported for the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02531113 and EudraCT, number 2015-002025-19, and is completed.

69 patients were enrolled between Nov 17, 2015, and Aug 18, 2016. At week 12, the mean change from baseline in SES-CD was -2·2 (SD 6·0); 16 (23·2%, 95% CI 13·9-34·9) patients experienced endoscopic response. A reduction from baseline in Crohn's Disease Activity Index (CDAI) score also was observed (mean change -130·4 [SD 103·9]). Clinical remission (CDAI <150 points) was shown in 27 (39·1%, 95% CI 27·6-51·6) patients and response (CDAI decrease from baseline ≥100) in 39 (56·5%, 95% CI 44·0-68·4) of patients. The mean change from baseline in two-item patient-reported outcome (PRO2, stool frequency, abdominal pain scores) score was -66·1 (SD 65·4). Mean change from baseline in Geboes Histology Activity Score (GHAS) was -5·9 (SD 11·0) and in Robart's Histopathology Index (RHI) -10·6 (25·1). Adverse events were most frequently those attributed to Crohn's disease, most commonly Crohn's disease (flare) in 18 (26%) patients. The most commonly reported serious treatment-related adverse events were Crohn's disease (six [9%]) and abdominal abscess (two [3%]).

Endoscopic, histological, and clinical improvements were seen within 12 weeks of initiating ozanimod therapy in patients with moderately to severely active Crohn's disease. Phase 3 placebo-controlled trials have been initiated.

Celgene Corporation.

Vedolizumab (VDZ) is effective for treating both adult and pediatric onset inflammatory bowel disease (IBD). Clinical outcomes, however, have been reported to be superior in patients naïve to anti-tumor necrosis factor (TNF). With the growing interest in endoscopic endpoints, we aimed to describe rates of mucosal healing in pediatric patients being treated with VDZ and examine the influence of anti-TNF on outcomes.

We conducted a retrospective review of all IBD patients ≤21 years of age who initiated VDZ and underwent endoscopy. Primary outcome was mucosal healing (composite of endoscopic [SES-CD] and Mayo score UC) and histological remission [Nancy index-UC and Crohn disease (CD) histologic activity]. Descriptive statistics summarized the data. Comparisons were made for endpoints based on anti-TNF exposure using univariate testing.

Sixty-eight patients were included in the final analysis; 35 with UC and 33 with CD. Thirty-two patients (22 UC and 10 CD) were anti-TNF-naïve and 36 patients (13 UC and 23 CD) were anti-TNF-exposed. The median duration on VDZ before endoscopic assessment was 49 (IQR 32-73) weeks. A total of 38% (25/66) of patients met the primary outcome of mucosal healing and did not differ between anti-TNF-naïve or anti-TNF-exposed. Endoscopic remission was achieved by 51% with significantly more anti-TNF naïve patients reaching this endpoint (66% vs 40%, P = 0.03). Histologic remission was achieved by 42% of patients with a nonsignificant trend towards improved histologic remission rates in anti-TNF-naïve patients (52% vs 33%, P = 0.13).

VDZ is associated with mucosal healing in pediatric IBD. Anti-TNF exposure significantly impacted endoscopic remission, but not histologic remission in children on VDZ.

The appropriate location for biopsy procurement relative to an ulcer in active Crohn's disease is unknown.

To explore the relationship between biopsy location, histological disease activity, proinflammatory gene expression and the presence of inflammatory cells.

Fifty-one patients with Crohn's disease and ulcers >0.5 cm diameter in the colon and/or ileum were prospectively enrolled at three centres. Biopsies were obtained from 0 mm, 7 to 8 mm and 21 to 24 mm from the edge of the largest ulcer. Histological activity was blindly assessed with the Global Histological Disease Activity Score, the Robarts Histopathology and Nancy Histological indices. Messenger ribonucleic acid (mRNA) levels for interleukins-6, -8 and -23 (p19 and p40 subunits), CD31 and S100A9 were measured using quantitative polymerase chain reaction. The number of CD3+, CD68+ and myeloperoxidase-positive cells was quantified by immunohistochemistry. Data were analysed using mixed models with location and segment as fixed effects and patients as random effect to account for correlation among segments within a patient.

Histological disease activity scores (P < 0.0001), proinflammatory gene expression levels (P < 0.005) and numbers of myeloperoxidase-positive cells (P < 0.0001) were highest in biopsies from the ulcer edge in the colon and ileum, with decreasing gradients observed with distance from the edge (P < 0.05). No differences between colonic and ileal samples were detected for the parameters measured at any location.

Biopsies from the ulcer edge in patients with Crohn's disease yielded the greatest histological disease activity and mRNA levels and had similar readouts in the colon and ileum. Research is needed to confirm this conclusion for other measures.

Aim: Our aim was to evaluate the correlation and concordance measures between clinical, endoscopic and histologic remission in Crohn's disease (CD) under treatment. Method: Twenty-four patients with CD under treatment were included in a prospective consecutive cross-sectional study from January to September 2018. Clinical activity was assessed by Crohn's Disease Activity Index (CDAI). All of the patients were submitted an ileocolonoscopy with biopsy and classified by Simple Endoscopic Score (SES-CD). Histologic activity was assessed by Global Histologic Activity Score (GHAS) modified. Remission was considered with CDAI <150; SES-CD ≤2 and GHAS ≤4. Results: Clinical remission was established in 53%, however, only 50% had mucosal healing (MH) and 70% had inflammatory histologic activity. Correlation between endoscopic and histological measures was strong and positive (σ = 0.73, p < .0003). The concordance remission agreement between SES-CD and GHAS was weak with (κ) = 0.3 (IC 95%: -0.09; 0.69). The greatest disparity arose when clinical activity (CDAI) was compared with histological measures (σ = 0.20, p = .45), (κ) = 0.26 (IC = -0.03; 0.56). Conclusion: The score SES-CD correlates well with histological score GHAS in CD under treatment, however, there is low concordance between both mainly in patients with anti-TNFs treatment. CDAI score had low correlation and concordance with histological score GHAS. In this sample, patients under treatment and without symptoms had low MH and histologic healing.

Activating transcription factor 4 (ATF4) regulates genes involved in the inflammatory response, amino acid metabolism, autophagy, and endoplasmic reticulum stress. We investigated whether its activity is altered in patients with inflammatory bowel diseases (IBDs) and mice with enterocolitis.

We obtained biopsy samples during endoscopy from inflamed and/or uninflamed regions of the colon from 21 patients with active Crohn's disease (CD), 22 patients with active ulcerative colitis (UC), and 38 control individuals without IBD and of the ileum from 19 patients with active CD and 8 individuals without IBD in China. Mice with disruption of Atf4 specifically in intestinal epithelial cells (Atf4ΔIEC mice) and Atf4-floxed mice (controls) were given dextran sodium sulfate (DSS) to induce colitis. Some mice were given injections of recombinant defensin α1 (DEFA1) and supplementation of l-alanyl-glutamine or glutamine in drinking water. Human and mouse ileal and colon tissues were analyzed by quantitative real-time polymerase chain reaction, immunoblots, and immunohistochemistry. Serum and intestinal epithelial cell (IEC) amino acids were measured by high-performance liquid chromatography-tandem mass spectrometry. Levels of ATF4 were knocked down in IEC-18 cells with small interfering RNAs. Microbiomes were analyzed in ileal feces from mice by using 16S ribosomal DNA sequencing.

Levels of ATF4 were significantly decreased in inflamed intestinal mucosa from patients with active CD or active UC compared with those from uninflamed regions or intestinal mucosa from control individuals. ATF4 was also decreased in colonic epithelia from mice with colitis vs mice without colitis. Atf4ΔIEC mice developed spontaneous enterocolitis and colitis of greater severity than control mice after administration of DSS. Atf4ΔIEC mice had decreased serum levels of glutamine and reduced levels of antimicrobial peptides, such as Defa1, Defa4, Defa5, Camp, and Lyz1, in ileal Paneth cells. Atf4ΔIEC mice had alterations in ileal microbiomes compared with control mice; these changes were reversed by administration of glutamine. Injections of DEFA1 reduced the severity of spontaneous enteritis and DSS-induced colitis in Atf4ΔIEC mice. We found that expression of solute carrier family 1 member 5 (SLC1A5), a glutamine transporter, was directly regulated by ATF4 in cell lines. Overexpression of SLC1A5 in IEC-18 or primary IEC cells increased glutamine uptake and expression of antimicrobial peptides. Knockdown of ATF4 in IEC-18 cells increased expression of inflammatory cytokines, whereas overexpression of SLC1A5 in the knockdown cells reduced cytokine expression. Levels of SLC1A5 were decreased in inflamed intestinal mucosa of patients with CD and UC and correlated with levels of ATF4.

Levels of ATF4 are decreased in inflamed intestinal mucosa from patients with active CD or UC. In mice, ATF4 deficiency reduces glutamine uptake by intestinal epithelial cells and expression of antimicrobial peptides by decreasing transcription of Slc1a5. ATF4 might therefore be a target for the treatment of IBD.

Faecal calprotectin (FC) is a marker of mucosal inflammation.

The aim of this study was to determine the diagnostic accuracy of FC to (a) differentiate between perianal fistulizing Crohn's disease (pCD) and cryptoglandular perianal fistulas; and (b) detect mucosal inflammation in pCD.

Patients with active perianal fistulas who had FC measured and a complete ileocolonoscopy within 10 weeks were retrospectively included.

Fifty-six patients were included (pCD, n = 37) of whom 19 pCD patients exhibited ulcers. FC was significantly higher in pCD compared to cryptoglandular fistulas (µg/g) (708.0 (207.0-1705.0) vs 32.0 (23.0-77.0), p < 0.001). Area-under-the-curve (AUC) value for FC receiver operating characteristic (ROC) statistics was 0.900. Optimal FC cut-off was ≥ 150 µg/g. To differentiate pCD from cryptoglandular fistulas in the absence of luminal inflammation, optimal cut-off remained ≥ 150 µg/g (AUC = 0.857, sensitivity = 0.81, specificity = 0.89, positive predictive value (PPV) = 93.8% and negative predictive value (NPV) = 70.8%). In pCD, FC was significantly increased in the presence of ulcers (1672.0 vs 238.0, p = 0.004). Optimal cut-off was ≥ 250 µg/g (AUC = 0.776; sensitivity = 0.89, specificity = 0.56, PPV - 68.0% and NPV = 83.0%).

FC discriminates pCD from cryptoglandular fistulas, even in the absence of intestinal ulcers. In active pCD, an elevated FC does not accurately predict the presence of ulcers and should be interpreted with caution.

Eosinophilic colitis is a rare condition, with a prevalence rate in the USA of 2-3/100 000 persons (0.003%), but diagnosed in 0.1% of biopsies in those colonoscoped for diarrhoea. Secondary colonic eosinophilia is more common and associated with systemic, colonic and infectious diseases. In this review, the latest advances in diagnosis, treatment and prognosis are summarized and discussed.

What constitutes a 'normal' count of eosinophils is poorly documented but there are recent studies that establish normal colonic eosinophil ranges as well as distinguishing histological and clinical findings in primary eosinophilic colitis and secondary colonic eosinophilia in children and adults. Primary eosinophilic colitis is rare, relatively straightforward to diagnose, but may be difficult to treat. Colonic eosinophilia may be overt in parasite infection and connective tissue disease. More subtle, secondary colonic eosinophilia is a useful biomarker for gastrointestinal diseases, such as inflammatory bowel disease, colonic spirochaetosis and collagenous colitis, but the eosinophilia may more often be overlooked. A limited number of drugs are also known to cause left sided colonic eosinophilia such as clopidogrel, ibuprofen and oestroprogestinic agents.

Advances in our understanding of primary eosinophilic colitis and secondary colonic eosinophilia is progressing and if present, colonic eosinophilia should point the clinician and pathologist to a list of differential diagnoses worth considering to direct optimal management.

Histologic assessment of mucosal disease activity has been increasingly used in clinical trials of treatment for Crohn's disease. However, the operating properties of the currently existing histologic scoring indices remain unclear.

A systematic review was undertaken to evaluate the development and operating characteristics of available histologic disease activity indices in Crohn's disease.

Electronic searches of MEDLINE, EMBASE, PubMed, and the Cochrane Library (CENTRAL) databases from inception to 20 July 2016 were supplemented by manual reviews of bibliographies and abstracts submitted to major gastroenterology meetings (Digestive Disease Week, United European Gastroenterology Week, European Crohn's and Colitis Organisation).

Any study design (e.g. randomised controlled trial, cohort study, case series) that evaluated a histologic disease activity index in patients with Crohn's disease was considered for inclusion. Study participants included adult patients (> 16 years), diagnosed with Crohn's disease using conventional clinical, radiographic or endoscopic criteria.

Two authors independently reviewed the titles and abstracts of the studies identified from the literature search. The full text of potentially relevant citations were reviewed for inclusion and the study investigators were contacted as needed for clarification. Any disagreements regarding study eligibility were resolved by discussion and consensus with a third author.Two authors independently extracted and recorded data using a standard form. The following data were recorded from each eligible study: number of patients enrolled; number of patients per treatment arm; patient characteristics: age and gender distribution; description of histologic disease activity index utilized; and outcomes such as content validity, construct validity, criterion validity, responsiveness, intra-rater reliability, inter-rater reliability, and feasibility.

Sixteen reports of 14 studies describing 14 different numerical histological indices fulfilled the inclusion criteria.Inter-rater reliability was assessed in one study. For the Naini and Cortina Score, estimates of correlation were 'almost perfect', ranging from r = 0.94 to 0.96. The methodological quality of this study with respect to reliability was 'good'.With respect to validity, correlation estimates between various histological scoring systems and Crohn's disease activity as measured by objective markers of inflammation (including C-reactive protein, erythrocyte sedimentation rate, fecal calprotectin and fecal lactoferrin); endoscopic disease activity scores; clinical disease activity scores; and quality of life questionnaires were reported. Comparisons between histologic scoring indices and endoscopic scoring indices ranged from no correlation to 'substantial' (r = 0.779). The methodological quality of the studies that explored validity ranged form 'poor' to 'good'.Responsiveness data were available in seven studies. After subjects were administered a treatment of known efficacy, statistically significant change in the index score was demonstrated in five studies with respect to six indices. Two studies failed to indicate whether there was statistically significant change in the index score post-treatment. With regard to methodological quality, six of the studies were rated as 'poor' and one of the studies was rated as 'fair'.Feasibility was assessed by one study. The Naini and Cortina Score was shown to be simple to use and feasible for every given case.

Currently there is no fully validated histological scoring index for evaluation of Crohn's disease activity. Development of a validated histological scoring index for Crohn's disease is a clinical and research priority.

Colonic involvement in pediatric inflammatory bowel disease is common. Magnetic resonance (MR) enterography is considered the best imaging modality for pediatric inflammatory bowel disease evaluation. It is unclear whether the lack of a dedicated large bowel preparation prevents a reliable colonic assessment.

To determine the diagnostic performance of standard MR enterography in detecting and grading colonic inflammatory activity.

We retrospectively evaluated children who underwent both MR enterography and ileocolonoscopy with biopsies <4 weeks apart. Two radiologists independently reviewed MR examinations and quantified inflammation in each of the five colonic segments using a standardized MR score system. Findings were compared with histological examination of the corresponding segment. Mann-Whitney, Kruskal-Wallis, Jonckheere-Terpstra and Bland-Altman statistics were used.

One hundred seventy-five segments from 37 examinations were included. MR enterography diagnostic performance for inflammation was as follows: sensitivity 94% (95% confidence interval [CI]: 90-97%), specificity: 64% (95% CI: 57-71%). A significant positive correlation was found between MR score and inflammatory activity histologically graded (P<0.001, Jonckheere-Terpstra test). The interobserver agreement was good (mean difference between MR enterography scores was -0.03; limits of agreement -2.8 to 2.7).

Standard MR enterography is sensitive for the detection of actively inflamed colonic segments. MR enterography might provide useful information for guiding biopsies and its role as an alternative to ileocolonoscopy in monitoring colonic disease activity in children should be further investigated.

Histologic evaluation of disease activity in the setting of inflammatory bowel disease is gaining interest within the gastroenterology community. Recent data suggests that histologic measurements of inflammation in ulcerative colitis are more sensitive at detecting disease activity and perform better than endoscopic measurements in predicting clinical outcomes. Histologic measurements are also increasingly used in ulcerative colitis clinical trials to assess response to new therapies. Histologic measurements of disease activity are less well studied in Crohn's disease, but are gaining attention. Current published treatment algorithms in inflammatory bowel disease do not take into consideration histologic activity; however, this may change in the near future. In order for histologic measurements to be included in clinical decision-making, validated, reliable, and responsive histologic scoring systems are needed. In this review, the recent literature on the significance of histologic activity in both ulcerative colitis and Crohn's disease is summarized. Histologic scoring systems are also briefly discussed.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, commonly accompanied by cognitive dysfunction, sleeping disturbances, orthostatic intolerance, fever, lymphadenopathy, and irritable bowel syndrome (IBS). The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. We pursued rigorous clinical characterization, fecal bacterial metagenomics, and plasma immune molecule analyses in 50 ME/CFS patients and 50 healthy controls frequency-matched for age, sex, race/ethnicity, geographic site, and season of sampling.

Topological analysis revealed associations between IBS co-morbidity, body mass index, fecal bacterial composition, and bacterial metabolic pathways but not plasma immune molecules. IBS co-morbidity was the strongest driving factor in the separation of topological networks based on bacterial profiles and metabolic pathways. Predictive selection models based on bacterial profiles supported findings from topological analyses indicating that ME/CFS subgroups, defined by IBS status, could be distinguished from control subjects with high predictive accuracy. Bacterial taxa predictive of ME/CFS patients with IBS were distinct from taxa associated with ME/CFS patients without IBS. Increased abundance of unclassified Alistipes and decreased Faecalibacterium emerged as the top biomarkers of ME/CFS with IBS; while increased unclassified Bacteroides abundance and decreased Bacteroides vulgatus were the top biomarkers of ME/CFS without IBS. Despite findings of differences in bacterial taxa and metabolic pathways defining ME/CFS subgroups, decreased metabolic pathways associated with unsaturated fatty acid biosynthesis and increased atrazine degradation pathways were independent of IBS co-morbidity. Increased vitamin B6 biosynthesis/salvage and pyrimidine ribonucleoside degradation were the top metabolic pathways in ME/CFS without IBS as well as in the total ME/CFS cohort. In ME/CFS subgroups, symptom severity measures including pain, fatigue, and reduced motivation were correlated with the abundance of distinct bacterial taxa and metabolic pathways.

Independent of IBS, ME/CFS is associated with dysbiosis and distinct bacterial metabolic disturbances that may influence disease severity. However, our findings indicate that dysbiotic features that are uniquely ME/CFS-associated may be masked by disturbances arising from the high prevalence of IBS co-morbidity in ME/CFS. These insights may enable more accurate diagnosis and lead to insights that inform the development of specific therapeutic strategies in ME/CFS subgroups.

Small bowel villous atrophy can represent a diagnostic challenge for gastroenterologists and pathologists. In Western countries small bowel atrophy and mild non-atrophic alterations are frequently caused by celiac disease. However, other pathology can mimic celiac disease microscopically, widening the differential diagnosis. The several novelties on this topic and the introduction of the device-assisted enteroscopy in the diagnostic flowchart make an update of the literature necessary. Areas covered: In this review, a description of the different clinical scenarios when facing with small bowel mucosal damage, particularly small bowel atrophy, is described. The published literature on this subject has been summarized and reviewed. Expert commentary: When an intestinal mucosal alteration is histologically demonstrated, the pathology report forms part of a more complex workup including serological data, clinical presentation and clinical history. A multidisciplinary team, including pathologists and enteroscopy-devoted endoscopists, is frequently required to manage patients with small bowel alterations, especially in cases of severe malabsorption syndrome.

The highest attrition rates during drug development programmes occur at the proof of concept stage. Given the large number of molecules under development for Crohn's disease, a need exists to improve the efficiency of early drug development by fast-tracking promising agents and terminating ineffective ones. Multiple opportunities are available to achieve these goals, including the use of more responsive outcome measures, and the incorporation of sophisticated pharmacokinetic modelling and/or highly specific pharmacodynamic markers into exposure-based dosing regimens and novel trial designs. In this article we review these strategies and propose an integrated paradigm of early drug development in Crohn's disease.

Filgotinib (GLPG0634, GS-6034) is a once-daily, orally administered, Janus kinase 1 (JAK1)-selective inhibitor. The FITZROY study examined the efficacy and safety of filgotinib for the treatment of moderate-to-severe Crohn's disease.

We did a randomised, double-blind, placebo-controlled phase 2 study, which recruited patients from 52 centres in nine European countries. We enrolled eligible patients aged 18-75 years with a documented history of ileal, colonic, or ileocolonic Crohn's disease for 3 months or more before screening, as assessed by colonoscopy and supported by histology, and a Crohn's Disease Activity Index (CDAI) score during screening between 220 and 450 inclusive. Patients were randomly assigned (3:1) to receive filgotinib 200 mg once a day or placebo for 10 weeks. Patients were stratified according to previous anti-tumour necrosis factor alpha exposure, C-reactive protein concentration at screening (≤10 mg/L or >10 mg/L), and oral corticosteroid use at baseline, using an interactive web-based response system. The primary endpoint was clinical remission, defined as CDAI less than 150 at week 10. After week 10, patients were assigned based on responder status to filgotinib 100 mg once a day, filgotinib 200 mg once a day, or placebo for an observational period lasting a further 10 weeks. The filgotinib and placebo treatment groups were compared using ANCOVA models and logistic regression models containing baseline values and randomisation stratification factors as fixed effects. Analyses were done on the intention-to-treat non-responder imputation set. The trial was registered at ClinicalTrials.gov, number NCT02048618.

Between Feb 3, 2014, and July 10, 2015, we enrolled 174 patients with active Crohn's disease confirmed by centrally read endoscopy (130 in the filgotinib 200 mg group and 44 in the placebo group). In the intention-to-treat population, 60 (47%) of 128 patients treated with filgotinib 200 mg achieved clinical remission at week 10 versus ten (23%) of 44 patients treated with placebo (difference 24 percentage points [95% CI 9-39], p=0·0077). In a pooled analysis of all periods of filgotinib and placebo exposure over 20 weeks, serious treatment-emergent adverse effects were reported in 14 (9%) of 152 patients treated with filgotinib and three (4%) of 67 patients treated with placebo.

Filgotinib induced clinical remission in significantly more patients with active Crohn's disease compared with placebo, and had an acceptable safety profile.

Galapagos.

For patients with Crohn's disease (CD) who have colonoscopy during periods of clinical remission, the utility of taking ileocolonic biopsy specimens to assess disease activity is disputed.

We explored the clinical implications of histologic disease activity in such patients.

We reviewed medical records of CD patients who underwent elective colonoscopy while in clinical remission at our VA Medical Center from 2000 to 2013, and who had at least 6 months of follow-up. We correlated endoscopic and histologic disease activity with the subsequent development of flares.

We identified 62 CD patients who had a total of 103 colonoscopies during clinical remission; 55 colonoscopies revealed complete endoscopic healing and 48 showed active disease. Flares within 6, 12, and 24 months of colonoscopy were not more common in patients with endoscopic activity than those with complete endoscopic healing. In contrast, patients with any of 5 histologic features of active inflammation (erosions, cryptitis, crypt abscess, increased neutrophils, or increased eosinophils in the lamina propria) had more flares than patients without those changes (P<0.05). Among the individual histologic features, an increase in eosinophils or neutrophils in the lamina propria and cryptitis were associated with higher flare rates (P<0.05).

For CD patients who have a colonoscopy while in clinical remission, biopsy seems to provide important prognostic information beyond that provided by endoscopic assessment of disease activity alone. In particular, increased eosinophils or neutrophils in the lamina propria and cryptitis are strongly associated with an increased risk of clinical flares within 1 to 2 years.

to analyze the generally accepted histological criteria for diagnosing the activity of inflammatory bowel disease (IBD) in patients with therapy-induced endoscopic remission.

Colon biopsy specimens from 57 patients aged from 19 to 52 years (mean age 31±2.5 years), including 41 patients with ulcerative colitis (UC) and 16 with Crohn's disease (CD) affecting the colon, were examined. All the patients had no clinical signs of disease activity; endoscopic examination diagnosed remission (none or minimal changes). The biopsy specimens were taken from all colon segments during colonoscopy and processed by conventional methods.

Persistence in chronic inflammation with signs of its activity (neutrophils in an infiltrate and cryptitis) and mucosal structural changes (no histological remission) were found in 29.3% of the patients with UC and 37.5% of those with CD (only in 31.6% of the patients). Persistence in chronic inflammation without signs of its activity and/or mucosal structural changes (incomplete histological remission) were detected in 80.5, 81.25, and 80.7% of the patients, respectively. Complete histological remission without mucosal inflammatory and structural changes was observed only in 19.5, 18.75, and 19.3% of the patients, respectively.

The investigation shows that histological remission is still difficult to achieve to date, despite the use of the present-day treatment protocols for IBD. On the other hand, the conventional morphological criteria for the diagnosis of histological remission in IBD are quite subjective and need further discussion and agreement. Whether there may be a complete structural and functional recovery of the colon mucosa remains open.

Crohn's disease (CD) is an idiopathic inflammatory disorder of the gastrointestinal tract traditionally treated by the step-wise use of corticosteroids, antimetabolites and TNF-α antagonists. However, recent evidence indicates that the early introduction of drug combinations might be a superior strategy to step-care.

In this article, we review existing literature regarding the efficacy and safety of combination drug therapy for the management of CD. Five major databases: MEDLINE, EMBASE, PubMed, the Cochrane Library (CENTRAL) and DDW abstracts were electronically searched from inception to February 2015 for any relevant studies.

Existing data strongly support the use of combination therapy for CD. The benefit of this approach appears to outweigh any associated risks. Until the role of gut selective therapies are better established, combination therapy should be considered the standard treatment approach for CD.