Talat Bessissow

Prognostic value of serologic and histologic markers on clinical relapse in ulcerative colitis patients with mucosal healing.

OBJECTIVES:Endoscopic mucosal healing is a key endpoint for the treatment of ulcerative colitis (UC). The role of microscopic activity in predicting disease relapse has not been fully assessed. We aimed to investigate the predictive role of serologic and histologic markers on disease relapse in UC patients with endoscopically inactive disease.METHODS:Adult UC patients with endoscopically inactive disease (Mayo 0) and a 12-month follow-up between 2008 and 2011 were retrospectively included. An expert pathologist evaluated all colonic biopsies for histologic activity (Geboes score) and the presence of basal plasmacytosis. Blood samples collected around the time of endoscopy were analyzed. Disease relapse, defined as a clinical Mayo score ≥3, was documented during follow-up.RESULTS:The study cohort consisted of 75 patients (53% men, median age 47 years). Despite normal endoscopy, histology showed inflammatory activity with a Geboes score ≥3.1 in 40% and basal plasmacytosis in 21% of patients. At 12 months, clinical relapse was observed in 20% (n=15) of patients. Presence of basal plasmacytosis (P=0.007) and a Geboes score ≥3.1 (P=0.007) were predictive of disease relapse. Using multivariate analysis, the presence of basal plasmacytosis was predictive of clinical relapse (odds ratio (OR) 5.13 (95% confidence interval (CI): 1.32–19.99), P=0.019), whereas the use of biologicals at endoscopy favored remission (OR 0.24 (95% CI: 0.05–1.01), P=0.052).CONCLUSIONS:We demonstrated that the presence of basal plasmacytosis predicts UC clinical relapse in patients with complete mucosal healing. We recommend closer follow-up and optimization of medical therapy in patients with basal plasmacytosis.

Subcutaneous ustekinumab for the treatment of anti-TNF resistant Crohn's disease—The McGill experience

BACKGROUNDnUstekinumab is a fully human IgG1κ monoclonal antibody that blocks the biologic activity of interleukin-12/23. Ustekinumab is approved for treatment of plaque psoriasis and has been shown to be effective for induction and maintenance of clinical response in anti-TNF resistant Crohns disease (CD). The aim of the study was to describe the real-life experience with open-label use of ustekinumab in anti-TNF resistant CD patients.nnnMETHODSnA retrospective observational open-label study. Clinical response was defined by physicians global assessment combined with decision to continue therapy. The clinical response was evaluated at 3, 6, 12months and last follow-up.nnnRESULTSnThirty-eight patients were included in the study. Initial clinical response was achieved in 28/38 (73.7%) of the patients. Among the initial responders, 80% with follow-up data maintained their response for 6months. At 12months of follow-up, 88.9% of patients responding at 6months maintained their response. At the last follow-up (7.9±5.2 mo) 27/38 (71%) of the patients were responding, and 73.3% were able to discontinue corticosteroids. Dose escalation was required in 47.7% of the patients and was successful in 61.1% of them.nnnSUMMARYnIn this real-life cohort of severe anti-TNF resistant CD, an initial clinical response to subcutaneous ustekinumab was observed in 73.7% of the patients. The initial response was successfully maintained in the majority of patients for up to 12months. Subcutaneous ustekinumab is an effective therapeutic option in this challenging patient cohort. The optimal dosing and injection schedule remain to be established in future studies.

Small bowel capsule endoscopy in the management of established Crohn's disease: clinical impact, safety, and correlation with inflammatory biomarkers.

Background:Multiple studies have established the superior diagnostic accuracy of video capsule endoscopy (VCE) for the diagnosis of small bowel (SB) Crohns disease (CD). However, data on the clinical impact of VCE in patients with established CD are scarce. The aim of this study was to examine the impact and safety of VCE on the clinical management of patients with established CD. Methods:A retrospective, multicenter, cross-sectional study. The study cohort included consecutive patients with established SB CD who underwent VCE in 4 tertiary referral centers (1 Canada, 1 Sweden, and 2 United Kingdom) from January 2008 to October 2013. Patients were excluded if VCE was performed as a part of the initial diagnostic workup. The presence of SB mucosal inflammation was quantified using the Lewis score. Inflammatory biomarkers (C-reactive protein and fecal calprotectin) were measured and correlated with the Lewis score. Results:The study included 187 patients. No SB inflammation was observed in 28.4%, mild-to-moderate inflammation in 26.6%, and moderate-to-severe inflammation in 45% of the patients (median Lewis score, 662; range, 0–6400). A change in management was recommended in 52.3% of the patients based on VCE findings. Elevated C-reactive protein, fecal calprotectin, or the combination of both were poorly correlated with significant SB inflammation. SB capsule retention occurred in 4 patients (2.1%). Conclusions:VCE in patients with established CD is safe, and the results often have a significant clinical impact. VCE should not be limited to CD patients with positive inflammatory markers because their predictive value for significant SB inflammation is poor.

Review article: non-malignant haematological complications of anti-tumour necrosis factor alpha therapy

Tumour necrosis factor‐alpha (TNF‐α) is an important mediator of the molecular cascade leading to chronic inflammation. TNF‐α inhibitors have proven their safety and efficacy in the treatment of inflammatory diseases.

Vitamin B12 Deficiency in Inflammatory Bowel Disease: Prevalence, Risk Factors, Evaluation, and Management

Background:Management of vitamin B12 (cobalamin, Cbl) deficiency in inflammatory bowel disease (IBD) is often not evidenced-based because of uncertainty on whether it causes enough malabsorption to result in clinical disease. This systematic review examines whether IBD predisposes to Cbl deficiency. We provide an approach to the management of abnormal Cbl values in IBD based on current literature and consensus-based guidelines. Methods:An extensive search of the Ovid MEDLINE and EMBASE databases by independent reviewers identified 42 articles with a total of 3732 patients evaluating Cbl deficiency in IBD. Results:Crohns disease without ileal resection, regardless of disease location in the ileum, did not increase the risk for Cbl deficiency. Ileal resections greater than 30 cm were associated with Cbl deficiency in Crohns disease, whereas those less than 20 cm were not. The effects of 20 to 30 cm resections were inconsistent. Ulcerative colitis did not predispose to deficiency. All studies failed to use confirmatory biomarker testing as stipulated by diagnostic guidelines for Cbl deficiency. Conclusions:This literature does not support an association of Crohns disease in general, regardless of ileal involvement, with Cbl deficiency. Only ileal resections greater than 20 cm in Crohns disease predispose to deficiency and warrant treatment. Based on these findings, we suggest a diagnostic and therapeutic algorithm. All findings and recommendations require verification in further studies using confirmatory biomarkers as per diagnostic guidelines for Cbl deficiency. Serum Cbl levels alone are likely insufficient to diagnose deficiency in asymptomatic patients.

Evidence for Neuronal and Structural Changes in Submucous Ganglia of Patients With Functional Dyspepsia

OBJECTIVES:An intact and well-functioning enteric nervous system is necessary to efficiently organize gut function. Functional gastrointestinal disorders are pathological entities in which gut function is impaired without a clearly established pathophysiology. On the basis of the relative ease with which intestinal biopsies can be obtained, and taking advantage of a recently developed optical recording technique, we evaluated whether functional neuronal defects exist in enteric nerves of patients with functional dyspepsia (FD).METHODS:The submucous plexus isolated from duodenal biopsies taken from FD patients and control subjects was used to functionally and morphologically examine nerves and ganglionic architecture (neurons and glial cells). In light of previous studies reporting eosinophil and mast cell infiltration in the gut mucosa of FD patients, we also examined whether these cells infiltrated the submucous plexus and whether this correlated with neuronal activity and specific clinical symptoms.RESULTS:We demonstrate that neuronal functioning is impaired in the submucous plexus of FD patients, as shown by decreased calcium responses to depolarization and electrical stimulation. Glial (S100) and neuronal (HuCD) markers show signs of gliosis, altered ganglionic architecture, and neuronal abnormalities in the submucous plexus of FD patients. We found that eosinophils and mast cells infiltrated the submucous layer of FD patients to a much larger extent than in controls. A significant correlation was found between the number of these cells and the calcium transient amplitudes measured in submucous ganglia.CONCLUSIONS:We provide the first direct evidence that FD is characterized by functional and structural abnormalities within the submucous ganglion plexus, which may be of future predictive and diagnostic value in the treatment of FD patients.

The Modified Mayo Endoscopic Score (MMES): A New Index for the Assessment of Extension and Severity of Endoscopic Activity in Ulcerative Colitis Patients

BACKGROUND AND AIMSnCurrent endoscopic activity scores for ulcerative colitis (UC) do not take into account the extent of mucosal inflammation. We have developed a simple endoscopic index for UC that takes into account the severity and distribution of mucosal inflammation.nnnMETHODSnIn this multicentre trial, UC patients undergoing colonoscopy were prospectively enrolled. For the Modified Score (MS), the sum of Mayo Endoscopic Subscores (MESs) for five colon segments (ascending, transverse, descending, sigmoid and rectum) was calculated. The Extended Modified Score (EMS) was obtained by multiplying the MS by the maximal extent of inflammation. The Modified Mayo Endoscopic Score (MMES) was obtained by dividing the EMS by the number of segments with active inflammation. Colon biopsies were obtained from the rectum and sigmoid, as well as from all inflamed segments, by standard methods. Clinical activity was scored according to the Partial Mayo Score (PMS). Biological activity was scored according to C-reactive protein (CRP) and faecal calprotectin (FC) levels. Histological activity was scored according to the Geboes Score (GS).nnnRESULTSnOne hundred and seventy-one UC patients (38% female, median age 47 years, median disease duration 13 years) were included. The MMES correlated significantly with the PMS (r = 0.535), CRP (r = 0.238), FC (r = 0.730) and GS (r = 0.615) (all p < 0.001). Median MMES scores were significantly higher in patients with clinical, biological or histological activity (all p ≤ 0.001) CONCLUSIONS: The MMES is an easy to use endoscopic index for UC that combines the severity analysis of the MES with disease extent, and correlates very well with clinical, biological and histological disease activity.

Anxiety is associated with impaired tolerance of colonoscopy preparation in inflammatory bowel disease and controls

BACKGROUND AND AIMnPain and nausea are often reported during bowel cleansing (BC) for ileocolonoscopy (IC). We aimed to explore putative mechanisms associated with impaired tolerance to BC.nnnMETHODSnA 1:1 (100 IBD and 100 controls) sex and age matched case-control study was performed. Patients completed the hospital anxiety and depression scale (HADS-A/HADS-D), visceral sensitivity index (VSI) and state-trait anxiety inventory, state scale (STAI-S), in addition to self-assessment of BC and abdominal pain and nausea ratings during BC. Endoscopists reported the Mayo score, Harvey Bradshaw index (HBI), simple endoscopic score for Crohns disease, and Boston bowel preparation scale (BBPS).nnnRESULTSnHigher VSI and depression scores were observed in IBD patients. VSI (P<0.0001) and age (P=0.008) showed a positive and negative association with abdominal pain during BC, respectively. HADS-A (P=0.009) and female sex (P=0.02) were positively associated with nausea during BC, while age (P=0.02) showed a negative association. Disease activity was not associated with worse BBPS or nausea during BC, while a higher HBI was associated with more pain during BC (P=0.0006). Nausea (P=0.007) and abdominal pain (P=0.003) during BC, and less previous ICs (P=0.03) were independently associated with anxiety prior to IC (STAI-S). Significant correlations were found between VSI and STAI-S and disease activity.nnnCONCLUSIONnHigher gastrointestinal-specific anxiety and co-morbid anxiety are associated with increased pain and nausea during BC, respectively. Pain and nausea during BC were in turn associated with higher anxiety levels at the moment of IC, potentially creating a vicious circle. Measures taken to reduce anxiety could improve BC and IC tolerance.

Advanced endoscopic imaging for dysplasia surveillance in ulcerative colitis

Ulcerative colitis is a well-characterized chronic inflammatory bowel disease with a significantly increased risk for developing colorectal neoplasia. A rigorous colonoscopy surveillance program has been shown to undoubtedly reduce this risk. White light endoscopy with random 4-quadrant biopsies in addition to target biopsies of suspicious lesions has been considered the standard of care. However, interval cancers between successive surveillance colonoscopies have been identified. Recently, multiple new endoscopic imaging technologies such as standard chromoendoscopy with methylene blue, virtual chromoendoscopy, autofluorescence imaging, confocal laser endomicroscopy and endocytoscopy were developed to provide a more detailed visualization of the mucosa by enhancing morphology and vascularization. This review will provide a comprehensive approach to advanced endoscopic imaging useful for dysplasia surveillance in longstanding ulcerative colitis patients.

A Simplified Geboes Score for Ulcerative Colitis

Background and AimsnThe original Geboes Score [OGS] is the most commonly used histological score in ulcerative colitis [UC], but rather complicated to use in daily clinical practice. The aim of this study was to develop a Simplified Geboes Score [SGS] and to compare it with the OGS in patients newly diagnosed with UC.nnnMethodsnAll patients diagnosed with UC at a tertiary referral centre between 2005 and 2010, who had serial colonoscopies with biopsies, were retrospectively included. The 5-year endoscopic/histological evolution after diagnosis was recorded. Histological activity was scored by an experienced inflammatory bowel disease pathologist and three trained readers using the OGS and also the new SGS that only includes variables linked to active inflammatory disease. The correlation between endoscopic and histological activity and the histological inter-observer agreement were measured.nnnResultsnA total of 528 slides from 339 colonoscopies of 103 UC patients were reviewed. Forty [12%] colonoscopies presented Mayo 0, 74 [22%] Mayo 1, 107 [31%] Mayo 2 and 118 [35%] Mayo 3. Active microscopic disease [≥ 3.1 in both scores] was described in 10/40 [25%] patients who were in complete endoscopic remission [Mayo 0], and 62/74 [84%] with mild endoscopic lesions [Mayo 1]. The correlation analysis between endoscopy and OGS/SGS did not show significant differences between the histological scores. The inter-observer agreement was moderate for all the grades of the SGS.nnnConclusionsnThe assessments of histological activity based on the OGS and the SGS were comparable in newly diagnosed active UC patients. Further prospective validation should now be done to replace the OGS with the SGS.