Exploring Predictive Biomarkers of Relapse in Ulcerative Colitis: A Proteomics Approach.

INTRODUCTION AND AIMS: Risk stratification of subjects with a history of inflammatory bowel disease (IBD) into those likely to relapse and those who will remain quiescent continues to be a significant challenge. The aim of this study was to investigate whether certain proteomic signature profiles or biomarkers during remission are associated with future disease relapse in patients with ulcerative colitis (UC). METHODS: Endoscopic rectal samples from patients with UC in clinical, endoscopic, and histological remission at index endoscopy were collected, as well as samplers from normal control individuals. The patients were stratified to early relapsers (ERs) if they developed clinical signs of UC flare within 6 months of index endoscopy or nonrelapsers (NRs) if there was no relapse after 36 months of follow-up. The pooled rectal samples from ERs, NRs, and control individuals were subjected to nano-liquid chromatography and tandem mass spectrometry as per standard iTRAQ (isobaric tags for relative and absolute quantitation) workflow methodology. Selected proteomics-yielded candidates were subjected to orthogonal validation via immunoblotting, in a biomarker discovery exercise. RESULTS: Sixty-one patients were included, of whom 8 had clinical relapse within 6 months from the index endoscopy, and 43 patients had no clinical symptoms of relapse within the 36-month follow-up period. Ten patients who had clinical signs of relapse between 6 and 36 months were excluded. Seventeen control individuals were also included. Soluble proteomics analyses between ERs, NRs, and control individuals revealed a series of upregulated and downregulated proteins. Following orthogonal validation, upregulated TRX (P = .001) and IGHA1 (P = .001) were observed in ERs relative to NRs. CONCLUSIONS: Several novel candidate tissue biomarkers have been identified in this study, which could discriminate patients with UC at risk of early relapse from those in long-term sustained remission. Our findings may pave the way for pre-emptive UC disease monitoring and therapeutic decision making.

This study aimed to investigate if certain proteins (biomarkers) could predict whether patients with Ulcerative Colitis (UC) would have a disease relapse. Rectal samples were collected from UC patients who were in remission and from healthy individuals. The patients were categorised into two groups: those who had a flare-up within 6 months (early relapsers) and those who did not have a relapse after 36 months (non-relapsers). Using proteomics methodology, it was found that certain proteins were more common in the early relapsers compared to the non-relapsers and healthy individuals. Two proteins, TRX and IGHA1, were significantly higher in the early relapsers. These proteins could potentially be used as markers to identify UC patients who are at risk of having an early relapse. This could help monitoring UC patients more effectively and making better treatment decisions.

A propensity score-matched, real-world comparison of ustekinumab vs vedolizumab as a second-line treatment for Crohn's disease. The Cross Pennine study II.

BACKGROUND: The optimal choice of biological agents after failure of anti-tumour-necrosis-factor-(TNF)α agent in Crohn's disease (CD) is yet to be defined. AIMS: To assess the effectiveness and safety of ustekinumab compared to vedolizumab as second-line treatment in CD patients who failed anti-TNFα therapy. METHODS: Retrospective analysis of clinical response and remission at 14 and 52 weeks to ustekinumab by physician global assessment (PGA). A propensity score-matched analysis with a cohort treated with vedolizumab was performed. RESULTS: Of 282 patients (mean age 40 ± 15, F:M ratio 1.7:1) treated with ustekinumab, clinical response or remission was reached by 200/282 patients (70.9%) at 14 weeks, and 162/259 patients (62.5%) at 52 weeks. Overall, 74 adverse events occurred, of which 26 were labelled as serious (8.3 per 100 person-year). After exclusion of patients without prior anti-TNFα exposure and patients previously exposed to vedolizumab or ustekinumab, we analysed 275/282 patients (97.5%) on ustekinumab and 118/135 patients (87.4%) on vedolizumab. Propensity score analysis revealed that at 14 weeks, patients treated with ustekinumab were 38% (95% CI 25%-50%; P < 0.001) more likely to achieve clinical remission, while at 52 weeks, the difference of 9% (95% CI -15% to 33%; P = 0.462) was not significant. CONCLUSIONS: Ustekinumab was effective and well tolerated in this real-world cohort. While ustekinumab proved more effective at 14-weeks, we found no statistically significant differences at 52 weeks compared to vedolizumab.

Endoscopic resection of early squamous neoplasia of the oesophagus: long-term follow-up in a UK population from a tertiary hospital.

AIM: To review the efficacy and outcomes of endoscopic resection in the diagnosis and treatment of oesophageal squamous dysplasia and early neoplasia. METHODS: This was a retrospective study between May 2012-2018. Twenty-one patients were treated with or considered for treatment with endoscopic resection at a tertiary hospital in the UK. The primary outcome was curative resection, defined as histologically proven complete resection of the lesion with deep/vertical margin ≥1 mm from neoplasia. Secondary outcomes were changes in staging from endoscopic resection histology, whether there was a complete reversal of dysplasia at 12-months or the latest endoscopic follow-up and 5-year overall survival rate. RESULTS: Seventeen patients (mean age = 66.5 years) with 20 lesions (35% en-bloc; 65% piecemeal resections) had endoscopic resection performed. Complete resection was achieved in 90% of lesions by endoscopic criteria, but this was confirmed in fewer lesions histologically. Curative resection was achieved histologically in 60% of lesions (11 patients) and noncurative resection in 40% of lesions (6 patients). Changes in staging from endoscopic resection histology were found in 79.2% of lesions (41.7% upstaged; 37.5% downstaged). No patients were found to have recurrence at their 12-month endoscopic follow-up. Eight of the 11 patients (72.7%) with curative resection remained clear of dysplasia/neoplasia throughout their follow-up (mean, 24.3 months; median, 19 months). The five-year overall survival rate was 64%. CONCLUSION: In UK, endoscopic resection is useful in the management of early squamous neoplasia both for staging and (by piecemeal endoscopic resection in elderly unfit) for medium- to long-term disease clearance.

Long-term follow-up of endoscopic submucosal dissection of gastric dysplasia and early neoplasia in a United Kingdom Caucasian population - a tertiary centre experience.

Introduction: Endoscopic submucosal dissection (ESD) is extensively performed for the treatment of early gastric cancer (EGC) in the Eastern countries due to its favourable outcomes compared to gastrectomy in terms of lower complication rates, shorter hospital stays, better quality of life, with similar 5-year survival rate. Yet, its use is still limited in the UK.Aim: A long-term follow-up study to evaluate the outcome of ESD in the treatment of EGC in a Caucasian population at a tertiary referral centre in the United Kingdom.Methods: Data for the 35 Caucasian patients, who underwent ESD in a tertiary referral centre between May 2012 and June 2017 were collected. The selected patients were followed-up until May 2018. Curative resection (CR) and survival rates were used to measure the efficacy of ESD.Results: ESD was attempted on 46 lesions and completed on 37. En-bloc and CR rates of 57% and 19% were achieved, respectively. 24% of the lesions were non-CR and 57% were indefinite for non-CR/CR and 41% of the lesions showed change in histological grade post-ESD. Complete reversal of dysplasia/neoplasia was seen in 60% of the 'indefinite' group and 100% of the CR group at latest FU (18 months, mean). Recurrence was seen in 23% of the patients at latest FU. Seventy-one months' survival rate was 77%, while the disease-specific mortality was 0%.Conclusions: This study demonstrates the positive long-term outcome of ESD for gastric neoplasia in a UK Caucasian population, encouraging further development and implementation of ESD in the UK.

Application of Proteomics to Inflammatory Bowel Disease Research: Current Status and Future Perspectives.

Inflammatory bowel disease (IBD) is a chronic relapsing/remitting inflammatory illness of the gastrointestinal tract of unknown aetiology. Despite recent advances in decoding the pathophysiology of IBD, many questions regarding disease pathogenesis remain. Genome-wide association studies (GWAS) and knockout mouse models have significantly advanced our understanding of genetic susceptibility loci and inflammatory pathways involved in IBD pathogenesis. Despite their important contribution to a better delineation of the disease process in IBD, these genetic findings have had little clinical impact to date. This is because the presence of a given gene mutation does not automatically correspond to changes in its expression or final metabolic or structural effect(s). Furthermore, the existence of these gene susceptibility loci in the normal population suggests other driving prerequisites for the disease manifestation. Proteins can be considered the main functional units as almost all intracellular physiological functions as well as intercellular interactions are dependent on them. Proteomics provides methods for the large-scale study of the proteins encoded by the genome of an organism or a cell, to directly investigate the proteins and pathways involved. Understanding the proteome composition and alterations yields insights into IBD pathogenesis as well as identifying potential biomarkers of disease activity, mucosal healing, and cancer progression. This review describes the state of the art in the field with respect to the study of IBD and the potential for translation from biomarker discovery to clinical application.

A real-world, long-term experience on effectiveness and safety of vedolizumab in adult patients with inflammatory bowel disease: The Cross Pennine study.

BACKGROUND: Real-life data on vedolizumab effectiveness in inflammatory bowel disease (IBD) are still emerging. Data on the comparative safety of the gut selective profile are of particular interest. AIMS: To assess clinical outcome and safety in IBD patients treated with vedolizumab. METHODS: We retrospectively collected data of patients treated with vedolizumab at eight UK hospitals (August 2014-January 2018). Clinical response and remission at 14 and 52 weeks evaluated through Physician Global Assessment (PGA) and adverse events were recorded. Possible predictors of clinical response were examined. RESULTS: Two hundred and three IBD patients (mean treatment 16 ±â€¯8 months) were included. Of these, 135 patients (mean age 40.6 ±â€¯16.0 years; F:M 1.9:1) had CD and 68 (mean age 44.5 ±â€¯18.1 years; F:M 1:1.2) had UC. According to PGA, 106/135 (78.5%) CD and 62/68 (91.2%) UC patients (p = 0.02) had a clinical response/remission at 14 weeks, whereas 76/119 (63.9%) CD and 52/63 (82.5%) UC patients (p < 0.01) showed a sustained response or remission at 52 weeks, with a high adherence rate (97%). No predictors of clinical response were found. The cumulative incidence of infectious diseases was 11.9 per 100 person-years. CONCLUSION: Vedolizumab is an effective therapy for inducing and maintaining remission of IBD, with better results for UC, and with a good safety profile.

Inflammation decreases keratin level in ulcerative colitis; inadequate restoration associates with increased risk of colitis-associated cancer.

BACKGROUND: Keratins are intermediate filament (IF) proteins, which form part of the epithelial cytoskeleton and which have been implicated pathology of inflammatory bowel diseases (IBD). METHODS: In this study biopsies were obtained from IBD patients grouped by disease duration and subtype into eight categories based on cancer risk and inflammatory status: quiescent recent onset (<5 years) UC (ROUC); UC with primary sclerosing cholangitis; quiescent long-standing pancolitis (20-40 years) (LSPC); active colitis and non-inflamed proximal colonic mucosa; pancolitis with dysplasia-both dysplastic lesions (DT) and distal rectal mucosa (DR); control group without pathology. Alterations in IF protein composition across the groups were determined by quantitative proteomics. Key protein changes were validated by western immunoblotting and immunohistochemical analysis. RESULT: Acute inflammation resulted in reduced K8, K18, K19 and VIM (all p<0.05) compared to controls and non inflamed mucosa; reduced levels of if- associated proteins were also seen in DT and DR. Increased levels of keratins in LSPC was noted relative to controls or ROUC (K8, K18, K19 and VIM, p<0.05). Multiple K8 forms were noted on immunoblotting, with K8 phosphorylation reduced in progressive disease along with an increase in VIM:K8 ratio. K8 levels and phosphorylation are reduced in acute inflammation but appear restored or elevated in subjects with clinical and endoscopic remission (LSPC) but not apparent in subjects with elevated risk of cancer. CONCLUSIONS: These data suggest that keratin regulation in remission may influence subsequent cancer risk.

Small bowel patency assessment using the patency device and a novel targeted (limited radiation) computed tomography-based protocol.

BACKGROUND AND AIM: Excretion of the patency capsule (PC) within a certain time frame may be used to demonstrate luminal patency prior to capsule endoscopy (CE). We aimed to determine how often further radiological imaging is needed to confirm luminal patency after PC, assess radiologists' ability to locate the PC on plain abdominal films, and evaluate the outcomes of a novel computed tomography (CT) protocol for PC localization. METHODS: A study of the ability of radiologists to localize PC using plain abdominal films was performed. A novel protocol targeting a limited CT at the level of the PC identified on the "scout" film if retained 30 h post-ingestion was prospectively evaluated in 400 consecutive patients undergoing PC. RESULTS: In a study of the confidence with which radiologists could localize the PC on plain films, radiologists preferred abdominal CT to localize PCs identified on plain films in 74% of cases. In a protocol based on the use of a PC and targeted, limited CT scan to confirm small bowel patency in those failing to excrete the PC 30 h post-ingestion, the sensitivity, specificity, positive, and negative predictive value were 99.4%, 90.0%, 99.7%, and 81.0%, respectively. Crohn's disease was the only statistically significant predictor associated with higher risk of luminal stricture (P=0.001) in post-hoc analysis. CONCLUSIONS: Excretion of the PC 30 h post-ingestion reliably predicts safe CE passage. Plain abdominal radiology is unreliable and a scout film targeted, limited CT scan offers an accurate minimal radiation method of determining small bowel patency.

Diagnosing and managing inflammatory bowel disease.

The two major types of inflammatory bowel disease (IBD) are ulcerative colitis and Crohn's disease. Both are characterised by a relapsing and remitting course. In ulcerative colitis the mucosal inflammation affects the rectum and to a variable extent the areas proximal to the rectum in a continuous pattern. Crohn's disease is characterised by discontinuous areas of transmural inflammation that can affect any part of the GI tract but most frequently involves the distal small intestine and proximal colon. IBD has a prevalence of around 400 per 100,000 in the UK. There is a bimodal age of presentation with an initial peak in the second and third decades of life followed by another peak in the sixth decade. Acute ulcerative colitis typically presents with bloody diarrhoea with the passage of mucus, urgency and cramping abdominal pain. A severe attack is usually considered to be associated with bloody stools six times a day or more plus one of the features of systemic toxicity. Severe attacks require intensive inpatient treatment. Inflammatory markers in the blood are not always raised in ulcerative colitis. The diagnosis is confirmed by typical histological features on biopsy. Crohn's disease presents with a typical combination of abdominal pain, diarrhoea and weight loss. Pain or fever may also signify the development of an abscess and stricture formation will lead to obstructive symptoms. Perianal disease in the form of abscesses or fistulae may affect 35-45% of patients during the course of their disease. Because of the chronic and, at times, debilitating nature of IBD special attention to the psychosocial aspects of the disease is very important.

Evaluation of bronchial hypersensitivity in veterans with sulfur mustard gas-induced skin or eye manifestations without respiratory symptoms: 15 years after exposure.

The authors evaluated the prevalence of bronchial hypersensitivity in subjects who had confirmed exposure to sulfur mustard gas (SMG) but no overt respiratory manifestations. They chose 30 patients who had proven skin or eye manifestations secondary to SMG, and performed baseline and provocative pulmonary function testing with cold air and methacholine. The authors performed the same procedure on 30 control volunteers. After challenge testing with cold air and methacholine, bronchial hypersensitivity was detected in 7 (23.3%) and 9 (30%) of cases, respectively. Only 1 control subject showed hypersensitivity after provocation testing with cold air (p = approximately .05); the same control subject showed a positive challenge testing result with 10 mg/ml of methacholine (p < .02). The kappa coefficient for evaluating the effectiveness of the cold air, as a provocative agent for challenge testing, was 93.3%.