Effects of Vedolizumab in Patients With Primary Sclerosing Cholangitis and Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Gut-homing lymphocytes that express the integrin α4ß7 and CCR9 might contribute to development of primary sclerosing cholangitis (PSC). Vedolizumab, which blocks the integrin α4ß7, is used to treat patients with inflammatory bowel diseases (IBD), but there are few data on its efficacy in patients with PSC. We investigated the effects of vedolizumab in a large international cohort of patients with PSC and IBD. METHODS: We collected data from European and North American centers participating in the International PSC Study Group from patients with PSC and IBD who received at least 3 doses of vedolizumab (n = 102; median vedolizumab treatment duration, 412 days). Demographic and clinical data were collected from baseline and during the follow-up period (until liver transplantation, death, or 56 days after the final vedolizumab infusion). We analyzed overall changes in biochemical features of liver and proportions of patients with reductions in serum levels of alkaline phosphatase (ALP) of 20% or more, from baseline through last follow-up evaluation. Other endpoints included response of IBD to treatment (improved, unchanged, or worsened, judged by the treating clinician, as well as endoscopic score) and liver-related outcomes. RESULTS: In the entire cohort, the median serum level of ALP increased from 1.54-fold the upper limit of normal at baseline to 1.64-fold the upper limit of normal at the last follow-up examination (P = .018); serum levels of transaminases and bilirubin also increased by a small amount between baseline and the last follow-up examination. Serum levels of ALP decreased by 20% or more in 21 patients (20.6%); only the presence of cirrhosis (odds ratio, 4.48; P = .019) was independently associated with this outcome. Of patients with available endoscopic data, 56.8% had a response of IBD to treatment. Liver-related events occurred in 21 patients (20.6%), including bacterial cholangitis, cirrhosis decompensation, or transplantation. CONCLUSIONS: In an analysis of patients with PSC and IBD in an international study group, we found no evidence for a biochemical response to vedolizumab, although serum level of ALP decreased by 20% or more in a subset of patients. Vedolizumab appears to be well tolerated and the overall response of IBD was the same as expected for patients without PSC.

Prevalence and long-term outcome of sub-clinical primary sclerosing cholangitis in patients with ulcerative colitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is closely associated with inflammatory bowel disease, particularly ulcerative colitis (UC), with an increased risk of biliary and colorectal malignancy. We sought to clarify the prevalence, characteristics and long-term outcome of sub-clinical PSC diagnosed by magnetic resonance cholangiogram (MRC) in patients with UC and normal liver biochemistry, with or without colorectal dysplasia (CRD). METHODS: In this prospective case-control study, 70 patients with UC and normal liver function (51 extensive UC, 19 CRD), 28 healthy volunteers (negative controls) and 28 patients with PSC and cholestasis (positive controls) underwent MRC and blood evaluation. MRC scans were interpreted blindly by two radiologists who graded individually, the scans as definitive for PSC, possible for PSC or normal. Clinical outcome was assessed by blood monitoring, abdominal imaging and endoscopic surveillance. RESULTS: 7/51 (14%) with extensive UC and 4/19 (21%) with CRD had biliary abnormalities on MRC consistent with PSC. 7/11 (64%) with sub-clinical PSC had isolated intrahepatic duct involvement. Sub-clinical PSC was associated with advanced age (P = .04), non-smoking (P = .03), pANCA (P = .04), quiescent colitis (P = .02), absence of azathioprine (P = .04) and high-grade CRD (P = .03). Inter-observer (kappa = 0.88) and intra-observer (kappa = 0.96) agreement for MRC interpretation was high. No negative controls were assessed as definite PSC, 4/28 were considered on blinding as possible PSC. During follow-up of sub-clinical PSC (median 10.1(3.1-11.9) years), four patients developed abnormal liver biochemistry, two had radiological progression of PSC and seven developed malignancy, including two biliary and one colorectal carcinoma. CONCLUSIONS: Prevalence of sub-clinical PSC appears high in patients with extensive UC and normal liver biochemistry, with or without CRD. Disease progression and malignancy were identified on long-term follow-up. MRC should be considered for all patients with extensive UC or CRD to stratify surveillance.

Consensus Statement by an Expert Panel on the Diagnosis and Management of Iron Deficiency Anemia in the Gulf Cooperation Council Countries.

BACKGROUND: Iron deficiency (ID) and ID anemia (IDA) are common in the member states of the Gulf Cooperation Council (GCC). The unique genetic and lifestyle factors of the patient population in the region have necessitated the development of recommendations to help educate health-care professionals on appropriate diagnosis and management of ID/IDA. METHODS: A panel of regional experts, including gastroenterologists and hematologists with expertise in the treatment of IDA, was convened to develop regional practice recommendations for ID/IDA. After reviewing the regional and international literature, the expert panel developed consensus recommendations for screening, diagnosis, and treatment of patients with IDA in the GCC region. RESULTS: The recommendations proposed were customized to the patient population keeping in view the increasingly recognized burden of coeliac disease, high fertility and obesity rates, high prevalence of alpha- and beta-thalassemia traits, and poor tolerance and low treatment compliance with oral iron therapy. CONCLUSIONS: This consensus statement proposes recommendations for screening, diagnosis, and treatment of IDA in the GCC region.

Circulating and Tissue-Resident CD4+ T Cells With Reactivity to Intestinal Microbiota Are Abundant in Healthy Individuals and Function Is Altered During Inflammation.

BACKGROUND & AIMS: Interactions between commensal microbes and the immune system are tightly regulated and maintain intestinal homeostasis, but little is known about these interactions in humans. We investigated responses of human CD4+ T cells to the intestinal microbiota. We measured the abundance of T cells in circulation and intestinal tissues that respond to intestinal microbes and determined their clonal diversity. We also assessed their functional phenotypes and effects on intestinal resident cell populations, and studied alterations in microbe-reactive T cells in patients with chronic intestinal inflammation. METHODS: We collected samples of peripheral blood mononuclear cells and intestinal tissues from healthy individuals (controls, n = 13-30) and patients with inflammatory bowel diseases (n = 119; 59 with ulcerative colitis and 60 with Crohn's disease). We used 2 independent assays (CD154 detection and carboxy-fluorescein succinimidyl ester dilution assays) and 9 intestinal bacterial species (Escherichia coli, Lactobacillus acidophilus, Bifidobacterium animalis subsp lactis, Faecalibacterium prausnitzii, Bacteroides vulgatus, Roseburia intestinalis, Ruminococcus obeum, Salmonella typhimurium, and Clostridium difficile) to quantify, expand, and characterize microbe-reactive CD4+ T cells. We sequenced T-cell receptor Vß genes in expanded microbe-reactive T-cell lines to determine their clonal diversity. We examined the effects of microbe-reactive CD4+ T cells on intestinal stromal and epithelial cell lines. Cytokines, chemokines, and gene expression patterns were measured by flow cytometry and quantitative polymerase chain reaction. RESULTS: Circulating and gut-resident CD4+ T cells from controls responded to bacteria at frequencies of 40-4000 per million for each bacterial species tested. Microbiota-reactive CD4+ T cells were mainly of a memory phenotype, present in peripheral blood mononuclear cells and intestinal tissue, and had a diverse T-cell receptor Vß repertoire. These cells were functionally heterogeneous, produced barrier-protective cytokines, and stimulated intestinal stromal and epithelial cells via interleukin 17A, interferon gamma, and tumor necrosis factor. In patients with inflammatory bowel diseases, microbiota-reactive CD4+ T cells were reduced in the blood compared with intestine; T-cell responses that we detected had an increased frequency of interleukin 17A production compared with responses of T cells from blood or intestinal tissues of controls. CONCLUSIONS: In an analysis of peripheral blood mononuclear cells and intestinal tissues from patients with inflammatory bowel diseases vs controls, we found that reactivity to intestinal bacteria is a normal property of the human CD4+ T-cell repertoire, and does not necessarily indicate disrupted interactions between immune cells and the commensal microbiota. T-cell responses to commensals might support intestinal homeostasis, by producing barrier-protective cytokines and providing a large pool of T cells that react to pathogens.

Glucocorticoids Suppress CCR9-Mediated Chemotaxis, Calcium Flux, and Adhesion to MAdCAM-1 in Human T Cells.

CCR9 expressed on T lymphocytes mediates migration to the small intestine in response to a gradient of CCL25. CCL25-stimulated activation of α4ß7 integrin promotes cell adherence to mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed by vascular endothelial cells of the intestine, further mediating gut-specific homing. Inflammatory bowel disease is a chronic inflammatory condition that primarily affects the gastrointestinal tract and is characterized by leukocyte infiltration. Glucocorticoids (GCs) are widely used to treat inflammatory bowel disease but their effect on intestinal leukocyte homing is not well understood. We investigated the effect of GCs on the gut-specific chemokine receptor pair, CCR9 and CCL25. Using human peripheral blood-derived T lymphocytes enriched for CCR9 by cell sorting or culturing with all-trans retinoic acid, we measured chemotaxis, intracellular calcium flux, and α4ß7-mediated cell adhesion to plate-bound MAdCAM-1. Dexamethasone (DEX), a specific GC receptor agonist, significantly reduced CCR9-mediated chemotaxis and adhesion to MAdCAM-1 without affecting CCR9 surface expression. In contrast, in the same cells, DEX increased CXCR4 surface expression and CXCL12-mediated signaling and downstream functions. The effects of DEX on human primary T cells were reversed by the GC receptor antagonist mifepristone. These results demonstrate that GCs suppress CCR9-mediated chemotaxis, intracellular calcium flux, and α4ß7-mediated cell adhesion in vitro, and these effects could contribute to the efficacy of GCs in treating intestinal inflammation in vivo.

Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease.

OBJECTIVE: Patients with Niemann-Pick disease type C1 (NPC1), a lysosomal lipid storage disorder that causes neurodegeneration and liver damage, can present with IBD, but neither the significance nor the functional mechanism of this association is clear. We studied bacterial handling and antibacterial autophagy in patients with NPC1. DESIGN: We characterised intestinal inflammation in 14 patients with NPC1 who developed IBD. We investigated bacterial handling and cytokine production of NPC1 monocytes or macrophages in vitro and compared NPC1-associated functional defects to those caused by IBD-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) variants or mutations in X-linked inhibitor of apoptosis (XIAP). RESULTS: Patients with the lysosomal lipid storage disorder NPC1 have increased susceptibility to early-onset fistulising colitis with granuloma formation, reminiscent of Crohn's disease (CD). Mutations in NPC1 cause impaired autophagy due to defective autophagosome function that abolishes NOD2-mediated bacterial handling in vitro similar to variants in NOD2 or XIAP deficiency. In contrast to genetic NOD2 and XIAP variants, NPC1 mutations do not impair NOD2-receptor-interacting kinase 2 (RIPK2)-XIAP-dependent cytokine production. Pharmacological activation of autophagy can rescue bacterial clearance in macrophages in vitro by increasing the autophagic flux and bypassing defects in NPC1. CONCLUSIONS: NPC1 confers increased risk of early-onset severe CD. Our data support the concept that genetic defects at different checkpoints of selective autophagy cause a shared outcome of CD-like immunopathology linking monogenic and polygenic forms of IBD. Muramyl dipeptide-driven cytokine responses and antibacterial autophagy induction are parallel and independent signalling cascades downstream of the NOD2-RIPK2-XIAP complex.

Surgery versus surveillance in ulcerative colitis patients with endoscopically invisible low-grade dysplasia: a cost-effectiveness analysis.

BACKGROUND AND AIMS: There is uncertainty regarding the optimal management of endoscopically invisible (flat) low-grade dysplasia in ulcerative colitis. Such a finding does not currently provide an automatic indication for colectomy; however, a recommendation of surveillance instead of surgery is controversial. The aim of this study was to determine the clinical and cost-effectiveness of colonoscopic surveillance versus colectomy for endoscopically invisible low-grade dysplasia of the colon in ulcerative colitis. METHODS: A Markov model was used to evaluate the costs and health outcomes of surveillance and surgery over a 20-year timeframe. Outcomes evaluated were life years gained and quality-adjusted life years (QALYs). Cohorts of patients aged 25 to 75 were modeled, including estimates from a validated surgical risk calculator and considering none, 1, or both of 2 key comorbidities: heart failure and obstructive airway disease. RESULTS: Surveillance is associated with more life years and QALYs compared with surgery from age 61 for those with no comorbidities, age 51 for those with 1 comorbidity and age 25 for those with 2 comorbidities. At the current United Kingdom National Institute for Health and Care Excellence threshold of $25,800 per QALY, ongoing surveillance was cost-effective at age 65 in those without comorbidities and at age 60 in those with either 1 or more comorbidities. CONCLUSIONS: Surveillance can be recommended from age 65 for those with no comorbidities; however, in younger patients with typical postsurgical quality of life, colectomy may be more effective clinically and more cost-effective. The results were sensitive to the colorectal cancer incidence rate in patients under surveillance and to quality of life after surgery.

Beyond endoscopic mucosal healing in UC: histological remission better predicts corticosteroid use and hospitalisation over 6†years of follow-up.

BACKGROUND: Endoscopic mucosal healing is an established treatment target for UC, yet the value of achieving histological remission remains unclear. AIMS: To evaluate histological remission compared to endoscopic mucosal healing for predicting patient outcomes in UC. METHODS: Blinded assessment of endoscopic and histological measures of disease activity was performed on patients with established UC at baseline. Concordance and prognostic values of endoscopic mucosal healing (defined by Baron score ≤1) and histological remission (defined by Truelove and Richards' index) for predicting outcomes of corticosteroid use, hospitalisation and colectomy were determined over a median 6 years follow-up, including κ statistics and Cox regression multivariate analysis. RESULTS: 91 patients with UC were followed up for a median 72 months (IQR 54-75 months). Overall, concordance between endoscopic and histological remission was moderate (κ=0.56, 95% CI 0.36 to 0.77); 24% patients had persistent inflammation despite endoscopic remission. Histological remission predicted corticosteroid use and acute severe colitis requiring hospitalisation over the follow-up period (HR 0.42 (0.2 to 0.9), p=0.02; HR 0.21 (0.1 to 0.7), p=0.02; respectively), whereas endoscopic mucosal healing did not (HR 0.86, 95% CI 0.5 to 1.7, p0.65; HR 0.83 95% CI 0.3 to 2.4, p0.74; respectively). CONCLUSIONS: Histological remission is a target distinct from endoscopic mucosal healing in UC and better predicts lower rates of corticosteroid use and acute severe colitis requiring hospitalisation, over a median of 6 years of follow-up. Our findings support the inclusion of histological indices in both UC clinical trials and practice, towards a target of 'complete remission'.

Tralokinumab for moderate-to-severe UC: a randomised, double-blind, placebo-controlled, phase IIa study.

OBJECTIVE: Interleukin-13 (IL-13) has been implicated as a key driver of UC. This trial evaluates the efficacy and safety of tralokinumab, an IL-13-neutralising antibody, as add-on therapy in adults with moderate-to-severe UC despite standard treatments. DESIGN: Non-hospitalised adults with UC (total Mayo score ≥6) were randomised to receive tralokinumab 300 mg or placebo subcutaneously every 2 weeks for 12 weeks. The primary end point was the rate of clinical response at week 8. Secondary efficacy end points included clinical remission and mucosal healing rates at week 8 and changes in total Mayo score, total modified Riley score, partial Mayo score and disease activity markers. RESULTS: Clinical response rate was 38% (21/56) for tralokinumab vs. 33% (18/55) for placebo (p=0.406). Clinical remission rate was 18% (10/56) vs. 6% (3/55) (p=0.033) and mucosal healing rate was 32% (18/56) vs. 20% (11/55) (p=0.104) for tralokinumab vs placebo. Changes to week 8 in total Mayo score and total modified Riley score were similar for tralokinumab and placebo (least-squares mean difference between groups: -0.49 (p=0.394) and 0.25 (p=0.449), respectively). Partial Mayo score at week 4 was lower with tralokinumab than placebo (least-squares mean difference between groups: -0.90 (p=0.041)). No consistent patterns were observed for disease activity markers. Tralokinumab had an acceptable safety profile. CONCLUSIONS: Add-on therapy with tralokinumab did not significantly improve clinical response. However, the higher clinical remission rate with tralokinumab than placebo suggests that tralokinumab may benefit some patients with UC. Tralokinumab was well tolerated. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number: NCT01482884.

Managing intractable proctitis and the problematic pouch.

Proctitis accounts for a significant proportion of cases of ulcerative colitis (UC), and some patients subsequently develop more extensive disease. However, most patients continue to have limited inflammation, although the changes in the distal colon and rectum can occasionally be severe, and symptoms of increased frequency, rectal bleeding and urgency can be as disabling as they are for patients with more extensive colitis. Furthermore, although symptoms are typically well controlled with standard medications, medically refractory proctitis poses particular problems. Patients generally are not systemically unwell, and there is no added fear of cancer. Therefore, the prospect of colectomy for such limited disease is resisted by patients, physicians and surgeons alike. Unusual therapies, often delivered locally by enema or suppository, have been tested in small case series without definitive outcomes. The pathogenesis of such limited, yet intractable inflammation remains unclear, and the differential diagnosis should be carefully reviewed to ensure that local disease, whether it is infectious, vascular, or a result of injury or degeneration, is not overlooked. Ileo-anal pouch formation is the surgery of choice for about 20% of patients with UC who undergo colectomy. In the majority of cases, this surgery results in an acceptable quality of life and freedom from a stoma. However, in a sizeable minority of cases, pouch dysfunction can cause intractable problems. The causes of pouch dysfunction are varied and must all be considered carefully, particularly in refractory cases. Pouchitis is a common issue and is usually transient and easily treated. However, refractory and chronic pouchitis can be challenging. Ischaemia, injury, infection and Crohn's disease can all cause refractory pouch dysfunction. In a minority of cases, there appears to be no apparent organic pathology, and the presumptive diagnosis is that of a functional pouch disorder. Although it is much rarer, neoplastic changes in the pouch must also be considered, and the risk managed appropriately. The management of both intractable proctitis and the problematic pouch is made more challenging by the wide differential diagnosis that must be considered and by the paucity of high-quality clinical trials to support any one therapy. Key strategies to overcoming these limitations include methodical and systematic investigation and review, and a willingness to tailor therapy to the individual patient. Clinical trials of new treatments should be supported, and data from the experience with small cohorts of patients should be meticulously collected, critically analysed and widely disseminated.

A basal gradient of Wnt and stem-cell number influences regional tumour distribution in human and mouse intestinal tracts.

OBJECTIVE: Wnt signalling is critical for normal intestinal development and homeostasis. Wnt dysregulation occurs in almost all human and murine intestinal tumours and an optimal but not excessive level of Wnt activation is considered favourable for tumourigenesis. The authors assessed effects of pan-intestinal Wnt activation on tissue homeostasis, taking into account underlying physiological Wnt activity and stem-cell number in each region of the bowel. DESIGN: The authors generated mice that expressed temporally controlled, stabilised ß-catenin along the crypt-villus axis throughout the intestines. Physiological Wnt target gene activity was assessed in different regions of normal mouse and human tissue. Human intestinal tumour mutation spectra were analysed. RESULTS: In the mouse, ß-catenin stabilisation resulted in a graduated neoplastic response, ranging from dysplastic transformation of the entire epithelium in the proximal small bowel to slightly enlarged crypts of non-dysplastic morphology in the colorectum. In contrast, stem and proliferating cell numbers were increased in all intestinal regions. In the normal mouse and human intestines, stem-cell and Wnt gradients were non-identical, but higher in the small bowel than large bowel in both species. There was also variation in the expression of some Wnt modulators. Human tumour analysis confirmed that different APC mutation spectra are selected in different regions of the bowel. CONCLUSIONS: There are variable gradients in stem-cell number, physiological Wnt activity and response to pathologically increased Wnt signalling along the crypt-villus axis and throughout the length of the intestinal tract. The authors propose that this variation influences regional mutation spectra, tumour susceptibility and lesion distribution in mice and humans.

Molecular epidemiology of Clostridium difficile strains in children compared with that of strains circulating in adults with Clostridium difficile-associated infection.

Molecular analysis of Clostridium difficile (28 isolates) from children (n = 128) in Oxfordshire, United Kingdom, identified eight toxigenic genotypes. Six of these were isolated from 27% of concurrent adult C. difficile-associated infections studied (n = 83). No children carried hypervirulent PCR ribotype 027. Children could participate in the transmission of some adult disease-causing genotypes.

Characterization of CCX282-B, an orally bioavailable antagonist of the CCR9 chemokine receptor, for treatment of inflammatory bowel disease.

The chemokine system represents a diverse group of G protein-coupled receptors responsible for orchestrating cell recruitment under both homeostatic and inflammatory conditions. Chemokine receptor 9 (CCR9) is a chemokine receptor known to be central for migration of immune cells into the intestine. Its only ligand, CCL25, is expressed at the mucosal surface of the intestine and is known to be elevated in intestinal inflammation. To date, there are no reports of small-molecule antagonists targeting CCR9. We report, for the first time, the discovery of a small molecule, CCX282-B, which is an orally bioavailable, selective, and potent antagonist of human CCR9. CCX282-B inhibited CCR9-mediated Ca(2+) mobilization and chemotaxis on Molt-4 cells with IC(50) values of 5.4 and 3.4 nM, respectively. In the presence of 100% human serum, CCX282-B inhibited CCR9-mediated chemotaxis with an IC(50) of 33 nM, and the addition of α1-acid glycoprotein did not affect its potency. CCX282-B inhibited chemotaxis of primary CCR9-expressing cells to CCL25 with an IC(50) of 6.8 nM. CCX282-B was an equipotent inhibitor of CCL25-directed chemotaxis of both splice forms of CCR9 (CCR9A and CCR9B) with IC(50) values of 2.8 and 2.6 nM, respectively. CCX282-B also inhibited mouse and rat CCR9-mediated chemotaxis. Inhibition of CCR9 with CCX282-B results in normalization of Crohn's disease such as histopathology associated with the TNF(ΔARE) mice. Analysis of the plasma level of drug associated with this improvement provides an understanding of the pharmacokinetic/pharmacodynamic relationship for CCR9 antagonists in the treatment of intestinal inflammation.

Lymphocyte Activation Gene (LAG)-3 Is Associated With Mucosal Inflammation and Disease Activity in Ulcerative Colitis.

BACKGROUND AND AIMS: Lymphocyte activation gene [LAG]-3 is an immune checkpoint and its expression identifies recently activated lymphocytes that may contribute to inflammation. We investigated the role of LAG-3 by analysing its expression and function in immune cells from blood and tissue of patients with ulcerative colitis [UC]. METHODS: The phenotypic properties of LAG-3+ T cells were determined by flow cytometry, qRT-PCR and single-cell RNA-sequencing. LAG-3+ cells were quantified and correlated with disease activity. The functional effects of LAG-3+ cells were tested using a depleting anti-LAG-3 monoclonal antibody [mAb] in a mixed lymphocyte reaction [MLR]. RESULTS: LAG-3+ cells in the blood were negligible. LAG-3+ lymphocytes were markedly increased in inflamed mucosal tissue and both frequencies of LAG-3+ T cells and transcript levels of LAG3 correlated with endoscopic severity. LAG-3 expression was predominantly on effector memory T cells, and single-cell RNA-sequencing revealed LAG3 expression in activated and cytokine-producing T cell subsets. Foxp3+CD25hi Tregs also expressed LAG-3, although most mucosal Tregs were LAG-3-. Mucosal LAG-3+ cells produced mainly interferon γ [IFNγ] and interleukin-17A. LAG-3+ cell numbers decreased in patients who responded to biologics, and remained elevated in non-responders. Treatment with a depleting anti-LAG-3 mAb led to a reduction in proliferation and IFNγ production in an MLR. CONCLUSIONS: LAG-3+ cells are increased in the inflamed mucosa, predominantly on effector memory T cells with an activated phenotype and their cell numbers positively correlate with disease activity. Depleting LAG-3 eliminates activated proliferating T cells, and hence LAG-3 could be a therapeutic target in UC.

The Use of Biologics in Patients with Inflammatory Bowel Disease and Primary Sclerosing Cholangitis.

PURPOSE OF REVIEW: Biologics are well established in the treatment of many immuno-inflammatory diseases including inflammatory bowel disease (IBD). However, although primary sclerosing cholangitis (PSC) is closely associated with IBD, the role of biologics in PSC remains uncertain. Many new biologics are becoming available to treat IBD, and this review aims to use the experience of biologics in PSC so far to guide more effective evaluation of emerging therapies in the future. RECENT FINDINGS: Antibodies to TNF-α were the first biologics used in IBD, and retrospective analysis suggests that they may have some benefit in PSC, even though an early randomised controlled trial (RCT) showed no effect. Mechanistic studies suggest that TNF-α may have a pathogenic role in PSC. An antibody to integrin α4ß7 is effective in IBD, and there are emerging data on its effects in PSC, although no RCT data are available. Mechanistic studies suggest that interrupting the migration of lymphocytes is relevant in PSC. Two biologics, targeting vascular adhesion protein-1 (VAP-1), and lysyl oxidase-like 2 (LOXL2) have been tested in RCTs. The trial of anti-VAP1 is ongoing, whilst the anti-LOXL2 trial was negative. SUMMARY: Anti-TNF antibodies may benefit PSC when used to treat concomitant IBD, and this may be a direct effect on the liver in a subgroup of patients, or may be an indirect effect of treating IBD. Similarly, anti-integrin therapy may benefit a subset of patients with IBD and PSC. RCTs could decide the role of emerging biologics in PSC, although future trials should be guided by biomarkers that could predict response to the pathway being targeted.

Defining Faecal Calprotectin Thresholds as a Surrogate for Endoscopic and Histological Disease Activity in Ulcerative Colitis-a Prospective Analysis.

BACKGROUND: Faecal calprotectin [FCal] levels are used as a surrogate marker for mucosal inflammation, but thresholds for defining endoscopic or histological disease activity in ulcerative colitis [UC] remain unclear. METHODS: Using validated indices, prospective measurements of FCal, symptoms [Simple Colitis Clinical Activity Index, SCCAI], endoscopic [Ulcerative Colitis Endoscopic Index of Severity, UCEIS] and histological activity [Nancy index] were made over 6 months in patients enrolled into the TrueColours UC web-based monitoring programme. Repeated measurements correlation was performed between FCal and SCCAI, UCEIS, and Nancy indices using definitions for remission and active disease [UCEIS: remission ≤1, active ≥4; Nancy: remission ≤1, active ≥2; combined criteria: remission UCEIS ≤1 and Nancy ≤1, active UCEIS ≥4 and Nancy ≥2]. Receiver operating characteristic curves investigated FCal thresholds after maximising sensitivity for active disease. RESULTS: In 39 patients followed prospectively for 6 months, correlation coefficients between FCal and SCCAI, UCEIS, and Nancy indices were 0.271 (95% confidence interval [CI] 0.114-0.415), 0.741 [95% CI 0.289-0.922], and 0.876 [95% CI 0.605-0.965], respectively. Median FCal thresholds for remission using endoscopic, histological, or combined criteria were 71 µg/g [range 8-624], 91 µg/g [range 8-858], and 67 µg/g [range 8-479], respectively. The FCal threshold above which active disease was confirmed was 187 µg/g for UCEIS (area under the curve [AUC] 0.915), 72 µg/g for Nancy [AUC 0.824], and 187 µg/g for combined endoscopic and histological criteria [AUC 0.936]. CONCLUSIONS: Correlation between FCal and symptoms in UC is weak. In contrast, the correlation between FCal and endoscopic or histological activity is strong. An FCal ≥72 µg/g indicates histological inflammation [Nancy ≥2] and ≥187 µg/g indicates endoscopically active disease [UCEIS ≥4], whether combined with histopathology or not.

Real-time data monitoring for ulcerative colitis: patient perception and qualitative analysis.

BACKGROUND/AIMS: TrueColours ulcerative colitis (TCUC) is a comprehensive web-based program that functions through email, providing direct links to questionnaires. Several similar programs are available, however patient perspectives are unexplored. METHODS: A pilot study was conducted to determine feasibility, usability and patient perceptions of real-time data collection (daily symptoms, fortnightly quality of life, 3 monthly outcomes). TCUC was adapted from a web-based program for patients with relapsing-remitting bipolar disorder, using validated UC indices. A semi-structured interview was developed and audio-recorded face-to-face interviews were conducted after 6 months of interaction with TCUC. Transcripts were coded in NVivo11, a qualitative data analysis software package. An inductive approach and thematic analysis was conducted. RESULTS: TCUC was piloted in 66 patients for 6 months. Qualitative analysis currently defies statistical appraisal beyond "data saturation," even if it has more influence on clinical practice than quantitative data. A total of 28 face-to-face interviews were conducted. Six core themes emerged: awareness, control, decision-making, reassurance, communication and burden of treatment. There was a transcending overarching theme of patient empowerment, which cut across all aspects of the TCUC experience. CONCLUSIONS: Patient perception of the impact of real-time data collection was extremely positive. Patients felt empowered as a product of the self-monitoring format of TCUC, which may be a way of improving self-management of UC whilst also decreasing the burden on the individual and healthcare services.

Correlation Between Endoscopic and Histological Activity in Ulcerative Colitis Using Validated Indices.

BACKGROUND AND AIMS: Endoscopy and histopathology are pivotal for evaluating disease activity in ulcerative colitis [UC]; correlation between validated endoscopic and histological indices has not been examined. We aim to correlate the Ulcerative Colitis Endoscopic Index of Severity [UCEIS] with two new validated histological indices in patients with established UC. METHODS: This was a single-centre cohort of patients with established UC, who underwent flexible sigmoidoscopy or colonoscopy by a single endoscopist. The UCEIS was scored at the worst affected area in the distal colon, which was biopsied; histological disease activity using Nancy [NI] and Robarts' Histological [RHI] indices was scored by a pathologist blinded to the endoscopy. Spearman correlation between the UCEIS, NI, and RHI, and between NI and RHI, was performed. RESULTS: A total of 125 patients, median age 37 years [range 16-81 years], with UCEIS scores [scale 0-8]: 0, n = 21; 1-3, n = 48; 4-6, n = 51; and 7-8, n = 5, were included. Correlation coefficients between UCEIS and NI [scale 0-4] were r = 0.84 (95% confidence interval [CI] 0.76-0.89, p < 0.001) and between UCEIS and RHI [scale 0-33] r = 0.86 [95% CI 0.80-0.90, p < 0.001]. The difference in correlation was not significant [p = 0.57]. There was excellent correlation between the two histological indices [r = 0.92, 95% CI 0.87-0.95, p < 0.001]. Quiescent disease activity defined as the absence of neutrophils [Nancy 0-1, Robarts 0-3] was most closely correlated with UCEIS = 0. CONCLUSIONS: The UCEIS strongly correlates with both NI and RHI. Complete mucosal healing is best defined as a UCEIS = 0/8, since this correlates with the absence of microscopic disease activity.