Development of the first disability index for inflammatory bowel disease based on the international classification of functioning, disability and health

Objective: The impact of inflammatory bowel disease (IBD) on disability remains poorly understood. The World Health Organization's integrative model of human functioning and disability in the International Classification of Functioning, Disability and Health (ICF) makes disability assessment possible. The ICF is a hierarchical coding system with four levels of details that includes over 1400 categories. The aim of this study was to develop the first disability index for IBD by selecting most relevant ICF categories that are affected by IBD. Methods: Relevant ICF categories were identified through four preparatory studies (systematic literature review, qualitative study, expert survey and cross-sectional study), which were presented at a consensus conference. Based on the identified ICF categories, a questionnaire to be filled in by clinicians, called the ‘IBD disability index’, was developed. Results: The four preparatory studies identified 138 second-level categories: 75 for systematic literature review (153 studies), 38 for qualitative studies (six focus groups; 27 patients), 108 for expert survey (125 experts; 37 countries; seven occupations) and 98 for cross-sectional study (192 patients; three centres). The consensus conference (20 experts; 17 countries) led to the selection of 19 ICF core set categories that were used to develop the IBD disability index: seven on body functions, two on body structures, five on activities and participation and five on environmental factors. Conclusions: The IBD disability index is now available. It will be used in studies to evaluate the long-term effect of IBD on patient functional status and will serve as a new endpoint in disease-modification trials

The management of iron deficiency in inflammatory bowel disease

__Background__ Iron deficiency is a common and undertreated problem in inflammatory bowel disease (IBD). __Aim__ To develop an online tool to support treatment choice at the patient-specific level. __Methods__ Using the RAND/UCLA Appropriateness Method (RUAM), a European expert panel assessed the appropriateness of treatment regimens for a variety of clinical scenarios in patients with non-anaemic iron deficiency (NAID) and iron deficiency anaemia (IDA). Treatment options included adjustment of IBD medication only, oral iron supplementation, high-/low-dose intravenous (IV) regimens, IV iron plus erythropoietin-stimulating agent (ESA), and blood transfusion. The panel process consisted of two individual rating rounds and three plenary discussion meetings. __Results__ The panel reached agreement on 71% of treatment indications. 'No treatment' was never considered appropriate, and repeat treatment after previous failure was generally discouraged. For 98% of scenarios, at least one treatment was appropriate. Adjustment of IBD medication was deemed appropriate in all patients with active disease. Use of oral iron was mainly considered an option in NAID and mildly anaemic patients without disease activity. IV regimens were often judged appropriate, with high-dose IV iron being the preferred option in 77% of IDA scenarios. Blood transfusion and IV+ESA were indicated in exceptional cases only. __Conclusions__ The RUAM revealed high agreement amongst experts on the management of iron deficiency in patients with IBD. High-dose IV iron was more often considered appropriate than other options. To facilitate dissemination of the recommendations, panel outcomes were embedded in an online tool, accessible via http://ferroscope.com/

Extended haplotype association study in Crohn’s disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-κB pathway gene, HEATR3

The Ashkenazi Jewish population has a several-fold higher prevalence of Crohn’s disease compared to non-Jewish European ancestry populations and has a unique genetic history. Haplotype association is critical to Crohn’s disease etiology in this population, most notably at NOD2, in which three causal, uncommon, and conditionally independent NOD2 variants reside on a shared background haplotype. We present an analysis of extended haplotypes which showed significantly greater association to Crohn’s disease in the Ashkenazi Jewish population compared to a non-Jewish population (145 haplotypes and no haplotypes with P-value < 10−3, respectively). Two haplotype regions, one each on chromosomes 16 and 21, conferred increased disease risk within established Crohn’s disease loci. We performed exome sequencing of 55 Ashkenazi Jewish individuals and follow-up genotyping focused on variants in these two regions. We observed Ashkenazi Jewish-specific nominal association at R755C in TRPM2 on chromosome 21. Within the chromosome 16 region, R642S of HEATR3 and rs9922362 of BRD7 showed genome-wide significance. Expression studies of HEATR3 demonstrated a positive role in NOD2-mediated NF-κB signaling. The BRD7 signal showed conditional dependence with only the downstream rare Crohn’s disease-causal variants in NOD2, but not with the background haplotype; this elaborates NOD2 as a key illustration of synthetic association

Prevalence and clinical impact of endoscopic pseudomembranes in patients with inflammatory bowel disease and Clostridium difficile infection

Background and aim: Limited data suggests that pseudomembranes are uncommon in patients with inflammatory bowel disease (IBD) and C. difficile associated disease (CDAD), but the reason for this is unknown. We aimed to evaluate the rate of pseudomembranes in this population, identify predictive factors for pseudomembranes' presence and assess its clinical impact. Methods: This was a sub-study of a retrospective European Crohn's & Colitis Organization (ECCO) multi-center study on the outcome of hospitalized IBD patients with C. difficile. The present study included only patients who underwent lower endoscopy during hospitalization, and compared demographic and clinical parameters in the group of patients with discernable pseudomembranes versus those without. Results: Out of 155 patients in the original cohort, 93 patients underwent lower endoscopy and constituted the study population. Endoscopic pseudomembranes were found in 12 (13%) of these patients. Patients with pseudomembranes presented more commonly with fever (p=0.02) compared to patients without pseudomembranes. No difference between the two groups was found with respect to the use of immunosuppressant drugs, background demographics or disease characteristics. Neither was there a difference between the group with or without pseudomembranes in the frequency of severe adverse clinical outcome or in the duration of hospitalization. On multi-variate analysis the presence of fever remained independently associated with the finding of pseudomembranes (OR 6, 95% CI 1.2–32, p=0.03). Conclusions: This study documents that hospitalized IBD patients with CDAD have low rate of endoscopic pseudomembranes, which is not accounted for by the use of immunosuppressant drugs. IBD patients with CDAD and discernable pseudomembranes more commonly present with fever, but their clinical outcome is similar to patients without pseudomembranes. © 2009 Published by Elsevier B.V. on behalf of European Crohn's and Colitis Organisation

Detection of anti-infliximab antibodies is impacted by antibody titer, infliximab level and IgG4 antibodies: a systematic comparison of three different assays

Background: There is scant information on the accuracy of different assays used to measure anti-infliximab antibodies (ADAs), especially in the presence of detectable infliximab (IFX). We thus aimed to evaluate and compare three different assays for the detection of IFX and ADAs and to clarify the impact of the presence of circulating IFX on the accuracy of the ADA assays.Methods: Blood samples from 79 ulcerative colitis (UC) patients treated with infliximab were assessed for IFX levels and ADAs using three different assays: an in-house assay and two commercial kits, Immundiagnostik and Theradiag. Sera samples with ADAs and undetectable levels of IFX were spiked with exogenous IFX and analyzed for ADAs.Results: The three assays showed 81-96% agreement for the measured IFX level. However, the in-house assay and Immundiagnostik assays detected ADAs in 34 out of 79 samples, whereas Theradiag only detected ADAs in 24 samples. Samples negative for ADAs with Theradiag, but ADA-positive in both the in-house and Immundiagnostik assays, were positive for IFX or IgG4 ADAs. In spiking experiments, a low concentration of exogenous IFX (5 mu g/ml) hampered ADA detection with Theradiag in sera samples with ADA levels of between 3 and 10 mu g/ml. In the Immundiagnostik assay detection interference was only observed at concentrations of exogenous IFX higher than 30 mu g/ml. However, in samples with high levels of ADAs (> 25 mu g/ml) interference was only observed at IFX concentrations higher than 100 mu g/ml in all three assays. Binary (IFX/ADA) stratification of the results showed that IFX+/ADA and IFX-/ADAs + were less influenced by the assay results than the double-positive (IFX+/ADAs+) and double-negative (IFX-/ADAs-) combination.Conclusions: All three methodologies are equally suitable for measuring IFX levels. However, erroneous therapeutic decisions may occur when patients show double-negative (IFX-/ADAs) or double-positive (IFX+/ADAs+) status, since agreement between assays is significantly lower in these circumstances

Accuracy of Capsule Colonoscopy in Detecting Colorectal Polyps in a Screening Population

BACKGROUND & AIMS: Capsule colonoscopy is a minimally invasive imaging method. We measured the accuracy of this technology in detecting polyps 6 mm or larger in an average-risk screening population. METHODS: In a prospective study, asymptomatic subjects (n = 884) underwent capsule colonoscopy followed by conventional colonoscopy (the reference) several weeks later, with an endoscopist blinded to capsule results, at 10 centers in the United States and 6 centers in Israel from June 2011 through April 2012. An unblinded colonoscopy was performed on subjects found to have lesions 6 mm or larger by capsule but not conventional colonoscopy. RESULTS: Among the 884 subjects enrolled, 695 (79%) were included in the analysis of capsule performance for all polyps. There were 77 exclusions (9%) for inadequate cleansing and whole-colon capsule transit time fewer than 40 minutes, 45 exclusions (5%) before capsule ingestion, 15 exclusions (2%) after ingestion and before colonoscopy, and 15 exclusions (2%) for site termination. Capsule colonoscopy identified subjects with 1 or more polyps 6 mm or larger with 81% sensitivity (95% confidence interval [CI], 77%-84%) and 93% specificity (95% CI, 91%-95%), and polyps 10 mm or larger with 80% sensitivity (95% CI, 74%-86%) and 97% specificity (95% CI, 96%-98%). Capsule colonoscopy identified subjects with 1 or more conventional adenomas 6 mm or larger with 88% sensitivity (95% CI, 82%-93) and 82% specificity (95% CI, 80%-83%), and 10 mm or larger with 92% sensitivity (95% CI, 82%-97%) and 95% specificity (95% CI, 94%-95%). Sessile serrated polyps and hyperplastic polyps accounted for 26% and 37%, respectively, of false-negative findings from capsule analyses. CONCLUSIONS: In an average-risk screening population, technically adequate capsule colonoscopy identified individuals with 1 or more conventional adenomas 6 mm or larger with 88% sensitivity and 82% specificity. Capsule performance seems adequate for patients who cannot undergo colonoscopy or who had incomplete colonoscopies. Additional studies are needed to improve capsule detection of serrated lesions. Clinicaltrials.gov number: NCT01372878

A Genome-Wide Scan of Ashkenazi Jewish Crohn's Disease Suggests Novel Susceptibility Loci

Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD–susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2–4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10−6). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10−8; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10−9; OR = 1.16), 8q21.11 (rs12677663, p = 2×10−8; OR = 1.15), 10q26.3 (rs10734105, p = 3×10−8; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10−9; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim

Taking Crohn’s Disease Personally

Crohn’s disease (CD) is a heterogeneous disorder that can involve any segment of the gastrointestinal tract. The pathogenesis of CD is unknown but is thought to involve an uncontrolled immune response triggered by an environmental factor in a genetically susceptible host. The heterogeneity of disease pathogenesis and clinical course, combined with the variable response to treatment and its associated side effects, creates an environment of complex therapeutic decisions. Despite this complexity, significant progress has been made which allows physicians to start and predict disease behavior and natural course, response to therapy, and factors associated with significant side effects. In this manuscript the data pertaining to these variables including clinical, endoscopic and the various biological and genetic markers are reviewed, and the possibility of tailoring personal treatment is discussed

One Size Does Not Fit All: The Case for Translational Medicine

Therapy for inflammatory bowel diseases (IBD) has developed during recent years. Despite the availability of new therapeutic modalities, overall therapy success remains modest, and complete remission is usually achieved and maintained in approximately 30% of patients only. This observation can be explained by a number of reasons. First, the involvement of multiple genetic loci combined with differential environmental exposures suggests that IBD represent a continuum of disorders rather than distinct homogeneous disease entities. This diversity is translated into different disease course patterns, wherein some patients experience quiescent disease whereas others suffer from a relentless disease course. Hence, basic disease pathogenesis sets the stage for differential treatment responses. To date, IBD therapy is based on immunosuppression which does not take basic disease variability into account. Treatments are prescribed based on statistical considerations related to the response of the average patient in clinical trials rather than on personal considerations. Treatment outcomes can potentially be improved if physiologic considerations are integrated into the drug selection process. In one approach, drugs can be targeted at known patient dysfunctional processes such as in the case of patients carrying autophagy-related genetic polymorphisms being treated with rapamycin, a drug that inhibits mTOR inhibitor and enhances autophagy. Another alternative would be to use a systems approach to perform unsupervised, high-throughput screening in order to derive predictive treatment biomarkers and mechanistic insights associated with response to specific drug therapy. Additional predictive markers for drug safety are needed as well. Caveats and directions for needed future studies are outlined

Flare-up of ulcerative colitis after systemic corticosteroids: A strong case for Strongyloides

Super-imposed infection with intestinal organisms can mimic a flare-up of underlying disease in patients with inflammatory bowel disease (IBD). We report a case of patient with long standing ulcerative colitis (UC), who presented with abdominal pain, diarrhea and low-grade fever after receiving systemic corticosteroids for an unrelated disorder. Despite a negative stool examination, a peripheral eosinophilia reappeared upon tapering down of a corticosteroid dose. Subsequently, duodenal biopsies showed evidence for Strongyloides, presumably acquired 20 years ago when the patient was residing in Brazil. The patient fully recovered following anti-helmintic therapy. This case underscores the importance of considering Strongyloides in the work-up of flaring-up IBD patients, even if a history of residing or traveling to endemic areas is in the distant past