Treatment patterns and intensification within 5 year of follow-up of the first-line anti-TNFα used for the treatment of IBD : Results from the VERNE study

Altres ajuts: Takeda Farmacéutica España S.A.Background: Anti-TNFα represent one of the main treatment approaches for the management of inflammatory bowel diseases (IBD). Therefore,the evaluation of their treatment patterns over time provides valuable insights about the clinical value of therapies and associated costs. Aims: To assess the treatment patterns with the first anti-TNFα in IBD. Methods: Retrospective, observational study. Results: 310 IBD patients were analyzed along a 5-year follow-up period. 56.2% of Crohn's disease (CD) patients started with adalimumab (ADA), while 43.8% started with infliximab (IFX). 12.9% of ulcerative colitis (UC) patients initiated with ADA, while 87.1% initiated with IFX. Treatment intensification was required in 28.9% of CD and 37.1% of UC patients. Median time to treatment intensification was shorter in UC than in CD (5.3 vs. 14.3 months; p = 0.028). Treatment discontinuation due to reasons other than remission were observed in 40.7% of CD and 40.5% of UC patients, although, in UC patients there was a trend to lower discontinuation rates with IFX (36.6%) than with ADA (66.7%). Loss of response accounted for approximately one-third of discontinuations, in both CD and UC. Conclusions: Around one-third of IBD biologic-naive patients treated with an anti-TNFα required treatment intensification (earlier in UC) and around 40% discontinued the anti-TNFα due to inappropriate disease control

Impact of comorbidities on anti-TNF alpha response and relapse in patients with inflammatory bowel disease: the VERNE study

Objective: To evaluate the impact of comorbidities and extraintestinal manifestations of inflammatory bowel disease on the response of patients with inflammatory bowel disease to antitumour necrosis factor alpha (anti-TNFalpha) therapy. Design: Data from 310 patients (194 with Crohn's disease and 116 with ulcerative colitis) treated consecutively with the first anti-TNFalpha in 24 Spanish hospitals were retrospectively analysed. Univariate and multivariate logistic regression analyses were performed to assess the associations between inflammatory bowel disease comorbidities and extraintestinal manifestations with anti-TNFalpha treatment outcomes. Key clinical features, such as type of inflammatory bowel disease and concomitant treatments, were included as fixed factors in the model. Results: Multivariate logistic regression analyses (OR, 95% CI) showed that chronic obstructive pulmonary disease (2.67, 1.33 to 5.35) and hepato-pancreato-biliary diseases (1.87, 1.48 to 2.36) were significantly associated with primary non-response to anti-TNFalpha, as was the use of corticosteroids and the type of inflammatory bowel disease (ulcerative colitis vs Crohn's disease). It was also found that myocardial infarction (3.30, 1.48 to 7.35) and skin disease (2.73, 1.42 to 5.25) were significantly associated with loss of response, along with the use of corticosteroids and the type of inflammatory bowel disease (ulcerative colitis vs Crohn's disease). Conclusions: Our results suggest that the presence of some comorbidities in patients with inflammatory bowel disease, such as chronic obstructive pulmonary disease and myocardial infarction, and of certain extraintestinal manifestations of inflammatory bowel disease, such as hepato-pancreato-biliary conditions and skin diseases, appear to be related to failure to anti-TNFalpha treatment. Therefore, their presence should be considered when choosing a treatment. Trial registration number: NCT02861118

Experimental and genetic evidence for the impact of CD5 and CD6 expression and variation in inflammatory bowel disease

Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) resulting from the interaction of multiple environmental, genetic and immunological factors. CD5 and CD6 are paralogs encoding lymphocyte co-receptors involved in fine-tuning intracellular signals delivered upon antigen-specific recognition, microbial pattern recognition and cell adhesion. While CD5 and CD6 expression and variation is known to influence some immune-mediated inflammatory disorders, their role in IBD remains unclear. To this end, Cd5- and Cd6-deficient mice were subjected to dextran sulfate sodium (DSS)-induced colitis, the most widely used experimental animal model of IBD. The two mouse lines showed opposite results regarding body weight loss and disease activity index (DAI) changes following DSS-induced colitis, thus supporting Cd5 and Cd6 expression involvement in the pathophysiology of this experimental IBD model. Furthermore, DNA samples from IBD patients of the ENEIDA registry were used to test association of CD5 (rs2241002 and rs2229177) and CD6 (rs17824933, rs11230563, and rs12360861) single nucleotide polymorphisms with susceptibility and clinical parameters of CD (n=1352) and UC (n=1013). Generalized linear regression analyses showed association of CD5 variation with CD ileal location (rs2241002CC) and requirement of biological therapies (rs2241002C-rs2229177T haplotype), and with poor UC prognosis (rs2241002T-rs2229177T haplotype). Regarding CD6, association was observed with CD ileal location (rs17824933G) and poor prognosis (rs12360861G), and with left-sided or extensive UC, and absence of ankylosing spondylitis in IBD (rs17824933G). The present experimental and genetic evidence support a role for CD5 and CD6 expression and variation in IBD's clinical manifestations and therapeutic requirements, providing insight into its pathophysiology and broadening the relevance of both immunomodulatory receptors in immune-mediated disorders

Changes in the requirement for early surgery in inflammatory bowel disease in the era of biological agents

This is the peer reviewed version of the following article: Changes in the requirement for early surgery in inflammatory bowel disease in the era of biological agents. Journal of Gastroenterology and Hepatology (2020): 29 April, which has been published in final form at https://doi.org/10.1111/jgh.15084. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsBiological therapies may be changing the natural history of inflammatory bowel diseases, reducing the need for surgical intervention. We aimed to assess whether the availability of anti‐TNF agents impacts the need for early surgery in Crohn's disease (CD) and ulcerative colitis (UC). Methods Retrospective, cohort study of patients diagnosed within a 6‐year period before and after the licensing of anti‐TNFs (1990‐1995 and 2007‐2012 for CD; 1995‐2000 and 2007‐2012 for UC) were identified in the ENEIDA Registry. Surgery‐free survival curves were compared between cohorts. Results A total of 7,370 CD patients (2,022 in Cohort 1 and 5,348 in Cohort 2) and 8,069 UC patients (2,938 in Cohort 1 and 5,131 in Cohort 2) were included. Immunosuppressants were used significantly earlier and more frequently in both CD and UC post‐biological cohorts. The cumulative probability of surgery was lower in CD following anti‐TNF approval (16% and 11%, 22% and 16%, and 29% and 19%, at 1, 3 and 5 years, respectively p<0.0001), though not in UC (3% and 2%, 4% and 4%, and 6% and 5% at 1, 3 and 5 years, respectively; p=0.2). Ileal involvement, older age at diagnosis and active smoking in CD, and extensive disease in UC, were independent risk factors for surgery, whereas high‐volume IBD centres (in both CD and UC) and immunosuppressant use (in CD) were protective factors. Conclusions Anti‐TNF availability was associated with a reduction in early surgery for CD (driven mainly by earlier and more widespread immunosuppressant use) but not in U

Identification of Novel Predictor Classifiers for Inflammatory Bowel Disease by Gene Expression Profiling

BACKGROUND: Improvement of patient quality of life is the ultimate goal of biomedical research, particularly when dealing with complex, chronic and debilitating conditions such as inflammatory bowel disease (IBD). This is largely dependent on receiving an accurate and rapid diagnose, an effective treatment and in the prediction and prevention of side effects and complications. The low sensitivity and specificity of current markers burden their general use in the clinical practice. New biomarkers with accurate predictive ability are needed to achieve a personalized approach that take the inter-individual differences into consideration. METHODS: We performed a high throughput approach using microarray gene expression profiling of colon pinch biopsies from IBD patients to identify predictive transcriptional signatures associated with intestinal inflammation, differential diagnosis (Crohn's disease or ulcerative colitis), response to glucocorticoids (resistance and dependence) or prognosis (need for surgery). Class prediction was performed with self-validating Prophet software package. RESULTS: Transcriptional profiling divided patients in two subgroups that associated with degree of inflammation. Class predictors were identified with predictive accuracy ranging from 67 to 100%. The expression accuracy was confirmed by real time-PCR quantification. Functional analysis of the predictor genes showed that they play a role in immune responses to bacteria (PTN, OLFM4 and LILRA2), autophagy and endocytocis processes (ATG16L1, DNAJC6, VPS26B, RABGEF1, ITSN1 and TMEM127) and glucocorticoid receptor degradation (STS and MMD2). CONCLUSIONS: We conclude that using analytical algorithms for class prediction discovery can be useful to uncover gene expression profiles and identify classifier genes with potential stratification utility of IBD patients, a major step towards personalized therapy

Genetic variation associated with cardiovascular risk in autoimmune diseases

Autoimmune diseases have a higher prevalence of cardiovascular events compared to the general population. The objective of this study was to investigate the genetic basis of cardiovascular disease (CVD) risk in autoimmunity. We analyzed genome-wide genotyping data from 6,485 patients from six autoimmune diseases that are associated with a high socio-economic impact. First, for each disease, we tested the association of established CVD risk loci. Second, we analyzed the association of autoimmune disease susceptibility loci with CVD. Finally, to identify genetic patterns associated with CVD risk, we applied the cross-phenotype meta-analysis approach (CPMA) on the genome-wide data. A total of 17 established CVD risk loci were significantly associated with CVD in the autoimmune patient cohorts. From these, four loci were found to have significantly different genetic effects across autoimmune diseases. Six autoimmune susceptibility loci were also found to be associated with CVD risk. Genome-wide CPMA analysis identified 10 genetic clusters strongly associated with CVD risk across all autoimmune diseases. Two of these clusters are highly enriched in pathways previously associated with autoimmune disease etiology (TNF? and IFN? cytokine pathways). The results of this study support the presence of specific genetic variation associated with the increase of CVD risk observed in autoimmunity

Performance of Screening Strategies for Latent Tuberculosis Infection in Patients with Inflammatory Bowel Disease: Results from the ENEIDA Registry of GETECCU

(1) Aims: Patients receiving antitumor necrosis factor (anti-TNF) therapy are at risk of developing tuberculosis (TB), usually due to the reactivation of a latent TB infection (LTBI). LTBI screening and treatment decreases the risk of TB. This study evaluated the diagnostic performance of different LTBI screening strategies in patients with inflammatory bowel disease (IBD). (2) Methods: Patients in the Spanish ENEIDA registry with IBD screened for LTBI between January 2003 and January 2018 were included. The diagnostic yield of different strategies (dual screening with tuberculin skin test [TST] and interferon-gamma-release assay [IGRA], two-step TST, and early screening performed at least 12 months before starting biological treatment) was analyzed. (3) Results: Out of 7594 screened patients, 1445 (19%; 95% CI 18-20%) had LTBI. Immunomodulator (IMM) treatment at screening decreased the probability of detecting LTBI (20% vs. 17%, p = 0.001). Regarding screening strategies, LTBI was more frequently diagnosed by dual screening than by a single screening strategy (IGRA, OR 0.60; 95% CI 0.50-0.73, p < 0.001; TST, OR 0.76; 95% CI 0.66-0.88, p < 0.001). Two-step TST increased the diagnostic yield of a single TST by 24%. More cases of LTBI were diagnosed by early screening than by routine screening before starting anti-TNF agents (21% [95% CI 20-22%] vs. 14% [95% CI 13-16%], p < 0.001). The highest diagnostic performance for LTBI (29%) was obtained by combining early and TST/IGRA dual screening strategies in patients without IMM. (4): Conclusions: Both early screening and TST/IGRA dual screening strategies significantly increased diagnostic performance for LTBI in patients with IBD, with optimal performance achieved when they are used together in the absence of IMM

Effectiveness and Safety of the Sequential Use of a Second and Third Anti-TNF Agent in Patients With Inflammatory Bowel Disease: Results From the Eneida Registry

Background: The effectiveness of the switch to another anti-tumor necrosis factor (anti-TNF) agent is not known. The aim of this study was to analyze the effectiveness and safety of treatment with a second and third anti-TNF drug after intolerance to or failure of a previous anti-TNF agent in inflammatory bowel disease (IBD) patients. Methods: We included patients diagnosed with IBD from the ENEIDA registry who received another anti-TNF after intolerance to or failure of a prior anti-TNF agent. Results: A total of 1122 patients were included. In the short term, remission was achieved in 55% of the patients with the second anti-TNF. The incidence of loss of response was 19% per patient-year with the second anti-TNF. Combination therapy (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.8-3; P < 0.0001) and ulcerative colitis vs Crohn's disease (HR, 1.6; 95% CI, 1.1-2.1; P = 0.005) were associated with a higher probability of loss of response. Fifteen percent of the patients had adverse events, and 10% had to discontinue the second anti-TNF. Of the 71 patients who received a third anti-TNF, 55% achieved remission. The incidence of loss of response was 22% per patient-year with a third anti-TNF. Adverse events occurred in 7 patients (11%), but only 1 stopped the drug. Conclusions: Approximately half of the patients who received a second anti-TNF achieved remission; nevertheless, a significant proportion of them subsequently lost response. Combination therapy and type of IBD were associated with loss of response. Remission was achieved in almost 50% of patients who received a third anti-TNF; nevertheless, a significant proportion of them subsequently lost response

Systematic search for new predictors associated with IBD.

<p>Predictors were built using the tool Prophet and the 54,675 probes contained in the chip, using the leave-one-out cross-validation strategy, to identify classifiers genes for inflammatory bowel disease, IBD (A), Crohn’s disease, CD (B), ulcerative colitis, UC (C), CD <i>vs.</i> UC (D), low inflammation subtypes of CD and UC (E), and high inflammation subtypes of CD <i>vs.</i> UC (F). Data are represented as box and whiskers plots, where the error bars designate the smallest and largest observations and dots designate the outliers. Data was analyzed by two-way ANOVA followed by Bonferroni post test, <i>p</i> values higher than 0.05 were considered not significant (ns), *<i>p</i><0.01, **<i>p</i><0.001.</p