Influence of familial forms of inflammatory bowel disease on the use of immunosuppressants, biological agents, and surgery in the era of biological therapies. Results from the ENEIDA project.

BACKGROUND AND AIMS: Familial inflammatory bowel disease (IBD) history is a controversial prognostic factor in IBD. We aimed to evaluate the impact of a familial history of IBD on the use of medical and surgical treatments in the biological era. METHODS: Patients included in the prospectively maintained ENEIDA database and diagnosed with IBD after 2005 were included. Familial forms were defined as those cases with at least one first-degree relative diagnosed with IBD. Disease phenotype, the use of biological agents, or surgical treatments were the main outcomes. RESULTS: A total of 5263 patients [2627 Crohn's disease (CD); 2636 ulcerative colitis (UC)] were included, with a median follow-up of 31 months. Of these, 507 (10%) corresponded to familial forms. No clinical differences were observed between familial and sporadic IBD forms except a lower age at IBD diagnosis and a higher rate of males in familial forms of UC. In CD, the proportions of patients treated with thiopurines (54.4% vs 46.7%; P = .015) and survival time free of thiopurines (P = .009) were lower in familial forms. No differences were found regarding the use of biological agents. Concerning surgery, a higher rate of intestinal resections was observed in sporadic CD (14.8% vs 9.9%, P = .027). No differences were observed in UC. CONCLUSIONS: In the era of biological therapies, familial and sporadic forms of IBD show similar phenotypes and are managed medically in a similar way; whether these is due to lack of phenotypical differences or an effect of biological therapies is uncertain. What is already known on this topic: IBD's etiopathogenesis points to an interaction between environmental and genetic factors, being familial history a controversial prognostic factor. Biological agents use and need for surgery regarding familial or sporadic forms of IBDs present conflicting results. What this study adds: Familial and sporadic forms of IBD have similar phenotypes and are managed medically and surgically in a similar way. How this study might affect research, practice or policy: Familial aggregation should not be considered a factor associated with more aggressive disease.

Serum and Urine Metabolomic Profiling of Newly Diagnosed Treatment-Naïve Inflammatory Bowel Disease Patients.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a prevalent chronic noncurable disease associated with profound metabolic changes. The discovery of novel molecular indicators for unraveling IBD etiopathogenesis and the diagnosis and prognosis of IBD is therefore pivotal. We sought to determine the distinctive metabolic signatures from the different IBD subgroups before treatment initiation. METHODS: Serum and urine samples from newly diagnosed treatment-naïve IBD patients and age and sex-matched healthy control (HC) individuals were investigated using proton nuclear magnetic resonance spectroscopy. Metabolic differences were identified based on univariate and multivariate statistical analyses. RESULTS: A total of 137 Crohn's disease patients, 202 ulcerative colitis patients, and 338 HC individuals were included. In the IBD cohort, several distinguishable metabolites were detected within each subgroup comparison. Most of the differences revealed alterations in energy and amino acid metabolism in IBD patients, with an increased demand of the body for energy mainly through the ketone bodies. As compared with HC individuals, differences in metabolites were more marked and numerous in Crohn's disease than in ulcerative colitis patients, and in serum than in urine. In addition, clustering analysis revealed 3 distinct patient profiles with notable differences among them based on the analysis of their clinical, anthropometric, and metabolomic variables. However, relevant phenotypical differences were not found among these 3 clusters. CONCLUSIONS: This study highlights the molecular alterations present within the different subgroups of newly diagnosed treatment-naïve IBD patients. The metabolomic profile of these patients may provide further understanding of pathogenic mechanisms of IBD subgroups. Serum metabotype seemed to be especially sensitive to the onset of IBD.

Usefulness of monitoring antitumor necrosis factor serum levels during the induction phase in patients with Crohn's disease.

AIMS: The aims of this study were (a) to know the kinetics of antitumor necrosis factor (TNF) drug serum levels during the induction phase in patients with Crohn's disease; (b) to identify variables associated with these levels; and (c) to assess the relation between these levels and short-term effectiveness in Crohn's disease patients. METHODS: Patients with Crohn's disease naïve to anti-TNF treatment were prospectively included. Remission was defined as a Crohn's disease activity index (CDAI) score <150 after 14 weeks of treatment. Blood samples were obtained at baseline and at weeks 4, 8, and 14. Adalimumab and infliximab levels were measured, receiver operating characteristic (ROC) curves were constructed, and the area under the ROC curve was calculated. RESULTS: One-hundred fifty patients with Crohn's disease were included, 79 (53%) received infliximab and 71 (47%) had CDAI > 150 at study entry. At week 14, 52 out of 71 patients with CDAI > 150 at baseline (73%) had clinical remission. There were no differences in infliximab levels between patients with and without remission (8 vs. 9.1 µg/mL, P > 0.05) or with and without response (7 vs. 11 µg/mL, P > 0.05) at week 14. There was a trend to higher levels of adalimumab concentration in responders in comparison with nonresponders (13 vs. 6.7 µg/mL, P = 0.05) and in patients who achieved remission in comparison with nonremitters (13.5 vs. 8.4 µg/mL, P = 0.06). In the multivariate analysis, no variable was predictive of short-term remission, including infliximab and adalimumab serum levels. CONCLUSION: Determining anti-TNF serum levels during the induction phase is not useful for predicting short-term remission in patients with Crohn's disease.

Functional rare variants influence the clinical response to anti-TNF therapy in Crohn's disease.

BACKGROUND: The effect of low-frequency functional variation on anti-tumor necrosis factor alpha (TNF) response in Crohn's disease (CD) patients remains unexplored. The objective of this study was to investigate the impact of functional rare variants in clinical response to anti-TNF therapy in CD. METHODS: CD anti-TNF naïve patients starting anti-TNF treatment due to active disease [Crohn's Disease Activity Index (CDAI > 150)] were included. The whole genome was sequenced using the Illumina Hiseq4000 platform. Clinical response was defined as a CDAI score <150 at week 14 of anti-TNF treatment. Low-frequency variants were annotated and classified according to their damaging potential. The whole genome of CD patients was screened to identify homozygous loss-of-function (LoF) variants. The TNF signaling pathway was tested for overabundance of damaging variants using the SKAT-O method. Functional implication of the associated rare variation was evaluated using cell-type epigenetic enrichment analyses. RESULTS: A total of 41 consecutive CD patients were included; 3250 functional rare variants were identified (2682 damaging and 568 LoF variants). Two homozygous LoF mutations were found in HLA-B and HLA-DRB1 genes associated with lack of response and remission, respectively. Genome-wide LoF variants were enriched in epigenetic marks specific for the gastrointestinal tissue (colon, p = 4.11e-4; duodenum, p = 0.011). The burden of damaging variation in the TNF signaling pathway was associated with response to anti-TNF therapy (p = 0.016); damaging variants were enriched in epigenetic marks from CD8+ (p = 6.01e-4) and CD4+ (p = 0.032) T cells. CONCLUSIONS: Functional rare variants are involved in the response to anti-TNF therapy in CD. Cell-type enrichment analysis suggests that the gut mucosa and CD8+ T cells are the main mediators of this response.