The role of vascular endothelial growth factor (VEGF) in inflammatory bowel disease

Background: Vascular endothelial growth factor (VEGF) is a candidate susceptibility gene to inflammatory bowel disease (IBD), both from a functional as well as genetic perspective. Moreover, serum VEGF (sVEGF) levels are increased in IBD and correlate with disease activity. Both VEGF expression and sVEGF levels may be influenced by VEGF gene polymorphisms. Aims: To study VEGF polymorphisms in IBD susceptibility and their impact on sVEGF levels. Methods: Four functional VEGF polymorphisms (-C2578A, -G1154A, -G634C, and C936T) were genotyped in two independent cohorts (cohort 1: 372 IBD trios, cohort 2: 452 unrelated IBD patients, 271 healthy controls [HC]; and 93 patients with non-IBD gastrointestinal inflammation [non-IBD GI]), using polymerase chain reaction with restriction fragment length polymorphism and TaqMan minor groove binding. Phenotypical data on all patients as well as sVEGF levels were correlated with the genetic data. Results: Both the VEGF genotype and haplotype frequencies did not differ between IBD patients and controls, and no distortion of transmission was observed. sVEGF levels were increased in IBD but also in non-IBD GI patients, compared with HC, and were only influenced by VEGF polymorphisms in patients with Crohn's disease (-G1154A genotype and -2578/-1154/-634 AAG promoter haplotype). Conclusions: The VEGF polymorphisms studied are not implicated in susceptibility to IBD and do not predict sVEGF levels. Although increased sVEGF and angiogenesis are important features of IBD, they do not appear genetically determined

Influence of Trough Serum Levels and Immunogenicity on Long-term Outcome of Adalimumab Therapy in Crohn's Disease

International audienceBACKGROUND & AIMS: Adalimumab is an efficacious therapy for active Crohn's disease, but long-term data are scarce. We conducted an observational study to assess the long-term clinical benefit of adalimumab in patients who failed to respond to infliximab, specifically focusing on the influence of trough serum concentration and antibodies against adalimumab on clinical outcome. METHODS: A total of 168 patients with Crohn's disease treated with adalimumab in a tertiary center were included in a prospective follow-up program. Trough serum concentration and antibodies against adalimumab were measured at predefined time points using enzyme-linked immunosorbent assays. RESULTS: A total of 71% and 67% of patients responded by weeks 4 and 12, respectively; among them, 61.5% demonstrated sustained clinical benefit until the end of follow-up (median [interquartile range], 20.4 [11.7-30.0] months). Of the 156 patients receiving maintenance therapy, 102 (65.4%) had to step up to 40 mg weekly and 60 (38.5%) eventually stopped adalimumab therapy mainly due to loss of response. Significantly lower adalimumab trough serum concentrations were measured throughout the follow-up period in patients who discontinued therapy as compared with patients who stayed on adalimumab. Antibodies against adalimumab were present in 9.2% of the patients and affected trough serum concentration. Serious adverse events occurred in 12% of the patients. CONCLUSIONS: Introduction of adalimumab after failure of infliximab therapy resulted in a sustained clinical benefit in two thirds of patients during a median follow-up period of almost 2 years. Discontinuation was directly related to low adalimumab trough serum concentration, which was observed more frequently in patients who developed antibodies against adalimumab

Clustering of (auto)immune diseases with early-onset and complicated inflammatory bowel disease

Studies in adult inflammatory bowel disease (IBD) patients have highlighted associations with genetic and serologic markers and suggest an association with disease location, behaviour and natural history. Data on patients with Crohn's disease (CD, n = 80), ulcerative colitis (UC, n = 15) and indeterminate colitis (n = 4) were collected. All individuals were analysed for CARD15 R702W, G908R and L1007fs for toll-like receptor 4 (TLR4) Asp299Gly and for anti-Saccharomyces cerevisiae antibodies (ASCA) and atypical perinuclear antineutrophil cytoplasmatic antibodies (pANCA). After a mean of 10.7 years of follow up, the disease behaviour changed in 45% of CD patients, in contrast to disease location, where only 12.5% had a change (p < 0.001). The younger the age at diagnosis, the more patients presented with colonic disease (p = 0.021). Also, more TLR4 Asp299 Gly variants were found when the age at onset was younger (p = 0.018). A large number of concomitant diseases were observed. There was no difference in the prevalence of TLR4 variants nor ASCA or pANCA between the patients with or without concomitant diseases. Patients who progressed more often needed surgery as compared to patients who remained free of stenosing or fistulising disease (27/32 or 84% versus 3/35 or 8.6%, respectively, p < 0.0001) and more often had concomitant immune-mediated diseases and a trend for more seroreactivity towards ASCA