We used coding and noncoding polymorphisms evenly spaced across the ABCB1/MDR1 gene to perform association analysis in Slovenian patients with inflammatory bowel diseases and to obtain haplotype structure and patterns of linkage disequilibrium (LD) in the MDR1 gene. A disease association study was performed in 307 IBD patients, including 144 patients with ulcerative colitis (UC) and 163 patients with Crohn's disease (CD), and 355 healthy controls. Here we report an association between MDR1 alleles, polymorphisms and haplotypes and refractory CD patients, who do not respond to standard therapy, including patients who develop fistulas. We also report an association with UC and MDR1 polymorphisms in a Slovenian population. Haplotypes significantly associated with diseases were defined by single-nucleotide polymorphisms (SNPs) in exons 12 (1236 C4A), 21(A893S), and 26 (3435 C4T). In addition, two intronic SNPs in LD with the disease haplotype, one in intron 13 (rs2235035) and another in intron 16 (rs1922242), were significantly associated with refractory Crohn (P ¼ 0.026, odds ratio (OR) 2.7 and P ¼ 0.025, OR 2.8, respectively), as well as with UC (P ¼ 0.006, OR 1.8 and P ¼ 0.026, OR 1.9, respectively). Our results suggest that MDR1 is a potential target for therapy in refractory CD patients and in patients with UC.

Our results suggest ADA response in CD patients is genetically predisposed by SNPs in CD risk genes and suggest ATG16L1 as most promising candidate gene for drug response in ADA treatment. Original submitted 24 September 2014; Revision submitted 1 December 2014.

High infliximab trough levels provide better control of inflammation in inflammatory bowel disease without increasing the risk of infection.

Cytomegalovirus (CMV) reactivation is a common complication in patients with inflammatory bowel diseases (IBD), particularly in those with steroid-resistant ulcerative colitis. It is usually diagnosed by histopathologic and immunohistochemical examination of the colon biopsy. The introduction of quantitative, real-time polymerase chain reaction (qPCR) has been recommended to improve the sensitivity, but there is little consensus on how to use it. We compared the two methods in samples from resected bowel of patients with IBD. Twelve patients with IBD who had undergone bowel resection were analysed for CMV, using qPCR and immunohistochemistry. In all cases, tissue samples from the base and the edge of ulcers and from uninvolved mucosa were obtained. The highest densities of CMV-positive cells were found in samples from the base of ulcers (immunohistochemistry 0-0.47 positive cells/mm(2); qPCR 10-3809 viral copies/mg) or the edge of ulcers (immunohistochemistry 0.06-0.32 positive cells/mm(2); qPCR 35-1049 viral copies/mg). In samples of uninvolved mucosa, immunohistochemistry was negative, whereas qPCR was either negative or showed very low values (0-3 viral copies/mg). We conclude that both immunohistochemistry and qPCR can be successfully used for diagnosing CMV reactivation in patients with IBD. The base and the edge of ulcers are the optimal sites for endoscopic biopsies. The density of CMV-positive cells was low and their distribution within the colon uneven. It therefore seems that the number of sampled biopsies and/or the number of investigated levels is more important that the choice of diagnostic method.

EUS proved to be as sensitive as ERCP for detection of CBS in patients with acute biliary pancreatitis. Therefore, EUS could be used as the first-line procedure in patients with acute biliary pancreatitis when therapeutic ERCP is not needed. By this approach a substantial number of unnecessary diagnostic ERCP procedures could be avoided.

Background: Combination treatment with azathioprine for 6-12 months is the preferred strategy for starting infliximab due to improved pharmacokinetics. However, optimised infliximab monotherapy with proactive dose escalations in case of low trough levels is a potentially safer but under-studied alternative.Aim: To compare the clinical success and infliximab consumption of combination vs optimised monotherapy strategies.Methods: We studied the clinical success and infliximab consumption with both strategies in 149 patients (94 Crohn's disease; 55 ulcerative colitis) starting infliximab and undergoing intensive drug monitoring assisted treatment optimisation.Results: The drug retention rates were similar for optimised monotherapy and combination treatment after induction (96% vs 97%, P = 0.73), after the first year (90% vs 83%, P = 0.23) and at the end of follow-up (74% vs 75%, P = 0.968). Similarly, no significant differences were observed for steroid use at year 1 (5% vs 14%, P = 0.08) or mucosal healing at the end of follow-up (64% vs 67%, P = 0.8). Higher infliximab consumption (7.6 mg/kg q8 weeks [interquartile range (IQR): 5.9-10.3] vs 6.4 mg/kg q8 weeks [IQR: 5.2-8.0], P = 0.019) combined with lower trough levels (1.7 µg/mL [IQR: 0.3-6.6] vs 5.0 µg/mL [2.5-8.7], P = 0.012) resulted in almost 3-fold higher drug-to-trough ratio (3.9 vs 1.5) in monotherapy compared to combination strategy at year 1. At the end of follow-up, when azathioprine had been discontinued for a median of 14 [IQR: 3-33] months, these differences disappeared. Conclusions:In this study, optimised infliximab monotherapy was as clinically effective as combination therapy, but was associated with significantly higher infliximab consumption. The infliximab-sparing effect disappeared after azathioprine withdrawal.

Background The relationship between vedolizumab trough levels and combined endoscopic and clinical remission is unknown. Objective To compare vedolizumab trough levels in patients with and without combined remission within the first year of treatment. Methods We prospectively collected vedolizumab trough levels in 51 consecutive patients (28 Crohn's disease (CD) and 23 ulcerative colitis (UC)) before all infusions up to week 22, and at weeks 38 and 54, with concentrations measured after study completion. Centrally read endoscopy was performed at a median of 46 weeks. The primary outcome was combined endoscopic (CD: Simple endoscopic score for CD (SES-CD) < 4 without ulceration; UC: Mayo endoscopic subscore ≤ 1) and clinical remission (CD: resolution of abdominal pain; UC: resolution of rectal bleeding; both: resolution of altered bowel habit). Results Median vedolizumab trough levels at weeks 6 (25.7 vs 15.6 µg/mL; P = 0.015) and 22 (15.1 vs 4.9 µg/mL; P = 0.001) were higher in patients with combined remission. A threshold of 22 µg/mL at week 6 (area under the curve (AUC) 0.733; 95% confidence interval 0.567–0.899) and 8 µg/mL at week 22 (AUC 0.819; 95% confidence interval 0.692–0.946) predicted combined remission. Conclusion Early vedolizumab trough levels predicted combined endoscopic and clinical remission highlighting their possible use in clinical practice.

Crohn's disease is often treated with the anti-tumor necrosis factor-α drug adalimumab. However, about 20%-40% of patients do not display adequate therapeutic response. We prospectively evaluated, during a routine therapy of Crohn's disease patients, the candidate autophagy-related genes ATG12 and ATG5 and the inflammation-related genes NFKB1, NFKBIA, and CRP as potential predictors of adalimumab treatment response (pharmacodynamics). The associations of haplotypes and SNPs in these genes with response to drug therapy, biochemical parameters, and body mass were determined at baseline and after 4, 12, 20, and 30 weeks of therapy. Association analysis showed that haplotypes defined with the SNPs rs9373839 and rs510432 in ATG5 gene were significantly associated with positive response to therapy (p < 0.002). In addition, allele C and genotypes CC and CT of the rs1130864 in the CRP gene were positively associated with therapeutic response (p < 0.002). To the best of our knowledge, this is the first report that supports the association of SNPs in ATG5 and CRP genes with response to adalimumab therapy in Crohn's disease. Further study of these biological pathways in larger and independent clinical samples is warranted as novel streams of research on precision medicine and diagnostics for Crohn's disease.