Jørn Brynskov

Microbiotas from UC patients display altered metabolism and reduced ability of LAB to colonize mucus

We compared fecal microbial communities derived either from Ulcerative Colitis (UC) patients in remission (n = 4) or in relapse (n = 4), or from healthy subjects (n = 4). These communities were used for inoculation of a dynamic in vitro gut model, which contained integrated mucin-covered microcosms. We found that the microbiota of the ‘mucus’ largely differed from that of the ‘lumen’. This was partly due to decreased mucus-associated populations of lactic acid producing bacterial populations (LAB), as LAB originating from UC patients had a significantly decreased capacity to colonize the mucin-covered microcosms as compared to those originating from healthy subjects. We found significant differences between the metabolomes of UC patients in relapse and remission, respectively, while the metabolome of patients in remission resembled that of healthy subjects. These novel findings constitute an important contribution to the understanding of the complex etiology of UC.

Confocal laser endomicroscopy: a novel method for prediction of relapse in Crohn's disease.

BACKGROUND AND STUDY AIMSnConfocal laser endomicroscopy (CLE) has been shown to predict relapse in ulcerative colitis in remission, but little is currently known about its role in Crohns disease. The aim of this study was to identify reproducible CLE features in patients with Crohns disease and to examine whether these are risk factors for relapse.nnnPATIENTS AND METHODSnThis was a single-center prospective feasibility study of CLE imaging in patients with Crohns disease. CLE imaging was performed in the terminal ileum and four colorectal sites, and was correlated with histopathology and macroscopic appearance. Clinical relapse, defined as the need for treatment escalation or surgical intervention, was recorded during follow-up.nnnRESULTSnThe study included 50 patients: 39 with Crohns disease (20 in remission), and 11 controls. Ileal fluorescein leakage and microerosions were significantly more frequent in patients with endoscopically active Crohns disease compared with patients with inactive Crohns disease and controls (Pu200a=u200a0.005 and (Pu200a=u200a0.006, respectively). The same applied to colorectal fluorescein leakage and vascular alterations ((Pu200a=u200a0.043 and (Pu200a=u200a0.034, respectively). During a 12-month follow-up period, ileal fluorescein leakage and microerosions were significant risk factors for relapse in the subgroup of patients in remission (log rank (Pu200a=u200a0.009 and (Pu200a=u200a0.007, respectively) as well as in the entire group of patients with Crohns disease (log rank (Pu200a=u200a0.006 and (Pu200a=u200a0.01, respectively). Inter- and intraobserver reproducibility was almost perfect (κu200a>u200a0.80) or substantial (κu200a>u200a0.60) for the majority of CLE parameters.nnnCONCLUSIONSnCLE can identify reproducible microscopic changes in the terminal ileum that are risk factors for relapse in patients with otherwise inactive Crohns disease.nnnTRIAL REGISTRATIONnClinicalTrials.gov (NCT01738529).

Confocal laser endomicroscopy in ulcerative colitis: a longitudinal study of endomicroscopic changes and response to medical therapy (with videos)

BACKGROUND AND AIMSnConfocal laser endomicroscopy enables real-time inxa0vivo microscopy during endoscopy and can predict relapse in patients with inflammatory bowel disease in remission. However, little is known about how endomicroscopic features change with time. The aim of this longitudinal study was to correlate colonic confocal laser endomicroscopy (CLE) in ulcerative colitis with histopathology and macroscopic appearance before and after intensification of medical treatment.nnnMETHODSnTwenty-two patients with ulcerative colitis in clinical relapse and 7 control subjects referred for colonoscopy were enrolled. The colonic mucosa was examined with high-definition colonoscopy, histopathology, and CLE at 4 colonic sites. Subsequently, patients requiring medical treatment escalation were referred for repeat endoscopy with CLE after 6 to 8 weeks.nnnRESULTSnThe baseline frequency of fluorescein leakage (Pxa0< .001), microerosions (Pxa0< .001), tortuosity of thexa0crypts (Pxa0= .001), distortion of the crypts openings (Pxa0= .001), presence of inflammatory infiltrates (Pxa0<xa0.001), and decreased crypt density (Pxa0< .001) were significantly higher in active ulcerative colitis compared with inactive ulcerative colitis and control subjects. A decrease in histopathologic score after medical treatment escalation was correlated with improvement in crypt tortuosity (rsxa0= .35, Pxa0= .016), distortion of crypt openings (rsxa0= .30, Pxa0= .045), and decreased crypt density (rsxa0= .33, Pxa0= .026) but not in other features.nnnCONCLUSIONSnCLE is an emerging endoscopic technique that reproducibly identifies mucosal changes in ulcerative colitis. With the exception of crypt changes, endomicroscopic features appear to improve slowly with time after medical treatment. (nnnCLINICAL TRIAL REGISTRATION NUMBERnNCT01684514.).

Confocal Laser Endomicroscopy in Inflammatory Bowel Disease--A Systematic Review.

BACKGROUND AND AIMSnConfocal laser endomicroscopy is an endoscopic method that provides in vivo real-time imaging of the mucosa at a cellular level, elucidating mucosal changes that are undetectable by white light endoscopy. This paper systematically reviews current indications and perspectives of confocal laser endomicroscopy for inflammatory bowel disease.nnnMETHODSnAvailable literature was searched systematically for studies applying confocal laser endomicroscopy in Crohns disease or ulcerative colitis. Relevant literature was reviewed and only studies reporting original clinical data were included. Next, eligible studies were analysed with respect to several parameters, such as technique and clinical aim and definitions of outcomes.nnnRESULTSnConfocal laser endomicroscopy has been used for a wide range of purposes in inflammatory bowel disease, covering assessment of inflammatory severity, prediction of therapeutic response and relapse and adenoma surveillance in patients with ulcerative colitis. Methods for measurement of the histological changes ranged from subjective grading to objective quantification analysed by computer-aided models. The studies derived their conclusions from assessment of histological features such as colonic crypts, epithelial gaps and epithelial leakiness to fluorescein.nnnCONCLUSIONSnConfocal laser endomicroscopy remains an experimental but emerging tool for assessment of inflammatory bowel disease. It is the only method that enables in vivo functional assessment of intestinal barrier function. There is great heterogeneity in the literature and no single approach has been validated and reproduced to the level of general acceptance.

A Role for Thiopurine Metabolites in the Synergism Between Thiopurines and Infliximab in Inflammatory Bowel Disease

BackgroundnInteractions between principal cytotoxic thiopurine metabolites, that is 6-thioguanine nucleotides [6-TGN], and infliximab [IFX] and anti-IFX antibodies [Abs] may contribute to higher effectiveness of IFX-thiopurine combination therapy than monotherapies in inflammatory bowel disease.nnnMethodsnTo examine if thiopurine metabolites influenced trough IFX and anti-IFX Abs, 89 patients previously assessed for anti-IFX Abs were included. To assess if IFX influenced thiopurine metabolites, eight patients who had responded to 12 weeks of intensified IFX at a constant thiopurine dosing were included.nnnResultsnIn the first cohort, IFX-thiopurine combination therapy reduced anti-IFX Ab detection [8/40; 20%] as compared with IFX monotherapy [22/49; 45%], odds ratio [OR] 0.31 [0.12-0.80], p < 0.05. 6-TGN was significantly lower in anti-IFX Ab-positive patients (50 pmol/8 × 108 red blood cells [RBC] vs 105, p < 0.01). All anti-IFX Ab-positive patients had 6-TGN < 117 pmol/8 × 108 RBC (sensitivity 100% [63-100], specificity 47% [29-65], area under the curveROC = 0.82, p < 0.01). Trough IFX was similar between anti-IFX Ab-negative patients in IFX monotherapy and IFX-thiopurine combination therapy [5.1 μg/mL vs 4.9, p = 0.76]. 6-TGN and IFX did not correlate [rP = 0.04, p = 0.83; rS = 0.02, p = 0.89, respectively]. In the second cohort, trough IFX increased during IFX intensification [ΔIFX median 6.5 μg/mL, p = 0.02], but 6-TGN was stable [6-TGN at Weeks 0, 4, 8, 12: 90 pmol/8 × 108 RBC, 93, 101, 90; p > 0.05]. Methylated mercaptopurine metabolite associations were consistently negative.nnnConclusionsnSuperior effect of IFX-thiopurine combination therapy over monotherapies partly relates to decrease in anti-IFX Abs, which associates with 6-TGN levels and has a lower therapeutic threshold than during thiopurine monotherapy. Additional benefit likely ascribes to synergy between different anti-inflammatory modes of action rather than direct drug interactions.

Biodegradable stents for the treatment of bowel strictures in Crohn's disease: technical results and challenges

Background and study aims: In patients with Crohn’s disease, the idea of biodegradable stents for treatment of bowel strictures with limited effect of endoscopic balloon dilation is tempting and initial results have been promising. The aim of this study was to evaluate the technical and clinical success of biodegradable stents for treatment of inflamed Crohn’s strictures refractory to endoscopic balloon dilatation. Patients and methods: Consecutive patients treated with biodegradable stents due to Crohn’s disease and inflamed bowel strictures refractory to endoscopic balloon dilatation were included. Technical and clinical success were evaluated. Results: Six patients were included in the study. Technical success was obtained in five patients (83u200a%). Clinical success was limited to one patient (20u200a%); failure was observed due to mucosal overgrowth (nu200a=u200a2), stent migration (nu200a=u200a1), and stent collapse (nu200a=u200a1). Conclusions: In Crohn’s disease, it is technically feasible to treat bowel strictures with biodegradable stents. However, we have stopped using biodegradable stents due to lack of clinical success and side effects such as mucosal overgrowth and stent collapse.

Comment on ‘Predicting the response to infliximab from trough serum levels’

We read with great interest the commentary by Rutgeerts et al 1 on the value of predicting patient responses from trough serum levels of monoclonal antibodies (mAbs) against tumour necrosis factor-α (TNF). In fact, we have proposed therapeutic monitoring for rational use of anti-TNF mAb for quite some time.2nnThe authors point to the importance of low drug trough levels and ask how this can be explained in the absence of anti-drug antibodies (ADAs). They also pose the question whether ADAs are not always detected by routine assays. From experience with anti-TNF-treated patients with rheumatoid arthritis (RA) and Crohns disease (CD), we can say that standard solid-phase assays (ELISAs) often fail to detect ADA because of high background values, matrix effects, for example epitope masking, and inability to detect ADA in the presence of the drug itself. Furthermore, …

Vitamin D and Inflammatory Bowel Disease: Mendelian Randomization Analyses in the Copenhagen Studies and UK Biobank

ContextnVitamin D may be a modifiable risk factor for inflammatory bowel disease (IBD).nnnObjectivesnWe tested the hypothesis that plasma 25-hydroxyvitamin D levels are causally associated with risk of Crohn disease (CD) and ulcerative colitis (UC).nnnDesign, Setting, Patients, and InterventionsnWe used a Mendelian randomization design to study 120,013 individuals from the Copenhagen City Heart Study, the Copenhagen General Population Study, and a Copenhagen-based cohort of patients with IBD. Of these, 35,558 individuals had plasma 25-hydroxyvitamin D measurements available, and 115,110 were genotyped for rs7944926 and rs11234027 in DHCR7 and rs10741657 and rs12794714 in CYP2R1, all variants associated with plasma 25-hydroxyvitamin D levels. We identified 653 cases of CD and 1265 cases of UC, of which 58 and 113, respectively, had 25-hydroxyvitamin D measurements available. We also included genetic data from 408,455 individuals from the UK Biobank, including 1707 CD cases and 3147 UC cases.nnnMain Outcome MeasurenHazard ratios for higher plasma 25-hydroxyvitamin D levels.nnnResultsnThe multivariable-adjusted hazard ratios for 10 nmol/L higher 25-hydroxyvitamin D level were 1.04 (95% CI: 0.93 to 1.16) for CD and 1.13 (95% CI: 1.06 to 1.21) for UC. A combined 25-hydroxyvitamin D allele score was associated with a 1.4-nmol/L increase in plasma 25-hydroxyvitamin D level and hazard ratios of 0.98 (95% CI: 0.94 to 1.03) for CD and 1.01 (95% CI: 0.97 to 1.05) for UC. Combining genetic data from the Copenhagen studies and the UK Biobank, genetically determined vitamin D did not appear to influence the risk of CD or UC.nnnConclusionsnOur results do not support a major role for vitamin D deficiency in the development of IBD.

Interactions Between Thiopurine Metabolites, Adalimumab, and Antibodies Against Adalimumab in Previously Infliximab-Treated Patients with Inflammatory Bowel Disease

BackgroundInteractions between thiopurines and infliximab presumably contribute to superior effect of infliximab–thiopurine combination therapy in patients with inflammatory bowel disease (IBD). We examined whether principal cytotoxic thiopurine metabolites influence adalimumab (ADL) and anti-ADL antibodies (Abs).MethodsNinety-eight IBD patients previously treated with infliximab (96%) in whom trough ADL and anti-ADL Abs had been assessed as part of their clinical care were included. Thiopurine metabolites [6-thioguanine nucleotides (6-TGN) and methylated mercaptopurine metabolites (6-MeMP)] were determined at similar time points.ResultsADL–thiopurine combination therapy was not associated with reduced anti-ADL Ab positivity compared to ADL monotherapy: 8/31 (26%) versus 19/67 (28%), pu2009=u20091.00. Concentrations of thiopurine metabolites were similar in anti-ADL Ab-positive and negative patients (6-TGN median 109xa0pmol/8xa0×xa0108 RBC vs. 112, pu2009=u20090.80; 6-MeMP 448 RBC vs. 720, pu2009=u20090.94). ADL trough levels did not differ between anti-ADL Ab-negative patients on ADL–thiopurine combination therapy and those on monotherapy (9.5xa0μg/mL vs. 7.6, pu2009=u20090.31). ADL levels were also comparable between patients on ADL mono- and combination therapy after stratification for 6-TGN/6-MeMP quartiles. There were no correlations between levels of 6-TGN and ADL (rPu2009=u2009−u20090.17, pu2009=u20090.45; rSu2009=u2009−u20090.38, pu2009=u20090.08), or 6-MeMP and ADL (rPu2009=u2009−u20090.23, pu2009=u20090.31; rSu2009=u2009−u20090.35, pu2009=u20090.11). Anti-ADL Ab positivity was associated with ADL treatment failure (OR 6 [2–20], pu2009<u20090.01). Higher trough ADL (9.6xa0μg/mL vs. 7.3, pu2009<u20090.05), but not concomitant thiopurine treatment, metabolite levels, or dosage, was associated with clinical remission.ConclusionEffectiveness of ADL therapy associated with circulating ADL levels and anti-ADL Ab formation. In this study, there appeared no direct interactions between thiopurine metabolites and ADL or anti-ADL Abs.