A comprehensive metabolite fingerprint of fibrostenosis in patients with Crohn's disease.

Intestinal fibrostenosis in patients with Crohn's disease (CD) is a common and untreatable comorbidity that is notoriously difficult to monitor. We aimed to find metabolites associated with the presence of fibrostenosis in patients with CD using targeted and untargeted metabolomics analyses of serum and primary cell cultures using hyphenated ultra-high performance liquid chromatography high-resolution mass spectrometry. Targeted metabolomics revealed 11 discriminating metabolites in serum, which were enriched within the arginine and proline metabolism pathway. Based on untargeted metabolomics and discriminant analysis, 166 components showed a high predictive value. In addition, human intestinal fibroblasts isolated from stenotic tissue were characterized by differential levels of medium-chain dicarboxylic acids, which are proposed as an energy source through beta-oxidation, when oxidative phosphorylation is insufficient. Another energy providing pathway in such situations is anaerobic glycolysis, a theory supported by increased expression of hexokinase 2 and solute carrier family 16 member 1 in stenotic fibroblasts. Of interest, four (unannotated) metabolic components showed a negative correlation with hexokinase 2 gene expression. Together, this study provides a discriminative metabolic fingerprint in the serum and in intestinal fibroblasts of stenotic and non-stenotic patients with CD suggestive for increased production of building blocks for collagen synthesis and increased glycolysis.

MRI texture analysis of T2-weighted images is preferred over magnetization transfer imaging for readily longitudinal quantification of gut fibrosis.

OBJECTIVES: To investigate the value of magnetization transfer (MT) MRI and texture analysis (TA) of T2-weighted MR images (T2WI) in the assessment of intestinal fibrosis in a mouse model. METHODS: Chronic colitis was induced in mice by cyclic administration of dextran sodium sulphate (DSS) resulting in chronic inflammation and progressive bowel fibrosis. Mice underwent 7-T MR imaging at various time points. Bowel wall MT ratio (MTR) and textural features (skewness, kurtosis, entropy), extracted by a filtration histogram technique, were correlated with histopathology. Performance of both techniques were validated using antifibrotic therapy. Finally, a retrospective study was conducted in five patients with Crohn's disease (CD) who underwent bowel surgery. RESULTS: MTR and texture entropy correlated with histopathological fibrosis (r = .85 and .81, respectively). Entropy was superior to MTR for monitoring bowel fibrosis in the presence of coexisting inflammation (linear regression R2 = .93 versus R2 = .01). Furthermore, texture entropy was able to assess antifibrotic therapy response (placebo mice versus treated mice at endpoint scan; Δmean = 0.128, p < .0001). An increase in entropy was indicative of fibrosis accumulation in human CD strictures (inflammation: 1.29; mixed strictures: 1.4 and 1.48; fibrosis: 1.73 and 1.9). CONCLUSION: MT imaging and TA of T2WI can both noninvasively detect established intestinal fibrosis in a mouse model. However, TA is especially useful for the longitudinal quantification of fibrosis in mixed inflammatory-fibrotic tissue, as well as for antifibrotic treatment response evaluation. This accessible post-processing technique merits further validation as the benefits for clinical practice as well as antifibrotic trial design would be numerous. KEY POINTS: • Magnetization transfer MRI and texture analysis of T2-weighted MR images can detect established bowel fibrosis in an animal model of gut fibrosis. • Texture entropy is able to identify and monitor bowel fibrosis progression in an inflammatory context and can assess the response to antifibrotic treatment. • A proof-of-concept study in five patients with Crohn's disease suggests that texture entropy can detect and grade fibrosis in human intestinal strictures.

Anti-CD74 IgA antibodies show diagnostic potential for axial spondyloarthritis but are not associated with microscopic gut inflammation.

OBJECTIVES: Gut inflammation commonly occurs in axial SpA (axSpA), and is linked to disease activity and outcome. Given the role of IgA in mucosal immunity, we explored the association between anti-CD74 IgA antibodies, gut inflammation and axSpA. METHODS: Anti-CD74 IgA was measured by ELISA in serum samples of axSpA patients, fulfilling the 2009 Assessment of SpondyloArthritis international Society classification criteria. A group of fibromyalgia (FM) and RA patients served as non-inflammatory and inflammatory controls. Newly diagnosed axSpA patients underwent ileocolonoscopy; mucosal biopsies were histopathologically assessed as normal, acute or chronically inflamed. Optimal anti-CD74 IgA cut-off values were determined with a receiver operating characteristics curve. RESULTS: axSpA patients (n = 281) showed higher anti-CD74 IgA levels [mean (s.d.) 18.8 (12.4) U/ml] compared with 100 FM patients [10.9 (5.0) U/ml, P < 0.001] and 34 RA patients [13.7 (9.6) U/ml, P = 0.02]. The area under the receiver operating characteristics curve for diagnosis (axSpA vs FM) was 0.70, providing a sensitivity of 60% and specificity of 87% (cut-off 15 U/ml). Antibody concentrations were not significantly different between axSpA patients with (n = 40) and without (n = 69) gut inflammation (P = 0.83), yielding an area under the receiver operating characteristics curve of 0.51. Anti-CD74 IgA levels were not associated with degree of bone marrow oedema on MRI of the sacroiliac joints, CRP or any other disease-specific feature such as the use of NSAIDs or biological treatment. CONCLUSION: Serum anti-CD74 IgA is a potentially useful diagnostic biomarker for axSpA. However, antibody levels do not correlate with any phenotypical feature, including microscopic gut inflammation, suggesting this to be a disease-specific rather than an inflammatory marker.

Effect of 5-Hydroxytryptophan on Fatigue in Quiescent Inflammatory Bowel Disease: A Randomized Controlled Trial.

BACKGROUND & AIMS: Fatigue is highly prevalent among patients with inflammatory bowel disease (IBD), and only limited treatment options are available. Based on the hypothetical link between low serum tryptophan concentrations and fatigue, we determined the effect of 5-hydroxytryptophan supplementation on fatigue in patients with inactive IBD. METHODS: A multicenter randomized controlled trial was performed at 13 Belgian hospitals, including 166 patients with IBD in remission but experiencing fatigue, defined by a fatigue visual analog scale (fVAS) score of ≥5. Patients were treated in a crossover manner with 100 mg oral 5-hydroxytryptophan or placebo twice daily for 2 consecutive periods of 8 weeks. The primary end point was the proportion of patients reaching a ≥20% reduction in fVAS after 8 weeks of intervention. Secondary outcomes included changes in serum tryptophan metabolites, Functional Assessment of Chronic Illness Therapy Fatigue scale, and scores for depression, anxiety, and stress. The effect of the intervention on the outcomes was evaluated by linear mixed modeling. RESULTS: During 5-hydroxytryptophan treatment, a significant increase in serum 5-hydroxytryptophan (estimated mean difference, 52.66 ng/mL; 95% confidence interval [CI], 39.34-65.98 ng/mL; P < .001) and serotonin (3.0 ng/mL; 95 CI, 1.97-4.03 ng/mL; P < .001) levels was observed compared with placebo. The proportion of patients reaching ≥20% reduction in fVAS was similar in placebo- (37.6%) and 5-hydroxytryptophan (35.6%)-treated patients (P = .830). The fVAS reduction (-0.18; 95% CI, -0.81 to 0.46; P = .581) and Functional Assessment of Chronic Illness Therapy Fatigue scale increase (0.68; 95% CI, -2.37 to 3.73; P = .660) were both comparable between 5-hydroxytryptophan and placebo treatment as well as changes in depression, anxiety, and stress scores. CONCLUSIONS: Despite a significant increase in serum 5-hydroxytryptophan and serotonin levels, oral 5-hydroxytryptophan did not modulate IBD-related fatigue better than placebo. (Trial Registration: Belgian Federal Agency for Medication and Health Products, EudraCT number: 2017-005059-10 and ClinicalTrials.gov: NCT03574948, https://clinicaltrials.gov/ct2/show/NCT03574948.).

The Impact of Vedolizumab and Ustekinumab on Articular Extra-Intestinal Manifestations in Inflammatory Bowel Disease Patients: A Real-Life Multicentre Cohort Study.

BACKGROUND AND AIMS: Extra-intestinal manifestations are frequently reported in inflammatory bowel diseases. However, data comparing the effect of vedolizumab and ustekinumab on articular extra-intestinal manifestations are limited. The aim here was to evaluate differences in new-onset and the evolution of pre-existing joint extra-intestinal manifestations during both treatments. METHODS: An international multicentre retrospective study was performed on inflammatory bowel disease patients who started vedolizumab or ustekinumab between May 2010 and December 2020. Extra-intestinal manifestations were assessed at baseline and joint extra-intestinal manifestations were evaluated throughout the 2-year follow-up. Arthropathy was defined by joint inflammation [arthritis/sacroiliitis], diagnosed by a rheumatologist, and arthralgia as articular pain without confirmed inflammation. Additionally, skin, ocular and hepatic extra-intestinal manifestations were assessed at baseline. Uni- and multivariate analyses were performed. RESULTS: In total, 911 patients [vedolizumab: 584; ustekinumab: 327] were included. Deterioration of pre-existing arthropathy and rate of new-onset arthropathy were not significantly associated with vedolizumab over ustekinumab. Arthropathy was used as reason to stop treatment in six vedolizumab and two ustekinumab patients. The odds of developing new arthralgia within 6 months was higher in patients who took vedolizumab compared to ustekinumab (adjusted odds ratio [aOR]: 2.28 [1.01-5.15], p = 0.047). However, this effect was not sustained during the 2-year follow-up (aOR: 1.35 [0.80-2.29], p = 0.259). Deterioration of pre-existing arthralgia was comparable between ustekinumab and vedolizumab-treated patients. In two vedolizumab-treated patients arthralgia was given as the reason to stop treatment. CONCLUSIONS: Vedolizumab and ustekinumab can be used safely in patients with articular extra-intestinal manifestations. Only a temporary increased risk for developing arthralgia has been observed under vedolizumab.

Prevalence of Fatigue and Unrecognized Depression in Patients with Inflammatory Bowel Disease in Remission under Immunosuppressants and Biologicals.

BACKGROUND: Although highly prevalent among inflammatory bowel disease (IBD) patients, fatigue remains an unmet clinical need. The aim was to describe the prevalence of fatigue in an IBD population in remission and identify factors associated with fatigue. METHODS: IBD patients in clinical and biochemical remission under treatment with immunomodulators or biologicals were included. Fatigue, physical tiredness and depression were assessed using the fatigue Visual Analogue Scale (fVAS), the Shortened Fatigue Questionnaire (SFQ) and the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR), respectively. Relevant clinical and biochemical parameters were included in regression analyses to identify factors associated with physical fatigue. RESULTS: In total, 157 IBD patients were included. Up to 45.9% of patients reported fatigue, physical tiredness was observed in 51% and depression in 10.8%. The majority of patients with subclinical depression were fatigued. Female sex (OR = 4.17 [1.55-6.78], p = 0.002) was independently associated with physical fatigue. Transferrin saturation (OR = -0.11 [-0.22--0.007], p = 0.037) and treatment with adalimumab (compared to infliximab, OR = -3.65 [-7.21--0.08], p = 0.045) entailed a lower risk of fatigue. CONCLUSION: Fatigue is observed in about half of IBD patients in remission and can be a symptom of underlying undetected depression. Sex, transferrin saturation and medication were identified as independent risk factors.

Long-Term Environmental Hypoxia Exposure and Haematopoietic Prolyl Hydroxylase-1 Deletion Do Not Impact Experimental Crohn's Like Ileitis.

Environmental hypoxia and hypoxia-induced signalling in the gut influence inflammatory bowel disease pathogenesis, however data is limited to colitis. Hence, we investigated the effect of environmental hypoxia and immune cell-specific deletion of oxygen sensor prolyl hydroxylase (PHD) 1 in a Crohn's like ileitis mouse model. Therefore, 5-week-old C57/BL6 TNF∆ARE/+ mice and wildtype (WT) littermates were housed in normoxia (21% O2) or hypoxia (8% O2) for 10 weeks. Systemic inflammation was assessed by haematology. Distal ileal hypoxia was evaluated by pimonidazole staining. The ileitis degree was scored on histology, characterized via qPCR and validated in haematopoietic Phd1-deficient TNF∆ARE/+ mice. Our results demonstrated that hypoxia did not impact body weight evolution in WT and TNF∆ARE/+ mice. Hypoxia increased red blood cell count, haemoglobin, haematocrit and increased pimonidazole intensity in the ileum. Interestingly, hypoxia evoked an increase in circulatory monocytes, ileal mononuclear phagocytes and proinflammatory cytokine expression in WT mice. Despite these alterations, no histological or ileal gene expression differences could be identified between TNF∆ARE/+ mice housed in hypoxia versus normoxia nor between haematopoietic Phd1-deficient TNF∆ARE/+ and their WT counterparts. Therefore, we demonstrated for the first time that long-term environmental hypoxia or haematopoietic Phd1-deletion does not impact experimental ileitis development.

Evolution of Endoscopic Lesions in Steroid-Refractory Acute Severe Ulcerative Colitis Responding to Infliximab or Cyclosporine.

BACKGROUND/AIMS: Few data on the evolution of endoscopic findings are available in patients with acute severe ulcerative colitis (ASUC). The aim of this study was to describe this evolution in a prospective cohort. METHODS: Patients admitted for a steroid-refractory ASUC and included in a randomized trial comparing infliximab and cyclosporine were eligible if they achieved steroid-free clinical remission at day 98. Flexible sigmoidoscopies were performed at baseline, days 7, 42 and 98. Ulcerative colitis endoscopic index of severity (UCEIS) and its sub-scores - vascular pattern, bleeding and ulceration/erosion - were post-hoc calculated. Global endoscopic remission was defined by a UCEIS of 0, and partial endoscopic remission by any UCEIS sub-score of 0. RESULTS: Among the 55 patients analyzed (29 infliximab and 26 cyclosporine), 49 (83%) had UCEIS ≥6 at baseline at baseline. Partial endoscopic remission rates were higher for bleeding than for vascular pattern and for ulcerations/erosions at day 7 (20% vs. 4% and 5% (n = 55); p = .004 and p=.04), for bleeding and ulceration/erosion than for vascular pattern at day 42 [63% and 65% vs. 33% (n=54); p<.001 for both] and at day 98 [78% and 92% vs. 56% (n = 50); p = .007 and p < .001]. Global endoscopic remission rates at day 98 were higher in patients treated with infliximab than with cyclosporine [73% vs. 25% (n = 26 and 24); p < .001]. CONCLUSION: In steroid-refractory ASUC patients responding to a second-line medical therapy, endoscopic remission process started with bleeding remission and was not achieved in half the patients at day 98 for vascular pattern. Infliximab provided a higher endoscopic remission rate than cyclosporine at day 98.

Fecal Microbiota Transplantation Reduces Symptoms in Some Patients With Irritable Bowel Syndrome With Predominant Abdominal Bloating: Short- and Long-term Results From a Placebo-Controlled Randomized Trial.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder associated with intestinal dysbiosis. Given the reported promising results of open-label fecal microbiota transplantation (FMT) therapy in patients with predominant abdominal bloating, we studied efficacy of this treatment in a randomized, placebo-controlled trial. METHODS: Patients with refractory IBS, defined as failure of ≥3 conventional therapies, were randomly assigned to single-dose nasojejunal administration of donor stools (n = 43) or autologous stools (n = 19) in a double-blind study, performed from December 2015 through October 2017, and were followed up for 1 year. IBS-related symptoms were assessed by using a daily symptom diary to determine general abdominal discomfort, abdominal bloating, abdominal pain, and flatulence on a scale of 1-6. Number of daily bowel movements, consistency of the stools, and abdominal circumference were also recorded. Patients completed the IBS-specific quality of life questionnaire. Primary endpoints were improvement of IBS symptoms and bloating at 12 weeks (response). Secondary endpoints were changes in IBS symptom scores and quality of life. Stool samples were collected for microbiota amplicon sequencing. Open-label retransplantation was offered after the trial. RESULTS: At week 12, 56% of patients given donor stool reported improvement in both primary endpoints compared with 26% of patients given placebo (P = .03). Patients given donor stool had significant improvements in level of discomfort (mean reduction, 19%; median score before FMT, 3.98; range, 2.13-6.00; median score after FMT, 3.1; range, 951.29-5.90), stool frequency (mean reduction, 13%; median score before FMT, 2.10; range, 0.57-14.29; median score after FMT 1.7; range, 0.71-4.29), urgency (mean reduction, 38%; median score before FMT, 0.61; range, 0.00-1.00; median score after FMT, 0.37; range, 0.00-1.00), abdominal pain (mean reduction, 26%; median score before FMT, 3.88; range, 1.57-5.17; median score after FMT, 2.80; range, 1.14-4.94), flatulence (mean reduction, 10%; median score before FMT, 3.42; range, 0.71-6.00; median score after FMT, 3.07; range, 0.79-4.23), and quality of life (mean increase, 16%; median score before FMT 32.6; range, 11-119; median score after FMT, 43.1; range, 32.25-99). A significantly higher proportion of women given donor stool (69%) had a response than men (29%) (P = .01). Fecal samples from responders had higher diversity of microbiomes before administration of donor material than fecal samples from nonresponders (P = .04) and distinct baseline composition (P = .04), but no specific marker taxa were associated with response. After single FMT, 21% of patients given donor stool reported effects that lasted for longer than 1 year compared with 5% of patients given placebo stool. A second FMT reduced symptoms in 67% of patients with an initial response to donor stool but not in patients with a prior nonresponse. CONCLUSIONS: In a randomized trial of patients with treatment-refractory IBS with predominant bloating, FMT relieved symptoms compared with placebo (autologous transplant), although the effects decreased over 1 year. A second FMT restored the response patients with a prior response. Response was associated with composition of the fecal microbiomes before FMT; this might be used to as a biomarker to select patients for this treatment. ClinicalTrials.gov, Number: NCT02299973.

Translational research into the effects of cigarette smoke on inflammatory mediators and epithelial TRPV1 in Crohn's disease.

Crohn's disease is a pathological condition of the gastro-intestinal tract, causing severe transmural inflammation in the ileum and/or colon. Cigarette smoking is one of the best known environmental risk factors for the development of Crohn's disease. Nevertheless, very little is known about the effect of prolonged cigarette smoke exposure on inflammatory modulators in the gut. We examined the effect of cigarette smoke on cytokine profiles in the healthy and inflamed gut of human subjects and in the trinitrobenzene sulphonic acid mouse model, which mimics distal Crohn-like colitis. In addition, the effect of cigarette smoke on epithelial expression of transient receptor potential channels and their concurrent increase with cigarette smoke-augmented cytokine production was investigated. Active smoking was associated with increased IL-8 transcription in ileum of controls (p < 0,001; n = 18-20/group). In the ileum, TRPV1 mRNA levels were decreased in never smoking Crohn's disease patients compared to healthy subjects (p <0,001; n = 20/group). In the colon, TRPV1 mRNA levels were decreased (p = 0,046) in smoking healthy controls (n = 20/group). Likewise, healthy mice chronically exposed to cigarette smoke (n = 10/group) showed elevated ileal Cxcl2 (p = 0,0075) and colonic Kc mRNA levels (p = 0,0186), whereas TRPV1 mRNA and protein levels were elevated in the ileum (p = 0,0315). Although cigarette smoke exposure prior to trinitrobenzene sulphonic acid administration did not alter disease activity, increased pro-inflammatory cytokine production was observed in the distal colon (Kc: p = 0,0273; Cxcl2: p = 0,104; Il1-ß: p = 0,0796), in parallel with the increase of Trpv1 mRNA (p < 0,001). We infer that CS affects pro-inflammatory cytokine expression in healthy and inflamed gut, and that the simultaneous modulation of TRPV1 may point to a potential involvement of TRPV1 in cigarette smoke-induced production of inflammatory mediators.

Publisher Correction: Revisiting the gut-joint axis: links between gut inflammation and spondyloarthritis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Revisiting the gut-joint axis: links between gut inflammation and spondyloarthritis.

Gut inflammation is strongly associated with spondyloarthritis (SpA), as exemplified by the high prevalence of inflammatory bowel disease (IBD) and the even higher occurrence of subclinical gut inflammation in patients with SpA. The gut-joint axis of inflammation in SpA is further reinforced by similarities in immunopathogenesis at both anatomical sites and by the clinical success of therapies blocking TNF and IL-23 in IBD and in some forms of SpA. Many genetic risk factors are shared between SpA and IBD, and changes in the composition of gut microbiota are seen in both diseases. Current dogma is that inflammation in SpA initiates in the gut and leads to joint inflammation; however, although conceptually attractive, some research does not support this causal relationship. For example, therapies targeting IL-17A are efficacious in the joint but not the gut, and interfering with gut trafficking by targeting molecules such as α4ß7 in IBD can lead to onset or flares of SpA. Several important knowledge gaps remain that must be addressed in future studies. Determining the true nature of the gut-joint axis has real-world implications for the treatment of patients with co-incident IBD and SpA and for the repurposing of therapeutics from one disease to the other.

Risk of Development of More-advanced Lesions in Patients With Inflammatory Bowel Diseases and Dysplasia.

BACKGROUND & AIMS: Patients with inflammatory bowel diseases (IBD) have increased risks of dysplasia and colitis-associated cancer (CAC). We evaluated the risk of development of high-grade dysplasia (HGD) or CAC after diagnosis of dysplasia using data from a national cohort of patients with IBD. METHODS: We performed a multicenter retrospective analysis of data collected from 7 tertiary referral regional or academic centers in Belgium. In searches of IBD pathology databases, we identified 813 lesions (616 low-grade dysplasias [LGDs], 64 high-grade dysplasias [HGDs], and 133 CACs) in 410 patients with IBD: 299 had dysplasia (73%) and 111 had CAC (27%). The primary aim was to determine the risk of more-advanced lesions after diagnosis of LGD or HGD. RESULTS: Of the 287 patients with LGD, 21 (7%) developed more-advanced lesions (HGD or CAC) after a median time period of 86 months (interquartile range, 34-214). Of the 28 patients with HGD, 4 (14%) developed CAC after a median time period of 180 months (interquartile range, 23-444). The overall cumulative incidence of CAC at 10 years after an initial diagnosis of HGD was 24.3% and after an initial diagnosis of LGD was 8.5% (P < .05). Metachronous lesions, non-polypoid lesions, and colonic stricture were associated with risk of occurrence of more-advanced lesions after LGD (P < .05). Of the 630 dysplastic lesions identified during endoscopy, 545 (86%) were removed during the same procedure or during a follow-up endoscopy or by surgery. Of 111 patients with CAC, 95 (86%) did not have prior detection of dysplasia and 64 of these 95 patients (67%) developed CAC outside of the screening or surveillance period recommended by the European Crohn's and Colitis Organisation. CONCLUSIONS: In an analysis of pathology data from 7 medical centers in Belgium, we found a low rate of detection of more-advanced lesions following detection of LGD or HGD-taking into account that most of the lesions were removed. Main risk factors for development of more-advanced lesions after LGD were metachronous lesions, non-polypoid lesions, and colon strictures.

Expert consensus: practical algorithms for management of inflammatory bowel disease patients presenting with back pain or peripheral arthropathies.

BACKGROUND: Spondyloarthritis is the most frequent extra-intestinal manifestation of IBD. AIM: To present simple strategies to identify and differentiate inflammatory joint pain in IBD patients. METHODS: A panel of Belgian gastroenterologists and rheumatologists developed seven algorithms for IBD patients with joint symptoms based on a Delphi exercise conducted between April and December 2016. Here, we focus on referral strategies for patients with chronic back pain (evidence-based strategy), large joint monoarthritis, oligo- or polyarticular arthritis or arthralgia (based on expert opinion). We also present management tools for IBD patients with acute back pain and small joint monoarthritis (Supplementary file). RESULTS: The reported algorithm for IBD patients with chronic back pain uses basic clinical criteria to identify which patients should be referred to the emergency room (spondylodiscitis), physical medicine and rehabilitation (mechanical back pain) or rheumatologist (spondyloarthritis). IBD patients with large joint monoarthritis should be referred to emergency room if septic arthritis is suspected; in other patients, blood analyses and referral to a rheumatologist for articular puncture with evacuation of synovial fluid are recommended. The analysis of synovial fluid allows for identification of non-inflammatory (e.g., osteoarthritis) and inflammatory (e.g., [pseudo]-gout, peripheral spondyloarthritis and Borrelia burgdorferi arthritis) conditions. In patients with inflammatory oligoarticular or polyarticular arthralgia, erythrocyte sedimentation rate, concomitant therapies, anti-nuclear factor and anti-double-stranded DNA antibody levels should be evaluated; in anti-tumour necrosis factor-treated patients, a drug-induced lupus-like syndrome should be considered. CONCLUSION: We propose straightforward strategies for IBD patients with joint symptoms, which are specific enough to select initial treatment and referral pattern.

Long-term Clinical Effectiveness of Ustekinumab in Patients with Crohn's Disease Who Failed Biologic Therapies: A National Cohort Study.

BACKGROUND: Ustekinumab [UST] was recently approved in Europe for the treatment of moderate to severe Crohn's disease [CD]. Long-term real-world data are currently scarce for CD patients previously exposed to several biologics. METHODS: This is an observational, national, retrospective multicentre study. Patients received intravenous UST ~6 mg/kg at baseline, with 90 mg subcutaneously thereafter every 8 weeks. Response and remission rates were assessed at Weeks 8, 16, and 52. RESULTS: Data from 152 patients were analysed. All patients were exposed to at least one anti-TNFα agent, with 69.7% were exposed to even two anti-TNFα and vedolizumab. After 1 year, 42.1% and 25.7% of patients had experienced clinical response and clinical remission, respectively, and 38.8% and 24.3% had achieved steroid-free clinical response and remission, respectively; 38.8% of patients discontinued therapy during the 12 months of follow-up. Colonic location was predictive of clinical response at 1 year, and low body mass index [BMI] at baseline was a negative predictor of clinical remission. Resolution of arthralgia was associated with clinical response over time. De novo arthralgia was reported by 17.9% of patients at Week 8 and 13.5% of patients at Week 52. No impact of UST on arthralgia was observed in patients with concomitant ankylosing spondylitis [n = 17]. Others adverse events were reported in 7.2% of patients. CONCLUSIONS: This real-world cohort study confirms the effectiveness of UST in CD patients previously exposed to several biologics. Ustekinumab was well tolerated with respect to adverse events. PODCAST: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.

Feasibility study using iodine quantification on dual-energy CT enterography to distinguish normal small bowel from active inflammatory Crohn's disease.

BACKGROUND: Assessment of Crohn's disease (CD) activity is important to identify patients with active inflammation for therapy management. Quantitative analysis can provide objective measurement of disease presence. PURPOSE: To evaluate the feasibility of quantitative analysis of contrast-enhanced dual-energy computed tomography (DECT) data in detection of small bowel inflammation in patients with CD with an emphasis on iodine quantification. MATERIAL AND METHODS: DECT enterography was prospectively performed in 20 patients with active CD and in 20 healthy individuals, as the control group. Iodine overlay images were created. Wall thickness, attenuation, absolute iodine density, relative iodine density, and fat fraction were measured in the terminal ileum of all patients by two radiologists. Intraclass correlation coefficients were calculated to assess inter-rater agreement. Parameters were compared between patient groups using mixed model analysis. Receiver operating characteristic (ROC) analysis was performed. RESULTS: Both absolute and relative iodine density were significantly higher in active disease than in normal small bowel (all P < 0.001). In contrast, measurement of fat fraction was not significantly different in affected terminal ileal loops compared to normal terminal ileum ( P = 0.075). ROC analysis demonstrated a similar excellent diagnostic accuracy of wall thickness, attenuation, and absolute and relative iodine density with area under the ROC curve (AUC) values in the range of 0.96 for attenuation to 1 for relative iodine density. CONCLUSION: DECT with iodine quantification can be used in distinguishing normal small bowel from active inflammatory CD. Further research should investigate the value of iodine quantification in grading CD activity and in monitoring therapeutic response.

IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes.

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.

Efficacy of vedolizumab for induction of clinical response and remission in patients with moderate to severe inflammatory bowel disease who failed at least two TNF antagonists.

BACKGROUND: Vedolizumab is a recently available monoclonal antibody targeting α4ß7 integrin for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). OBJECTIVE: The objective of this article is to evaluate the efficacy of vedolizumab induction therapy in anti-TNF-refractory/intolerant UC and CD patients in real life. METHODS: A cohort of 149 moderately to severely active UC and CD patients who failed or showed intolerance to at least two TNF antagonists participated in a medical need program and received vedolizumab in 37 Belgian centers (April-September 2015). Rates of clinical response and remission were retrospectively evaluated at Week 10 for UC and Week 14 for CD using the physician's global assessment (PGA), Mayo score and Harvey Bradshaw index (HBI) or Crohn's disease activity score (CDAI) scores. RESULTS: Eighty-four patients (29 UC, 55 CD) had sufficient data for analysis. For UC patients, clinical response was observed in 76% based on PGA and 59% based on the Mayo score. The corresponding percentages for CD patients were 80% for PGA and 65% for HBI/CDAI. Clinical remission rates were 10% and 40% for UC and CD, respectively. Steroid-free remission was observed in respectively 10% and 35%. Globally, corticosteroids were stopped in 14 out of 48 patients (29%). No new safety signals were reported. CONCLUSION: Up to 70% TNF-refractory/intolerant UC and CD patients achieved a clinical response after 10 to 14 weeks of vedolizumab treatment in this real-life cohort.

Analysis of Genes Associated With Monogenic Primary Immunodeficiency Identifies Rare Variants in XIAP in Patients With Crohn's Disease.

BACKGROUND & AIMS: A few rare monogenic primary immunodeficiencies (PIDs) are characterized by chronic intestinal inflammation that resembles Crohn's disease (CD). We investigated whether 23 genes associated with 10 of these monogenic disorders contain common, low-frequency, or rare variants that increase risk for CD. METHODS: Common and low frequency variants in 1 Mb loci centered on the candidate genes were analyzed using meta-data corresponding to genotypes of approximately 17,000 patients with CD or without CD (controls) in Europe. The contribution of rare variants was assessed by high-throughput sequencing of 4750 individuals, including 660 early-onset and/or familial cases among the 2390 patients with CD. Variants were expressed from vectors in SW480 or HeLa cells and functions of their products were analyzed in immunofluorescence, luciferase, immunoprecipitation, and immunoblot assays. RESULTS: We reproduced the association of the interleukin 10 locus with CD (P = .007), although none of the significantly associated variants modified the coding sequence of interleukin 10. We found XIAP to be significantly enriched for rare coding mutations in patients with CD vs controls (P = .02). We identified 4 previously unreported missense variants associated with CD. Variants in XIAP cause the PID X-linked lymphoproliferative disease type 2, yet none of the carriers of these variants had all the clinical features of X-linked lymphoproliferative disease type 2. Identified XIAP variants S123N, R233Q, and P257A were associated with an impaired activation of NOD2 signaling after muramyl dipeptide stimulation. CONCLUSIONS: In a systematic analysis of variants in 23 PID-associated genes, we confirmed the association of variants in XIAP with CD. Further screenings for CD-associated variants and analyses of their functions could increase our understanding of the relationship between PID-associated genes and CD pathogenesis.