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ObjectiveEarlier studies on antibiotics exposure and development of IBD (Crohn’s disease (CD) and ulcerative colitis (UC)) may have been biased by familial factors and gastroenteritis. We aimed to estimate the association between antibiotics during pregnancy or infantile age and very early onset (VEO) IBD.DesignIn this cohort study of 827 239 children born in Sweden between 2006 and 2013, we examined the link between exposure to systemic antibiotics and VEO-IBD (diagnosis <6 years of age), using Cox proportional hazard regression models. Information on antibiotics and IBD was retrieved from the nationwide population-based Swedish Prescribed Drug Register and the National Patient Register. We specifically examined potential confounding from parental IBD and gastroenteritis.ResultsChildren exposed to antibiotics during pregnancy were at increased risk of IBD compared with general population controls (adjusted HR (aHR) 1.93; 95% CI 1.06 to 3.50). Corresponding aHRs were 2.48 (95% CI 1.01 to 6.08) for CD and 1.25 (95% CI 0.47 to 3.26) for UC, respectively. For antibiotics in infantile age, the aHR for IBD was 1.11 (95% CI 0.57 to 2.15); for CD 0.72 (95% CI 0.27 to 1.92) and 1.23 (95% CI 0.45 to 3.39) for UC. Excluding children with gastroenteritis 12 months prior to the first IBD diagnosis retained similar aHR for antibiotics during pregnancy and CD, while the association no longer remained significant for IBD.ConclusionWe found that exposure to antibiotics during pregnancy, but not in infantile age, is associated with an increased risk of VEO-IBD regardless of gastroenteritis. The risk increase for exposure in pregnancy may be due to changes in the microbiota.

To determine the risk of inflammatory bowel disease (IBD) in patients with celiac disease (CeD) (and vice versa) compared to general-population comparators. Using Swedish histopathology and healthcare register data, we identified 48,551 patients with CeD and 83,529 with IBD diagnosed in 1969-2016. Each patient was compared to age- and sex-matched general-population comparators (CeD: n=240,136; IBD: n=408,195). Cox regression estimated hazard ratios (HRs) for IBD in CeD patients and vice versa. Our main analyses were limited to events beyond the first year of follow-up to reduce potential surveillance bias. During follow-up, 784 (1.6%) CeD patients were diagnosed with IBD compared to 1015 (0.4%) matched comparators. In CeD patients the HR for IBD was 3.91 (95%CI 3.56-4.31), with largely similar HRs for Crohn's disease (4.36; 3.72-5.11) and ulcerative colitis (3.40; 3.00-3.85). During follow-up, 644 (0.8%) IBD patients and 597 (0.1%) comparators were diagnosed with CeD. The HR for CeD in IBD patients was 5.49 (95%CI 4.90-6.16), with the highest risk estimates seen in ulcerative colitis (HR=6.99; 6.07-8.05), the HR for Crohn's disease was 3.31 (2.69-4.06).In patients with CeD and IBD the diagnostic interval was usually <1 year; however, HRs of 3-4 were seen even after 10 years of follow-up. During 20 years of follow-up, 2.5% of CeD patients developed incident IBD and 1.3% of IBD patients developed CeD. The bidirectional association between CeD diagnosis and IBD warrants attention in the initial assessment and follow-up of these conditions. Their co-occurrence, independent of temporal sequence, suggests shared etiology.

BackgroundReal-world data on starting intravenous (IV) vedolizumab (VDZ) and transitioning to subcutaneous (SC) treatment in inflammatory bowel disease (IBD) are scarce.AimsTo assess treatment outcomes of patients with IBD starting IV VDZ and switching to SC VDZ in routine clinical care.MethodsAdult patients with IBD switching from IV to SC VDZ treatment between 1 March 2020 and 31 December 2021 were identified from the Swedish IBD quality register. The primary outcome was SC VDZ persistence. Secondary outcomes included clinical remission, changes in quality of life (QoL) according to EuroQual 5-Dimensions 5-Levels (EQ-5D-5L) and the Short-Health Scale (SHS) and inflammatory markers, including faecal Calprotectin (FCP).ResultsAltogether, 406 patients with IBD (Crohn's disease, n = 181; ulcerative colitis, n = 225) were identified. After a median follow-up of 30 months from starting IV VDZ treatment, the persistence rates were 98%(178/181) in Crohn's disease and 94% (211/225) in ulcerative colitis. Most patients (84%) transitioned during maintenance therapy, and the median follow-up from switch to SC VDZ was 10 months. Compared to baseline, statistically significant improvements were observed in all domains of the SHS, EQ-5D index value and visual analogue scale. Median (interquartile range) FCP concentrations (μg/g) decreased from 459 (185–1001) to 65 (26–227) in Crohn's disease (n = 45; p < 0.001) and from 646 (152–1450) to 49 (20–275) in ulcerative colitis (n = 58; p < 0.001).ConclusionInitiating IV VDZ and switching to SC treatment was associated with high persistence rates and improvements in measures of QoL and FCP. These findings are reassuring for patients who start IV VDZ and switch to SC VDZ.

The function of the Laccase domain-containing 1 ( LACC1 ) gene is unknown, but genetic variation at this locus has been reported to consistently affect the risk of Crohn's disease (CD) and leprosy. Recently, a LACC1 missense mutation was found in patients suffering from monogenic forms of CD, but also systemic juvenile idiopathic arthritis. We tested the hypothesis that LACC1 single nucleotide polymorphisms (SNPs), in addition to CD, are associated with juvenile idiopathic arthritis (JIA, non-systemic), and another major form of inflammatory bowel disease, ulcerative colitis (UC). We selected 11 LACC1 tagging SNPs, and tested their effect on disease risk in 3855 Swedish individuals from three case–control cohorts of CD, UC and JIA. We detected false discovery rate corrected significant associations with individual markers in all three cohorts, thereby expanding previous results for CD also to UC and JIA. LACC1’s link to several inflammatory diseases suggests a key role in the human immune system and justifies further characterization of its function(s).

BackgroundIrritable bowel syndrome (IBS) is the most common gastrointestinal disorder, affecting more than 10% of the general population worldwide. Although a genetic component is suspected, unambiguous susceptibility genes have so far not been identified. This study tested the hypothesis that genes contributing to epithelial barrier integrity, control of mucosal immune responses and interactions with bacteria in the gut are associated with IBS.MethodsSingle nucleotide polymorphisms (SNPs) corresponding to top signals of association with Crohn's disease at 30 known susceptibility loci were tested for their effect on IBS risk in 1992 individuals from two independent case–control cohorts from Sweden and the USA. Association tests included a conservative Bonferroni correction for multiple comparisons, and were also performed on specific subgroups of patients characterised by constipation (IBS-C), diarrhoea (IBS-D) or alternating constipation and diarrhoea (IBS-A).ResultsThe Crohn's disease risk allele rs4263839 G in the TNFSF15 gene was significantly associated with an increased risk of both IBS (p=2.2×10−5; OR 1.37) and more pronouncedly, IBS-C (p=8.7×10−7; OR 1.79) in the entire sample. Similar associations and risk effects of the same magnitude were observed in the two cohorts analysed separately. A correlation between rs4263839 genotype and TNFSF15 mRNA expression was detected both in peripheral blood and in rectal mucosal biopsies from healthy individuals (combined p=0.0033).ConclusionsTNFSF15 is a susceptibility gene for IBS and IBS constipation. As TL1A, the protein encoded by TNFSF15, contributes to the modulation of inflammatory responses, the results support a role of immune activation in IBS.

Background: Normal gastrointestinal (GI) mucosa on endoscopy has been linked to a lower risk of colorectal cancer (CRC) but its association to overall death is unknown. Methods: We identifed 466,987 individuals with a first GI biopsy 1965-2016 with normal mucosa (60.6% upper GI and 39.4% lower GI) through all Swedish pathology departments (n = 28). They were individually matched to 2,321,217 reference individuals without a GI biopsy and also compared to 505,076 full siblings. Flexible parametric models were applied to estimate hazard ratio (HRs) and 95% confidence interval (95% CI) for death. Results: During a median follow-up of ~11 years, 85,859 (18.39%) of individuals with normal mucosa and 377,653 (16.27%) of reference individuals died. This corresponded to incidence rates of 147.56/10,000 vs 127.90/10,000 person-years respectively (rate difference: 19.66/10,000 person-years), with the multivariable-adjusted HR of 1.21 (95% CI: 1.20-1.22). Excess mortality was seen for both upper and lower biopsy with normal mucosa. Particularly higher HRs for death were seen in males, individuals biopsied when aged <40 years, those without a prior record of GI disease, and those with high education. Mortality risk was most increased in the first five years after biopsy (HR = 1.34; 95% CI: 1.32-1.36) but decreased thereafter. Having a GI biopsy with normal mucosa was associated with excess mortality from cardiovascular (CVD)disease (HR = 1.02; 95% CI: 1.01-1.03), cancer (HR = 1.58; 95% CI: 1.56-1.61), GI disease (HR = 1.65; 95% CI: 1.58-1.71), and other causes (HR = 1.10; 95% CI: 1.08-1.11). Sibling comparisons yielded similar results. Conclusion: Compared with individuals without a GI biopsy, those with a normal GI biopsy due to clinical symptoms had a higher mortality particularly in the first five years after biopsy, and especially from GI disease and cancer. Keywords: normal mucosa, screening, mortality, cohort

As part of the IBD Character initiative, we examined an inception cohort and investigated mucosal microbiota composition and transcriptional activity in relation to clinical outcomes. A cohort of 237 individuals were included from five countries: Crohn's disease (CD, n = 72), ulcerative colitis (UC, n = 57), symptomatic non-IBD controls (SC, n = 78) and healthy controls (HC, n = 30). Rectal/colonic biopsies were obtained at inclusion, and DNA and RNA were extracted from the same biopsy and examined by sequencing the 16S rRNA V4 region. Beta diversity measurements separated IBD from both HC and SC. IBD and SC exhibited reduced intra-individual diversity compared with HC. When comparing taxonomy at DNA and RNA level, six bacteria were found to differ in abundance and/or transcriptional activity between IBD and symptomatic control, while there were 14 and three between symptomatic control and CD and UC, respectively. A limited number of bacterial taxa were responsible for the largest difference between presence and activity, separating patients and controls. Multiple bacterial taxa were associated with treatment escalation in both UC and CD. Machine-learning models separated IBD from symptomatic controls and treatment escalators from non-escalators (AUC >0.8). However, the differential effects were mainly driven by clinical biomarkers, such as f-calprotectin, s-albumin, and b-hemoglobin. Differences between presence and transcriptional activity were found among multiple taxa when assessing 16S rRNA at DNA and RNA level. Symptomatic controls were more similar to the IBD patients compared to HC. The analyses suggest that the mucosal microbiota carries a moderate diagnostic and predictive potential, outcompeted by f-calprotectin.

Ulcerative colitis (UC) is a risk factor for colorectal cancer (CRC). However, available studies reflect older treatment and surveillance paradigms, and most have assessed risks for incident CRC without taking surveillance and lead-time bias into account, such as by assessing CRC incidence by tumour stage, or stage-adjusted mortality from CRC. We aimed to compare both overall and country-specific risks of CRC mortality and incident CRC among patients with UC. In this population-based cohort study of 96 447 patients with UC in Denmark (n=32 919) and Sweden (n=63 528), patients were followed up for CRC incidence and CRC mortality between Jan 1, 1969, and Dec 31, 2017, and compared with matched reference individuals from the general population (n=949 207). Patients with UC were selected from national registers and included in the analysis if they had two or more records with a relevant International Classification of Disease in the patient register (in the country in question) or one such record plus a colorectal biopsy report with a morphology code suggestive of inflammatory bowel disease. For every patient with UC, we selected matched reference individuals from the total population registers of Denmark and Sweden, who were matched for sex, age, birth year, and place of residence. We used Cox regression to compute hazard ratios (HRs) for incident CRC, and for CRC mortality, taking tumour stage into account. During follow-up, we observed 1336 incident CRCs in the UC cohort (1·29 per 1000 person-years) and 9544 incident CRCs in reference individuals (0·82 per 1000 person-years; HR 1·66, 95% CI 1·57–1·76). In the UC cohort, 639 patients died from CRC (0·55 per 1000 person-years), compared with 4451 reference individuals (0·38 per 1000 person-years; HR 1·59, 95% CI 1·46–1·72) during the same time period. The CRC stage distribution in people with UC was less advanced (p<0·0001) than in matched reference individuals, but taking tumour stage into account, patients with UC and CRC remained at increased risk of CRC death (HR 1·54, 95% CI 1·33–1·78). The excess risks declined over calendar periods: during the last 5 years of follow-up (2013–17, Sweden only), the HR for incident CRC in people with UC was 1·38 (95% CI 1·20–1·60, or one additional case per 1058 patients with UC per 5 years) and the HR for death from CRC was 1·25 (95% CI 1·03–1·51, or one additional case per 3041 patients with UC per 5 years). Compared with those without UC, individuals with UC are at increased risk of developing CRC, are diagnosed with less advanced CRC, and are at increased risk of dying from CRC, although these excess risks have declined substantially over time. There still seems to be room for improvement in international surveillance guidelines. The Swedish Medical Society, Karolinska Institutet, Stockholm County Council, Swedish Research Council, Swedish Foundation for Strategic Research, Independent Research Fund Denmark, Forte Foundation, Swedish Cancer Foundation.

Patients with Crohn's disease have increased work loss. We aimed to describe changes in work ability in relation to pharmacological and surgical treatments. We linked data from the Swedish National Patient Register, The Swedish Quality Register for Inflammatory Bowel Disease SWIBREG, The Prescribed Drug Register, The Longitudinal Integrated Database for Health Insurance and Labour Market Studies, and the Social Insurance Database. We identified working-age (19-59 years) patients with incident Crohn's disease 2006-2013 and population comparator subjects matched by sex, birth year, region, and education level. We assessed the number of lost workdays due to sick leave and disability pension before and after treatments. Of 3956 patients (median age 34 years, 51% women), 39% were treated with aminosalicylates, 52% with immunomodulators, 22% with TNF inhibitors, and 18% with intestinal surgery during a median follow-up of 5.3 years. Most patients had no work loss during the study period (median=0 days). For all treatments, the mean number of lost workdays increased during the months before treatment initiation, peaked during the first month of treatment and decreased thereafter, and was heavily influenced by sociodemographic factors and amount of work loss before first Crohn's disease diagnosis. The mean increase in work loss days compared to pre-therapeutic level was ~3 days during the first month of treatment for all pharmacological therapies and 11 days for intestinal surgery. Three months after treatment initiation, 88% of patients treated surgically and 90-92% of patients treated pharmacologically had the same amount of work loss as before treatment start. Median time to return to work was 2 months for all treatments. In this regular clinical setting, patients treated surgically had more lost workdays than patients treated pharmacologically, but return to work was similar between all treatments.

Background: Improved mucosal immune profiling in active and quiescent colonic inflammatory bowel disease (IBD) is needed to develop therapeutic options for treating and preventing flares. This study therefore aimed to provide a comprehensive mucosal characterization with emphasis on immunological host response of patients with active ulcerative colitis (UC active), UC during remission (UC remission) and active colonic Crohn's disease (CD active). Methods: Colonic biopsies from 47 study subjects were collected for gene expression and pathway analyses using the NanoString host-response panel, including 776 genes and 56 immune-related pathways. Results: The majority of mucosal gene expression and signaling pathway scores were increased in active IBD (n=27) compared to healthy subjects (n=10). However, both active IBD and UC remission (n=10) demonstrated decreased gene expression and signaling pathway scores related to autophagy, alpha kinase-1 and IL-17 signaling pathways compared to healthy subjects. Further, UC remission was characterized by decreased scores of several signaling pathways linked to homeostasis along with increased mononuclear cell migration pathway score as compared to healthy subjects. No major differences in the colonic mucosal gene expression between CD active (n=7) and UC (n=20) active were observed. Conclusion: This study indicates that autophagy, alpha kinase-1 and IL-17 signaling pathways are persistently downregulated in UC irrespective of disease activity. Further, UC patients in remission present a unique mucosal environment, potentially preventing patients from reaching and sustaining true homeostasis. These findings may enable better comprehension of the remitting and relapsing pattern of colonic IBD and guide future treatment and prevention of flares. Keywords: inflammatory bowel diseases, gene expression, mucosal transcriptome, homeostasis, host response