Salivary calprotectin and neutrophils in inflammatory bowel disease in relation to oral diseases.

OBJECTIVE: Calprotectin is elevated in saliva from inflammatory bowel disease (IBD) patients, but it is also affected by oral disease. We assessed the salivary concentration of calprotectin in IBD patients, in relation to intestinal and oral diseases. Furthermore, we investigated the phenotype of salivary neutrophils from IBD patients, and their ability to secrete calprotectin. MATERIALS AND METHODS: Thirty IBD patients and 26 controls were orally examined and sampled for stimulated saliva. Twenty-five IBD patients provided fresh fecal samples. Calprotectin concentrations in saliva and feces were determined by an enzyme-linked immunosorbent assay. Expression of CD11b, CD15, and CD16 on oral neutrophils was assessed by flow cytometry. Secretion of calprotectin was evaluated in cultured oral neutrophils. RESULTS: Calprotectin was significantly elevated in saliva of IBD patients compared to controls, particularly in Crohn's disease, irrespective of caries or periodontitis. Salivary calprotectin did not correlate to fecal calprotectin. CD11b expression was significantly reduced in salivary neutrophils from IBD patients. Salivary neutrophils from IBD patients tended to secrete more calprotectin than controls. CONCLUSIONS: Salivary calprotectin is elevated in IBD regardless of oral diseases. Furthermore, salivary neutrophils secrete calprotectin, and display lower CD11b expression in IBD.

Differences in Whole-Blood Transcriptional Profiles in Inflammatory Bowel Disease Patients Responding to Vedolizumab Compared with Non-Responders.

Vedolizumab is efficacious in the treatment of Crohn's disease (CD) and ulcerative colitis (UC). However, a significant proportion of patients present with a non-response. To investigate whether differences in the clinical response to vedolizumab is reflected in changes in gene expression levels in whole blood, samples were collected at baseline before treatment, and at follow-up after 10-12 weeks. Whole genome transcriptional profiles were established by RNA sequencing. Before treatment, no differentially expressed genes were noted between responders (n = 9, UC 4, CD 5) and non-responders (n = 11, UC 3, CD 8). At follow-up, compared with baseline, responders displayed 201 differentially expressed genes, and 51 upregulated (e.g., translation initiation, mitochondrial translation, and peroxisomal membrane protein import) and 221 downregulated (e.g., Toll-like receptor activating cascades, and phagocytosis related) pathways. Twenty-two of the upregulated pathways in responders were instead downregulated in non-responders. The results correspond with a dampening of inflammatory activity in responders. Although considered a gut-specific drug, our study shows a considerable gene regulation in the blood of patients responding to vedolizumab. It also suggests that whole blood is not optimal for identifying predictive pre-treatment biomarkers based on individual genes. However, treatment outcomes may depend on several interacting genes, and our results indicate a possible potential of pathway analysis in predicting response to treatment, which merits further investigation.

Inverse and Concordant Mucosal Pathway Gene Expressions in Inflamed and Non-Inflamed Ulcerative Colitis Patients: Potential Relevance to Aetiology and Pathogenesis.

Ulcerative colitis (UC) arises from a complex interplay between host and environmental factors, but with a largely unsolved pathophysiology. The pathophysiology was outlined by RNA-sequencing of mucosal biopsies from non-inflamed and inflamed colon of UC patients (14 and 17, respectively), and from 27 patients without intestinal inflammation. Genes differentially expressed (DE), or present in enriched gene sets, were investigated using statistical text analysis of functional protein information. Compared with controls, inflamed and non-inflamed UC mucosa displayed 9360 and 52 DE genes, respectively. Seventy-three non-pseudogenes were DE relative to both gender and inflammation. Mitochondrial processes were downregulated in inflamed and upregulated in non-inflamed UC mucosa, whereas angiogenesis and endoplasmic reticulum (ER) stress were upregulated in both tissue states. Immune responses were upregulated in inflamed mucosa, whereas the non-inflamed UC mucosa presented both up- and downregulated gene sets. DE and enriched genes overlapped with genes present in inflammatory bowel disease genome-wide associated loci (p = 1.43 × 10-18), especially regarding immune responses, respiratory chain, angiogenesis, ER stress, and steroid hormone metabolism. Apart from confirming established pathophysiological mechanisms of immune cells, our study provides evidence for involvement of less described pathways (e.g., respiratory chain, ER stress, fatty-acid oxidation, steroid hormone metabolism and angiogenesis).

Clinical effectiveness of golimumab in ulcerative colitis: a prospective multicentre study based on the Swedish IBD Quality Register, SWIBREG.

OBJECTIVES: Clinical trials demonstrated that golimumab is effective in anti-TNF naïve patients with ulcerative colitis. We aimed to assess the clinical effectiveness of golimumab in a real-world setting. MATERIALS AND METHODS: This was a prospective cohort study, conducted at 16 Swedish hospitals. Data were collected using an electronic case report form. Patients with active ulcerative colitis, defined as Mayo endoscopic subscore ≥2 were eligible for inclusion. The primary outcomes were clinical effectiveness at 12 weeks and 52 weeks, i.e. response (defined as a decrease in Mayo score by ≥3 points or 30% from baseline) and remission (defined as a Mayo score of ≤2 with no individual subscores >1). RESULTS: Fifty patients were included. At study entry, 70% were previously exposed to anti-TNF, 16% to vedolizumab, and 96% to immunomodulators. The 12 and 52-week drug continuation rates were 37/50 (74%) and 23/50 (46%), respectively. The 12-week response rate was 14/50 (28%), the remission rate, 8/50 (16%) and the corresponding figures at week 52 were 13/50 (26%) and 10/50 (20%). Among patients who continued golimumab, the median Mayo score decreased from 7 (6-9) at baseline to 1 (0-5) at 52 weeks (p < .01) and the faecal calprotectin decreased from 862 (335-1759) µg/g to 90 (34-169) µg/g (p < .01). Clinical response at week 12 was highly predictive of clinical remission at week 52 (adjusted OR: 73.1; 95% CI: 4.5‒1188.9). CONCLUSIONS: The majority of golimumab treated patients represented a treatment refractory patient-group. Despite this, our results confirm that golimumab is an effective therapy in ulcerative colitis.

Whipple's disease: the great masquerader-a high level of suspicion is the key to diagnosis.

BACKGROUND: Whipple's disease is a chronic infectious disease that primarily affects the small intestine, but several organs can simultaneously be involved. The disease is caused by a gram-positive bacterium called Tropheryma whipplei. The disease is difficult to suspect because it is rare with unspecific and long-term symptoms; it can be lethal if not properly treated. CASE PRESENTATION: We here present three patients who presented with a plethora of symptoms, mainly long-standing seronegative arthritis and gastrointestinal symptoms in the form of diarrhea with blood, weight loss, fever, and lymphadenopathy. They were after extensive investigations diagnosed with Whipple's disease, in two of them as long as 8 years after the first occurrence of joint manifestations. The diagnosis was made by PCR targeting the T. whipplei 16S rRNA gene from small bowel specimen in all three patients, and, besides from histopathologic findings from the duodenum and distal ileum in one and mesenteric lymph nodes in another patient. CONCLUSIONS: This report aims to raise awareness of a very rare disease that presents with a combination of symptoms mimicking other and significantly more common diseases.

Effects of Tumor Necrosis Factor Antagonists in Patients With Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: Few patients with primary sclerosing cholangitis (PSC) and inflammatory bowel diseases (IBDs) are exposed to tumor necrosis factor (TNF) antagonists because of the often mild symptoms of IBD. We assessed the effects of anti-TNF agents on liver function in patients with PSC and IBD, and their efficacy in treatment of IBD. METHODS: We performed a retrospective analysis of 141 patients with PSC and IBD receiving treatment with anti-TNF agents (infliximab or adalimumab) at 20 sites (mostly tertiary-care centers) in Europe and North America. We collected data on the serum level of alkaline phosphatase (ALP). IBD response was defined as either endoscopic response or, if no endoscopic data were available, clinical response, as determined by the treating clinician or measurements of fecal calprotectin. Remission was defined more stringently as endoscopic mucosal healing. We used linear regression analysis to identify factors associated significantly with level of ALP during anti-TNF therapy. RESULTS: Anti-TNF treatment produced a response of IBD in 48% of patients and remission of IBD in 23%. There was no difference in PSC symptom frequency before or after drug exposure. The most common reasons for anti-TNF discontinuation were primary nonresponse of IBD (17%) and side effects (18%). At 3 months, infliximab-treated patients had a median reduction in serum level of ALP of 4% (interquartile range, reduction of 25% to increase of 19%) compared with a median 15% reduction in ALP in adalimumab-treated patients (interquartile range, reduction of 29% to reduction of 4%; P = .035). Factors associated with lower ALP were normal ALP at baseline (P < .01), treatment with adalimumab (P = .090), and treatment in Europe (P = .083). CONCLUSIONS: In a retrospective analysis of 141 patients with PSC and IBD, anti-TNF agents were moderately effective and were not associated with exacerbation of PSC symptoms or specific side effects. Prospective studies are needed to investigate the association between use of adalimumab and reduced serum levels of ALP further.

Suppression of Aiolos and Ikaros expression by lenalidomide reduces human ILC3-ILC1/NK cell transdifferentiation.

The Ikaros family of transcription factors (TFs) are important regulators of lymphocyte function. However, their roles in human innate lymphoid cell (ILC) function remain unclear. Here, we found that Ikaros (IKZF1) is expressed by all ILC subsets, including NK cells, in blood, tonsil, and gut, while Helios (IKZF2) is preferentially expressed by ILC3 in tonsil and gut. Aiolos (IKZF3) followed the expression pattern of T-bet and Eomes, being predominantly expressed by ILC1 and NK cells. Differentiation of IFN-γ-producing ILC1 and NK cells from ILC3 by IL-1ß plus IL-12-stimulation was associated with upregulation of T-bet and Aiolos. Selective degradation of Aiolos and Ikaros by lenalidomide suppressed ILC1 and NK cell differentiation and expression of ILC1 and NK cell-related transcripts (LEF1, PRF1, GRZB, CD244, NCR3, and IRF8). In line with reduced ILC1/NK cell differentiation, we observed an increase in the expression of the ILC3-related TF Helios, as well as ILC3 transcripts (TNFSF13B, IL22, NRP1, and RORC) and in the frequency of IL-22 producing ILC3 in cultures with IL-1ß and IL-23. These data suggest that suppression of Aiolos and Ikaros expression inhibits ILC1 and NK cell differentiation while ILC3 function is maintained. Hence, our results open up for new possibilities in targeting Ikaros family TFs for modulation of type 1/3 immunity in inflammation and cancer.

Rapid weight gain in infliximab treated Crohn's disease patients is sustained over time: real-life data over 12 months.

BACKGROUND: Infliximab (IFX) is used in active Crohn's disease for induction and maintenance of remission. There are scanty data on weight gain in IBD-patients under anti-TNF treatment. We investigated changes in weight and blood chemistry in anti-TNF-naïve Crohn's disease patients during their first course of IFX. METHODS: Retrospective analysis of 110 patients (77 men, 33 women) aged 34 years (range 14-73), 54 with luminal and 56 with fistulising disease, given at least 3 infusions of IFX (range 3-11). Data regarding body weight, height, C-reactive protein (CRP), haemoglobin and S-albumin at baseline, before the third infusion, at three months and at 12 months were collected. RESULTS: At 6 weeks, 65 (59%) increased in weight, 73% and 76% at three and 12 months, respectively. There was an increase in median weight (1.7 kg, IQR = 3.1 kg) and BMI (0.5 kg/m2, IQR = 1.2 kg/m2) at 6 weeks, which persisted at three and 12 months (all p < .001). There was no difference between men and women. Young patients, patients with underweight or fistulising disease increased most in weight. Disease activity assessed by PGA and SES-CD decreased at all time points (p < .05). Increases in weight and BMI correlated with an increase in serum albumin and a decrease in CRP. CONCLUSION: Approximately 60% of Crohn's disease patients experience weight gain within the first six weeks of infliximab treatment. The weight increment correlates with improvements in inflammatory markers and disease activity. The causes of weight gain may be related to treatment induced metabolic changes and reduced inflammatory burden.

Short and long-term efficacy of adalimumab in ulcerative colitis: a real-life study.

Objective: Randomized controlled trials have shown the effectiveness of Adalimumab in ulcerative colitis. However, real-life data is scarce. We aimed to assess the effectiveness and predictive factors of effectiveness in a large Swedish cohort.Methods: Retrospective capture of data from local registries at five Swedish IBD centers. Clinical response and remission rates were assessed at three months after starting adalimumab treatment and patients were followed until colectomy or need for another biological. Bio-naive patients were compared to bio experienced patients. Factors associated with short term responses were assessed using logistic regression model. Failure on drug was assessed using a Cox proportional hazards regression model.Results: 118 patients (59 males, 59 females) with median age 34.4 years (IQR 27.0-51.4) were included. Median disease duration was 4.3 years (IQR 2.0-9.0) and follow-up 1.27 years (IQR 0.33-4.1). A clinical corticosteroid-free remission was achieved by 38/118 (32.2%) and response by 91/118 (77%) after three months. CRP >3 mg/l at baseline was predictive of short-term failure to reach corticosteroid-free remission. Factors associated with survival on the drug were male gender, CRP <3 mg/l and absence of primary sclerosing cholangitis. Patients >42 years of age at diagnosis were more likely to respond to adalimumab and remain on treatment compared to patients <20 years.Conclusions: An elevated CRP-level, primary sclerosing cholangitis and female gender were predictors of treatment failure. In contrast older age at diagnosis was a predictor of short-term clinical response and drug survival. Prior infliximab failure, regardless of cause, did not influence the outcome of adalimumab treatment.

Vitamin D downregulates the IL-23 receptor pathway in human mucosal group 3 innate lymphoid cells.

BACKGROUND: Vitamin D deficiency is a risk factor for inflammatory bowel disease (IBD). The IL-23-driven tissue-resident group 3 innate lymphoid cells (ILC3s) play essential roles in intestinal immunity, and targeting IL-23/12 is a promising approach in IBD therapy. OBJECTIVE: We set out to define the role of 1α,25-dihydroxy vitamin D3 (1,25D) in regulating functional responses of human mucosal ILC3s to IL-23 plus IL-1ß stimulation. METHODS: Transcriptomes of sorted tonsillar ILC3s were assessed by using microarray analysis. ILC3 cytokine production, proliferation, and differentiation were determined by means of flow cytometry, ELISA, and multiplex immunoassay. Intestinal cell suspensions and ILC3s sorted from gut biopsy specimens of patients with IBD were also analyzed along with plasma 25-hydroxy vitamin D3 (25D) detection. RESULTS: ILC3s stimulated with IL-23 plus IL-1ß upregulated the vitamin D receptor and responded to 1,25D with downregulation of the IL-23 receptor pathway. Consequently, 1,25D suppressed IL-22, IL-17F, and GM-CSF production from tonsillar and gut ILC3s. In parallel, 1,25D upregulated genes linked to the IL-1ß signaling pathway, as well as the IL-1ß-inducible cytokines IL-6, IL-8, and macrophage inflammatory protein 1α/ß. The 1,25D-triggered skewing in ILC3 function was not accompanied or caused by changes in viability, proliferation, or phenotype. Finally, we confirmed low 25D plasma levels in patients with IBD with active inflammation. CONCLUSION: In light of the beneficial targeting of IL-23/12 in patients with IBD, 1,25D appears as an interesting therapeutic agent that inhibits the IL-23 receptor pathway, providing a novel mechanism for how ILC3s could be manipulated to regulate intestinal inflammation.

Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS: We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. RESULTS: Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 41-50 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P < .001 and HR, 0.90; P = .03, respectively) and malignancy (HR, 0.68; P = .008 and HR, 0.77; P = .004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P < .001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P = .002 and HR, 0.68; P < .001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P < .001 and adjusted HR for women, 0.48; P = .003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn's disease (HR, 1.56; P < .001) or no IBD (HR, 1.15; P = .002). CONCLUSIONS: In an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients with PSC and select patients for clinical trials.

Infliximab restores colonic barrier to adherent-invasive E. coli in Crohn's disease via effects on epithelial lipid rafts.

OBJECTIVE: Infliximab is important in the therapeutic arsenal of Crohn's disease (CD). However, its effect on mucosal barrier function is not fully understood. Adherent-invasive Escherichia coli (AIEC) are important in CD pathophysiology, but the transmucosal uptake routes are partly unknown. We investigated effects of infliximab on uptake of colon-specific AIEC HM427 across CD colonic mucosa. MATERIALS AND METHODS: Endoscopic biopsies from non-inflamed colon of seven patients with CD, before and after two infliximab infusions, and eight non-inflammation controls, were mounted in Ussing chambers. Paracellular permeability (51Cr-EDTA) and transmucosal passage of GFP-expressing HM427 were studied. Mechanisms of HM427 transepithelial transport were investigated in Caco-2 monolayers treated with TNF, in the presence of infliximab and/or endocytosis inhibitors. RESULTS: Before infliximab treatment, colonic passage of HM427 [CD: 2475 CFU (450-3000); controls 1163(225-1950)] and 51Cr-EDTA permeability were increased in CD (p < .05), but were restored to control levels by infliximab (CD: 150 (18.8-1069)). In TNF-exposed Caco-2 monolayers HM427 transport and lipid rafts/HM427 co-localization was decreased by infliximab. The lipid raft inhibitor methyl-ß-cyclodextrin decreased HM427 transport. CONCLUSION: Infliximab restored the colonic barrier to AIEC in CD; an effect partially mediated by blocking lipid rafts in epithelial cells. This ability likely contributes to infliximab's clinical efficacy in colonic CD.

Genetic Variation and Gene Expression Levels of Tight Junction Genes Indicates Relationships Between PTEN as well as MAGI1 and Microscopic Colitis.

BACKGROUND AND AIM: Microscopic colitis (MC) has been associated with increased paracellular permeability. Therefore, we aimed to investigate potential associations between MC and several genes encoding tight junction (TJ) proteins reported to interact with each other. METHODS: The association between MC and single nucleotide polymorphisms (SNP; n = 63) within TJ genes (F11R, MAGI1, MAGI2, MAGI3, PARD3, PTEN, and TJP1) were investigated in a case-control study (n MC patients = 104 and n controls = 423). The genes that exhibited an association with MC were further investigated for gene expression related to genotype, MC phenotype, and gender using colonic biopsies from MC patients (n = 25) and controls (n = 58). RESULTS: Based on the number of investigated genes and after correction for multiple testing, an association was detected between a SNP marker in PTEN (rs1234224) and both MC overall (OR = 1.70, 95% CI 1.23-2.34, p = 0.001) and collagenous colitis (CC; OR = 1.79, 95% CI 1.22-2.62, p = 0.003). Further, SNP markers in MAGI1 (rs17417230) and F11R (rs790055) were associated with MC overall (OR = 1.58, 95% CI 1.14-2.19, p = 0.006) and with CC (OR = 2.58, 95% CI 1.27-5.25, p = 0.007), respectively. However, none of the associated SNPs contributed markedly to the expression of the respective genes. Nonetheless, decreased MAGI1 (p = 3.47 × 10-4) and PTEN (p = 0.004) expression was associated with lymphocytic colitis (LC) and CC, respectively, compared to controls. CONCLUSIONS: Decreased expression of PTEN and MAGI1 in the colonic mucosa might contribute to the pathogenesis of MC and its sub-phenotypes. Furthermore, our study indicates that genetic variants of TJ components are predisposing factors in the etiology of MC. Finally, F11R, MAGI1, and PTEN are new candidate genes that exhibit an association with MC.

Dense genotyping of immune-related loci identifies HLA variants associated with increased risk of collagenous colitis.

OBJECTIVE: Collagenous colitis (CC) is a major cause of chronic non-bloody diarrhoea, particularly in the elderly female population. The aetiology of CC is unknown, and still poor is the understanding of its pathogenesis. This possibly involves dysregulated inflammation and immune-mediated reactions in genetically predisposed individuals, but the contribution of genetic factors to CC is underinvestigated. We systematically tested immune-related genes known to impact the risk of several autoimmune diseases for their potential CC-predisposing role. DESIGN: Three independent cohorts of histologically confirmed CC cases (N=314) and controls (N=4299) from Sweden and Germany were included in a 2-step association analysis. Immunochip and targeted single nucleotide polymorphism (SNP) genotype data were produced, respectively, for discovery and replication purposes. Classical human leucocyte antigen (HLA) variants at 2-digit and 4-digit resolution were obtained via imputation from single marker genotypes. SNPs and HLA variants passing quality control filters were tested for association with CC with logistic regression adjusting for age, sex and country of origin. RESULTS: Forty-two markers gave rise to genome-wide significant association signals, all contained within the HLA region on chromosome 6 (best p=4.2×10-10 for SNP rs4143332). Among the HLA variants, most pronounced risk effects were observed for 8.1 haplotype alleles including DQ2.5, which was targeted and confirmed in the replication data set (p=2.3×10-11; OR=2.06; 95% CI (1.67 to 2.55) in the combined analysis). CONCLUSIONS: HLA genotype associates with CC, thus implicating HLA-related immune mechanisms in its pathogenesis.

Long-term effectiveness of vedolizumab in inflammatory bowel disease: a national study based on the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG).

OBJECTIVES: Clinical trials have demonstrated the efficacy of vedolizumab in inflammatory bowel disease (IBD). However, these findings may not reflect the clinical practice. Therefore, we aimed to describe a vedolizumab-treated patient population and assess long-term effectiveness. MATERIALS AND METHODS: Patients initiating vedolizumab between 1 June 2014 and 30 May 2015 were identified through the Swedish National Quality Registry for IBD. Prospectively collected data on treatment and disease activity were extracted. Clinical remission was defined as Patient Harvey Bradshaw index <5 in Crohn's disease (CD) and Patient Simple Clinical Colitis Activity index <3 in ulcerative colitis (UC). RESULTS: Two-hundred forty-six patients (147 CD, 92 UC and 7 IBD-Unclassified) were included. On study entry, 86% had failed TNF-antagonist and 48% of the CD patients had undergone ≥1 surgical resection. After a median follow-up of 17 (IQR: 14-20) months, 142 (58%) patients remained on vedolizumab. In total, 54% of the CD- and 64% of the UC patients were in clinical remission at the end of follow-up, with the clinical activity decreasing (p < .0001 in both groups). Faecal-calprotectin decreased in CD (p < .0001) and in UC (p = .001), whereas CRP decreased in CD (p = .002) but not in UC (p = .11). Previous anti-TNF exposure (adjusted HR: 4.03; 95% CI: 0.96-16.75) and elevated CRP at baseline (adjusted HR: 2.22; 95% CI: 1.10-4.35) seemed to be associated with discontinuation because of lack of response. Female sex was associated with termination because of intolerance (adjusted HR: 2.75; 95% CI: 1.16-6.48). CONCLUSION: Vedolizumab-treated patients represent a treatment-refractory group. A long-term effect can be achieved, even beyond 1 year of treatment.

Genetic variation and expression levels of tight junction genes identifies association between MAGI3 and inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with increased intestinal permeability, which involves paracellular passage regulated through tight junctions (TJ). The aim of the study was to investigate single nucleotide polymorphisms (SNP) located in genes encoding interacting TJ proteins and corresponding expressions, in relation to IBD. METHODS: Allelic associations between TJ-related genes (F11R, MAGI1, MAGI2, MAGI3, PARD3, PTEN, and TJP1) and IBD, Crohn's disease (CD), or ulcerative colitis (UC) were investigated. PTPN22 was included since it's located in the same genetic region as MAGI3. Gene expression levels were investigated in relation to genotype, inflammatory status, phenotype, and medical treatment. RESULTS: The two strongest allelic associations were observed between IBD and SNPs in MAGI2 (rs6962966) and MAGI3 (rs1343126). Another MAGI3 SNP marker (rs6689879) contributed to increased ileal MAGI3 expression level in non-IBD controls. Furthermore, association between inflammation and decreased expression levels of MAGI3, PTEN, and TJP1 in colonic IBD as well as UC mucosa, and between inflammation and increased expression of PTPN22 in colonic IBD mucosa, was observed. CONCLUSIONS: Our findings lend support to a genetic basis for modulation of intestinal epithelial barrier in IBD, and we have identified MAGI3 as a new candidate gene for IBD.

Systemic Chemokine Levels with "Gut-Specific" Vedolizumab in Patients with Inflammatory Bowel Disease-A Pilot Study.

Vedolizumab, a gut-specific biological treatment for inflammatory bowel disease (IBD), is an antibody that binds to the α4ß7 integrin and blocks T-cell migration into intestinal mucosa. We aimed to investigate chemokine levels in serum of IBD-patients treated with vedolizumab. In this pilot study, we included 11 IBD patients (8 Crohn's disease, 3 ulcerative colitis) previously non-respondent to anti-tumor necrosis factor (TNF)-agents. Patients received vedolizumab at week 0, 2 and 6 and were evaluated for clinical efficacy at week 10. Clinical characteristics and routine laboratory parameters were obtained and patients were classified as responders or non-responders. Expression of 21 chemokines in serum was measured using Proximity Extension Assay and related to clinical outcome. At week 10, 6 out of 11 patients had clinically responded. Overall expression of CCL13 increased after treatment. In non-responders, expression of CCL13 and CXCL8 increased after treatment, and CCL20 and CXCL1 expressions were higher compared to responders. In responders, CCL28 decreased after treatment. C-reactive protein (CRP) correlated negatively with 6 chemokines before therapy, but not after therapy. Systemic CCL13 expression increases in IBD-patients after vedolizumab therapy and several chemokine levels differ between responders and non-responders. An increased CCL13-level when starting vedolizumab treatment, might indicate potential prognostic value of measuring chemokine levels when starting therapy with vedolizumab. This study provides new information on modulation of systemic chemokine levels after vedolizumab treatment.

Pregnancy and childbirth in women with autoimmune hepatitis is safe, even in compensated cirrhosis.

INTRODUCTION: Autoimmune hepatitis (AIH) is a liver disease that primarily affects women. Many become ill during childbearing age, and medication can be lifelong. Few studies exist on pregnancy outcome in women with AIH. Objectives The aim was to assess the outcome of women with AIH and their children during pregnancy and postpartum. MATERIALS AND METHODS: Sixty-four women from a well-characterised cohort with AIH filled out a questionnaire with information about their disease, miscarriage/abortion, pregnancies and potential birth defects in 2012. In 2004, 106 women answered the same questionnaire and their results were analysed along with the new questionnaires. RESULTS: One hundred and thirty-eight women have completed the questionnaire and 100 children have been born by 58 women. Fifty-seven women (41%) had cirrhosis. In 84% of the pregnancies, the AIH was stable or milder, 32% had an increase in activity postpartum. The proportion of preterm births (before week 38) was 22%, caesarean sections 17%, malformations 3%, and two children died. Twenty-three women with cirrhosis had children after diagnosis of cirrhosis but without more complications than for non-cirrhotic mothers. However, they did have a higher prevalence of caesarean sections. CONCLUSION: Pregnancy and childbirth in AIH appear to be safe for both child and mother, even in women with compensated liver cirrhosis.

Interleukin 34: a new modulator of human and experimental inflammatory bowel disease.

IBD (inflammatory bowel disease), where CD (Crohn's disease) and UC (ulcerative colitis) represent the two main forms, are chronic inflammatory conditions of the intestine. Macrophages play a central role in IBD pathogenesis and are regulated by major differentiation factors such as CSF-1 (colony-stimulating factor 1) in homoeostasis and inflammation. IL (interleukin)-34 has recently been discovered as a second ligand for CSF-1R (CSF-1 receptor). However, expression and involvement of IL-34 in IBD remain unknown. In the present paper, we investigated the expression of IL34, CSF1 and their shared receptor CSF1R in normal human ileum and colon, in inflamed and non-inflamed tissues of CD and UC patients, and in a mouse model of experimental colitis. We found distinct expression patterns of IL34 and CSF1 in ileum and colon, with higher IL34 in ileum and, in contrast, higher CSF1 in colon. Furthermore, IL34 and CSF1 expression was increased with inflammation in IBD patients and in experimental colitis. In humans, infiltrating cells of the lamina propria and intestinal epithelial cells expressed IL-34, and TNF-α (tumour necrosis factor α) regulated IL-34 expression in intestinal epithelial cells through the NF-κB (nuclear factor κB) pathway. These data demonstrate the expression pattern of IL-34 in ileum and colon and suggest IL-34 as a new modulator of inflammation in IBD.