Publications by authors named "Gerhard Rogler"

460 Publications

Effects of anti-TNF therapy and immunomodulators on anxiety and depressive symptoms in patients with inflammatory bowel disease: a 5-year analysis.

Therap Adv Gastroenterol 2021 31;14:17562848211033763. Epub 2021 Aug 31.

Department of Consultation-Liaison Psychiatry and Psychosomatic Medicine, University Hospital Zurich, Switzerland.

Background And Aims: Anxiety and depression are prevalent in patients with inflammatory bowel diseases (IBD), especially during IBD flares. IBD therapies can profoundly affect the mood of patients with IBD. We aimed to determine the long-term impact of anti-tumor necrosis factor (anti-TNF) and immunomodulators (IM) on anxiety and depressive symptoms in IBD patients.

Methods: We compared three treatment groups with IM only (group A), anti-TNF ± IM (group B) and no such therapy (group C). Patients completed the hospital anxiety and depression scale (HADS) at 1 year, 3 years, and 5 years after start of treatment.

Results: In total, 581 patients with IBD (42.9% Crohn's disease, 57.1% ulcerative colitis/IBD unclassified) participated in this study. Effects of treatment were analyzed in a mixed effects model, with and without correction for confounders. Compared with group C, group B showed a significant treatment-related improvement in both anxiety and depressive symptoms within the first 2.5 years and also thereafter. Group A showed a significant long-term improvement of anxiety and both short-term and long-term improvement in depressive symptoms. The significance of these results was maintained after correction for confounders, including corticosteroid treatment. Additionally, both groups A and B showed a significant decrease in disease activity in the first 2.5 years after start of treatment and also thereafter. Anti-TNF and IM treatment were associated with a similarly significant decrease in anxiety and depressive symptoms over an observation period of up to 5 years.

Conclusion: Besides a clear benefit for disease activity, anti-TNF and IM apparently improve the mood of patients with IBD.
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http://dx.doi.org/10.1177/17562848211033763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411653PMC
August 2021

Commensal Clostridiales strains mediate effective anti-cancer immune response against solid tumors.

Cell Host Microbe 2021 Oct 27;29(10):1573-1588.e7. Epub 2021 Aug 27.

Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Despite overall success, T cell checkpoint inhibitors for cancer treatment are still only efficient in a minority of patients. Recently, intestinal microbiota was found to critically modulate anti-cancer immunity and therapy response. Here, we identify Clostridiales members of the gut microbiota associated with a lower tumor burden in mouse models of colorectal cancer (CRC). Interestingly, these commensal species are also significantly reduced in CRC patients compared with healthy controls. Oral application of a mix of four Clostridiales strains (CC4) in mice prevented and even successfully treated CRC as stand-alone therapy. This effect depended on intratumoral infiltration and activation of CD8 T cells. Single application of Roseburia intestinalis or Anaerostipes caccae was even more effective than CC4. In a direct comparison, the CC4 mix supplementation outperformed anti-PD-1 therapy in mouse models of CRC and melanoma. Our findings provide a strong preclinical foundation for exploring gut bacteria as novel stand-alone therapy against solid tumors.
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http://dx.doi.org/10.1016/j.chom.2021.08.001DOI Listing
October 2021

Modulation of the Mucosa-Associated Microbiome Linked to the PTPN2 Risk Gene in Patients with Primary Sclerosing Cholangitis and Ulcerative Colitis.

Microorganisms 2021 Aug 17;9(8). Epub 2021 Aug 17.

Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, 8091 Zürich, Switzerland.

Gut microbiota appears to be involved in the pathogenesis of primary sclerosing cholangitis (PSC). The protein tyrosine phosphatase nonreceptor 2 (PTPN2) gene risk variant rs1893217 is associated with gut dysbiosis in inflammatory bowel disease (IBD), and PTPN2 was mentioned as a possible risk gene for PSC. This study assessed the microbial profile of ulcerative colitis (UC) patients with PSC and without PSC (non-PSC). Additionally, effects of the PTPN2 risk variant were assessed. In total, 216 mucosal samples from ileum, colon, and rectum were collected from 7 PSC and 42 non-PSC patients, as well as 28 control subjects (non-IBD). The microbial composition was derived from 16S rRNA sequencing data. Overall, bacterial richness was highest in PSC patients, who also had a higher relative abundance of the genus compared to non-PSC, as well as , , and compared to non-IBD, as well as a lower relative abundance of compared to non-PSC and non-IBD, respectively. After exclusion of patients with the PTPN2 risk variant, was higher in PSC compared to non-PSC, while, solely in colon samples, and were higher in PSC vs. non-IBD. In conclusion, this study underlines the presence of gut mucosa-associated microbiome changes in PSC patients and rather weakens the role of PTPN2 as a PSC risk gene.
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http://dx.doi.org/10.3390/microorganisms9081752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399714PMC
August 2021

The impact of colectomy on the course of extraintestinal manifestations in Swiss inflammatory bowel disease cohort study patients.

United European Gastroenterol J 2021 Aug 25. Epub 2021 Aug 25.

Department of Gastroenterology, University Hospital Zurich (USZ), University of Zurich, Zurich, Switzerland.

Background And Aims: Extraintestinal manifestations are reported to occur in up to 45% of inflammatory bowel disease (IBD) patients during the course of disease. It is unknown whether colectomy reduces the rate of de novo extraintestinal manifestations (EIMs) or impacts on severity of EIMs following a parallel versus independent disease course from underlying IBD.

Methods: Using data from the Swiss Inflammatory Bowel Disease Cohort Study we aimed to analyse the course of EIMs in ulcerative colitis (UC) and Crohn's disease (CD) patients undergoing colectomy during the cohort's prospective follow-up.

Results: One hundred and twenty-one IBD patients (33 CD, 81 UC and seven unclassified) underwent colectomy during prospective follow-up in the Swiss Inflammatory Bowel Disease Cohort Study. Within the 114 patients with UC or CD any EIM was reported in 40 (nine CD and 31 UC) patients. Activity of EIMs ceased entirely after colectomy in 21 patients (52.5%). Complete cessation of EIM after colectomy was higher in patients with UC versus CD with 58.1% versus 33.3%. After colectomy, 29 out of the 114 patients (25.4%) experienced any EIM. Two thirds of these (19 patients) represented persisting EIMs, while in one third (10 patients) EIM represented a de-novo event after colectomy. Overall, 13.5% of IBD patients developed a de-novo EIM after colectomy.

Conclusions: In IBD patients undergoing colectomy, EIMs present prior to surgery will persist in about half of patients. Complete cessation of EIM after colectomy may be less common in CD than in UC. In patients who never experienced EIMs prior to colectomy de-novo manifestations thereafter should be expected in up to one in seven patients.
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http://dx.doi.org/10.1002/ueg2.12125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435245PMC
August 2021

Extraintestinal Manifestations of Inflammatory Bowel Disease: Current Concepts, Treatment, and Implications for Disease Management.

Gastroenterology 2021 Oct 3;161(4):1118-1132. Epub 2021 Aug 3.

University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, Illinois. Electronic address:

Inflammatory bowel diseases (IBDs) are systemic diseases that manifest not only in the gut and gastrointestinal tract, but also in the extraintestinal organs in many patients. The quality of life for patients with IBD can be substantially affected by these extraintestinal manifestations (EIMs). It is important to have knowledge of the prevalence, pathophysiology, and clinical presentation of EIMs in order to adapt therapeutic options to cover all aspects of IBD. EIMs can occur in up to 24% of patients with IBD before the onset of intestinal symptoms, and need to be recognized to initiate appropriate diagnostic procedures. EIMs most frequently affect joints, skin, or eyes, but can also affect other organs, such as the liver, lung, and pancreas. It is a frequent misconception that a successful therapy of the intestinal inflammation will be sufficient to treat EIMs satisfactorily in most patients with IBD. In general, peripheral arthritis, oral aphthous ulcers, episcleritis, or erythema nodosum can be associated with active intestinal inflammation and can improve on standard treatment of the intestinal inflammation. However, anterior uveitis, ankylosing spondylitis, and primary sclerosing cholangitis usually occur independent of disease flares. This review provides a comprehensive overview of epidemiology, pathophysiology, clinical presentation, and treatment of EIMs in IBD.
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http://dx.doi.org/10.1053/j.gastro.2021.07.042DOI Listing
October 2021

Genotype-phenotype associations of polymorphisms within the gene locus of NOD-like receptor pyrin domain containing 3 in Swiss inflammatory bowel disease patients.

BMC Gastroenterol 2021 Aug 3;21(1):310. Epub 2021 Aug 3.

Department of Gastroenterology and Hepatology, University Hospital and University of Zurich, Zurich, Switzerland.

Background: Genetic variations within the regulatory region of the gene encoding NOD-like receptor pyrin domain containing 3 (NLRP3) have been associated with Crohn's Disease (CD). NLRP3 is part of the NLRP3-inflammasome that mediates the maturation of IL-1β and IL-18. Carrying the major allele of the single nucleotide polymorphisms (SNPs) rs10733113, rs4353135 and rs55646866 is associated with an increased risk for CD. We here studied the impact of these polymorphisms on clinical characteristics in patients of the Swiss IBD Cohort Study (SIBDCS).

Methods: We included 981 Crohn's disease (CD) patients and 690 ulcerative colitis (UC) patients of the SIBDCS. We analyzed whether three CD-associated NLRP3 polymorphisms have an impact on the clinical disease course in these patients.

Results: In CD patients presence of the major allele (G) of rs10733113 was associated with less surgeries and lower maximal CDAI and a similar trend was observed for rs55646866 and rs4353135. Presence of the major allele of all three SNPs was negatively correlated to maximal CDAI. In UC patients homozygous genotype for the major allele (CC) for rs55646866 was associated with a higher age at diagnosis and a higher MTWAI index. Homozygous genotype for the major allele of all three polymorphisms was associated with a higher number of ambulatory visits and longer hospital stays.

Conclusions: In CD patients presence of the major allele of all three polymorphisms was associated with markers of a less severe disease course, while in UC the homozygous genotype for all major alleles suggested a more severe disease activity.
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http://dx.doi.org/10.1186/s12876-021-01880-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336111PMC
August 2021

New Therapeutic Approach for Intestinal Fibrosis Through Inhibition of pH-Sensing Receptor GPR4.

Inflamm Bowel Dis 2021 Jul 28. Epub 2021 Jul 28.

Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.

Background: Patients suffering from inflammatory bowel diseases (IBDs) express increased mucosal levels of pH-sensing receptors compared with non-IBD controls. Acidification leads to angiogenesis and extracellular matrix remodeling. We aimed to determine the expression of pH-sensing G protein-coupled receptor 4 (GPR4) in fibrotic lesions in Crohn's disease (CD) patients. We further evaluated the effect of deficiency in Gpr4 or its pharmacologic inhibition.

Methods: Paired samples from fibrotic and nonfibrotic terminal ileum were obtained from CD patients undergoing ileocaecal resection. The effects of Gpr4 deficiency were assessed in the spontaneous Il-10-/- and the chronic dextran sodium sulfate (DSS) murine colitis model. The effects of Gpr4 deficiency and a GPR4 antagonist (39c) were assessed in the heterotopic intestinal transplantation model.

Results: In human terminal ileum, increased expression of fibrosis markers was accompanied by an increase in GPR4 expression. A positive correlation between the expression of procollagens and GPR4 was observed. In murine disease models, Gpr4 deficiency was associated with a decrease in angiogenesis and fibrogenesis evidenced by decreased vessel length and expression of Edn, Vegfα, and procollagens. The heterotopic animal model for intestinal fibrosis, transplanted with terminal ileum from Gpr4-/- mice, revealed a decrease in mRNA expression of fibrosis markers and a decrease in collagen content and layer thickness compared with grafts from wild type mice. The GPR4 antagonist decreased collagen deposition. The GPR4 expression was also observed in human and murine intestinal fibroblasts. The GPR4 inhibition reduced markers of fibroblast activation stimulated by low pH, notably Acta2 and cTgf.

Conclusions: Expression of GPR4 positively correlates with the expression of profibrotic genes and collagen. Deficiency of Gpr4 is associated with a decrease in angiogenesis and fibrogenesis. The GPR4 antagonist decreases collagen deposition. Targeting GPR4 with specific inhibitors may constitute a new treatment option for IBD-associated fibrosis.
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http://dx.doi.org/10.1093/ibd/izab140DOI Listing
July 2021

Dysbiotic microbiota interactions in Crohn's disease.

Gut Microbes 2021 Jan-Dec;13(1):1949096

Dpto Medicina Clínica, Universidad Miguel Hernández, San Juan De Alicante, Spain.

Crohn's disease (CD) is a major form of inflammatory bowel disease characterized by transmural inflammation along the alimentary tract. Changes in the microbial composition and reduction in species diversity are recognized as pivotal hallmarks in disease dynamics, challenging the gut barrier function and shaping a pathological immune response in genetically influenced subjects. The purpose of this review is to delve into the modification of the gut microbiota cluster network during CD progression and to discuss how this shift compromises the gut barrier integrity, granting the translocation of microbes and their products. We then complete the scope of the review by retracing gut microbiota dysbiosis interactions with the main pathophysiologic factors of CD, starting from the host's genetic background to the immune inflammatory and fibrotic processes, providing a standpoint on the lifestyle/exogenous factors and the potential benefits of targeting a specific gut microbiota.
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http://dx.doi.org/10.1080/19490976.2021.1949096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320851PMC
July 2021

Macrophages Compensate for Loss of Protein Tyrosine Phosphatase N in Dendritic Cells to Protect from Elevated Colitis.

Int J Mol Sci 2021 Jun 25;22(13). Epub 2021 Jun 25.

Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) plays a critical role in the pathogenesis of inflammatory bowel diseases (IBD). Mice lacking PTPN2 in dendritic cells (DCs) develop skin and liver inflammation by the age of 22 weeks due to a generalized loss of tolerance leading to uncontrolled immune responses. The effect of DC-specific PTPN2 loss on intestinal health, however, is unknown. The aim of this study was to investigate the DC-specific role of PTPN2 in the intestine during colitis development. PTPN2xCD11c mice were subjected to acute and chronic DSS colitis as well as T cell transfer colitis. Lamina propria immune cell populations were analyzed using flow cytometry. DC-specific PTPN2 deletion promoted infiltration of B and T lymphocytes, macrophages, and DCs into the lamina propria of unchallenged mice and elevated Th1 abundance during acute DSS colitis, suggesting an important role for PTPN2 in DCs in maintaining intestinal immune cell homeostasis. Surprisingly, those immune cell alterations did not translate into increased colitis susceptibility in acute and chronic DSS-induced colitis or T cell transfer colitis models. However, macrophage depletion by clodronate caused enhanced colitis severity in mice with a DC-specific loss of PTPN2. Loss of PTPN2 in DCs affects the composition of lamina propria lymphocytes, resulting in increased infiltration of innate and adaptive immune cells. However, this did not result in an elevated colitis phenotype, likely because increased infiltration of macrophages in the intestine upon loss of PTPN2 loss in DCs can compensate for the inflammatory effect of PTPN2-deficient DCs.
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http://dx.doi.org/10.3390/ijms22136820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269284PMC
June 2021

Hypoxia Reduces the Transcription of Fibrotic Markers in the Intestinal Mucosa.

Inflamm Intest Dis 2021 May 29;6(2):87-100. Epub 2021 Mar 29.

Department of Gastroenterology and Hepatology, University of Zurich, Zurich, Switzerland.

Introduction: Intestinal fibrosis, characterized by excessive deposition of extracellular matrix proteins, is a common and severe clinical complication of inflammatory bowel disease (IBD). However, the mechanisms underlying fibrosis remain elusive, and currently, there are limited effective pharmacologic treatments that target the development of fibrosis. Hypoxia is one of the key microenvironmental factors influencing intestinal inflammation and has been linked to fibrosis.

Objective: In the present study, we sought to elucidate the impact of hypoxia on fibrotic gene expression in the intestinal mucosa.

Methods: Human volunteers, IBD patients, and dextran sulphate sodium-treated mice were exposed to hypoxia, and colonic biopsies were collected. The human intestinal epithelial cell line Caco-2, human THP-1 macrophages, and primary human gut fibroblasts were subjected to hypoxia, and changes in fibrotic gene expression were assessed.

Results: Human volunteers subjected to hypoxia presented reduced transcriptional levels of fibrotic and epithelial-mesenchymal transition markers in the intestinal mucosa. IBD patients showed a trend towards a decrease in tissue inhibitor of metalloproteinase 1 protein expression. In mice, hypoxic conditions reduced the colonic expression of several collagens and matrix metalloproteinases. Hypoxic Caco-2 cells, THP-1 cells, and primary gut fibroblasts showed a significant downregulation in the expression of fibrotic and tissue remodelling factors.

Conclusions: Stabilization of hypoxia-inducible factors might represent a novel therapeutic approach for the treatment of IBD-associated fibrosis.
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http://dx.doi.org/10.1159/000513061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160569PMC
May 2021

Depressive Symptoms Predict Clinical Recurrence of Inflammatory Bowel Disease.

Inflamm Bowel Dis 2021 Jun 7. Epub 2021 Jun 7.

Neurology, Department of Biomedical Research, Bern University Hospital, University of Bern, Bern, Switzerland.

Background: Inflammatory bowel disease (IBD) patients are at high risk for depression, and depression has been shown to affect disease course. We examined interrelations between depression, genetic risk factors for depression, and IBD flares.

Method: In 1973 patients (1137 Crohn's disease, 836 ulcerative colitis) of the Swiss IBD Cohort Study (SIBDCS), depressive status (hospital anxiety and depression subscale for depression, HADS-D ≥11) was assessed on a yearly basis. We investigated the impact of depression on IBD-relevant clinical outcomes in Cox proportional hazards models. We used active disease (CDAI ≥150 or MTWAI ≥10) and 2 published composite flare definitions-FNCE (physician-reported flare, nonresponse to therapy, new complication, or extraintestinal manifestation) and AFFSST (active disease, physician-reported flare, fistula, stenosis, and new systemic therapy)-as clinical end points. Additionally, 62 preselected single nucleotide polymorphisms (SNPs) were screened for cross-sectional associations with depression, and if present, their predictive value for future depression and clinical deterioration was assessed.

Results: Depression was a strong risk factor for disease-related end points, including active disease (adjusted hazard ratio [aHR], 3.55; P < 0.001), AFFSST (aHR, 1.62; P < 0.001), and FNCE (aHR, 1.35; P = 0.019). The SNP rs2522833 was significantly associated with depression at enrollment (q = 0.059). The TC allele of rs588765 was negatively associated with the presence of depression at enrollment (q = 0.050) and after enrollment (aHR, 0.67; P = 0.035) and with fewer active disease states (aHR, 0.72; P = 0.045) during follow-up.

Conclusion: In IBD, depressive symptoms and inflammatory activity are intimately related. Depressive symptoms were a strong predictor of clinical deterioration, and genetic markers may play a role in this relationship.
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http://dx.doi.org/10.1093/ibd/izab136DOI Listing
June 2021

Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial.

Lancet 2021 Jun 3;397(10292):2372-2384. Epub 2021 Jun 3.

Department of Gastroenterology, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France. Electronic address:

Background: The global prevalence of ulcerative colitis is increasing, and induction and maintenance of remission is a crucial therapeutic goal. We assessed the efficacy and safety of filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, for treatment of ulcerative colitis.

Methods: This phase 2b/3, double-blind, randomised, placebo-controlled trial including two induction studies and one maintenance study was done in 341 study centres in 40 countries. Eligible patients were aged 18-75 years with moderately to severely active ulcerative colitis for at least 6 months before enrolment (induction study A: inadequate clinical response, loss of response to or intolerance to corticosteroids or immunosuppressants, naive to tumour necrosis factor [TNF] antagonists and vedolizumab [biologic-naive]; induction study B: inadequate clinical response, loss of response to or intolerance to any TNF antagonist or vedolizumab, no TNF antagonist or vedolizumab use within 8 weeks before screening [biologic-experienced]). Patients were randomly assigned 2:2:1 to receive oral filgotinib 200 mg, filgotinib 100 mg, or placebo once per day for 11 weeks. Patients who had either clinical remission or a Mayo Clinic Score response at week 10 in either induction study entered the maintenance study. Patients who received induction filgotinib were rerandomised 2:1 to continue their induction filgotinib regimen or to placebo. Patients who received induction placebo continued receiving placebo. The primary endpoint was clinical remission by Mayo endoscopic, rectal bleeding, and stool frequency subscores at weeks 10 and 58. For the induction studies, efficacy was assessed in all randomised patients who received at least one dose of study drug or placebo within that study. For the maintenance study, efficacy was assessed in all patients randomised to any filgotinib treatment group in the induction studies who received at least one dose of study drug or placebo in the maintenance study. Patients who received placebo throughout the induction and maintenance study were not included in the full analysis set for the maintenance study. Safety was assessed in all patients who received at least one dose of the study drug or placebo within each study. This trial is registered with ClinicalTrials.gov, NCT02914522.

Findings: Between Nov 14, 2016, and March 31, 2020, we screened 2040 patients for eligibility. 659 patients enrolled in induction study A were randomly assigned to receive filgotinib 100 mg (n=277), filgotinib 200 mg (n=245), or placebo (n=137). 689 patients enrolled into induction study B were randomly assigned to receive filgotinib 100 mg (n=285), filgotinib 200 mg (n=262), or placebo (n=142). 34 patients in induction study A and 54 patients in induction study B discontinued the study drug before week 10. After efficacy assessment at week 10, 664 patients entered the maintenance study (391 from induction study A, 273 from induction study B). 93 patients continued to receive placebo. 270 patients who had received filgotinib 100 mg in the induction study were randomly assigned to receive filgotinib 100 mg (n=179) or placebo (n=91). 301 patients who had received filgotinib 200 mg in the induction study were randomly assigned to receive filgotinib 200 mg (n=202) or placebo (n=99). 263 patients discontinued treatment in the maintenance study. At week 10, a greater proportion of patients given filgotinib 200 mg had clinical remission than those given placebo (induction study A 26·1% vs 15·3%, difference 10·8%; 95% CI 2·1-19·5, p=0·0157; induction study B 11·5% vs 4·2%, 7·2%; 1·6-12·8, p=0·0103). At week 58, 37·2% of patients given filgotinib 200 mg had clinical remission versus 11·2% in the respective placebo group (difference 26·0%, 95% CI 16·0-35·9; p<0·0001). Clinical remission was not significantly different between filgotinib 100 mg and placebo at week 10, but was significant by week 58 (23·8% vs 13·5%, 10·4%; 0·0-20·7, p=0·0420). The incidence of serious adverse events and adverse events of interest was similar between treatment groups. In the induction studies, serious adverse events occurred in 28 (5·0%) of 562 patients given filgotinib 100 mg, 22 (4·3%) of 507 patients given filgotinib 200 mg, and 13 (4·7%) of 279 patients given placebo. In the maintenance study, serious adverse events were reported in eight (4·5%) of 179 patients given filgotinib 100 mg, seven (7·7%) of 91 patients in the respective placebo group, nine (4·5%) of 202 patients in the filgotinib 200 mg group, and no patients in the respective placebo group. No deaths were reported during either induction study. Two patients died during the maintenance study; neither was related to treatment.

Interpretation: Filgotinib 200 mg was well tolerated, and efficacious in inducing and maintaining clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis.

Funding: Gilead Sciences.
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http://dx.doi.org/10.1016/S0140-6736(21)00666-8DOI Listing
June 2021

Type D personality is associated with depressive symptoms and clinical activity in inflammatory bowel disease.

Aliment Pharmacol Ther 2021 07 11;54(1):53-67. Epub 2021 May 11.

Clinic for Visceral Surgery and Medicine, Inselspital Bern and Bern University, Bern, Switzerland.

Background: Inflammatory bowel disease (IBD) can be exacerbated by stress and depression. Type D personality, characterised by high negative affectivity and social inhibition, represents a vulnerability towards stressors and is associated with adverse outcomes in coronary heart disease.

Aims: To assess the prevalence of Type D personality in IBD patients and investigate potential associations with disease course.

Methods: We tested for associations between Type D (Type D Scale-14), depressive symptoms (Hospital Anxiety and Depression Scale's depression subscore ≥11) and recurrent IBD amongst Swiss IBD cohort patients. We built regression models for cross-sectional and Cox proportional hazards models for time-to-event analyses. IBD disease course was assessed by the future occurrence of active disease (Crohn's Disease Activity Index ≥150/Modified Truelove & Witts activity index ≥10) and several IBD-relevant endpoints.

Results: Amongst 2275 patients (1005 ulcerative colitis, 1270 Crohn's disease), 672 (29.5%) had Type D. Type D was a significant risk factor for future active disease (adjusted hazard ratio, aHR: 1.60, corrected P value, q = 0.007) and predicted the future presence of depressive symptoms (aHR: 3.30, P < 0.001). The combination of Type D and depressive symptoms further increased the risk for active disease (aHR: 3.98, q < 0.001). However, Type D associated depressive symptoms seemed to be the main contributor to this effect as Type D's predictive power decreased considerably in models corrected for depressive symptoms (aHR: 1.32, CI: 0.97-1.79, q = 0.292).

Conclusions: Type D personality's prevalence amongst IBD patients was comparable with its prevalence in the general population. Type D was strongly associated with depressive symptoms and showed modest independent associations with IBD prognosis.
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http://dx.doi.org/10.1111/apt.16365DOI Listing
July 2021

Clinical Relevance of Anti-TNF Antibody Trough Levels and Anti-Drug Antibodies in Treating Inflammatory Bowel Disease Patients.

Inflamm Intest Dis 2021 Feb 20;6(1):38-47. Epub 2020 Nov 20.

Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Background And Aims: The majority of patients treated with anti-tumor necrosis factor (TNF) therapy develop anti-drug antibodies (ADAs), which might result in loss of treatment efficacy. Strict guidelines on measuring trough levels (TLs) and ADA in clinical routine do not exist. To provide real-world data, we took advantage of our tertiary inflammatory bowel disease (IBD) center patient cohort and determined indicators for therapeutic drug monitoring (TDM) and actual consequences in patient care.

Methods: We retrospectively collected clinical data of 104 IBD patients treated with infliximab or adalimumab in our IBD clinic. Patients with TL and ADA measurements between June 2015 and February 2018 were included.

Results: The main reason for determining TL was increased clinical disease. Subtherapeutic TLs were found in 33 patients, therapeutic TLs in 33 patients, and supratherapeutic TLs in 38 patients. Adjustments in anti-TNF therapy occurred more frequently ( = 0.01) in patients with subtherapeutic TL (24 of 33 patients; 73%) as compared to patients with therapeutic and supratherapeutic TLs (26 of 71 patients; 37%). No correlation could be found between TL and disease activity ( = 0.16). Presence of ADA was found in 16 patients, correlated with the development of infusion reactions (OR: 10.6, RR: 5.4, CI: 2.9-38.6), and was associated with subtherapeutic TL in 15 patients (93.8%). Treatment adaptations were based on TL and/or ADA presence in 36 of 63 patients.

Conclusions: TDM showed significant treatment adaptations in patients with subtherapeutic TL. Conversely, in patients with therapeutic and supratherapeutic TLs, reasons for adaptations were based on considerations other than TL, such as clinical disease activity. Further studies should focus on decision-making in patients presenting with supratherapeutic TL in remission.
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http://dx.doi.org/10.1159/000511296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015259PMC
February 2021

Combination of Vedolizumab With Tacrolimus Is More Efficient Than Vedolizumab Alone in the Treatment of Experimental Colitis.

Inflamm Bowel Dis 2021 Apr 13. Epub 2021 Apr 13.

Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich,  Switzerland.

Background: Vedolizumab is a widely used and safe therapy in inflammatory bowel disease, particularly in ulcerative colitis (UC), making it a promising candidate for enhanced efficacy by combining it with additional immunomodulatory medications. In this study, we studied the impact of vedolizumab monotreatment vs vedolizumab coadministration with other immunomodulatory drugs on intestinal inflammation and intestinal immune cells in vivo.

Methods: Colon tissue from human patients with UC with active disease or in remission with or without vedolizumab treatment was stained by immunohistochemistry. We reconstituted NOD-SCID-SGM3 mice with human CD34+ cells and treated them with dextran sodium sulfate to induce acute colitis. Mice were treated with vedolizumab alone, or in combination with tacrolimus, ozanimid, or tofacitinib.

Results: Vedolizumab reduced the number of CD3+ T cells and CD68+ monocytes/macrophages in the colon of patients with UC with active disease. Vedolizumab moderately decreased immune cell numbers in acute dextran sodium sulfate-induced colitis. The combination of vedolizumab with tacrolimus further reduced the number of infiltrating CD3+ T cells and CD68+ monocytes/macrophages and was superior in ameliorating intestinal inflammation when compared to vedolizumab monotreatment. In contrast, cotreatment using vedolizumab with ozanimod or tofacitinib had no additive effect.

Conclusions: Our data show that vedolizumab reduces the number of innate and adaptive immune cells in the mucosa of patients with UC. Further, the combination of vedolizumab with tacrolimus was more efficient to reduce immune cell numbers and to increase therapeutic efficacy than vedolizumab monotreatment. This finding indicates that combination treatment using these two drugs may be beneficial for patients who do not respond to vedolizumab monotherapy.
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http://dx.doi.org/10.1093/ibd/izab063DOI Listing
April 2021

Nutrition-or Lack Thereof-As a Source of Gut Inflammation: Evidence from Basic Science and Clinical Studies.

Mol Nutr Food Res 2021 03;65(5):e2001086

Department of Anesthesiology and Pain Medicine, Department of Pharmacology and Cardiovascular Research Centre, University of Alberta, Edmonton, Canada.

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http://dx.doi.org/10.1002/mnfr.202001086DOI Listing
March 2021

Perianal fistulodesis - A pilot study of a novel minimally invasive surgical and medical approach for closure of perianal fistulae.

World J Gastrointest Surg 2021 Feb;13(2):187-197

Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich 8091, Switzerland.

Background: Perianal fistulae strongly impact on quality of life of affected patients.

Aim: To challenge and novel minimally invasive treatment options are needed.

Methods: Patients with Crohn's disease (CD) in remission and patients without inflammatory bowel disease (non-IBD patients) were treated with fistulodesis, a method including curettage of fistula tract, flushing with acetylcysteine and doxycycline, Z-suture of the inner fistula opening, fibrin glue instillation, and Z-suture of the outer fistula opening followed by post-operative antibiotic prophylaxis with ciprofloxacin and metronidazole for two weeks. Patients with a maximum of 2 fistula openings and no clinical or endosonographic signs of a complicated fistula were included. The primary end point was fistula healing, defined as macroscopic and clinical fistula closure and lack of patient reported fistula symptoms at 24 wk.

Results: Fistulodesis was performed in 17 non-IBD and 3 CD patients, with a total of 22 fistulae. After 24 wk, all fistulae were healed in 4 non-IBD and 2 CD patients (overall 30%) and fistula remained closed until the end of follow-up at 10-25 mo. In a secondary per-fistula analysis, 7 out of 22 fistulae (32%) were closed. Perianal disease activity index (PDAI) improved in patients with fistula healing. Low PDAI was associated with favorable outcome ( = 0.0013). No serious adverse events were observed.

Conclusion: Fistulodesis is feasible and safe for perianal fistula closure. Overall success rates is at 30% comparable to other similar techniques. A trend for better outcomes in patients with low PDAI needs to be confirmed.
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http://dx.doi.org/10.4240/wjgs.v13.i2.187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898183PMC
February 2021

Higher educational level in patients with eosinophilic esophagitis: a comparative analysis.

Dis Esophagus 2021 Sep;34(9)

Department of Gastroenterology, University Hospital Zurich (USZ), University of Zurich, Zurich, Switzerland.

Background: Eosinophilic esophagitis is a chronic inflammatory gastrointestinal disease with a high prevalence in younger, atopic males. In our clinical practice, we observed a striking preponderance of patients having a high educational background. The purposes of this study were first to assess the level of education of eosinophilic esophagitis patients and second to compare the findings to patients with inflammatory bowel disease, another chronic immune-mediated condition of the gastrointestinal tract, and with the Swiss general population.

Methods: Using a questionnaire, we assessed the educational level of adult patients who have attended Swiss Eosinophilic Esophagitis Clinics in the past. In addition, the educational level of the parents was assessed as well. We calculated the proportions of patients and parents who have obtained a higher educational level. Data from the Swiss Inflammatory Bowel Disease Cohort Study and from the Swiss general population served as confirmation and as comparison, respectively.

Results: A total of 277 successfully contacted patients (response rate 69.1%; mean age 51.1 years, 73% male) participated. A significantly higher proportion of surveyed eosinophilic esophagitis patients had a high International Standard Classification of Education level (66.8%, P < 0.001) compared with inflammatory bowel disease patients (n = 2534; 34.2%, P < 0.001) and to the Swiss general population (n = 6,066,907; 30.5% P < 0.001).

Conclusion: Our analysis confirms the clinical observation that eosinophilic esophagitis patients have a significantly higher educational level compared with the general population and to patients with other chronic inflammatory diseases of the gastrointestinal tract. As a limitation, this impressive finding remains on a purely descriptive level.
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http://dx.doi.org/10.1093/dote/doab010DOI Listing
September 2021

Evaluating key characteristics of ideal colorectal cancer screening modalities: the microsimulation approach.

Gastrointest Endosc 2021 08 16;94(2):379-390.e7. Epub 2021 Feb 16.

Department of Visceral Surgery and Medicine, Inselspital Bern and Bern University, Bern, Switzerland.

Background And Aims: Screening for colorectal cancer (CRC) can effectively reduce CRC incidence and mortality. Besides colonoscopy, tests for the detection of biomarkers in stool, blood, or serum, including the fecal immunochemical test (FIT), ColoGuard, Epi proColon, and PolypDx, have recently been advanced. We aimed to identify the characteristics of theoretic, highly efficient screening tests and calculated the effectiveness and cost effectiveness of available screening tests.

Methods: Using the microsimulation-based colon modeling open-source tool (CMOST), we simulated 142,501 theoretic screening tests with variable assumptions for adenoma and carcinoma sensitivity, specificity, test frequency, and adherence, and we identified highly efficient tests outperforming colonoscopy. For available screening tests, we simulated 10 replicates of a virtual population of 2 million individuals, using epidemiologic characteristics and costs assumptions of the United States.

Results: Highly efficient theoretic screening tests were characterized by high sensitivity for advanced adenoma and carcinoma and high patient adherence. All simulated available screening tests were effective at 100% adherence to screening and at expected real-world adherence rates. All tests were cost effective below the threshold of 100,000 U.S. dollars per life year gained. With perfect adherence, FIT was the most effective and cost-efficient intervention, whereas Epi proColon was the most effective at expected real-world adherence rates. In our sensitivity analysis, assumptions for patient adherence had the strongest impact on effectiveness of screening.

Conclusions: Our microsimulation study identified characteristics of highly efficient theoretic screening tests and confirmed the effectiveness and cost-effectiveness of colonoscopy and available urine-, blood-, and stool-based tests. Better patient adherence results in superior effectiveness for CRC prevention in the whole population.
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http://dx.doi.org/10.1016/j.gie.2021.02.013DOI Listing
August 2021

Allogeneic expanded adipose-derived mesenchymal stem cell therapy for perianal fistulas in Crohn's disease: A case series.

Colorectal Dis 2021 06 5;23(6):1444-1450. Epub 2021 Mar 5.

Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Aim: Even with optimal medical and surgical therapy, perianal fistulas in patients with Crohn's disease (CD) have low closure rates. As a new therapeutic option, administration of local mesenchymal stem cells (MSCs) has proved to be an innovative option after failure of treatment with immunosuppressive or immunomodulatory agents. The aim of this work is to share our first experience with MSC administration and demonstrate its efficacy, safety and feasibility outside a clinical trial.

Method: A total of 11 CD patients with complex perianal fistulas with nonactive or mildly active luminal disease were treated with local injection of 120 million allogeneic adipose-derived stem cells at a tertiary hospital between February 2019 and June 2020.

Results: The mean age of the 11 patients was 38.3 years, 72.7% were men and 27.2% were smokers. The mean duration of fistula manifestation was 7.8 years and, except for one patient (therapy with tacrolimus), all other patients had been treated with an antitumour necrosis factor agent without fistula healing in the last 6 months. After a mean follow-up time of 41.5 weeks, 72.7% (8/11) of patients had complete closure of their fistula and three patients failed MSC treatment. Complete fistula healing could be observed 4-6 weeks postoperatively in half of the patients, while 36.5% (4/11) of patients developed a perianal abscess which had to be drained. One patient experienced cytomegalovirus viraemia 2 weeks after MSC administration and one patient developed a testicular carcinoma 16 weeks after treatment.

Conclusion: This case series demonstrates that the efficacy and safety of darvadstrocel in the ADMIRE trial can be replicated outside a clinical trial. This new modality in the treatment of complex perianal fistulas appears to be a promising therapeutic option for a challenging patient population.
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http://dx.doi.org/10.1111/codi.15587DOI Listing
June 2021

Abdominal pain in patients with inflammatory bowel disease: association with single-nucleotide polymorphisms prevalent in irritable bowel syndrome and clinical management.

BMC Gastroenterol 2021 Feb 5;21(1):53. Epub 2021 Feb 5.

Department of Gastroenterology, University Hospital Zurich (USZ), Zurich University, Zurich, Switzerland.

Background: Abdominal pain is a frequent symptom in patients with inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC). Pain can result from ongoing inflammation or functional disorders imitating irritable bowel syndrome (IBS). Several single-nucleotide polymorphisms (SNPs) have been associated with IBS. However, the impact of IBS genetics on the clinical course of IBD, especially pain levels of patients remains unclear.

Methods: Data of 857 UC and 1206 CD patients from the Swiss IBD Cohort Study were analysed. We tested the association of the maximum of the abdominal pain item of disease activity indices in UC and CD over the study period with 16 IBS-associated SNPs, using multivariate ANOVA models.

Results: In UC patients, the SNPs rs1042713 (located on the ADRB2 gene) and rs4663866 (close to the HES6 gene) were associated with higher abdominal pain levels (P = 0.044; P = 0.037, respectively). Abdominal pain was not associated with any markers of patient management in a model adjusted for confounders. In CD patients, higher levels of abdominal pain correlated with the number of physician contacts (P < 10), examinations (P < 10), medical therapies (P = 0.023) and weeks of hospitalisation (P = 0.0013) in a multivariate model.

Conclusions: We detected an association between maximal abdominal pain in UC patients and two IBS-associated SNPs. Abdominal pain levels had a pronounced impact on diagnostic and therapeutic procedures in CD but not in UC patients.
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http://dx.doi.org/10.1186/s12876-021-01622-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866750PMC
February 2021

Systemic Jak1 activation provokes hepatic inflammation and imbalanced FGF23 production and cleavage.

FASEB J 2021 02;35(2):e21302

Institute of Physiology, University of Zurich (UZH), and National Center of Competence in Research NCCR Kidney.CH, Zurich, Switzerland.

Fibroblast growth factor 23 (FGF23) is a main regulator of mineral homeostasis. Low and high circulating FGF23 levels are associated with bone, renal, cardiovascular diseases, and increased mortality. Understanding the factors and signaling pathways affecting FGF23 levels is crucial for the management of these diseases and their complications. Here, we show that activation of the Jak1/Stat3 signaling pathway leads to inflammation in liver and to an increase in hepatic FGF23 synthesis, a key hormone in mineral metabolism. This increased synthesis leads to massive C-terminal FGF23 circulating levels, the inactive C-terminal fragment, and increased intact FGF23 levels, the active form, resulting in imbalanced production and cleavage. Liver inflammation does not lead to activation of the calcineurin-NFAT pathway, and no signs of systemic inflammation could be observed. Despite the increase of active intact FGF23, excessive C-terminal FGF23 levels block the phosphaturic activity of FGF23. Therefore, kidney function and renal αKlotho expression are normal and no activation of the MAPK pathway was detected. In addition, activation of the Jak1/Stat3 signaling pathway leads to high calcitriol levels and low parathyroid hormone production. Thus, JAK1 is a central regulator of mineral homeostasis. Moreover, this study also shows that in order to assess the impact of high FGF23 levels on disease and kidney function, the source and the balance in FGF23 production and cleavage are critical.
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http://dx.doi.org/10.1096/fj.202002113RDOI Listing
February 2021

Diet and Inflammatory Bowel Disease: What Quality Standards Should Be Applied in Clinical and Laboratory Studies?

Mol Nutr Food Res 2021 03 22;65(5):e2000514. Epub 2021 Feb 22.

Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, 27599-7080, USA.

Many patients suffering from inflammatory bowel disease (IBD) follow restrictive diets, as many respective recommendations circulate. Efforts are made to evaluate and summarize the published information, for example, in a recent consensus manuscript by the International Organization for the Study of IBD (IOIBD). However, the standards that should be applied to make claims about dietary effects are poorly defined. In this manuscript, the scientific basis of recommendations for nutritional interventions in IBD is analyzed. Epidemiological evidence on diet in IBD is always biased by numerous factors, and the number of robust dietary intervention studies is limited due to methodological difficulties. Therefore, animal models are used to test hypotheses with respect to dietary factors and intestinal inflammation. Naturally, animal models have limitations, and knowledge of key characteristics of colitis animal models is crucial to understand their advantages and disadvantages. In recent years the important role of the microbiota for IBD and dietary factors has been discovered. Microbiota data are added to many publications on IBD and nutrition. The quality of those data varies largely. Subsequently, quality standards for microbiota analyses also are discussed. Finally, quality requirements to be applied on recommendations for dietary changes in patients with IBD are suggested.
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http://dx.doi.org/10.1002/mnfr.202000514DOI Listing
March 2021

Possible Adverse Effects of Food Additive E171 (Titanium Dioxide) Related to Particle Specific Human Toxicity, Including the Immune System.

Int J Mol Sci 2020 Dec 28;22(1). Epub 2020 Dec 28.

Netherlands Food and Consumer Product Safety Authority, P.O. Box 43006, 3540 AA Utrecht, The Netherlands.

Titanium dioxide (TiO) is used as a food additive (E171) and can be found in sauces, icings, and chewing gums, as well as in personal care products such as toothpaste and pharmaceutical tablets. Along with the ubiquitous presence of TiO and recent insights into its potentially hazardous properties, there are concerns about its application in commercially available products. Especially the nano-sized particle fraction (<100 nm) of TiO warrants a more detailed evaluation of potential adverse health effects after ingestion. A workshop organized by the Dutch Office for Risk Assessment and Research (BuRO) identified uncertainties and knowledge gaps regarding the gastrointestinal absorption of TiO, its distribution, the potential for accumulation, and induction of adverse health effects such as inflammation, DNA damage, and tumor promotion. This review aims to identify and evaluate recent toxicological studies on food-grade TiO and nano-sized TiO in ex-vivo, in-vitro, and in-vivo experiments along the gastrointestinal route, and to postulate an Adverse Outcome Pathway (AOP) following ingestion. Additionally, this review summarizes recommendations and outcomes of the expert meeting held by the BuRO in 2018, in order to contribute to the hazard identification and risk assessment process of ingested TiO.
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http://dx.doi.org/10.3390/ijms22010207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795714PMC
December 2020

Inflammatory bowel disease in sub-Saharan Africa: a protocol of a prospective registry with a nested case-control study.

BMJ Open 2020 12 22;10(12):e039456. Epub 2020 Dec 22.

Maurice Müller Laboratories, Department for Biomedical Research, University of Bern, Bern, Switzerland.

Introduction: The epidemiology of inflammatory bowel disease (IBD) in sub-Saharan Africa is poorly documented. We have started a registry to determine the burden, phenotype, risk factors, disease course and outcomes of IBD in Zimbabwe.

Methods And Analysis: A prospective observational registry with a nested case-control study has been established at a tertiary hospital in Harare, Zimbabwe. The registry is recruiting confirmed IBD cases from the hospital, and other facilities throughout Zimbabwe. Demographic and clinical data are obtained at baseline, 6 months and annually. Two age and sex-matched non-IBD controls per case are recruited-a sibling or second-degree relative, and a randomly selected individual from the same neighbourhood. Cases and controls are interviewed for potential risk factors of IBD, and dietary intake using a food frequency questionnaire. Stool is collected for 16S rRNA-based microbiota profiling, and along with germline DNA from peripheral blood, is being biobanked. The estimated sample size is 86 cases and 172 controls, and the overall registry is anticipated to run for at least 5 years. Descriptive statistics will be used to describe the demographic and phenotypic characteristics of IBD, and incidence and prevalence will be estimated for Harare. Risk factors for IBD will be analysed using conditional logistic regression. For microbial analysis, alpha diversity and beta diversity will be compared between cases and controls, and between IBD phenotypes. Mann-Whitney U tests for alpha diversity and Adonis (Permutational Multivariate Analysis of Variance) for beta diversity will be computed.

Ethics And Dissemination: Ethical approval has been obtained from the Parirenyatwa Hospital's and University of Zimbabwe's research ethics committee and the Medical Research Council of Zimbabwe. Findings will be discussed with patients, and the Zimbabwean Ministry of Health. Results will be presented at scientific meetings, published in peer reviewed journals, and on social media.

Trial Registration Number: NCT04178408.
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http://dx.doi.org/10.1136/bmjopen-2020-039456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757438PMC
December 2020

A Multicentre, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy, Safety, and Tolerability of the S1P Receptor Agonist KRP203 in Patients with Moderately Active Refractory Ulcerative Colitis.

Inflamm Intest Dis 2020 Nov 21;5(4):180-190. Epub 2020 Aug 21.

Evangelisches Krankenhaus, Cologne, Germany.

Background And Aims: KRP203 is a potent oral agonist of the sphingosine-1-phosphate receptor subtype 1 that induces the sequestration of peripheral lymphocytes, thereby potentially reducing the number of activated lymphocytes circulating to the gastrointestinal tract.

Methods: We conducted a multicentre, double-blind, placebo-controlled, parallel-group, proof-of-concept study to evaluate the efficacy, safety, and tolerability of KRP203 in patients with moderately active 5-aminosalicylate-refractory ulcerative colitis (UC). Patients were randomly assigned to receive 1.2 mg KRP203 or placebo daily for 8 weeks. Primary efficacy variable was clinical remission, defined as partial Mayo Score 0-1 and modified Baron Score 0-1 with rectal bleeding subscore 0.

Results: KRP203 was safe and well tolerated overall. The most common adverse events (AEs) were gastrointestinal disorders and headache. Importantly, no KRP203-related cardiac AEs were reported. Total peripheral lymphocytes and selectively affected lymphocyte subtypes decreased, causing marked decreases in naive and central memory CD4+ and CD8+ T cells, and also in B cells. Clinical remission occurred in 2/14 (14%) patients under KRP203, compared with 0/8 (0%) under placebo.

Conclusions: Overall, KRP203 was safe and well tolerated by patients with UC. Importantly, no cardiac AEs were reported. Although KRP203 did not meet the minimum clinically relevant threshold for efficacy, the results may suggest that KRP203 treatment is superior to placebo. However, in this small study population, the difference was insignificant. Based on these data, studies with an improved design and a larger population should be considered.
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http://dx.doi.org/10.1159/000509393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706482PMC
November 2020

The Influence of Breastfeeding, Cesarean Section, Pet Animals, and Urbanization on the Development of Inflammatory Bowel Disease: Data from the Swiss IBD Cohort Study.

Inflamm Intest Dis 2020 Nov 26;5(4):170-179. Epub 2020 Aug 26.

Clinic for Medical Oncology and Hematology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Introduction: The pathophysiology of inflammatory bowel disease (IBD) is incompletely understood. Current concepts imply that environmental factors (EFs) trigger disease onset as well as flares in genetically susceptible individuals.

Objective: The objective of this study is to analyze the association between IBD and various EFs, which may influence the pathogenesis of the disease.

Methods: 2,294 patients from the Swiss IBD Cohort Study (SIBDCS) received a questionnaire regarding EF including mode of delivery, breastfeeding, animals in household, and place of residence. The control group comprised patients' childhood friends, who grew up in a similar environment ("friends cohort").

Results: A total of 1,111 questionnaires were returned from SIBDCS patients (response rate: 48.4%). Breastfeeding for <6 months was associated with a decreased risk for ulcerative colitis/indeterminate colitis (UC/IC) (OR: 0.473, = 0.006). IBD patients reported less pet animals in the household than the control group ( = 0.004). The presence of cats or dogs (OR: 0.688, = 0.015) and pet rodents (OR: 0.598, = 0.001) in the household before the age of 20 was inversely associated with the risk for UC/IC.

Conclusion: The present study underlines the importance of EFs in the pathogenesis of IBD. Overall, the development of UC/IC seems to be more affected from environmental influences than from Crohn's disease. Our results imply a protective effect of possessing pet animals in household and short breastfeeding regarding the onset of UC/IC.
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http://dx.doi.org/10.1159/000509058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706488PMC
November 2020

Genetic risk factors predict disease progression in Crohn's disease patients of the Swiss inflammatory bowel disease cohort.

Therap Adv Gastroenterol 2020 19;13:1756284820959252. Epub 2020 Nov 19.

Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, Zurich, 8091, Switzerland.

Background: Crohn's disease (CD) may progress from an inflammatory to a stricturing or penetrating disease phenotype. The aim of our study was to identify single nucleotide polymorphisms (SNPs) that predict disease progression in patients of the Swiss IBD Cohort Study (SIBDCS).

Methods: We applied a multi-state Markov model for progression behavior of CD with three behavioral states according to the Montreal classification. The model considered transition from B1 to B2/B3 or from B2 to B3 stage. Model dynamics were summarized with transition intensities by including the effect of SNPs and calculating transition intensities for each SNP.

Results: We included 1276 CD patients [669 (52.4%) B1, 248 (19.4%) B2, 359 (28.1%) B3 patients] with a median follow-up of 6.8 (interquartile range = 3.6-9.1; range 0-11.6) years. Probability for a B1 patient to develop a stenosis (B1 to B2, q = 0.033) was twice as much as compared to developing a penetrating complication (B3) during the disease course. In contrast, the probability of entering B3 stage was similar regardless of whether antecedent stricture was present (B2 to B3, q = 0.016) or not (B1 to B3, q = 0.016). We identified SNPs within the gene loci encoding ZMIZ1, LOC105373831 and KSR1 as carrying the highest risk for progression to B3, while the presence of SNPs within gene loci TNFSF15 and CEBPB-PTPN1 protected from progression to B2 or B3.

Conclusion: We identified new genetic risk factors that can predict disease course in CD patients. A closer understanding on the functional impact of these genetic variations might improve our treatment options finally to prevent disease progression in CD patients.
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http://dx.doi.org/10.1177/1756284820959252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686597PMC
November 2020

Impact of obesity on disease activity and disease outcome in inflammatory bowel disease: Results from the Swiss inflammatory bowel disease cohort.

United European Gastroenterol J 2020 12;8(10):1196-1207

Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.

Objective: The purpose of this study was to investigate the impact of obesity on disease activity and disease outcome in patients with inflammatory bowel disease.

Patients And Methods: The impact of obesity on inflammatory bowel disease disease activity and outcome was retrospectively assessed in 3075 patients enrolled in the prospective nation-wide Swiss inflammatory bowel disease cohort between July 2006 and September 2018. Baseline characteristics, disease activity and disease course in 325 obese inflammatory bowel disease patients (body mass index ≥30 kg/m) were compared to 1725 normal weight inflammatory bowel disease individuals (body mass index 18.5-24.9).

Results: Among 3075 patients in the prospective Swiss inflammatory bowel disease cohort, 325 patients (10.6%) were obese, namely, 194 Crohn's disease patients, 131 ulcerative colitis, and inflammatory bowel disease-unclassified patients. Disease activity scores were elevated in obese Crohn's disease (Crohn's Disease Activity Index 33 vs 20,  = 0.001), but not ulcerative colitis patients. Obese Crohn's disease, but not ulcerative colitis patients were less likely to be in remission based on a Crohn's Disease Activity Index less than 100 and a calprotectin less than 100 ug/g. In a multivariate regression model, obesity was negatively associated with disease remission in Crohn's disease (odds ratio 0.610, 95% confidence interval 0.402-0.926,  = 0.020), but not ulcerative colitis. Increased soft stool frequency was observed in both obese Crohn's disease and ulcerative colitis patients. Adjusted Cox regression models revealed increased risk of complicated disease course in obese Crohn's disease patients (hazard ratio 1.197, 95% confidence interval 1.046-1.370,  = 0.009). No association between obesity and disease progression, index treatment failure was seen neither in Crohn's disease nor ulcerative colitis.

Conclusion: Obesity is associated with decreased rates of disease remission and increased risk of complicated disease course in Crohn's disease over a six-year follow-up period. No effects were seen on disease progression and index treatment failure neither in Crohn's disease nor ulcerative colitis.
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http://dx.doi.org/10.1177/2050640620954556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724522PMC
December 2020
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