Publications by authors named "Jens Kjeldsen"

84 Publications

Experiences and perceptions of patients with psoriatic arthritis participating in a trial of faecal microbiota transplantation: a nested qualitative study.

BMJ Open 2021 03 8;11(3):e039471. Epub 2021 Mar 8.

Department of Rheumatology, Odense University Hospital, Odense, Denmark.

Objectives: Patients' first-hand experiences of faecal microbiota transplantation (FMT) performed in a rheumatological care setting have yet to be elucidated. The objectives were to explore participants' perceptions of being part of an FMT trial thereby identifying potential trial participation effects and enlightening the patient perspective on the outlook for future FMT trials in rheumatic diseases.

Design: In a qualitative study nested within a double-blind, randomised, placebo-controlled trial (RCT) testing FMT as a potential new antirheumatic treatment, semistructured telephone interviews were conducted following the trial participants' final 26-week visit. Qualitative researchers, who did not take part in the main trial, performed the interviews and the primary analysis. The experiences explored related to the conduct of the RCT and changes in the participants' everyday life. The analysis was carried out using a thematic approach.

Setting: A Danish rheumatology university outpatient clinic with nationwide inclusion.

Participants: The study included 10 patients with psoriatic arthritis (PsA) who were unaware of their treatment allocation (FMT/sham transplantation) and completed the final 26-week trial visit.

Results: Participation in the RCT influenced the patients' understanding of PsA and induced positive changes in their everyday life. Renewed hopes for the future in addition to a feeling of enhanced care contributed to significant trial participation effects. FMT was deemed a tolerable and safe treatment.

Conclusions: Discrepancies between the clinical and the research setting should be considered when discussing the clinical relevance of the results of the RCT. Overall, patients with PsA who have participated in an RCT testing FMT find the treatment acceptable and safe encouraging more research into the field of microbiota-targeted interventions in rheumatic diseases.

Trial Registration Number: NCT03058900; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2020-039471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942243PMC
March 2021

Safety and efficacy of faecal microbiota transplantation for active peripheral psoriatic arthritis: an exploratory randomised placebo-controlled trial.

Ann Rheum Dis 2021 Apr 29. Epub 2021 Apr 29.

Rheumatology Research Unit, Department of Rheumatology, Odense University Hospital, Odense, Denmark

Objectives: Although causality remains to be established, targeting dysbiosis of the intestinal microbiota by faecal microbiota transplantation (FMT) has been proposed as a novel treatment for inflammatory diseases. In this exploratory, proof-of-concept study, we evaluated the safety and efficacy of FMT in psoriatic arthritis (PsA).

Methods: In this double-blind, parallel-group, placebo-controlled, superiority trial, we randomly allocated (1:1) adults with active peripheral PsA (≥3 swollen joints) despite ongoing treatment with methotrexate to one gastroscopic-guided FMT or sham transplantation into the duodenum. Safety was monitored throughout the trial. The primary efficacy endpoint was the proportion of participants experiencing treatment failure (ie, needing treatment intensification) through 26 weeks. Key secondary endpoints were change in Health Assessment Questionnaire Disability Index (HAQ-DI) and American College of Rheumatology (ACR20) response at week 26.

Results: Of 97 screened, 31 (32%) underwent randomisation (15 allocated to FMT) and 30 (97%) completed the 26-week clinical evaluation. No serious adverse events were observed. Treatment failure occurred more frequently in the FMT group than in the sham group (9 (60%) vs 3 (19%); risk ratio, 3.20; 95% CI 1.06 to 9.62; p=0.018). Improvement in HAQ-DI differed between groups (0.07 vs 0.30) by 0.23 points (95% CI 0.02 to 0.44; p=0.031) in favour of sham. There was no difference in the proportion of ACR20 responders between groups (7 of 15 (47%) vs 8 of 16 (50%)).

Conclusions: In this first preliminary, interventional randomised controlled trial of FMT in immune-mediated arthritis, we did not observe any serious adverse events. Overall, FMT appeared to be inferior to sham in treating active peripheral PsA.

Trial Registration Number: NCT03058900.
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http://dx.doi.org/10.1136/annrheumdis-2020-219511DOI Listing
April 2021

Outcome of COVID-19 in hospitalized patients with chronic inflammatory diseases. A population based national register study in Denmark.

J Autoimmun 2021 06 26;120:102632. Epub 2021 Mar 26.

Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark; Research Unit of Clinical Epidemiology, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.

Objective: COVID-19 has substantial morbidity and mortality. We studied whether hospitalized patients with COVID-19 and chronic inflammatory diseases experienced worse outcomes compared to patients hospitalized with COVID-19 without chronic inflammatory diseases.

Methods: Danish nationwide registers were used to establish a cohort of hospitalized patients with COVID-19 and inflammatory bowel diseases (IBD), rheumatoid arthritis (RA), spondyloarthropathy (SpA), or psoriatic arthritis (PsA) (exposed), and a control cohort without these diseases (unexposed) between March 1, 2020, and October 31, 2020. We compared median length of hospital stay, used median regression models to estimate crude and adjusted differences. When estimating crude and adjusted odds ratio (OR) for continuous positive airway pressure (CPAP) and mechanical ventilation, in-hospital death, 14-day and 30-day mortality, we used logistic regression models.

Results: We identified 132 patients with COVID-19 and IBD, RA, SpA, or PsA, and 2811 unexposed admitted to hospital with COVID-19. There were no differences between exposed and unexposed regarding length of hospital stay (6.8 days vs. 5.5 days), need for mechanical ventilation (7.6% vs. 9.4%), or CPAP (11.4% vs. 8.8%). Adjusted OR for in-hospital death was 0.71 (95% CI 0.42-1.22), death after 14-days 0.70 (95% CI 0.42-1.16), and death after 30-days 0.68 (95% CI 0.41-1.13).

Conclusion: Hospitalized patients with COVID-19 and chronic inflammatory diseases did not have statistically significant increased length of hospital stay, had same need for mechanical ventilation, and CPAP. Mortality was similar in hospitalized patients with COVID-19 and chronic inflammatory diseases, compared to patients hospitalized with COVID-19 and no chronic inflammatory diseases.
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http://dx.doi.org/10.1016/j.jaut.2021.102632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997392PMC
June 2021

High output cardiac failure in 3 patients with hereditary hemorrhagic telangiectasia and hepatic vascular malformations, evaluation of treatment.

Orphanet J Rare Dis 2020 11 26;15(1):334. Epub 2020 Nov 26.

HHT-Center Odense University Hospital, Part of VASCERN, Odense, Denmark.

Background: This report addresses how patients with hereditary hemorrhagic telangiectasia (HHT) and high output cardiac failure (HOCF) due to hepatic vascular malformations, should be evaluated and could be treated. HHT is a genetic disorder, leading to vascular abnormalities with potentially serious clinical implications. In the liver, arteriovenous malformations occur in more than 70% of patients, but only about 8% present clinical symptoms such as HOCF with pulmonary hypertension and less commonly portal hypertension, biliary ischemia and hepatic encephalopathy.

Results: Three female patients with HHT type 2 and HOCF caused by severe arteriovenous malformations in the liver are presented in this case series. The patients were seen at the HHT-Centre at Odense University Hospital. Treatment with either orthotopic liver transplantation (one patient) or bevacizumab (two patients) was initiated. All patients experienced marked symptom relief and objective improvement. New York Heart Association-class were improved, ascites, peripheral edema and hence diuretic treatment was markedly reduced or discontinued in all three patients. Bevacizumab also resulted in notable effects on epistaxis and anemia.

Conclusion: Our findings substantiate the importance of identification of symptomatic arteriovenous malformations in the liver in patients with HHT. Bevacizumab may possibly, as suggested in this case series and supported by previous case studies, postpone the time to orthotopic liver transplantation or even make it unnecessary. Bevacizumab represents a promising new treatment option, which should be investigated further in clinical trials.
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http://dx.doi.org/10.1186/s13023-020-01583-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691053PMC
November 2020

Hospitalization for COVID-19 in patients treated with selected immunosuppressant and immunomodulating agents, compared to the general population: A Danish cohort study.

Br J Clin Pharmacol 2021 04 2;87(4):2111-2120. Epub 2020 Dec 2.

Department of Medical Gastroenterology S, Odense University Hospital, Odense, Denmark.

Aims: In the Danish population, we examined whether patients treated with thiopurines, methotrexate, systemic corticosteroids, anti-tumour necrosis factor (TNF)-α agents, anti-interleukin therapeutic agents, selective immunosuppressive agents and cyclosporine/tacrolimus had an increased risk of hospitalization for COVID- 19, compared to the background population.

Methods: A nationwide cohort study including all people alive in Denmark on 1 March 2020. Exposed patients constituted those exposed to thiopurines (n = 5484), methotrexate (n = 17 977), systemic corticosteroids (n = 55 868), anti-TNF-α agents (n = 17 857), anti-interleukin therapeutic agents (n = 3744), selective immunosuppressive agents (n = 3026) and cyclosporine/tacrolimus (n = 1143) in a period of 12 months prior to 1 March 2020 (estimated time of outbreak in Denmark). We estimated the adjusted risk of hospitalization for COVID-19 for patients treated with the above-mentioned categories of medications, compared to the rest of the population.

Results: The adjusted odds ratios of hospitalization in patients treated with corticosteroids and cyclosporine/tacrolimus were 1.64 (95% confidence interval [CI] 1.35 to 2.00) and 4.75 (95% CI 1.96 to 11.49), respectively. The risks of hospitalization in patients treated with thiopurines, methotrexate, and anti-TNF-α agents, were 1.93 (95% CI 0.91 to 4.08), 0.74 (95% CI 0.43 to 1.28), 1.00 (95% CI 0.52 to 1.94), respectively. The number of outcomes in patients treated with anti-interleukin therapeutic agents and selective immunosuppressive agents was too small for analysis.

Conclusion: Patients treated with systemic corticosteroids and cyclosporine/tacrolimus had a significantly increased risk of being hospitalized for COVID-19. Our study does not uncover whether the increased risk is related to the drug itself, the underlying condition for which the patient is treated or other factors.
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http://dx.doi.org/10.1111/bcp.14622DOI Listing
April 2021

A positive diagnostic strategy is safe and saves endoscopies in patients with irritable bowel syndrome: A five-year follow-up of a randomized controlled trial.

Neurogastroenterol Motil 2021 03 7;33(3):e14004. Epub 2020 Oct 7.

Research Unit of General Practice, Department of Public Health, University of Southern Denmark, Odense, Denmark.

Background: Previously, the diagnosis of irritable bowel syndrome (IBS) required exclusion of organic causes by extensive diagnostic testing. Newer guidelines recommend IBS as a positive diagnosis based on symptoms with limited testing. We investigated the long-term safety and impact on use of health resources of a positive diagnostic strategy compared to a strategy of exclusion in patients with symptoms compatible with IBS.

Methods: In 2008-2010, primary care patients aged 18-50 years fulfilling the Rome III criteria for IBS without alarm signals were randomized to a positive diagnostic strategy (limited blood tests, n = 150) or a strategy of exclusion (extensive blood tests, fecal samples for intestinal parasites, and sigmoidoscopy with biopsies, n = 152). At five years, hospital-registered diagnoses and use of health resources including lower endoscopies were retrieved from national registries. Participants provided 5-year data on Rome III criteria for IBS, severity of symptoms, and quality of life.

Key Results: Baseline mean age was 31.4 (SD 9.1) years; 79% were female. No cases of celiac disease, and gastrointestinal or gynecological cancers were diagnosed within five years. Negligible and comparable numbers were diagnosed with inflammatory bowel disease, benign gynecological conditions, and upper GI conditions in the two groups. The positive diagnosis strategy carried a higher number of lower endoscopies from year 1 to 5 (23 patients versus 13 patients in the exclusion group), but overall saved endoscopies.

Conclusions & Inferences: A positive diagnosis of IBS was as safe as a diagnosis of exclusion in a five-year perspective and saved lower endoscopies; the study was registered at ClinicalTrials.gov numbers: NCT00659763/NCT01153295.
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http://dx.doi.org/10.1111/nmo.14004DOI Listing
March 2021

Infliximab, Immunomodulators and Treatment Failures in Paediatric and Adolescent Patients with Crohn's Disease: a Nationwide Cohort Study.

J Crohns Colitis 2021 Apr;15(4):575-582

Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark.

Background And Aims: In paediatric patients with Crohn's disease, the role of combination therapy, infliximab plus immunomodulators [thiopurine or methotrexate], is debated and data are sparse. We examined whether infliximab plus immunomodulators, compared to infliximab therapy alone, reduces the risk of treatment failure measured by intestinal surgery or switching type of anti-tumour necrosis factor [TNF] α agent within 24 months.

Design: Using Danish registries, we identified patients with Crohn's disease, aged ≤ 20 years at the time of the first infliximab treatment, and retrieved data on their co-medications. We used Cox regression models to examine surgery or switching type of anti-TNFα agent from January 1, 2003 to December 31, 2015.

Results: We included 581 patients. The 2-year cumulative percentage of surgery was 8.5% among patients receiving combination therapy and 14.5% in those receiving infliximab alone. The adjusted 2-year hazard ratio [HR] of surgeries was 0.53 (95% confidence interval [CI] 0.32-0.88) in patients receiving combination therapy, compared to patients receiving infliximab alone. When examining a switch of anti-TNFα we included 536 patients. Within 2 years, 18.3% experienced a switch among patients receiving combination therapy and 24.8% in patients treated with infliximab alone, corresponding to an adjusted HR of 0.66 [95% CI 0.45-0.97] in patients receiving combination therapy.

Conclusions: The HR of intestinal surgeries and the risk of a switch to another anti-TNFα was reduced in paediatric and adolescent patients receiving combination therapy, compared to patients receiving only infliximab. These results suggest a benefit for infliximab therapy combined with immunomodulators, but these need to be confirmed in data with additional clinical information.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa188DOI Listing
April 2021

The use of 5-aminosalicylate for patients with Crohn's disease in a prospective European inception cohort with 5 years follow-up - an Epi-IBD study.

United European Gastroenterol J 2020 10 26;8(8):949-960. Epub 2020 Jul 26.

Hull University Teaching Hospitals NHS Trust, Hull, UK.

Background: The lack of scientific evidence regarding the effectiveness of 5-aminosalicylate in patients with Crohn's disease is in sharp contrast to its widespread use in clinical practice.

Aims: The aim of the study was to investigate the use of 5-aminosalicylate in patients with Crohn's disease as well as the disease course of a subgroup of patients who were treated with 5-aminosalicylate as maintenance monotherapy during the first year of disease.

Methods: In a European community-based inception cohort, 488 patients with Crohn's disease were followed from the time of their diagnosis. Information on clinical data, demographics, disease activity, medical therapy and rates of surgery, cancers and deaths was collected prospectively. Patient management was left to the discretion of the treating gastroenterologists.

Results: Overall, 292 (60%) patients with Crohn's disease received 5-aminosalicylate period during follow-up for a median duration of 28 months (interquartile range 6-60). Of these, 78 (16%) patients received 5-aminosalicylate monotherapy during the first year following diagnosis. Patients who received monotherapy with 5-aminosalicylate experienced a mild disease course with only nine (12%) who required hospitalization, surgery, or developed stricturing or penetrating disease, and most never needed more intensive therapy. The remaining 214 patients were treated with 5-aminosalicylate as the first maintenance drug although most eventually needed to step up to other treatments including immunomodulators (75 (35%)), biological therapy (49 (23%)) or surgery (38 (18%)).

Conclusion: In this European community-based inception cohort of unselected Crohn's disease patients, 5-aminosalicylate was commonly used. A substantial group of these patients experienced a quiescent disease course without need of additional treatment during follow-up. Therefore, despite the controversy regarding the efficacy of 5-aminosalicylate in Crohn's disease, its use seems to result in a satisfying disease course for both patients and physicians.
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http://dx.doi.org/10.1177/2050640620945949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707880PMC
October 2020

Remote ischemic conditioning in active ulcerative colitis: An explorative randomized clinical trial.

Sci Rep 2020 06 12;10(1):9537. Epub 2020 Jun 12.

Department of Medical Gastroenterology, Odense University Hospital, Odense, Denmark.

Remote ischemic conditioning (RIC) by repetitive brief periods of limb ischemia and reperfusion renders organs more resistant to ischemic injury. The protection is partly through down-regulation of the inflammatory response. Our aim was to investigate the clinical and anti-inflammatory effects of RIC in patients with active ulcerative colitis (UC). We included 22 patients with active UC in this explorative, randomized, sham-controlled clinical trial. The patients were randomly assigned 1:1 to RIC (induced in the arm through four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff) or sham (incomplete inflation of the blood-pressure cuff) once daily for 10 days. Outcome variables were measured at baseline and on day 11. When compared with sham, RIC did not affect inflammation in the UC patients measured by fecal calprotectin, plasma C-reactive protein, Mayo Score, Mayo Endoscopic Subscore, Nancy Histological Index or inflammatory cytokines involved in UC and RIC. The mRNA and miRNA expression profiles in the UC patients were measured by RNA sequencing and multiplexed hybridization, respectively, but were not significantly affected by RIC. We used the Langendorff heart model to assess activation of the organ protective mechanism induced by RIC, but could not confirm activation of the organ protective mechanism in the UC patients.
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http://dx.doi.org/10.1038/s41598-020-65692-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293253PMC
June 2020

Treatment to target in patients with inflammatory bowel disease. What is the evidence?

Scand J Gastroenterol 2020 May 5;55(5):528-536. Epub 2020 Jun 5.

Department of Medical Gastrointestinal Diseases, Odense University Hospital, Odense, Denmark.

Inflammatory bowel diseases (IBD) are chronic, progressive diseases of the gastrointestinal tract. Current therapy has not been able to change the long-term course of the disease, but treatment to a specific therapeutic target could be a game-changer. To assess the evidence of a treat to target (T2T) algorithm being superior to clinical management in the treatment of IBD, a systematic review of the literature is conducted. A comprehensive survey of PubMed and Embase covering the period April 2018 to July 2019 including articles referenced in relevant studies. Both randomized clinical trials (RCT) and observational studies were included. To be eligible for inclusion, the studies had to describe or analyze the effects of T2T on remission and/or recurrence of disease in patients with IBD. Twenty-two studies were included in this review, seven RCTs, eight comparative and seven non-comparative observational studies. Large heterogeneity between T2T algorithms applied, type of IBD investigated and outcomes evaluated characterized the studies. The comprehensive search identified only 22 heterogeneous studies. Out of these, a total of 14 indicated a positive effect of a T2T algorithm. Out of the seven RCT studies, four indicated a positive effect. Thus, T2T algorithms may be superior to the clinical management of IBD. However, the evidence is sparse and inconsistent.
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http://dx.doi.org/10.1080/00365521.2020.1764091DOI Listing
May 2020

How do I establish a stool bank for fecal microbiota transplantation within the blood- and tissue transplant service?

Transfusion 2020 06 28;60(6):1135-1141. Epub 2020 May 28.

Department of Clinical Immunology, Odense University Hospital, Odense, Denmark.

Worldwide, there is a rising demand for thoroughly screened, high-quality fecal microbiota transplantation (FMT) products that can be obtained at a reasonable cost. In the light of this evolving therapeutic area of the intestinal microbiota, both private and public stool banks have emerged. However, some of the larger difficulties when establishing stool banks are caused by the absence of or international disagreement on regulation and legislative formalities. In this context, the establishment of a stool bank within a nonprofit blood and tissue transplant service has several advantages. Especially, this setting can ensure that every step of the donation process, laboratory handling, and donor-traceability is in agreement with the current expert guidelines and meets the requirements of the European Union's regulative directives on human cells and tissues. Although safety and documentation are the top priority of the stool bank setup presented here, cost-effectiveness of the production is possible due to a high donor screening success rate and the knowhow, infrastructure, facilities, personnel, and laboratory- and quality-management systems that were already in place. Overall, our experience is that a centralized, nonprofit, blood and tissue transplant service is an ideal and safe facility to run a stool bank of high quality FMT products that are based on stool donations from volunteer, unpaid, healthy, blood donors.
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http://dx.doi.org/10.1111/trf.15816DOI Listing
June 2020

Predictors of health-related quality of life in patients with moderate to severely active ulcerative colitis receiving biological therapy.

Scand J Gastroenterol 2020 Jun 22;55(6):656-663. Epub 2020 May 22.

Research Unit of General Practice, Department of Public Health, University of Southern Denmark, Odense C, Denmark.

: Patients with ulcerative colitis have reduced health-related quality of life compared to the general population. Current treatment strategy aims to reduce patients' symptoms and increase health-related quality of life. We investigated which symptoms of ulcerative colitis correlate to decreased health-related quality of life.: Among 743 patients with moderate to severely active ulcerative colitis receiving biological therapy in a cross-sectional national study, we determined which disease-related symptoms, as measured by the Simple Clinical Colitis Activity Index, worsened health-related quality of life scores across the Short Health Scale dimensions, while adjusting for treatment, age, and clinical manifestation, and stratifying for sex, by means of multiple linear regression.: Patients with active disease had decreased health-related quality of life compared to those with inactive disease (median 5.8 (range 4.5-7.5) vs. 2 (0.8-3.3)). Both sexes had decreased health-related quality of life in all dimensions for the symptoms: bowel frequency during daytime (0.37-0.86 and 0.46-0.84), urgency of defecation (0.54-0.79 and 0.49-0.65) and blood in stool (0.50-0.75 and 0.36-0.54) for men and women respectively. Women were more often negatively affected by bowel frequency during night-time (4 domains vs. 1) and arthritis (5 domains vs. 3). In non-stratified analysis female sex is an independent predictor of lower health-related quality of life for 3 domains (0.38-0.53).: Health-related quality of life was most prominently associated with bowel frequency during daytime, urgency of defecation, and blood in stool. Other symptoms associated for some health-related quality of life dimensions, and appear to vary between the sexes.
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http://dx.doi.org/10.1080/00365521.2020.1768282DOI Listing
June 2020

A Fragment of Collagen Type VI alpha-3 chain is Elevated in Serum from Patients with Gastrointestinal Disorders.

Sci Rep 2020 04 3;10(1):5910. Epub 2020 Apr 3.

Nordic Bioscience, Biomarkers and Research, Herlev, Denmark.

Extracellular matrix (ECM) remodeling is a hallmark of the pathology of gastrointestinal disorders. Collagen type VI (COL6) is produced by fibroblasts, and the COL6 α3-chain has shown to be elevated in patients with ulcerative colitis (UC), Crohn's disease (CD) and colorectal cancer (CRC). Measuring COL6α3 in serum may therefore have potential as a biomarker for gastrointestinal disorders. The aims of this study were to develop and validate a competitive ELISA targeting a specific neo-epitope of COL6α3 and evaluate its associations with the gastrointestinal disorders UC, CD and CRC, in comparison to healthy controls. A monoclonal antibody was raised against a matrix metalloproteinase-2 and -9 specific cleavage site of COL6α3 (C6Mα3) and employed in a competitive enzyme-linked immunosorbent assay (ELISA). The assay was developed and technically validated. Levels of C6Mα3 were measured in serum from patients with UC (n = 58), CD (n = 44) and CRC (n = 39) and compared to healthy controls (n = 32). The levels of C6Mα3 were elevated in patients with UC, CD and CRC patients compared to healthy controls (all p < 0.0001). The area under the receiver operating characteristics (AUROC) curve for separation of patients with UC from healthy controls was 0.972 (95% CI: 0.925-1.020, p < 0.0001), with CD from healthy controls was 0.947 (95% CI: 0.885-1.009, p < 0.0001) and with CRC from healthy controls was 0.890 (95% CI: 0.809-0.972, p < 0.0001). We developed a technically robust assay targeting a fragment of COL6, which was elevated in serum from patients with UC, CD and CRC.
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http://dx.doi.org/10.1038/s41598-020-62474-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125205PMC
April 2020

Health-care costs of inflammatory bowel disease in a pan-European, community-based, inception cohort during 5 years of follow-up: a population-based study.

Lancet Gastroenterol Hepatol 2020 05 13;5(5):454-464. Epub 2020 Feb 13.

Hull University Teaching Hospitals NHS Trust, Hull, UK; Hull York Medical School, Hull, UK.

Background: Inflammatory bowel disease (IBD) places a significant burden on health-care systems because of its chronicity and need for expensive therapies and surgery. With increasing use of biological therapies, contemporary data on IBD health-care costs are important for those responsible for allocating resources in Europe. To our knowledge, no prospective long-term analysis of the health-care costs of patients with IBD in the era of biologicals has been done in Europe. We aimed to investigate cost profiles of a pan-European, community-based inception cohort during 5 years of follow-up.

Methods: The Epi-IBD cohort is a community-based, prospective inception cohort of unselected patients with IBD diagnosed in 2010 at centres in 20 European countries plus Israel. Incident patients who were diagnosed with IBD according to the Copenhagen Diagnostic Criteria between Jan 1, and Dec 31, 2010, and were aged 15 years or older the time of diagnosis were prospectively included. Data on clinical characteristics and direct costs (investigations and outpatient visits, blood tests, treatments, hospitalisations, and surgeries) were collected prospectively using electronic case-report forms. Patient-level costs incorporated procedures leading to the initial diagnosis of IBD and costs of IBD management during the 5-year follow-up period. Costs incurred by comorbidities and unrelated to IBD were excluded. We grouped direct costs into the following five categories: investigations (including outpatient visits and blood tests), conventional medical treatment, biological therapy, hospitalisation, and surgery.

Findings: The study population consisted of 1289 patients with IBD, with 1073 (83%) patients from western Europe and 216 (17%) from eastern Europe. 488 (38%) patients had Crohn's disease, 717 (56%) had ulcerative colitis, and 84 (6%) had IBD unclassified. The mean cost per patient-year during follow-up for patients with IBD was €2609 (SD 7389; median €446 [IQR 164-1849]). The mean cost per patient-year during follow-up was €3542 (8058; median €717 [214-3512]) for patients with Crohn's disease, €2088 (7058; median €408 [133-1161]) for patients with ulcerative colitis, and €1609 (5010; median €415 [92-1228]) for patients with IBD unclassified (p<0·0001). Costs were highest in the first year and then decreased significantly during follow-up. Hospitalisations and diagnostic procedures accounted for more than 50% of costs during the first year. However, in subsequent years there was a steady increase in expenditure on biologicals, which accounted for 73% of costs in Crohn's disease and 48% in ulcerative colitis, in year 5. The mean annual cost per patient-year for biologicals was €866 (SD 3056). The mean yearly costs of biological therapy were higher in patients with Crohn's disease (€1782 [SD 4370]) than in patients with ulcerative colitis (€286 [1427]) or IBD unclassified (€521 [2807]; p<0·0001).

Interpretation: Overall direct expenditure on health care decreased over a 5-year follow-up period. This period was characterised by increasing expenditure on biologicals and decreasing expenditure on conventional medical treatments, hospitalisations, and surgeries. In light of the expenditures associated with biological therapy, cost-effective treatment strategies are needed to reduce the economic burden of inflammatory bowel disease.

Funding: Kirsten og Freddy Johansens Fond and Nordsjællands Hospital Forskningsråd.
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http://dx.doi.org/10.1016/S2468-1253(20)30012-1DOI Listing
May 2020

The impact of anti-TNFα therapy on colectomy rates and corticosteroid treatment among 3001 paediatric and adolescent patients with ulcerative colitis-a nationwide study from 1995 to 2015.

Aliment Pharmacol Ther 2019 11 3;50(10):1077-1085. Epub 2019 Oct 3.

Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark.

Background: The long-term effects of anti-TNFα therapy in ulcerative colitis are debatable.

Aim: To examine whether anti-TNFα therapy changed the colectomy proportion and reduced the use of corticosteroids.

Methods: A nationwide cohort study among patients (age 0-20) diagnosed with ulcerative colitis through 1995-2015 from Danish health registries. We calculated the cumulative 5-year risk of colectomy after diagnosis and used a Cox regression model for comparison between a historical pre-anti-TNFα cohort 1 (1995-2003) and a cohort 2 for the era of anti-TNFα (2004-2015). Based on anti-TNFα users, defined as patients who had at least four anti-TNFα treatments within 4 months, we examined the subsequent need for corticosteroids.

Results: We identified 3001 patients from 1995 to 2015. The 5-year cumulative proportion of colectomy in cohort 2 was 9.7% (95% confidence interval [CI] 8.4-11.1) and 12.3% (95% CI 10.4-14.6) in cohort 1. The adjusted 5-year hazard ratio (HR) was 0.76 (95% CI 0.60-0.96) for colectomy in cohort 2 compared to cohort 1. A total of 334 patients received anti-TNFα treatments, and 16.8% (56/334) were prescribed corticosteroids in the subsequent 3-month period. Corticosteroid treatment declined with follow-up after 6 and 12 months, 5.4% and 1.2%, respectively.

Conclusion: In patient's ≤20 years, the HR for colectomy within a period of 5 years from the time of diagnosis was reduced in the era of anti-TNFα compared to a historical cohort. In patients treated with anti-TNFα, prescriptions of corticosteroids were virtually ceased after 12 months.
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http://dx.doi.org/10.1111/apt.15510DOI Listing
November 2019

Editorial: anti-TNF therapy-a double-edged sword? Authors' reply.

Aliment Pharmacol Ther 2019 10;50(7):823-824

Division of Gastroenterology, Hepatology, and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

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http://dx.doi.org/10.1111/apt.15459DOI Listing
October 2019

Increased risk of developing Crohn's disease or ulcerative colitis in 17 018 patients while under treatment with anti-TNFα agents, particularly etanercept, for autoimmune diseases other than inflammatory bowel disease.

Aliment Pharmacol Ther 2019 08 2;50(3):289-294. Epub 2019 Jul 2.

Division of Gastroenterology, Hepatology, and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

Background: Anti-TNFα agents have revolutionised management of chronic inflammatory diseases. Paradoxically, these agents might provoke development of de novo autoimmune diseases.

Aim: To examine whether there is an increased risk of developing Crohn's disease (CD) and ulcerative colitis (UC) while under treatment with anti-TNFα agents for diseases other than inflammatory bowel disease (IBD) METHODS: A nationwide cohort study, based on Danish health registries, of all patients who utilised anti-TNFα agents for non-IBD indications. Included were patients, who had diseases for which anti-TNFα agent is indicated (rheumatoid arthritis, psoriasis/psoriatic arthritis, ankylosing spondylitis, others). The observation period for development of de novo IBD started from 2004. Exposed patients had received at least one dose of anti-TNFα.

Results: In total 17 018 individuals with autoimmune diseases were exposed to anti-TNFα (the vast majority had infliximab, etanercept and adalimumab), and 63 308 individuals were not. Patients treated with etanercept had an increased risk of being diagnosed with CD and UC while under treatment, adjusted hazard ratio 2.0 [95% CI: 1.4-2.8] and 2.0 [95% CI: 1.5-2.8], respectively. The corresponding hazards ratios for infliximab were 1.3 [95% CI: 0.8-2.2] and 1.0 [95% CI:0.6-1.6], and for adalimumab 1.2 [95% CI: 0.8-1.8] and 0.6 [95% CI: 0.3-1.0].

Conclusions: Patients treated for autoimmune diseases with anti-TNFα had an increased risk of being diagnosed with CD or UC while under treatment with etanercept. The nature of this association is uncertain. This finding has relevance to clinical care and insights into common mechanisms of the pathophysiology of these diseases.
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http://dx.doi.org/10.1111/apt.15370DOI Listing
August 2019

Serological Assessment of the Quality of Wound Healing Processes in Crohn's Disease.

J Gastrointestin Liver Dis 2019 Jun 1;28:175-182. Epub 2019 Jun 1.

Nordic Bioscience A/S, Herlev Hovedgade, Herlev, Denmark.

Background And Aims: Crohn's disease (CD) is a chronic inflammatory condition characterized by continuous mucosal damage and ongoing wound healing of the intestines. The fibrinolytic system is involved in early parts of the wound healing process. Fibrin is a key mediator of primary blood clot formation and is formed by cross-linking of fibrinogen. To gain insights into the dynamics of wound healing in CD patients we investigated the conversion of fibrinogen into fibrin by the pro-peptide FPA, the amount of factor XIII cross-linked fibrin and total fibrin clot.

Methods: Serum samples of 35 CD patients, 15 non-inflammatory bowel disease (non-IBD) patients and 39 age-matched healthy controls were analyzed for three novel neo-epitope markers: D-fragment and D-dimer, reflecting the degradation of total fibrin clot and factor XIII cross-linked fibrin, as well as FPA, reflecting synthesis of fibrin.

Results: Crohn's disease patients had a significantly lower D-dimer level (p=0.0001) compared to healthy controls. Crohn's disease and non-IBD patients had a significantly higher level of FPA (p<0.0001) and D-fragment/D-dimer ratio (p<0.0001 and p=0.02). FPA, D-dimer and D-fragment/D-dimer ratio could distinguish CD patients from healthy controls with area under the curve of 0.92 (95% CI 0.83-0.97), 0.78 (95% CI 0.67-0.87) and 0.85 (95% CI 0.75-0.93), respectively.

Conclusion: Wound healing parameters were clearly changed in CD patients. FPA levels were higher in CD patients as compared to healthy controls, indicating more ongoing wound healing. D-dimer levels were lower in CD patients than in healthy controls, indicating impaired wound healing due to poor quality of factor XIII cross-linked fibrin and clot resolution.
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http://dx.doi.org/10.15403/jgld-178DOI Listing
June 2019

Anti-TNF Therapy in Pregnant Women With Inflammatory Bowel Disease: Effects of Therapeutic Strategies on Disease Behavior and Birth Outcomes.

Inflamm Bowel Dis 2020 01;26(1):93-102

Department of Gastroenterology, St Vincent's Hospital, and University of Melbourne, Melbourne, Australia.

Background: Active inflammatory bowel disease (IBD) adversely affects pregnancy outcomes. Little is known about the risk of relapse after stopping anti-tumor necrosis factor (anti-TNF) treatment during pregnancy. We assessed the risk of relapse before delivery in women who discontinued anti-TNF treatment before gestational week (GW) 30, predictors of reduced infant birth weight, a marker associated with long-term adverse outcomes, and rates and satisfaction with counseling.

Methods: Pregnant women with IBD receiving anti-TNF treatment were prospectively invited to participate in an electronic questionnaire carried out in 22 hospitals in Denmark, Australia, and New Zealand from 2011 to 2015. Risk estimates were calculated, and birth weight was investigated using t tests and linear regression.

Results: Of 175 women invited, 153 (87%) responded. In women in remission, the relapse rate did not differ significantly between those who discontinued anti-TNF before GW 30 (1/46, 2%) compared with those who continued treatment (8/74, 11%; relative risk, 0.20; 95% confidence interval [CI], 0.02 to 1.56; P = 0.08). Relapse (P = 0.001) and continuation of anti-TNF therapy after GW 30 (P = 0.007) were independently associated with reduced mean birth weight by 367 g (95% CI, 145 to 589 g; relapse) and 274 g (95% CI, 77 to 471 g; anti-TNF exposure after GW 30). Of 134 (88%) women who received counseling, 116 (87%) were satisfied with the information provided.

Conclusions: To minimize fetal exposure in women in remission, discontinuation of anti-TNF before GW 30 seems safe. Relapse and continuation of anti-TNF therapy after GW 30 were each independently associated with lower birth weight, although without an increased risk for birth weight <2500 g. Most women received and were satisfied with counseling.
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http://dx.doi.org/10.1093/ibd/izz110DOI Listing
January 2020

Extracellular Matrix Fragments of the Basement Membrane and the Interstitial Matrix Are Serological Markers of Intestinal Tissue Remodeling and Disease Activity in Dextran Sulfate Sodium Colitis.

Dig Dis Sci 2019 11 24;64(11):3134-3142. Epub 2019 May 24.

Nordic Bioscience, Biomarkers and Research, Herlev Hovedgade 205-207, 2730, Herlev, Denmark.

Background: Chronic intestinal inflammation results in tissue damage partly caused by an increase in matrix metalloproteinases (MMP) activity causing degradation of extracellular matrix (ECM) proteins. We studied intestinal tissue remodeling by quantifying ECM protein fragments in serum in dextran sulfate sodium (DSS)-induced colitis, to investigate ECM protein fragments as serological biomarkers of intestinal tissue remodeling and disease activity.

Methods: Male Sprague-Dawley rats received 5% DSS in drinking water for 5 days followed by 11 days with regular water. Disease activity index (DAI) was scored daily. Serum was collected on day 0, 6, 7, and 16. ELISAs were used to quantify MMP-derived remodeling fragments of basement membrane type IV collagen (C4M and PRO-C4) and interstitial matrix type III collagen (C3M and rPRO-C3).

Results: In DSS rats, serum levels relative to baseline of C4M, PRO-C4, and C3M were elevated (P < 0.01; P < 0.001; P < 0.001) at day 7, which declined at day 16. Levels of rPRO-C3 were lower in DSS rats at day 7 and increased to normal levels at day 16. The ratio between C3M and rPRO-C3 showed an overall degradation (P < 0.0001) of collagen type III in DSS rats at day 7, which correlated to the DAI (r = 0.5588, P < 0.0001).

Conclusion: Our data suggest that remodeling of the basement membrane (C4M and PRO-C4) and the interstitial matrix (C3M and rPRO-C3) increased during DSS-induced colitis and declined with reversal of the disease. Thus, serological biochemical biomarkers of the ECM reflect tissue remodeling and could be studied as markers of disease activity in IBD.
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http://dx.doi.org/10.1007/s10620-019-05676-6DOI Listing
November 2019

Adalimumab in the treatment of chronic pouchitis. A randomized double-blind, placebo-controlled trial.

Scand J Gastroenterol 2019 Feb 10;54(2):188-193. Epub 2019 Feb 10.

d Department of Medical Gastroenterology , Odense University Hospital , Odense , Denmark.

Background: Pouchitis is a complication of ileal pouch-anal anastomosis and occurs in up to 50% of patients 10 years after IPAA with 10% developing refractory pouchitis.

Objective: To evaluate the effect of a TNF-α inhibitor (Adalimumab) in the treatment of refractory pouchitis.

Materials And Methods: A multicenter, randomized double-blind, placebo-controlled trial includes patients with refractory pouchitis for more than 4 weeks despite antibiotic treatment. Patients were randomized to Adalimumab or placebo for 12 weeks. Primary outcome was reduction in clinical pouchitis disease activity index (PDAI) of ≥2 at any time. Secondary endpoints were remission of pouchitis, endoscopic and histologic effect and quality of life.

Results: Thirteen patients were included; six patients received active treatment and seven patients received placebo. Nine patients (5/4, Adalimumab/placebo) completed the 12-week program. Reduction in clinical PDAI ≥ 2 was achieved in three patients in each group (50%/43%, Adalimumab/placebo, p > .5). Total PDAI improved in six patients treated with Adalimumab and two patients on placebo (100%/29%, p = .13). There were no differences in secondary endpoints between the groups.

Conclusions: In this randomized controlled trial of treatment with Adalimumab in patients with refractory pouchitis, we were not able to identify any clinical benefit in the primary or secondary endpoints.
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http://dx.doi.org/10.1080/00365521.2019.1569718DOI Listing
February 2019

Disease course of inflammatory bowel disease unclassified in a European population-based inception cohort: An Epi-IBD study.

J Gastroenterol Hepatol 2019 Jun 21;34(6):996-1003. Epub 2019 Jan 21.

Department of Gastroenterology, University Hospital of Ioannina, Ioannina, Greece.

Background And Aim: A definitive diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) is not always possible, and a proportion of patients will be diagnosed as inflammatory bowel disease unclassified (IBDU). The aim of the study was to investigate the prognosis of patients initially diagnosed with IBDU and the disease course during the following 5 years.

Methods: The Epi-IBD study is a prospective population-based cohort of 1289 IBD patients diagnosed in centers across Europe. Clinical data were captured prospectively throughout the follow-up period.

Results: Overall, 476 (37%) patients were initially diagnosed with CD, 701 (54%) with UC, and 112 (9%) with IBDU. During follow-up, 28 (25%) IBDU patients were changed diagnoses to either UC (n = 20, 71%) or CD (n = 8, 29%) after a median of 6 months (interquartile range: 4-12), while 84 (7% of the total cohort) remained IBDU. A total of 17 (15%) IBDU patients were hospitalized for their IBD during follow-up, while 8 (7%) patients underwent surgery. Most surgeries (n = 6, 75%) were performed on patients whose diagnosis was later changed to UC; three of these colectomies led to a definitive diagnosis of UC. Most patients (n = 107, 96%) received 5-aminosalicylic acid, while 11 (10%) patients received biologicals, of whom five remained classified as IBDU.

Conclusions: In a population-based inception cohort, 7% of IBD patients were not given a definitive diagnosis of IBD after 5 years of follow-up. One in four patients with IBDU eventually was classified as CD or UC. Overall, the disease course and medication burden in IBDU patients were mild.
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http://dx.doi.org/10.1111/jgh.14563DOI Listing
June 2019

Home parenteral support in patients with incurable cancer. Patient characteristics of importance for catheter related complications and overall survival.

Clin Nutr ESPEN 2018 12 12;28:88-95. Epub 2018 Oct 12.

Department of Medical Gastroenterology, Odense University Hospital, Denmark; Institute of Clinical Research, University of Southern Denmark, Denmark. Electronic address:

Purpose: It is uncertain if home parenteral support (HPS) is of advantage in patients with incurable cancer and intestinal failure, functional obstruction or severe malabsorption. From a single centre cohort we present characteristics of patients with incurable cancer treated with HPS.

Methods: Over a ten year period (2005-2015) data were retrospectively collected on patients with incurable cancer discharged on HPS from a Danish tertiary referral centre. Data on socio-demographics, catheters and parenteral nutrition, catheter related complications, re-admissions and mortality were analysed. The inflammation based score; modified Glasgow prognostic score (mGPS) was investigated as a prognostic score by Cox proportional hazard regression analyses adjusted for sex, age, diagnosis, and pathophysiological conditions.

Results: Eighty patients with incurable cancer, aged 25.1-83.6 (median 63.8) were identified. Patients with gynaecologic cancer accounted for 25% of the cohort, thus women predominated. Short bowel syndrome was more prevalent in the patients with gynaecologic or lower gastrointestinal cancer compared to the upper gastrointestinal cancer. Catheter related complications occurred in a minority of patients (31%); most frequent was catheter related bloodstream infection (CRBSI). CRBSI rate was overall 0.97 pr 1000 catheter days, depending on diagnosis. Eleven percent had several infections, and 75% did not have any. Patients self-administering the catheter were younger, less frail and had fewer CRBSI events. Re-admissions were prevalent, and only one fifth of the patients had no re-admissions after initiation of HPS. Patients with mGPS 0 or 1 survived significantly longer, median 372 (CI 39-2006) days versus patients scoring 2 in mGPS, median 43 (CI 6-578) (p < 0.01). In patients with mGPS 0 or 1 survival at six months was 75% and in patients with mGPS 2, 20%. In multivariate cox regression analyses mGPS 2 was a significant predictor of mortality (HR 4.66, 95% CI 2.65-8.20, p < 0.01).

Conclusions: It is feasible to offer HPS to patients with incurable cancer. Frequency of catheter related infections is acceptable but most patients will be re-readmitted after initiation of HPS. Predictors of survival in patients with incurable cancer on HPS may include mGPS. However, our study does not give a clear answer; when to prescribe HPS and who might possible benefit from the treatment in patients with incurable cancer.
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http://dx.doi.org/10.1016/j.clnesp.2018.09.073DOI Listing
December 2018

Natural Disease Course of Ulcerative Colitis During the First Five Years of Follow-up in a European Population-based Inception Cohort-An Epi-IBD Study.

J Crohns Colitis 2019 Feb;13(2):198-208

IBD Clinical and Research Centre, ISCARE, Prague, Czech Republic.

Background And Aims: Few population-based cohort studies have assessed the disease course of ulcerative colitis [UC] in the era of biological therapy and widespread use of immunomodulators. The aim of this study was to assess the 5-year outcome and disease course of patients with UC in the Epi-IBD cohort.

Methods: In a prospective, population-based inception cohort of unselected patients with UC, patients were followed up from the time of their diagnosis, which included the collection of their clinical data, demographics, disease activity, medical therapy, and rates of surgery, cancers, and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis.

Results: A total of 717 patients were included in the study. During follow-up, 43 [6%] patients underwent a colectomy and 163 [23%] patients were hospitalised. Of patients with limited colitis [distal to the left flexure], 90 [21%] progressed to extensive colitis. In addition, 92 [27%] patients with extensive colitis experienced a regression in disease extent, which was associated with a reduced risk of hospitalisation (hazard ratio [HR]: 0.5 95% CI: 0.3-0.8]. Overall, patients were treated similarly in both geographical regions; 80 [11%] patients needed biological therapy and 210 [29%] patients received immunomodulators. Treatment with immunomodulators was found to reduce the risk of hospitalisation [HR: 0.5 95% CI: 0.3-0.8].

Conclusions: Although patients in this population-based cohort were treated more aggressively with immunomodulators and biological therapy than in cohorts from the previous two decades, their disease outcomes, including colectomy rates, were no different. However, treatment with immunomodulators was found to reduce the risk of hospitalisation.
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http://dx.doi.org/10.1093/ecco-jcc/jjy154DOI Listing
February 2019

Population structure of Miscanthus sacchariflorus reveals two major polyploidization events, tetraploid-mediated unidirectional introgression from diploid M. sinensis, and diversity centred around the Yellow Sea.

Ann Bot 2019 10;124(4):731-748

Department of Crop Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

Background And Aims: Miscanthus, a C4 perennial grass native to East Asia, is a promising biomass crop. Miscanthus sacchariflorus has a broad geographic range, is used to produce paper in China and is one of the parents (along with Miscanthus sinensis) of the important biomass species Miscanthus × giganteus. The largest study of M. sacchariflorus population genetics to date is reported here.

Methods: Collections included 764 individuals across East Asia. Samples were genotyped with 34 605 single nucleotide polymorphisms (SNPs) derived from restriction site-associated DNA sequencing (RAD-seq) and ten plastid microsatellites, and were subjected to ploidy analysis by flow cytometry.

Key Results: Six major genetic groups within M. sacchariflorus were identified using SNP data: three diploid groups, comprising Yangtze (M. sacchariflorus ssp. lutarioriparius), N China and Korea/NE China/Russia; and three tetraploid groups, comprising N China/Korea/Russia, S Japan and N Japan. Miscanthus sacchariflorus ssp. lutarioriparius was derived from the N China group, with a substantial bottleneck. Japanese and mainland tetraploids originated from independent polyploidization events. Hybrids between diploid M. sacchariflorus and M. sinensis were identified in Korea, but without introgression into either parent species. In contrast, tetraploid M. sacchariflorus in southern Japan and Korea exhibited substantial hybridization and introgression with local diploid M. sinensis.

Conclusions: Genetic data indicated that the land now under the Yellow Sea was a centre of diversity for M. sacchariflorus during the last glacial maximum, followed by a series of migrations as the climate became warmer and wetter. Overall, M. sacchariflorus has greater genetic diversity than M. sinensis, suggesting that breeding and selection within M. sacchariflorus will be important for the development of improved M. × giganteus. Ornamental M. sacchariflorus genotypes in Europe and North America represent a very narrow portion of the species' genetic diversity, and thus do not well represent the species as a whole.
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http://dx.doi.org/10.1093/aob/mcy161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821896PMC
October 2019

Vitamin D deficiency in a European inflammatory bowel disease inception cohort: an Epi-IBD study.

Eur J Gastroenterol Hepatol 2018 11;30(11):1297-1303

Pekka Collin Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland.

Background: Serum vitamin D level is commonly low in patients with inflammatory bowel disease (IBD). Although there is a growing body of evidence that links low vitamin D level to certain aspects of IBD such as disease activity and quality of life, data on its prevalence and how it varies across disease phenotype, smoking status and treatment groups are still missing.

Materials And Methods: Patients diagnosed with IBD between 2010 and 2011 were recruited. Demographic data and serum vitamin D levels were collected. Variance of vitamin D level was then assessed across different treatment groups, disease phenotype, disease activity and quality of life scores.

Results: A total of 238 (55.9% male) patients were included. Overall, 79% of the patients had either insufficient or deficient levels of vitamin D at diagnosis. Patients needing corticosteroid treatment at 1 year had significantly lower vitamin D levels at diagnosis (median 36.0 nmol/l) (P=0.035). Harvey-Bradshaw Index (P=0.0001) and Simple Clinical Colitis Activity Index scores (P=0.0001) were significantly lower in patients with higher vitamin D level. Serum vitamin D level correlated significantly with SIBQ score (P=0.0001) and with multiple components of SF12. Smokers at diagnosis had the lowest vitamin D levels (vitamin D: 34 nmol/l; P=0.053).

Conclusion: This study demonstrates the high prevalence of low vitamin D levels in treatment-naive European IBD populations. Furthermore, it demonstrates the presence of low vitamin D levels in patients with IBD who smoke.
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http://dx.doi.org/10.1097/MEG.0000000000001238DOI Listing
November 2018

Serum type XVI collagen is associated with colorectal cancer and ulcerative colitis indicating a pathological role in gastrointestinal disorders.

Cancer Med 2018 09 20;7(9):4619-4626. Epub 2018 Jul 20.

Biomarkers & Research, Nordic Bioscience, Herlev, Denmark.

Altered extracellular matrix (ECM) remodeling is an important part of the pathology of gastrointestinal (GI) disorders. In the intestine, type XVI collagen (col-16) plays a role in pathogenesis by affecting ECM architecture and induce cell invasion. Measuring col-16 in serum may therefore have biomarker potential in GI disorders such as colorectal cancer (CRC) and ulcerative colitis (UC). The aim of this study was to determine whether col-16 can serve as a biomarker for altered ECM remodeling in patients with CRC and UC. A monoclonal antibody was raised against the C-terminal end of col-16 (PRO-C16), and a competitive enzyme-linked immunosorbent assay (ELISA) was developed and technically validated. Levels of PRO-C16 were measured in serum from patients with CRC (before (n = 50) and 3 months after (n = 23) tumor resections), UC (n = 39) and healthy controls (n = 50). The PRO-C16 ELISA was specific toward the C-terminal of col-16. PRO-C16 was significantly elevated both in serum from patients with CRC (P = 0.0026) and UC (P < 0.0001) compared to controls. No difference was detected in levels of PRO-C16 between patients with CRC at baseline and 3 months after tumor resections (P > 0.999). Levels of PRO-C16 identified patients with a GI disorder with a positive predictive value of 0.9 and an odds ratio of 12 (95%CI = 4.5-29.5, P < 0.0001). The newly developed assay detected significantly elevated levels of PRO-C16 in serum from patients with GI disorders compared to controls suggesting its potential as a biomarker in this setting. Future studies are needed to validate these findings.
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http://dx.doi.org/10.1002/cam4.1692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144245PMC
September 2018

Treatment Failure of TNF-α Inhibitors in Obese Patients With Inflammatory Bowel Disease-A Cohort Study.

Inflamm Bowel Dis 2018 11;24(12):2628-2633

Department of Medical Gastroenterology, Odense University Hospital, Odense, Denmark.

Background: In treatment of inflammatory bowel disease (IBD) with anti-tumor necrosis factor-α agents (anti-TNF-α), obesity has been suspected as a cause of accelerated loss of response (LOR). We sought to determine whether overweight IBD patients have accelerated LOR when treated with anti-TNF-α agents, compared with normal weight IBD patients.

Methods: We identified a cohort of adult IBD patients treated with anti-TNF-α agents at a Danish university hospital. Patients were grouped according to body mass index (BMI), and our main outcome was time to LOR. We performed survival analyses on LOR and calculated hazard ratios (HRs) with the normal weight group as the reference, while adjusting for confounders.

Results: Of 210 eligible patients, 92 (44%) experienced LOR. One hundred eighty patients were treated with infliximab and 30 with adalimumab, 114 (54%) were normal weight, 51 (24%) were overweight, and 45 (21%) were obese. Regression analysis produced the following adjusted HRs, compared with the normal weight group: overweight 0.89 (95% confidence interval [CI], 0.51-1.56) and obese 1.31 (95% CI, 0.76-2.24), thus showing no statistically significant association between BMI and time to LOR. Subgroup analyses produced similar results, except for obese ulcerative colitis patients having an adjusted HR of 2.42 (95% CI, 1.03-5.70).

Conclusions: In IBD patients treated with anti-TNF-α agents, we found no overall association between increased BMI and accelerated LOR.
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http://dx.doi.org/10.1093/ibd/izy178DOI Listing
November 2018

Efficacy and safety of faecal microbiota transplantation in patients with psoriatic arthritis: protocol for a 6-month, double-blind, randomised, placebo-controlled trial.

BMJ Open 2018 04 27;8(4):e019231. Epub 2018 Apr 27.

Department of Rheumatology, Odense University Hospital, Odense, Denmark.

Introduction: An unbalanced intestinal microbiota may mediate activation of the inflammatory pathways seen in psoriatic arthritis (PsA). A randomised, placebo-controlled trial of faecal microbiota transplantation (FMT) infused into the small intestine of patients with PsA with active peripheral disease who are non-responsive to methotrexate (MTX) treatment will be conducted. The objective is to explore clinical aspects associated with FMT performed in patients with PsA.

Methods And Analysis: This trial is a randomised, two-centre stratified, double-blind (patient, care provider and outcome assessor), placebo-controlled, parallel-group study. Eighty patients will be included and randomised (1:1) to either placebo (saline) or FMT provided from an anonymous healthy donor. Throughout the study, both groups will continue the weekly self-administered subcutaneous MTX treatment, remaining on the preinclusion dosage (15-25 mg/week). The clinical measures of psoriasis and PsA disease activity used include the Short (2-page) Health Assessment Questionnaire, the Dermatology Quality of Life Index, the Spondyloarthritis Research Consortium of Canada Enthesitis Index, the Psoriasis Area Severity Index, a dactylitis digit count, a swollen/tender joint count (66/68), plasma C reactive protein as well as visual analogue scales for pain, fatigue and patient and physician global assessments. The primary end point is the proportion of patients who experience treatment failure during the 6-month trial period. The number of adverse events will be registered throughout the study.

Ethics And Dissemination: This is a proof-of-concept clinical trial and will be performed in agreement with Good Clinical Practice standards. Approvals have been obtained from the local Ethics Committee (DK-S-20150080) and the Danish Data Protection Agency (15/41684). The study has commenced in May 2017. Dissemination will be through presentations at national and international conferences and through publications in international peer-reviewed journal(s).

Trial Registration Number: NCT03058900; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2017-019231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922473PMC
April 2018

Fecal Calprotectin During Pregnancy in Women With Moderate-Severe Inflammatory Bowel Disease.

Inflamm Bowel Dis 2018 03;24(4):839-848

Center for Clinical Epidemiology, Odense University Hospital, and Research Unit of Clinical Epidemiology, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.

Background: Fecal calprotectin (FC) is a biomarker used for assessing disease activity among IBD patients. Sparse knowledge exists as to whether FC correlates with clinical disease activity during pregnancy. Our aim was to assess FC and selected biomarkers in women with moderate-severe IBD and correlate them with clinical disease activity scores in pregnant women.

Methods: We identified a nationwide cohort of 219 singleton pregnancies in women with moderate-severe disease (all treated with anti-tumor recrosis factor-α [anti-TNF-α] therapy during pregnancy), and we reviewed the medical records to extract clinical details and information on biomarkers. FC, C-reactive protein (CRP), hemoglobin, and albumin were collected according to each trimester.

Results: A total of 346 FC measurements were obtained throughout the gestational periods. FC values were between 80-120, 259-349, and 778-1277 mg/kg in women with clinically inactive, mild, and moderate-severe disease activity, respectively, and were significantly higher among the women with clinical disease activity. ROC curves for disease activity were computed according to the preconception period: 0.81 (95% confidence interval [CI], 0.69-0.93), first trimester: 0.73 (95% CI, 0.60-0.86), second trimester: 0.74 (95% CI, 0.62-0.86), and third trimester: 0.76 (95% CI, 0.64-0.88), respectively. We found a sensitivity of 69.7%-80.0%, a specificity of 66.7%-73.3%, and a positive predictive value of 66.7%-74.4% over the 4 gestational periods when a cutoff of 200 mg/kg was used. We found no clinically significant differences in CRP, albumin, or hemoglobin.

Conclusions: FC in pregnant women with moderate-severe IBD treated with anti-TNF-α therapy was significantly higher in women with clinical disease activity compared with the women without. FC correlated with the level of clinical disease activity in all gestational periods.
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http://dx.doi.org/10.1093/ibd/izx055DOI Listing
March 2018