Publications by authors named "Ulf Helwig"

47 Publications

Transmural Response and Transmural Healing Defined by Intestinal Ultrasound - New Potential Therapeutic Targets?

J Crohns Colitis 2021 Jun 29. Epub 2021 Jun 29.

Department of Gastroenterology, Klinikum Lueneburg gGmbH, Lueneburg, Germany.

Background And Aims: Intestinal ultrasound (IUS) is a useful modality to monitor patients with inflammatory bowel diseases (IBD). Little is known about the use of IUS and appropriate definitions for transmural response (TR) and healing (TH). We aimed to establish the use of IUS in monitoring TH as a potential target in routine medical practice.

Methods: Based on the prospective, non-interventional, multicentre studies TRUST and TRUST&UC, we conducted a post-hoc analysis of 351 IBD patients with increased bowel wall thickness (BWT). We analysed the rates of patients achieving TR and TH, comparing three definitions of TH. In 137 Crohn's disease (CD) patients, the predictive value of TR and TH was investigated for the clinical and sonographic outcome at week 52.

Results: Within 12 weeks of treatment intensification, 65.6% (n = 118) of CD patients and 76.6% (n = 131) of ulcerative colitis (UC) patients showed a TR. Depending on the definition, 23.9%-37.2% (n=58/67/43) of CD patients and 45.0%-61.4% (n=90/105/77) of UC patients had TH at week 12. CD patients with TH were more likely to reach clinical remission at week 12 (OR 3.33 [1.09-10.2]; p = 0.044) and a favourable sonographic outcome (OR 5.59 [1.97-15.8]; p = 0.001) at week 52 compared with patients without TH.

Conclusions: IUS response and TH in a relevant proportion of patients suggests that IUS is a useful method to assess transmural inflammatory activity in daily clinical practice. TR and TH are predictive for the sonographic outcome at week 52.
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http://dx.doi.org/10.1093/ecco-jcc/jjab106DOI Listing
June 2021

Expression of the fructose transporter GLUT5 in patients with fructose malabsorption.

Z Gastroenterol 2021 Jun 15;59(6):531-539. Epub 2021 Jun 15.

Specialist Practice for Internal Medicine, Oldenburg, Oldenburg Germany.

Background:  Patients with abdominal symptoms are frequently diagnosed with fructose malabsorption (FM). Fructose is absorbed by monosaccharide transporters located in the brush border of the human small intestine. The aim of this study was to investigate the histoanatomical distribution of the main fructose transporter GLUT5.

Materials And Methods:  We studied 223 patients diagnosed with FM by a hydrogen breath test and grouped according to their response to a fructose-free diet. The control group were 42 healthy individuals and 29 patients with celiac disease (CD). The fructose breath test was done with 50 g fructose. The expression of Glut5 in duodenal biopsy specimens was studied by immunohistochemistry. The Kruskal-Wallis-test and Mann-Whitney U-test were used to carry out the statistical analysis.

Results:  The histoanatomical expression pattern of GLUT5 did not differ significantly between those patients with FM who responded completely to a fructose-free diet (n = 183) and healthy individuals (n = 42); nor did it correlate to H2 production measured in fructose breath testing. In patients with FM, the GLUT5 expression pattern did not differ between those individuals responding to a fructose-free diet and those who did not. However, GLUT5 expression pattern was significantly different in patients with CD (n = 29) compared to patients with FM and to healthy individuals (p = 0.009).

Conclusion:  GLUT5 expression patterns are not be related to adult patients with FM. However, in secondary malabsorption, a decreased GLUT5 expression was found. Further investigation is needed to understand the essential factors in FM and the influence on functional gastrointestinal disorders.
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http://dx.doi.org/10.1055/a-1156-4386DOI Listing
June 2021

Addendum to S3-Guidelines Crohn's disease and ulcerative colitis: Management of Patients with Inflammatory Bowel Disease in the COVID-19 Pandemic - open questions and answers.

Z Gastroenterol 2020 Oct 9;58(10):982-1002. Epub 2020 Oct 9.

Klinik für Innere Medizin, Gastroenterologie, Klinikum Lüneburg, Lüneburg.

The COVID-19 pandemic is a global outbreak of new onset infections with the SARS-CoV-2 virus. To date, more than 3.4 million people have been infected throughout the world. In Germany, approximately 450,000 patients suffer from inflammatory bowel disease; these patients generally require continuous expert care and support. Against the background of a rapidly accumulating knowledge base on SARS-CoV-2, 68 expert authors of the current DGVS guidelines for Crohn's disease and ulcerative colitis took part in a virtual meeting to compile up-to-date, practice-orientated recommendations aimed at improving the care of patients with IBD. These recommendations address the risk of infection, including the risk for specific patient groups, the possible course of the disease, and consequences for pharmacological and surgical therapies of the underlying disease, as well as general measures for infection prevention and adjuvant prophylactic and therapeutic options.
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http://dx.doi.org/10.1055/a-1234-8079DOI Listing
October 2020

Real-world clinical effectiveness and safety of vedolizumab and anti-tumor necrosis factor alpha treatment in ulcerative colitis and Crohn's disease patients: a German retrospective chart review.

BMC Gastroenterol 2020 Jul 8;20(1):211. Epub 2020 Jul 8.

Gastroenterology Outpatient Clinic, Heidelberg, Germany.

Background: Real-world comparisons of biologic treatment outcomes for ulcerative colitis (UC) or Crohn's disease (CD) patients are limited. We sought to evaluate the real-world effectiveness of vedolizumab (VDZ) and anti-tumor necrosis factor alpha (anti-TNFα) in UC and CD patients in Germany.

Methods: A retrospective chart review (15 sites) investigated UC and CD patients who were biologic-treatment naïve (biologic-naïve) or had received no more than one prior anti-TNFα before initiating treatment with VDZ or anti-TNFα between 15 July 2014 and 20 October 2015. Kaplan-Meier analyses assessed time to first chart-documented clinical remission (CR) and symptom resolution (UC: rectal bleeding [RB], stool frequency [SF]; CD: abdominal pain [AP], liquid stools [LS]) and outcome duration.

Results: A total of 133 UC (76 VDZ; 57 anti-TNFα) and 174 CD (69 VDZ; 105 anti-TNFα) patients were included. By Week 26, estimated cumulative rates of patients achieving CR or symptom resolution with VDZ vs anti-TNFα treatment were for UC: CR, 53.7% vs 31.7%; RB, 66.8% vs 55.8%; and SF, 59.8% vs 50.7%, respectively; and for CD: CR, 14.4% vs 32.8%; AP, 62.5% vs 56.0%; and LS, 29.9% vs 50.3%, respectively. Outcomes were sustained similarly between treatments, except RB (VDZ vs anti-TNFα: median 38.1 vs 15.1 weeks, P = 0.03). Treatment-related adverse events occurred in 5.3% vs 7.0% (UC) and 8.7% vs 19.0% (CD) of VDZ vs anti-TNFα patients, respectively.

Conclusions: Although there were differences in CR, symptom resolution, and safety profiles, real-world data support both VDZ and anti-TNFα as effective treatment options in UC and CD.
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http://dx.doi.org/10.1186/s12876-020-01332-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341567PMC
July 2020

A Prospective Multicenter Study on the Prevalence of Fructose Malabsorption in Patients with Chronic Inflammatory Bowel Disease.

Digestion 2021 9;102(3):397-403. Epub 2020 Jun 9.

Department of Internal and Integrative Medicine, Klinikum Bamberg, Bamberg, Germany.

Background And Aims: Patients with chronic inflammatory bowel disease (IBD) might have a higher prevalence of fructose malabsorption than healthy controls. This study's aim was to determine the prevalence and symptom severity of fructose malabsorption in patients with active and inactive IBD.

Methods: The present study was a multicenter noninterventional diagnostic pilot trial. Two hundred fifty-one participants were recruited from 12 outpatient clinics for internal medicine across Germany and from the University of Kiel. Fructose malabsorption was diagnosed by hydrogen breath testing. Patients diagnosed with bacterial overgrowth, non-H2 producers, and patients who were tested positive for lactose malabsorption were excluded. Gastrointestinal symptoms during breath testing were evaluated using four-point subjective items to determine severity of bloating, abdominal pain, and diarrhea.

Results: Two hundred five patients (45 with active IBD, 80 with IBD in remission, and 81 healthy controls) were analyzed. The number of patients diagnosed with fructose malabsorption - 35/44 (79.6%) in patients with active IBD, 59/80 (73.8%) inactive IBD, and 66/81 (81.5%) in healthy controls - did not differ between the groups (χ2 [2, N = 205] = 1.48, p = 0.48). However, abdominal pain was more frequent in patients with active IBD than patients with IBD in remission (z = -2.936, p = 0.010), and diarrhea was more frequent in patients with active IBD than in healthy controls (z = 2.489, p = 0.038).

Conclusions: Fructose malabsorption is not more common among patients with IBD than healthy subjects. However, the greater prevalence of patient-reported symptoms among patients with IBD may be of pathological and therapeutic relevance.
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http://dx.doi.org/10.1159/000507851DOI Listing
June 2020

Comparative Analysis of the 3-Year Persistence Rate with Second-Line Vedolizumab and Tumor Necrosis Factor-α Inhibitors in Patients with Inflammatory Bowel Disease Followed in Gastroenterology Practices in Germany.

Dig Dis 2020 11;38(6):466-473. Epub 2020 Feb 11.

Medical Clinic II, Department of Gastroenterology, Hepatology, Endocrinology, Diabetology and Infectious Diseases, Klinikum Fulda, Fulda, Germany.

Background: Our goal was to investigate the 3-year persistence rates with second-line vedolizumab and tumor necrosis factor-α (TNF-α) inhibitors (i.e., adalimumab, golimumab, infliximab) in patients with inflammatory bowel disease (IBD) who were followed in gastroenterology practices in Germany.

Methods: This study included patients aged ≥18 years who had received prescriptions for second-line biological drugs in Germany between 2014 and 2017 (n = 5,150) retrieved from the longitudinal prescription database. Vedolizumab users were matched to adalimumab, golimumab, and infliximab users based on age, sex, and index year. The primary outcome of the study was the rate of persistence with vedolizumab compared with the rate of persistence with adalimumab, golimumab, and infliximab within 3 years of second-line therapy initiation in IBD patients. Persistence was estimated as therapy time without discontinuation, with discontinuation being defined as at least 90 days without any prescription for the biological drug of interest.

Results: After matching patients who had received vedolizumab with those who had received adalimumab, the rate of persistence after 3 therapy years was 30.3% for vedolizumab and 27.9% for adalimumab (log-rank p = 0.005). The corresponding figures were 27.8 and 20.8% in the vedolizumab-golimumab matched-pair analysis (log-rank p < 0.001) and 29.5 and 25.2% in the vedolizumab-infliximab matched-pair analysis (log-rank p value = 0.008). Vedolizumab was associated with a significant 0.85-, 0.72-, and 0.86-fold decrease in the risk of discontinuation within 3 years of therapy initiation compared to adalimumab, golimumab, and infliximab, respectively.

Conclusions: Treatment persistence was higher for vedolizumab than for TNF-α inhibitors up to 3 years after initiating second-line biological therapy.
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http://dx.doi.org/10.1159/000506121DOI Listing
November 2020

Comparative Analysis of 3-Year Persistence With Vedolizumab Compared With Antibodies Against Tumor Necrosis Factor-Alpha in Patients With Inflammatory Bowel Disease in Germany: Retrospective Analysis of a Large Prescription Database.

J Clin Gastroenterol 2021 01;55(1):e1-e7

Department of Gastroenterology, Hepatology, Endocrinology, Diabetology and Infectious Diseases, Medical Clinic II, Klinikum Fulda, Fulda, Germany.

Aims: The goal of the study was to compare persistence with vedolizumab versus adalimumab, golimumab, and infliximab in biologics-naïve patients with inflammatory bowel disease treated in gastroenterological practices and outpatient clinics in Germany.

Methods: Patients aged 18 or older who had initiated a biological therapy (vedolizumab, infliximab, adalimumab, or golimumab) were included in the present study. Prescriptions between July 2014 and March 2017 of the respective biological drug emerging from gastroenterological practices or outpatient clinics in Germany were retrieved from the longitudinal prescription (LRx) database. Patients treated with vedolizumab were matched with patients treated with infliximab, adalimumab, or golimumab on the basis of age, gender, medication before biologic therapy, and index year. The primary outcome variable of the study was the rate of persistence with vedolizumab compared with antitumor necrosis factor biologics (infliximab, adalimumab, and golimumab) within 3 years of the first prescription in outpatient settings.

Results: Kaplan-Meier analysis was performed in 15,984 patients naïve to biologics revealing the statistically lower risk of discontinuation for vedolizumab compared with adalimumab, golimumab, or infliximab. In matched-pairs analyses, within 3 years after the first prescription, 39.5% of 2076 patients were persistent to vedolizumab compared with 33.5% of matched patients persistent to adalimumab (P<0.001). 37.6% of 716 patients were persistent to vedolizumab compared with 24.7% of matched patients persistent to golimumab (P<0.001). 35.7% of 2055 patients were persistent to vedolizumab compared with 30.2% of matched patients persistent to infliximab (P=0.119). Vedolizumab was associated with a significantly lower risk of therapy discontinuation compared with adalimumab [hazard ratio (HR)=0.86; 95% confidence interval (CI), 0.81-0.93] and golimumab (HR=0.60; 95% CI, 0.54-0.67), respectively; the vedolizumab risk of therapy discontinuation was numerically lower than infliximab but statistical significance was not achieved (HR=0.93; 95% CI, 0.85-1.02).

Conclusion: In biologics-naïve IBD patients treated in outpatient settings in Germany, matched-pair analyses showed that vedolizumab was associated with significantly improved drug persistence compared with adalimumab or golimumab, whereas numerical improvement was shown in comparison with infliximab.
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http://dx.doi.org/10.1097/MCG.0000000000001323DOI Listing
January 2021

Intestinal ultrasound for monitoring therapeutic response in patients with ulcerative colitis: results from the TRUST&UC study.

Gut 2020 09 20;69(9):1629-1636. Epub 2019 Dec 20.

Department of Gastroenterology, Stadtisches Klinikum Luneburg gGmbH, Luneburg, Germany.

Objective: Prospective evaluation of intestinal ultrasound (IUS) for disease monitoring of patients with ulcerative colitis (UC) in routine medical practice.

Design: TRansabdominal Ultrasonography of the bowel in Subjects with IBD To monitor disease activity with UC (TRUST&UC) was a prospective, observational study at 42 German inflammatory bowel disease-specialised centres representing different care levels. Patients with a diagnosis of a proctosigmoiditis, left-sided colitis or pancolitis currently in clinical relapse (defined as Short Clinical Colitis Activity Index ≥5) were enrolled consecutively. Disease activity and vascularisation within the affected bowel wall areas were assessed by duplex/Colour Doppler ultrasonography.

Results: At baseline, 88.5% (n=224) of the patients had an increased bowel wall thickness (BWT) in the descending or sigmoid colon. Even within the first 2 weeks of the study, the percentage of patients with an increased BWT in the sigmoid or descending colon decreased significantly (sigmoid colon 89.3%-38.6%; descending colon 83.0%-42.9%; p<0.001 each) and remained low at week 6 and 12 (sigmoid colon 35.4% and 32.0%; descending colon 43.4% and 37.6%; p<0.001 each). Normalisation of BWT and clinical response after 12 weeks of treatment showed a high correlation (90.5% of patients with normalised BWT had symptomatic response vs 9.5% without symptomatic response; p<0.001).

Conclusions: IUS may be preferred in general practice in a point-of-care setting for monitoring the disease course and for assessing short-term treatment response. Our findings give rise to the assumption that monitoring BWT alone has the potential to predict the therapeutic response, which has to be verified in future studies.
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http://dx.doi.org/10.1136/gutjnl-2019-319451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456734PMC
September 2020

[Appendicectomy prior to colectomy in ulcerative colitis?]

Authors:
Ulf Helwig

Z Gastroenterol 2019 12 11;57(12):1514. Epub 2019 Dec 11.

Facharzt für Innere Medizin und Gastroenterologie, Ernährungsmedizin.

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http://dx.doi.org/10.1055/a-0970-2291DOI Listing
December 2019

Monitoring of Vedolizumab Infusion Therapy (MOVE-IT) Response With Fecal Inflammation Markers, Ultrasound, and Trough Serum Level in Patients With Ulcerative Colitis: Protocol for a Multicentric, Prospective, Noninterventional Study.

JMIR Res Protoc 2019 Nov 8;8(11):e14335. Epub 2019 Nov 8.

University of Kiel, Kiel, Germany.

Background: Vedolizumab has been shown to induce clinical remission in patients with active ulcerative colitis. Treatment with anti-integrin vedolizumab leads to clinical remission in 16.9% and clinical response in 47.1% of cases after 6 weeks. However, in clinical practice, no decision to discontinue or continue vedolizumab therapy is made until 14 weeks at the earliest.

Objective: The aim of this study is to develop an algorithm for optimizing vedolizumab administration in patients with moderate-to-severe ulcerative colitis by calculating the probability of clinical response at week 14, on the basis of the data from week 6.

Methods: This is a prospective, single-arm, multicentric, noninterventional, observational study with no interim analyses and a sample size of 35 evaluable patients.

Results: The enrollment started in August 2018 and was still open at the date of submission. The study is expected to complete in September 2020.

Conclusions: The early identification of patients who are responding to an integrin antibody is therapeutically beneficial. At the same time, patients who are not responding can be identified earlier. The development of a therapeutic algorithm for identifying patients as responders or nonresponders can thus help prescribing physicians avoid ineffective treatments and stop these very early.
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http://dx.doi.org/10.2196/14335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874801PMC
November 2019

Predictive parameters for the clinical course of Crohn's disease: development of a simple and reliable risk model.

Int J Colorectal Dis 2019 Oct 24;34(10):1653-1660. Epub 2019 Aug 24.

Clinic for Internal Medicine IV, Jena University Hospital, Jena, Germany.

Purpose: The aim of our study was to identify clinical parameters in recently diagnosed Crohn's disease (CD) patients for prediction of their disease course.

Methods: EPIC (Early Predictive parameters of Immunosuppressive therapy in Crohn's disease) is a prospective, observational study in 341 patients with a recent CD diagnosis (≤ 6 months), and naïve to immunosuppressants (IS) and anti-tumor necrosis factor α (TNF) agents. Patient characteristics were documented up to 2 years. In line with national and international guidelines, a complicated disease course was defined as need for immunosuppressants and/or anti-TNF agents, and CD-related hospitalization with or without immunosuppressants and/or anti-TNF agents.

Results: A total of 212 CD patients were analyzed of whom 57 (27%) had an uncomplicated disease within 24 months, while 155 (73%) had a complicated disease course: need for IS and/or anti-TNF agents (N = 115), CD-related hospitalization with or without IS/anti-TNF agents (N = 40). Identified risk predictors for a complicated disease were as follows: age at onset < 40 years (OR 2.3; 95% CI 1.2-4.5), anemia (OR 2.1; 95% CI 1.1-4.2), and treatment with systemic corticosteroids at first flare (OR 2.2; 95% CI 1.1-4.7). These three parameters were used to develop a risk model allowing prediction of the future disease course.

Conclusion: Our three-parameter model enables an assessment of each CD patient's risk to develop a complicated disease course. Due to the easy accessibility of these parameters, this model can be utilized in daily clinical care to assist selecting the initial treatment for each individual patient.
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http://dx.doi.org/10.1007/s00384-019-03369-0DOI Listing
October 2019

Small bowel capsule endoscopy in ulcerative colitis: the capcolitis study: a prospective observational study.

Eur J Gastroenterol Hepatol 2019 Jul;31(7):766-772

Department Internal, Medicine-General Internal Medicine, University Medical Center Schleswig-Holstein, Kiel, Germany.

Background: Clinical phenotypes in inflammatory bowel disease (IBD) patients include ulcerative colitis (UC) and Crohn's disease (CD). Moreover, genetic aetiology studies suggest a continuum of phenotypes from exclusively ileal to left-sided colonic disease.

Patients And Methods: A nationwide registry (BioColitis Registry) prospectively recorded ∼900 UC-patients in Germany and in the CapColitis substudy, small bowel capsule endoscopy (SBCE) was consecutively offered at participating centres. The primary objective was to investigate the presence of small bowel lesions. In total, 127 UC-patients were included.

Results: SBCE was evaluable in 125 of 127 UC-patients. Small bowel lesions were found in 16/125 (13%) patients, of which nine were classified as clinically significant [backwash ileitis (n=4) or lesions suggestive of CD (n=5)], and seven were not significant [biopsy-induced lesions (n=3) or single small bowel lesions (n=4)]. The SBCE results prompted diagnostic workups in all patients with clinically relevant lesions, and all patients with lesions suggestive for CD (4%) were re-classified as CD by the treating physicians.

Conclusion: Systematic examination of 125 consecutive UC-patients failed to confirm a clinically important phenotype overlap with CD, as suggested by genetic aetiology studies. In five patients (4%) with small bowel lesions, the diagnosis was changed to CD.
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http://dx.doi.org/10.1097/MEG.0000000000001410DOI Listing
July 2019

The Predictive Value of the Hydrogen Breath Test in the Diagnosis of Fructose Malabsorption.

Digestion 2019 4;99(2):140-147. Epub 2018 Sep 4.

Department of Integrative Gastroenterology, Kliniken Essen-Mitte, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.

Background: Fructose malabsorption is commonly diagnosed by the hydrogen fructose (H2) breath test. However, the mechanisms behind fructose malabsorption in humans are not well understood and the clinical relevance of this test is considered controversial. Hence, the main aim of this study is to evaluate the predictive value of the H2 breath test.

Methods: Regarding exclusion criteria, the study enrolled 562 consecutive patients, enlisted to a gastroenterology clinic between 2009 and 2011 for testing malabsorption. In the final data analysis, 246 patients were included. Ecotrophologists used 3 categories to rate dietary success: complete response, partial response and no response to the diet. They also rated the occurrence of abdominal pain, diarrhoea and bloating during the H2 breath test. Ordinal regression analysis using SPSS was performed to evaluate whether H2 breath test results - measured as the maximum H2 level, the maximum increase in H2, and the area under the curve (AUC) - predicted dietary success or failure. Correlation analyses were applied to test whether symptoms of fructose malabsorption correlated with the H2 breath test measures. Finally, we evaluated whether cut-off-values of 40 or 60 parts per million (ppm) serve better than the test measure of 20 ppm to diagnose fructose malabsorption.

Results: When a fructose-free diet was administered it was found that 103 patients (41.9%) were complete responders, 116 (47.2%) were partial responders and 27 (11%) were non-responders. The H2 breath test with the 20 ppm cut-off-value, that is, the maximum H2 level, the maximum increase in H2, and the AUC did not predict dietary response (all 95% CI ns). This was also the case when using 40 or 60 ppm as cut-off-values (all 95% CI ns). Abdominal pain during the test correlated significantly with the AUC. Diarrhoea and bloating correlated significantly with the AUC, the maximum H2 level and the maximum increase in H2 (p < 0.05).

Conclusions: The H2 breath test produced no predictive value for the fructose-free diet outcomes; its value as a predictive test is therefore questionable. However, the symptoms of fructose malabsorption correlated significantly with the H2 breath test measures, and this is an indication that there is at least a degree of validity of the H2 breath test beyond the simple detection or exclusion of fructose malabsorption.
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http://dx.doi.org/10.1159/000489877DOI Listing
August 2019

Cyclophosphamide Pulse Therapy in Severe Refractory Crohn's Disease: A Retrospective Multicenter Case Series.

Inflamm Intest Dis 2018 Mar 22;2(3):139-146. Epub 2017 Nov 22.

Department of Internal Medicine I, University Hospital Schleswig-Holstein, Lübeck, Germany.

Background And Aims: In Crohn's disease (CD) patients still remain refractory to current regimens, including biologicals. Previous data from small single-center studies indicated cyclophosphamide pulse therapy (CPT) to be effective for induction of remission at least in steroid-refractory cases. The aim of the present study was to study the efficacy and safety of CPT in mainly tumor necrosis factor (TNF)-refractory complicated CD patients.

Methods: Patients with refractory CD undergoing CPT were identified in 13 centers of the German IBD Study Group and retrospectively registered. In total, 41 patients (12 male, 29 female, median age 36 years, range 18-72 years) were included for analysis. Seventy-eight percent of these had previously been treated with thiopurines and 90% had previously received anti-TNF antibodies. Former steroid treatment was found throughout the cohort.

Results: Patients received a median number of 5 (1-13) pulses every 28 (13-54) days in a period of 120 (12-411) days. A median dose of 766 (600-1,200) mg and a median cumulative dose of 4,500 (750-9,750) mg was given. A clinical response (reduction in the Harvey-Bradshaw Index [HBI] ≥2 points) was found in 68% of the patients and clinical remission (HBI <5 points) in 32%. Steroids could be reduced from 31 to 12 mg per day over all patients. Side effects were recorded in 71% ( = 29) of the patients. Three patients terminated CPT due to side effects. No patient died.

Conclusion: Our data point to CPT as a therapeutic alternative for induction of remission in patients with severe refractory courses of CD including TNF antagonists. CPT might serve as bridging for maintenance treatment.
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http://dx.doi.org/10.1159/000481820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988113PMC
March 2018

[Influence of anti-TNF antibodytherapy on the serum concentration of newborns and the effect on infections].

Authors:
Ulf Helwig

Z Gastroenterol 2018 03 12;56(3):305-306. Epub 2018 Mar 12.

Internistische Praxengemeinschaft Oldenburg.

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http://dx.doi.org/10.1055/s-0043-122752DOI Listing
March 2018

Identification of clinically relevant cytomegalovirus infections in patients with inflammatory bowel disease.

Mod Pathol 2018 03 1;31(3):527-538. Epub 2017 Dec 1.

Molecular Diagnostics, Practice of Pathology, Vechta, Germany.

Several lines of evidence indicate that cytomegalovirus infection can be substantially associated with onset of inflammatory bowel disease, especially in patients refractory to immunosuppressive treatment. As cytomegalovirus is widely spread in the population, here we present a quantitative detection system suitable to differentiate clinically relevant cytomegalovirus infection from common latent cytomegalovirus. Using a quantitative real-time PCR approach, cytomegalovirus viral load was evaluated in 917 formalin-fixed and paraffin-embedded colon biopsy samples of 136 patients diagnosed with inflammatory bowel disease. Besides initial cytomegalovirus testing, the PCR system was also used to monitor therapy response after antiviral treatment. Cytomegalovirus DNA was detected in 37 patients (27%) with varying viral loads ranging from 5 to 8.7 × 10 copies/10 cells. Thereof, 13 patients (35%) received an antiviral treatment with 12 of them going into remission (92%). Later, five patients displayed a relapse and three patients who agreed to restart antiviral treatment again showed positive therapy response. A retrospective comparison of viral loads with antiviral therapy response revealed a threshold of 600 cytomegalovirus copies/10 cells as indicative for clinically relevant infection. Of note, sensitivity of cytomegalovirus detection by immunohistochemistry was found to be insufficient to reliably identify antiviral therapy responders. In conclusion, quantitative real-time PCR using formalin-fixed biopsy samples is suitable for detection of cytomegalovirus infection in tissue samples of patients with inflammatory bowel disease. Moreover, it allows the definition of a viral load threshold, predictive for clinical relevance concerning antiviral therapy response.
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http://dx.doi.org/10.1038/modpathol.2017.149DOI Listing
March 2018

Proposal for an anti-TNF-exit strategy based on trough serum level.

Biologicals 2017 May 8;47:81-85. Epub 2017 Apr 8.

Department of Internal Medicine I - Gastroenterology, Hepatology, Nutrition and Geriatric Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Straße 3, 24105 Kiel, Germany.

Background And Aims: The aim of the study was to evaluate, if the strategy to stop anti-TNF treatment after determination of low trough serum levels and exclusion of inflammation is associated with lower relapse rates.

Methods: Since 2013 we followed an exit strategy in patients treated with anti-TNF treatment for inflammatory bowel disease based on trough serum levels. The relapse rates were observed prospectively, data analysis was performed in a retrospective manner of the collected clinical data.

Results: Forty patients were enrolled, who stopped anti-TNF therapy. 13 Patients followed the clinical algorithm, 27 patients were used as control group (13 patients with ulcerative colitis and 14 patients with Crohn's disease). 19 patients received Infliximab, 21 Adalimumab. The median follow-up time after discontinuation was 19 months (IQR 18). Relapses were observed in 22/40 patients (55%). Among the 13 patients with a targeted discontinuation of therapy based on the algorithm, three relapses were observed (23%), compared to 19/27 (70%) from the non-algorithm group (OR: 7.9; 95%-CI: 1.7-36.5). Relapse-free-survival after anti-TNF discontinuation was significantly higher in patients treated by the algorithm compared to the non-algorithm group (p = 0.032).

Conclusion: An exit strategy based on trough serum levels significantly reduces the relapse rate.
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http://dx.doi.org/10.1016/j.biologicals.2017.03.002DOI Listing
May 2017

[Relapse after withdrawal from anti-TNF therapy for inflammatory bowel disease].

Authors:
Ulf Helwig

Z Gastroenterol 2017 01 10;55(1):85. Epub 2017 Jan 10.

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http://dx.doi.org/10.1055/s-0042-114450DOI Listing
January 2017

Use of Intestinal Ultrasound to Monitor Crohn's Disease Activity.

Clin Gastroenterol Hepatol 2017 Apr 14;15(4):535-542.e2. Epub 2016 Nov 14.

Ambulanzzentrum Gastroenterologie, University Teaching Hospital Lüneburg, Lüneburg, Germany.

Background & Aims: We performed a multicenter study to determine whether transabdominal bowel wall ultrasonography, a noninvasive procedure that does not require radiation, can be used to monitor progression of Crohn's disease (CD).

Methods: We performed a 12-month prospective, noninterventional study at 47 sites in Germany, from December 2010 through September 2014. Our study included 234 adult patients with CD who experienced a flare, defined as Harvey-Bradshaw index score of ≥7. All patients received treatment intensification, most with tumor necrosis factor antagonists. Ultrasound parameters and clinical data were assessed at baseline and then after 3, 6, and 12 months. The primary endpoint was the change in ultrasound parameters within 12 months of study enrollment.

Results: All patients included had bowel wall alterations either within the terminal ileum and/or segments of the colon. After 3 and 12 months, ultrasonographic examination showed significant improvements of nearly all ultrasound parameters, including reductions in bowel wall thickening or stratification, decreased fibrofatty proliferation, and increased signals in color Doppler ultrasound (P < .01 for all parameters at months 3 and 12). Median Harvey-Bradshaw index scores decreased from 10 at baseline to 2 after 12 months. Improvement in bowel wall thickness correlated with reduced levels of C-reactive protein after 3 months (P ≤ .001).

Conclusions: In a multicenter prospective study, we found that ultrasonographic examination can be used to monitor disease activity in patients with active CD. Bowel ultrasonography seems to be an ideal follow-up method to evaluate early transmural changes in disease activity, in response to medical treatment. German Clinical Trials Register: drks.de/DRKS00010805.
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http://dx.doi.org/10.1016/j.cgh.2016.10.040DOI Listing
April 2017

CT-P13 (Inflectra™, Remsima™) monitoring in patients with inflammatory bowel disease.

Biologicals 2016 Sep 16;44(5):463-6. Epub 2016 Jul 16.

Medical Practice for Internal Medicine Oldenburg, Christian-Albrechts University Kiel, Neue Donnerschweer Str. 30, 26123 Oldenburg, Germany. Electronic address:

The approval of infliximab biosimilars Remsima™ and Inflectra™ (CT-P13) for patients with inflammatory bowel disease (IBD) is a promising step to reduce treatment costs. Since monitoring of Remicade™ serum trough levels and anti-Remicade™ immunogenicity hold an important significance in treatment modalities, no data about monitoring of drug serum trough levels or anti-drug antibody levels in IBD patients treated with Remsima™ or Inflectra™ are present to date. Therefore, in this study we applied a Remicade™-validated ELISA to determine drug serum levels of Remsima™ or Inflectra™. Serum concentrations were measured at identical levels compared to Remicade™ at multiple time points over 38 weeks, suggesting that the monitoring of serum trough levels is equally feasible for patients receiving Remsima™ or Inflectra™ and Remicade™. Additionally, anti-drug antibody levels were not significantly different in patients treated with Remsima™ or Inflectra™ compared to patients treated with Remicade™. To our knowledge this is the first real-life experience demonstrating the feasibility of drug monitoring in IBD patients treated with the infliximab biosimilars Remsima™ and Inflectra™.
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http://dx.doi.org/10.1016/j.biologicals.2016.06.011DOI Listing
September 2016

Early Monitoring of Response (MORE) to Golimumab Therapy Based on Fecal Calprotectin and Trough Serum Levels in Patients With Ulcerative Colitis: A Multicenter Prospective Study.

JMIR Res Protoc 2016 Jun 28;5(2):e124. Epub 2016 Jun 28.

Clinical Trial Support, Münster, Germany.

Background: The treatment of ulcerative colitis (UC) patients with moderate to severe inflammatory activity with anti-tumor necrosis factor alpha (TNFα) antibodies leads to a clinical remission rate of 10% after 8 weeks of therapy. However, it must be taken into account that patient selection in clinical trials clearly influences both response and remission rates. An unsatisfactory response to anti-TNFα medication after week 12 often leads to a discontinuation of treatment. The early prediction of clinical response could therefore help optimize therapy and potentially avoid ineffective treatments.

Objective: The aim of this study is to develop an algorithm for optimizing golimumab administration in patients with moderate to severe UC by calculating the probability of clinical response in Week 26 based on data from Week 6.

Methods: The study is designed as a prospective, single-arm, multicenter, non-interventional observational study with no interim analyses and a sample size of 58 evaluable patients. The primary outcome is the prediction of clinical response in Week 26 based on a 50% reduction in fecal calprotectin and a positive golimumab trough level in Week 6.

Results: Enrollment started in October 2014 and was still open at the date of submission. The study is expected to finish in December 2016.

Conclusions: The early identification of patients who are responding to an anti-TNFα antibody is therapeutically beneficial. At the same time, patients who are not responding can be identified earlier. The development of a therapeutic algorithm for identifying patients as responders or non-responders can thus help prescribing physicians to both avoid ineffective treatments and adjust dosages when necessary. This in turn promotes a higher degree of treatment tolerance and patient safety in the case of anti-TNFα antibody administration.

Clinicaltrial: German Clinical Trials Register, Deutsches Register Klinischer Studien DRKS00005940; https://drks-neu.uniklinik-freiburg.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00005940 (Archived by WebCite at http://www.webcitation.org/6i4Xoo1sH).
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http://dx.doi.org/10.2196/resprot.5791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942680PMC
June 2016

Azathioprine-induced Acute Pancreatitis in Patients with Inflammatory Bowel Diseases--A Prospective Study on Incidence and Severity.

J Crohns Colitis 2016 Jan 13;10(1):61-8. Epub 2015 Oct 13.

Universitätsklinikum, Jena, Germany.

Background And Aims: Azathioprine [AZA] is recommended for maintenance of steroid-free remission in inflammatory bowel disease IBD. The aim of this study has been to establish the incidence and severity of AZA-induced pancreatitis, an idiosyncratic and major side effect, and to identify specific risk factors.

Methods: We studied 510 IBD patients [338 Crohn's disease, 157 ulcerative colitis, 15 indeterminate colitis] with initiation of AZA treatment in a prospective multicentre registry study. Acute pancreatitis was diagnosed in accordance with international guidelines.

Results: AZA was continued by 324 [63.5%] and stopped by 186 [36.5%] patients. The most common cause of discontinuation was nausea [12.2%]. AZA-induced pancreatitis occurred in 37 patients [7.3%]. Of these: 43% were hospitalised with a median inpatient time period of 5 days; 10% had peripancreatic fluid collections; 24% had vomiting; and 14% had fever. No patient had to undergo nonsurgical or surgical interventions. Smoking was the strongest risk factor for AZA-induced acute pancreatitis [p < 0.0002] in univariate and multivariate analyses.

Conclusions: AZA-induced acute pancreatitis is a common adverse event in IBD patients, but in this study had a mild course in all patients. Smoking is the most important risk factor.
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http://dx.doi.org/10.1093/ecco-jcc/jjv188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692264PMC
January 2016

Epigenetic imprinting by commensal probiotics inhibits the IL-23/IL-17 axis in an in vitro model of the intestinal mucosal immune system.

J Leukoc Biol 2012 Oct 22;92(4):895-911. Epub 2012 Jun 22.

Department of Microbiology and Biotechnology, Max Rubner-Institute, Kiel, Germany.

The pathophysiology of IBD is characterized by a complex interaction between genes and the environment. Genetic and environmental differences are attributed to the heterogeneity of the disease pathway and to the epigenetic modifications that lead to altered gene expression in the diseased tissues. The epigenetic machinery consists of short interfering RNA, histone modifications, and DNA methylation. We evaluated the effects of Bifidobacterium breve (DSMZ 20213) and LGG (ATCC 53103), as representatives of commensal probiotics on the expression of IL-17 and IL-23, which play an important role in IBD, and on the epigenetic machinery in a 3D coculture model composed of human intestinal HT-29/B6 or T84 cells and PBMCs. The cells were treated with LPS in the presence or absence of bacteria for 48 h, and the expression of IL-17, IL-23, and CD40 at the mRNA and protein levels was assessed using TaqMan qRT-PCR and ELISA, respectively. Western blotting was used to assess the expression of the MyD88, the degradation of IRAK-1 and IκBα, the expression of the NF-κB p50/p65 subunits, the p-p38 MAPK and p-MEK1, as well as histone modifications. NF-κB activity was assessed by NF-κB-dependent luciferase reporter gene assays. The accumulation of Ac-H4 and DNA methylation was quantitatively assessed using colorimetric assays. B. breve and LGG diminished the LPS-induced expression of IL-17, IL-23, CD40, and histone acetylation, while slightly enhancing DNA methylation. These effects were paralleled by a decrease in the nuclear translocation of NF-κB, as demonstrated by a decrease in the expression of MyD88, degradation of IRAK-1 and IκBα expression of the nuclear NF-κB p50/p65 subunits, p-p38 MAPK and p-MEK1, and NF-κB-dependent luciferase reporter gene activity in LPS-stimulated cells. B. breve and LGG may exert their anti-inflammatory effects in the gut by down-regulating the expression of the IBD-causing factors (IL-23/IL-17/CD40) associated with epigenetic processes involving the inhibition of histone acetylation and the optimal enhancement of DNA methylation, reflected in the limited access of NF-κB to gene promoters and reduced NF-κB-mediated transcriptional activation. We describe a new regulatory mechanism in which commensal probiotics inhibit the NF-κB-mediated transcriptional activation of IBD-causing factors (IL-23/IL-17/CD40), thereby simultaneously reducing histone acetylation and enhancing DNA methylation.
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http://dx.doi.org/10.1189/jlb.0611286DOI Listing
October 2012

Influence of different CLA isomers on insulin resistance and adipocytokines in pre-diabetic, middle-aged men with PPARγ2 Pro12Ala polymorphism.

Genes Nutr 2012 Oct 8;7(4):499-509. Epub 2012 Mar 8.

Department of Physiology and Biochemistry of Nutrition, Max Rubner Institute, Kiel, Germany,

Conjugated linoleic acids (CLAs) are natural PPARγ ligands, which showed conflicting effects on metabolism in humans. We examined metabolic effects of different isomers of CLA in subjects with PPARγ2 Pro12Ala polymorphisms. A total of 35 men underwent four intervention periods in a crossover study design: subjects with either genotypes received c9, t11 CLA or t10, c12 CLA, a commercially available 1:1 mix of both isomers or reference oil (linoleic acid (LA)). Adipocytokines, insulin, glucose and triglycerides were assessed in the fasting state and after a standardized mixed meal. Across all genotypes, there was a significant (p = 0.025) CLA treatment effect upon postprandial (pp) HOMA-IR values, with c9, t11 CLA and CLA isomer mix improving, but t10, c12 CLA isomer worsening. In Ala12Ala subjects, the t10, c12 isomer caused weight gain (p = 0.03) and tended to increase postprandial insulin levels (p = 0.05). In Pro12Pro subjects, t10, c12 resulted in reduction in waist circumference (p = 0.03). The comparison of the different genotype groups revealed statistically different changes in fasting and postprandial insulin, HOMA-IR and leptin after intervention. c9, t11 CLA and the commercial CLA mix showed beneficial effects on insulin sensitivity compared with LA, while t10, c12 CLA adversely affects body weight and insulin sensitivity in different PPAR genotypes. CLA isomers have different effects on metabolism in Ala and Pro carriers.
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http://dx.doi.org/10.1007/s12263-012-0289-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448040PMC
October 2012

Corticosteroids and immunosuppressive therapy influence the result of QuantiFERON TB Gold testing in inflammatory bowel disease patients.

J Crohns Colitis 2012 May 19;6(4):419-24. Epub 2011 Oct 19.

Medical Practice for Internal Medicine Oldenburg/University of Kiel. Neue Donnerschweer. Str. 30, 26123 Oldenburg, Germany.

Introduction: Latent tuberculosis infection is detected by the tuberculin skin test before treating with anti-Tumour-Necrosis factor alpha (anti TNFα) reagents. More accurate are Interferon gamma release assays (IFNγ release assays) to identify patients with latent tuberculosis. Because of a positive control in this assay, it is possible to identify those patients in which a result of tuberculosis testing is not available due to a lack of stimulation capacity of lymphocytes (indeterminate result). Patients suffering from IBD are often treated with immunosuppressive agents, which may influence the results of tuberculosis testing.

Aim: The aim is to investigate the influence of immunosuppressive agents on the outcome of IFNγ-release assay.

Methods: 50 consecutive patients were documented before introducing anti-TNF-treatment in this single centre study between April 2009 and April 2010. Data of INFγ release assay for latent tuberculosis, skin test and laboratory data and current medication were enrolled.

Results: For the period of one year data of 45 consecutive patients was available for statistical analysis. 24 patients out of 45 (corresponding to 53.3%) received at least low doses of corticoid treatment and 27 patients out of 45 (corresponding to 60.0%) received immunosuppressive agents. 13 patients out of 45 (corresponding to 28.9%) had an indeterminate result of the QuantiFERON test. A correlation between the indeterminate result and combination therapy of corticosteroids was found. The concomitant therapy of immunosuppressive agents lead to a lower IFN release but no significance was found.

Conclusions: Steroid treatment and further combination therapy with immunosuppressive agents lead to a high risk of indeterminate QuantiFERON test.
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http://dx.doi.org/10.1016/j.crohns.2011.09.011DOI Listing
May 2012

The effect of FABP2 promoter haplotype on response to a diet with medium-chain triacylglycerols.

Genes Nutr 2012 Jul 24;7(3):437-45. Epub 2012 Jan 24.

Federal Research Centre for Nutrition and Food, Max-Rubner-Institut, Kiel, Germany,

The fatty-acid-binding protein-2 (FABP2) gene has been proposed as a candidate gene for diabetes because the encoded protein is involved in fatty acid absorption and therefore may affect insulin sensitivity and glucose metabolism. The rare haplotype (B) of its promoter was shown to be associated with a lower risk for type 2 diabetes. The aim of this study was to investigate whether a polymorphism in the FABP2 promoter does affect the metabolic response to either an medium-chain triacylglycerol (MCT) or an long-chain triacylglycerol (LCT) diet, which were suggested to differ in transport mechanisms, in affinity to FABP2, in activating transcription factors binding to the FABP2 promoter and in their effects on insulin sensitivity. We studied 82 healthy male subjects varying in the FABP2 promoter (42 homozygous for common haplotype (A), 40 homozygous for the rare haplotype (B)) in an interventional study with either an MCT or LCT diet over 2 weeks to examine gene-nutrient interaction. The saturation grade of MCT was adjusted to that of the LCT fat. We determined glucose, insulin, triacylglycerols (TGs), chylomicron triacylglycerols and cholesterol before and after a standardised mixed meal before and after the intervention. HDL cholesterol increased in all groups, which was most pronounced in subjects homozygous for the common promoter haplotype A who received MCT diet (P = 0.001), but not significant in homozygous rare haplotype B subjects who received MCT fat. Subjects homozygous for FABP2 haplotype A showed a significant decrease in fasting and postprandial glucose (P = 0.01, 0.04, respectively) and a decrease in insulin resistance (HOMA-IR, P = 0.04) during LCT diet. After correction for multiple testing, those effects did not remain significant. Fasting and postprandial triacylglycerols, LDL cholesterol, chylomicron TGs and cholesterol were not affected by genotype or diet. MCT diet increased HDL cholesterol dependent on the FABP2 promoter haplotype. The effects of the promoter haplotype B could be mediated by PPARγ, which is upregulated by medium-chain fatty acids.
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http://dx.doi.org/10.1007/s12263-012-0280-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380186PMC
July 2012

A variant in the heart-specific fatty acid transport protein 6 is associated with lower fasting and postprandial TAG, blood pressure and left ventricular hypertrophy.

Br J Nutr 2012 May 16;107(10):1422-8. Epub 2011 Sep 16.

Department of Microbiology and Biotechnology, Max Rubner-Institut, Federal Research Institute of Nutrition and Food, Hermann-Weigmann-Straße 1, D-24103 Kiel, Germany.

Fatty acid transport protein 6 (FATP6) is primarily expressed in the heart and seems to be involved in cardiac fatty acid uptake. Therefore, we investigated whether a variation in the 5'-untranslated region of the FATP6 gene is associated with features of the metabolic syndrome and signs of myocardial alteration or heart failure. A total of 755 male participants from a Metabolic Intervention Cohort Kiel were genotyped for the FATP6-7T>A polymorphism (rs2526246) and phenotyped for features of the metabolic syndrome. Participants underwent a glucose tolerance test and the postprandial assessment of metabolic variables after a standardised mixed meal. Left ventricular heart function was evaluated in fifty-four participants. Fasting (P = 0·01) and postprandial (P = 0·02) TAG concentrations were significantly lower in AA homozygotes when compared with wild-type carriers. Homozygosity of allele A was associated with significantly lower postprandial insulin concentrations after a glucose load and significantly lower systolic (P = 0·01) and diastolic (P = 0·01) blood pressure values compared with wild-type carriers. Accordingly, left ventricular heart mass was significantly lower in twenty-seven AA homozygotes in comparison with twenty-seven TT homozygotes, matched for BMI (P = 0·04). In conclusion, the effects of the FATP6 polymorphism on TAG are mediated by affluent dietary fat. The FATP6-7T>A polymorphism may protect from traits of the metabolic syndrome and CVD.
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http://dx.doi.org/10.1017/S0007114511004727DOI Listing
May 2012

CLA does not impair endothelial function and decreases body weight as compared with safflower oil in overweight and obese male subjects.

J Am Coll Nutr 2011 Feb;30(1):19-28

Max Rubner-Institut, Department of Physiology and Biochemistry of Nutrition, Haid-und-Neu-Straße 9, 76131 Karlsruhe, GERMANY.

Objective: Conjugated linoleic acid (CLA) showed a wide range of beneficial biological effects with relevance for cardiovascular health in animal models and humans. Most human studies used olive oil as a reference. This study assessed the effect of CLA as compared with safflower oil on endothelial function and markers of cardiovascular risk in overweight and obese men. Heated safflower oil and olive oil were given for additional descriptive control.

Methods: Eighty-five overweight men (aged 45-68 years, body mass index 25-35 kg/m(2)) were randomized to receive 4.5 g/d of the CLA isomeric mixture, safflower oil, heated safflower oil, or olive oil in a 4-week double-blind study. Endothelial function was assessed by peripheral arterial tonometry (PAT) index determination in the fasting and postprandial state (i.e., 4 hours after consumption of a fat- and sucrose-rich meal).

Results: CLA as compared with safflower oil consumption did not impair fasting or postprandial PAT index but decreased body weight. CLA as compared with safflower oil did not change total, low-density lipoprotein (LDL), or high-density lipoprotein (HDL) cholesterol; triglycerides; insulin sensitivity indices; C-reactive protein; soluble adhesion molecules; oxidized LDL; lipoprotein a (Lp[a]); paraoxonase; or platelet-activating factor acetylhydrolase (PAF-AH) activity, but significantly reduced arylesterase activity and increased concentrations of the F(2)-isoprostane 8-iso-prostaglandin F (PGF)(2α).

Conclusion: CLA did not impair endothelial function. Other parameters associated with metabolic syndrome and oxidative stress were not changed or were slightly improved. Results suggest that CLA does not increase cardiovascular risk. Increased F(2)-isoprostane concentrations in this context may not indicate increased oxidative stress.
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http://dx.doi.org/10.1080/07315724.2011.10719940DOI Listing
February 2011
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