Publications by authors named "Wolfgang Kruis"

69 Publications

What Are the Most Challenging Aspects of Inflammatory Bowel Disease? An International Survey of Gastroenterologists Comparing Developed and Developing Countries.

Inflamm Intest Dis 2021 May 5;6(2):78-86. Epub 2021 Feb 5.

Section of Gastroenterology, Max Rady School of Medicine and University of Manitoba IBD Clinical and Research Centre, Winnipeg, Manitoba, Canada.

Background And Aims: As inflammatory bowel disease (IBD) becomes more prevalent, the challenges that gastroenterologists face in managing these patients evolve. We aimed to describe the most important challenges facing gastroenterologists from around the world and compare these between those working in developed and developing countries.

Methods: An online questionnaire was developed, and a link distributed to gastroenterologists. Data were analyzed descriptively using Friedman and Wilcoxon matched-pair signed rank tests to compare rankings for responses. Mann-Whitney tests were used to compare rankings between responses from gastroenterologists from developed and developing countries. Lower scores reflected greater challenges.

Results: Of 872 who started, 397 gastroenterologists (45.5%) completed the survey. Respondents represented 65 countries (226 [56.9%] from developed countries). Overall, the challenge ranked most important (smallest number) was increasing IBD prevalence (13.6%). There were significant differences in mean ranking scores for many simple aspects of care for those from developing countries compared to providers from developed countries, such as access to simple IBD treatments (5.52 vs. 6.02, = 0.01), access to anti-TNF drugs including dose escalation (3.33 vs. 3.93, < 0.01), access to good stoma care (2.57 vs. 3.03, < 0.001), access to therapeutic drug monitoring (1.47 vs. 1.84, < 0.001), and access to care for people from low socioeconomic status (2.77 vs. 3.37, < 0.001).

Conclusions: Increasing IBD prevalence is seen by gastroenterologists as the greatest challenge facing them. There are significant differences between the IBD challenges facing gastroenterologists from developed and developing countries that reflect inequities in access to health care.
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http://dx.doi.org/10.1159/000512310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160566PMC
May 2021

Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease.

Gut 2021 Apr 22. Epub 2021 Apr 22.

Department of Medicine I, Institute of Cancer Research, Medical University Vienna, Vienna, Austria.

Objective: Haemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date.

Design: We conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry.

Results: We demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix.

Conclusion: HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.
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http://dx.doi.org/10.1136/gutjnl-2020-323868DOI Listing
April 2021

[Diverticular disease. Clinical appearance, conservative treatment, primary and secondary prophylaxis].

Chirurg 2021 Apr 14. Epub 2021 Apr 14.

Medizinische Fakultät, Universität Köln, Köln, Deutschland.

Diverticula of the colon are very common and usually asymptomatic but 20% of people with diverticulosis develop symptoms and sometimes also complications, such as diverticulitis with abscesses or perforation and bleeding. In the long-term stenoses or a conglomerate can occur. The treatment depends on the type of diverticular disease, on the knowledge of risk indicators and imaging with sonography or computed tomography (CT). The uncomplicated diverticular disease is treated on an outpatient and conservative basis, while complicated diverticular disease is treated on an inpatient basis and often surgically.
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http://dx.doi.org/10.1007/s00104-021-01401-0DOI Listing
April 2021

Perianal fistula-associated carcinoma in Crohn´s disease: a multicenter retrospective case control study.

J Crohns Colitis 2021 Mar 27. Epub 2021 Mar 27.

Department of Internal Medicine and Gastroenterology, Evangelisches Krankenhaus Kalk, University of Cologne, Buchforststrasse 2, Cologne, Germany.

Background & Aims: Carcinoma associated with perianal fistula in Crohn's disease is a pending threat for patients. This study was aimed to improve understanding and facilitate development of diagnostic and therapeutic strategies.

Methods: A retrospective case-control study was conducted at four German hospitals. The analysis included forty patients with proven malignancy associated with perianal Crohn's fistulas and forty randomly-selected controls with fistulizing perianal Crohn's disease. Differences between groups were analysed and multivariate calculations performed to describe risk factors for oncological outcomes.

Results: Histology revealed adenocarcinoma in 33/40 patients and squamous cell carcinoma in 7/40 patients. Compared to fistula patients without carcinoma, patients with malignancies associated to fistula had a diagnosis of Crohn's disease in younger age. Crohn's disease lasted longer in patients with malignancy (25.8 ± 9.0 vs. 19.6 ± 10.4; p=0.006).Fistula related findings differed significantly between both groups. Signs for complicated and severe fistulation including complex anatomy and chronic activity occurred significantly more often in patients with malignancy associated to fistula.Significant multivariate hazard ratios for overall mortality and progression-free survival were shown for histologic type of cancer, metastatic disease and R1 resection. Overall survival (OS) was 45.1±28.6 months and the 5-year survival rate was 65%.

Conclusions: In patients with adenocarcinoma or squamous cell carcinoma associated with perianal fistula in Crohn's disease, fistula characteristics determine risk for malignancy. Early diagnosis influences outcomes, while treatment of chronic fistula activity may be key to preventing malignancy. Expert multimodal therapy is paramount for successful treatment of perianal fistula-associated malignancies.
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http://dx.doi.org/10.1093/ecco-jcc/jjab057DOI Listing
March 2021

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

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

Evangelisches Krankenhaus, Cologne, Germany.

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

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

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

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

[Cost of illness of inflammatory bowel disease in Germany].

Z Gastroenterol 2020 Aug 31. Epub 2020 Aug 31.

Evangelisches Krankenhaus Kalk, Köln, Germany.

Introduction:  The prevalence of inflammatory bowel disease (IBD) in Germany is rising. Due to a disease onset at a young age, direct and indirect costs are important. The aim of the present study is to provide a comprehensive presentation of existing healthcare costs for these diseases in Germany and to compare them by inflation adjustments for 2018.

Material And Methods:  Performing a systematic literature search, monetary costs were extracted from German and English literature. Quality and relevance of the studies were assessed with a checklist.

Results:  The average outpatient cost for inflammatory bowel disease amounts between 18 and 87 Euro/pat/30 days, the average inpatient cost was between 1026 and 9083 Euro/case. Depending on the type of calculation, biologicals cause different amounts of cost. Few data are available for direct medical 82 and 618 Euro/pat/30 days, direct non-medical 63 and 84 Euro/pat/30 days and indirect costs 463 and 3493 Euro/pat/30 days. The total costs are about 533 Euro/pat/30 days, related to one year 6485 Euro/pat.

Conclusion:  For the first time, it is possible to compare existing medical costs for IBD in Germany. Current studies feature very heterogeneous methods and study populations of IBD. Depending on the collective, the total costs are up to 6485 Euro/patient/year.
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http://dx.doi.org/10.1055/a-1174-0670DOI Listing
August 2020

Thumb sucking or nail biting in childhood and adolescence is associated with an increased risk of Crohn's disease: results from a large case-control study.

Scand J Gastroenterol 2020 Sep 30;55(9):1028-1034. Epub 2020 Jul 30.

Medical Faculty, Friedrich Schiller University Jena, Jena, Germany.

Background: The hygiene hypothesis suggests that a reduction in microbial exposure contributes to an impaired immune response later in life and increases the incidence of immune-mediated diseases such as inflammatory bowel diseases (IBD). Thumb sucking and nail biting are two early habits that modulate the oral microbiota composition and antigen load.

Objective: We hypothesized a lower risk of Crohn's disease (CD) and ulcerative colitis (UC) in adults with prior thumb sucking and nail biting.

Methods: 918 IBD cases and their 918 siblings without IBD were asked to fill out a survey containing 32 questions on environmental factors in childhood and early adulthood. Prevalence of thumb sucking and/or nail biting at the usually well-remembered time of (1) school enrollment and (2) coming-of-age ceremonies was the predefined combined risk factor of this study.

Results: 65% of the patients were female and 57% suffered from CD. About 49% of IBD patients but only 44% of their siblings reported thumb sucking/nail biting at the time of school enrollment or coming-of-age ( = .007). Sensitivity analysis revealed that this difference was observed in patients with CD (50% versus 41%; RR= 1.22; 95% CI 1.09-1.37,  = .001) but not in patients with UC (49% versus 48%; RR= 1.02; 95% CI 0.90-1.17;  = .83).

Conclusion: Contrary to our expectation and challenging the hygiene hypothesis, we found that common oral habits are not protective against IBD. Instead, nail biting at the time of school enrollment and coming-of-age was a statistically significant risk factor for CD in our cohort. Key summary The hygiene hypothesis suggests that a reduction in microbial exposure due to improved health activities has contributed to an immunological imbalance in the intestine and an increased incidence of allergic and autoimmune diseases. A population-based birth cohort study has demonstrated that thumb-sucking and nail biting in children lead to a reduction of the risk of atopic sensitization, asthma, and hay fever. Contrary to the hypothesis, thumb sucking and nail biting were not associated with a reduced risk of IBD. Instead, thumb sucking and/or nail biting at the usually well-remembered points in time of school enrollment and of religious or secular coming-of-age ceremonies was associated with a higher risk of Crohn's disease but not of ulcerative colitis. Our data did not support the hygiene hypothesis, one pathogenic concept in the context of IBD.
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http://dx.doi.org/10.1080/00365521.2020.1797869DOI Listing
September 2020

Author Correction: Colonic diverticular disease.

Nat Rev Dis Primers 2020 06 17;6(1):50. Epub 2020 Jun 17.

IBD Center, Department of Gastroenterology, Humanitas Clinical and Research Center - IRCCS -, Rozzano, Italy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41572-020-0192-yDOI Listing
June 2020

Publisher Correction: Colonic diverticular disease.

Nat Rev Dis Primers 2020 04 29;6(1):35. Epub 2020 Apr 29.

IBD Unit, Humanitas Clinical Research Hospital, Rozzano, Milan, Italy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41572-020-0176-yDOI Listing
April 2020

Colonic diverticular disease.

Nat Rev Dis Primers 2020 03 26;6(1):20. Epub 2020 Mar 26.

IBD Center, Department of Gastroenterology, Humanitas Clinical and Research Center - IRCCS -, Rozzano, Italy.

Diverticula are outpouchings of the intestinal wall and are common anatomical alterations detected in the human colon. Colonic diverticulosis (the presence of diverticula in the colon; referred to as diverticulosis) remains asymptomatic in most individuals but ~25% of individuals will develop symptomatic diverticulosis, termed colonic diverticular disease (also known as diverticular disease). Diverticular disease can range in severity from symptomatic uncomplicated diverticular disease (SUDD) to symptomatic disease with complications such as acute diverticulitis or diverticular haemorrhage. Since the early 2000s, a greater understanding of the pathophysiology of diverticulosis and diverticular disease, which encompasses genetic alterations, chronic low-grade inflammation and gut dysbiosis, has led to improvements in diagnosis and management. Diagnosis of diverticular disease relies on imaging approaches, such as ultrasonography, CT and MRI, as biomarkers alone are insufficient to establish a diagnosis despite their role in determining disease severity and progression as well as in differential diagnosis. Treatments for diverticular disease include dietary fibre, pharmacological treatments such as antibiotics (rifaximin), anti-inflammatory drugs (mesalazine) and probiotics, alone or in combination, and eventually surgery. Despite being effective in treating primary disease, their effectiveness in primary and secondary prevention of complications is still uncertain.
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http://dx.doi.org/10.1038/s41572-020-0153-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486966PMC
March 2020

Hot Topics in Medical Treatment of Diverticular Disease: Evidence Pro and Cons.

J Gastrointestin Liver Dis 2019 Dec 19;28(suppl. 4):23-29. Epub 2019 Dec 19.

Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany.

Symptomatic Uncomplicated Diverticular Disease (SUDD) is the most common clinical form of Diverticular Disease (DD). The therapy should be aimed at reducing both the intensity and frequency of symptoms as well as preventing complications. The pharmacological treatments include fibers, not absorbable antibiotics (for example rifaximin), anti-inflammatory drugs (for example 5-amino-salycilic acid) and probiotics, alone or in combination with other drugs. Although some of these treatments seem to be effective in treating SUDD, but their efficacy in preventing complications of the disease is still uncertain. It has been hypothesized that microbial imbalance associated with bacterial overgrowth of the colon, may be the key to the development of diverticular disease (DD). Therefore, drugs that can manipulate gut microbiota such as probiotics or rifaximine are considered as a potential key therapy. Rifaximine is able to modulate the intestinal ecosystem, restoring eubiosis. Traditionally, DD of the colon is thought to be related to low grade of inflammation. By analogy with other inflammatory bowel diseases mesalazine has been studied also in DD. There are several evidences that may support the use of mesalazine in the SUDD. Unfortunately, mesalazine cannot be used to prevent diverticulitis because of the paucity of high-quality studies. Currently, mesalazine has a limited place for the management of SUDD. In SUDD probiotics have been proven as an effective therapy in reducing abdominal symptoms, but unfortunately there has been limited number of relevant studies regarding efficacy of this therapy.
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http://dx.doi.org/10.15403/jgld-554DOI Listing
December 2019

The DICA Endoscopic Classification for Diverticular Disease of the Colon Shows a Significant Interobserver Agreement among Community Endoscopists: an International Study.

J Gastrointestin Liver Dis 2019 Dec 19;28(suppl. 4):39-44. Epub 2019 Dec 19.

Department of Colorectal Surgery, King's College Hospital, London, United Kingdom.

Background And Aims: The Diverticular Inflammation and Complication Assessment (DICA) endoscopic classification of diverticulosis and diverticular disease (DD) is currently available. It scores severity of the disease as DICA 1, DICA 2 and DICA 3. Our aim was to assess the agreement on this classification in an international endoscopists community setting.

Methods: A total of 96 doctors (82.9% endoscopists) independently scored a set of DD endoscopic videos. The percentages of overall agreement on DICA score and a free-marginal multirater kappa (κ) coefficient were reported as statistical measures of interrater agreement.

Results: Overall agreement in using DICA was 91.8% with a free-marginal kappa of 88% (95% CI 80-95). The overall agreement levels were: DICA 1, 85.2%; DICA 2, 96.5%; DICA 3, 99.5%. The free marginal κ was: DICA 1 = 0.753, DICA 2 = 0.958, DICA 3 = 0.919. The agreement about the main endoscopic items was 83.4% (k 67%) for diverticular extension, 62.6% (k 65%) for number of diverticula for each district, 86.8% (k 82%) for presence of inflammation, and 98.5 (k 98%) for presence of complications.

Conclusions: The overall interrater agreement in this study ranges from good to very good. DICA score is a simple and reproducible endoscopic scoring system for diverticulosis and DD.
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http://dx.doi.org/10.15403/jgld-558DOI Listing
December 2019

International Consensus on Diverticulosis and Diverticular Disease. Statements from the 3rd International Symposium on Diverticular Disease.

J Gastrointestin Liver Dis 2019 Dec 19;28(suppl. 4):57-66. Epub 2019 Dec 19.

Division of Internal Medicine and Gastroenterology, CIC "Columbus", Catholic University - "A. Gemelli" University Hospital, Rome, Italy.

The statements produced by the Chairmen and Speakers of the 3rd International Symposium on Diverticular Disease, held in Madrid on April 11th-13th 2019, are reported. Topics such as current and evolving concepts on the pathogenesis, the course of the disease, the news in diagnosing, hot topics in medical and surgical treatments, and finally, critical issues on the disease were reviewed by the Chairmen who proposed 39 statements graded according to level of evidence and strength of recommendation. Each topic was explored focusing on the more relevant clinical questions. The vote was conducted on a 6-point scale and consensus was defined a priori as 67% agreement of the participants. The voting group consisted of 124 physicians from 18 countries, and agreement with all statements was provided. Comments were added explaining some controversial areas.
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http://dx.doi.org/10.15403/jgld-562DOI Listing
December 2019

Combination Treatment with Antibiotics and Glucocorticosteroids for Severe Ischemic Colitis.

Digestion 2020 6;101(5):500-505. Epub 2019 Nov 6.

Evangelisches Krankenhaus Kalk, Klinik für Gastroenterologie, Pulmologie und Allgemeine Innere Medizin, Teaching Hospital of the University of Cologne, Cologne, Germany.

Background/aims: Ischemic colitis (IC) is most common in the elderly and patients with multiple comorbidities. It carries significant mortality. As yet no evidence-based therapeutic management exists. Aim of the study was to test therapeutic efficacy of a combination of prednisolone and antibiotics.

Methods: Prospective cohort study with retrospective analysis performed in a single teaching hospital in Germany. Consecutive patients with strict diagnostic criteria of severe IC, including colonoscopy, histology, and laboratory tests, were recruited. Main outcome measures were in-hospital mortality and number of operations counted within the hospital stay. Severity scores were calculated and biomarkers determined during the course of the hospital stay.

Results: A total of 342 patients with an International Classification of Diseases of IC were identified. About 151 patients met the diagnostic criteria and a total of 44 patients fulfilled all inclusion and exclusion criteria of severe IC and constituted the group of patients eligible for analysis. Five out of 44 patients (11.4%) died (in-hospital mortality). Surgery was performed in 3 patients (6.8%), 2 patients survived. The hospital stay lasted 14.0 ± 8.5 day and was significantly correlated with comorbidity (rs = 0.314, p = 0.038). No serious adverse events were observed.

Conclusion: This is the first prospective study on therapeutic efficacy and safety in severe IC. The combination of intravenous antibiotics and intravenous prednisolone turned out to be safe and revealed promising efficacy.
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http://dx.doi.org/10.1159/000501515DOI Listing
June 2021

Novel Leucocyte/Thrombocyte Apheresis for Induction of Steroid-Free Remission in Ulcerative Colitis: A Controlled Randomized Pilot Study.

J Crohns Colitis 2019 Jul;13(7):949-953

Department of Pathology, University of Cologne, Germany.

Background And Aims: In active ulcerative colitis [UC] refractory to mesalazine, escalation to either steroids or immunosuppression is common practice. The efficacy and safety of alternative escalation therapy with a novel leukocyte apheresis device were studied.

Methods: This was a prospective, randomized, controlled multicentre pilot study comparing leukocyte apheresis with prednisolone in refractory UC (disease activity index [DAI] ≥ 4 and ≤8). Group A received weekly apheresis over five consecutive weeks. Group P received oral prednisolone 40 mg/day tapered to 0 mg at week 6. The primary end point was steroid-free clinical remission [DAI ≤ 2] at week 12. Clinical response was also analysed.

Results: Twenty-four patients were enrolled, 13 of whom were randomized into group A and 11 into group P. Clinical remission off steroids at week 12 was achieved in 3/12 patients [25.0%] with apheresis and 2/10 [20.0%] with prednisolone [p = 1.0]. The response rate after 12 weeks was 75.0% in group A and 50.0% in group P. Mean DAI scores improved in both treatment groups [p = 0.008]. C-reactive protein decreased from 6.0 ± 5.3 to 3.8 ± 3.7 mg/L at 12 weeks in group A and increased from 5.2 ± 6.0 to 6.3 ± 7.9 mg/mL in group P. Both treatments were well tolerated. No unexpected serious adverse events were seen in group A. In group P one symptomatic infection with Clostridium difficile occurred.

Conclusions: In patients with active UC refractory to mesalazine a novel leukocyte apheresis showed promising results. A comparison with prednisolone revealed similar therapeutic effectivity and excellent safety, providing the chance to escalate without systemic steroids.
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http://dx.doi.org/10.1093/ecco-jcc/jjz005DOI Listing
July 2019

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms.

Gut 2019 05 19;68(5):854-865. Epub 2019 Jan 19.

University of Exeter Medical School, University of Exeter, United Kingdom, Exeter, UK.

Objective: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.

Design: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry.

Results: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near with a p value of 2.3×10 and 0.002 (OR=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, (OR 1.32, 95% CI 1.12 to 1.56), (OR 1.21, 95% CI 1.04 to 1.42), (OR 1.17, 95% CI 1.03 to 1.33) and (OR 1.17, 95% CI 1.03 to 1.33).

Conclusion: In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.
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http://dx.doi.org/10.1136/gutjnl-2018-317619DOI Listing
May 2019

Granulomonocytapheresis as a cell-dependent treatment option for patients with inflammatory bowel disease: Concepts and clinical features for better therapeutic outcomes.

J Clin Apher 2019 Feb 8;34(1):51-60. Epub 2018 Nov 8.

Department of Gastroenterology, Pisa University Hospital, Pisa, Italy.

Ulcerative colitis (UC) and Crohn's disease (CD) are major phenotypes of the chronic inflammatory bowel disease (IBD), which afflicts millions of individuals throughout the world with debilitating symptoms. The chronic nature of IBD means that patients require life-long medications, and this may lead to drug dependency, loss of response together with adverse side effects as additional morbidity factors. The efficacy of antitumour necrosis factor (TNF)-α biologics has validated the role of inflammatory cytokines notably TNF-α in the exacerbation and perpetuation of IBD. However, cytokines are released by myeloid lineage leucocytes like the CD14 CD16 monocyte phenotype. Additionally in IBD, myeloid leucocytes are elevated with activation behavior, while lymphocytes are compromised. Therefore, patients' leucocytes appear logical targets of therapy. Adsorptive granulomonocytapheresis (GMA) with an Adacolumn uses carriers, which interact with the Fcγ receptor expressing leucocytes and deplete the elevated myeloid leucocytes, while the neutrophils, which re-enter the circulation via the Adacolumn outflow (≥40%) are phagocytosed by CD19 B-cells to become interleukin (IL)-10 producing Bregs or CD19 CD1D B-cells. IL-10 is an anti-inflammatory cytokine. GMA has been applied to treat patients with IBD. The efficacy outcomes have been impressive as well as disappointing, the clinical response to GMA defines the patients' disease course and severity at entry. Efficacy outcomes in patients with deep ulcers together with extensive loss of the mucosal tissue are not encouraging, while patients without these features respond well and attain a favorable long-term disease course. Accordingly, for responder patients, GMA fulfills a desire to be treated without drugs.
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http://dx.doi.org/10.1002/jca.21670DOI Listing
February 2019

Autochthonous acute hepatitis E mimicking CMV infection.

Clin Res Hepatol Gastroenterol 2018 09 11;42(4):e63-e65. Epub 2018 Jun 11.

Institute of pathology, university hospital Cologne, Kerpener Street 62, 50937 Cologne, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.clinre.2017.12.002DOI Listing
September 2018

Budesonide Suppositories Are Effective and Safe for Treating Acute Ulcerative Proctitis.

Clin Gastroenterol Hepatol 2019 01 24;17(1):98-106.e4. Epub 2018 Apr 24.

Medizinische Klinik für Gastroenterologie, Infektiologie, Rheumatologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Background & Aims: Although proctitis is the most limited form of ulcerative colitis, it causes unpleasant symptoms. Topical mesalamine, the standard treatment, is not always effective. We conducted a randomized phase 2 trial to determine the efficacy and safety of 2 doses of a budesonide suppository vs mesalamine suppositories vs combined budesonide and mesalamine suppositories for proctitis.

Methods: We performed a prospective, double-blind, double-dummy, multicenter trial in 337 patients with active proctitis to compare the efficacies of 4 different suppository treatments. Patients were randomly assigned to groups given 2 mg budesonide suppositories (2 mg BUS; n = 89 patients), 4 mg BUS (n = 79), 1 g mesalamine suppositories (1 g MES; n = 81), or the combination of 2 mg BUS and 1 g MES (n = 88). The study was performed from November 2013 through July 2015 at 36 study sites in Europe and Russia. The primary end point was the time to resolution of clinical symptoms, defined as the first of 3 consecutive days with a score of 0 for rectal bleeding and stool frequency.

Results: The mean time to resolution of symptoms in the 4 mg BUS (29.8 days) and combination of 2 mg BUS and 1 g MES (29.3 days) groups resembled that of the standard 1 g MES treatment (29.2 days), but was significantly longer in the 2 mg BUS group (35.5 days). Furthermore, proportions of patients with deep, clinical, and endoscopic remission, as well as mucosal healing, were similar among the 1 g MES, 4 mg BUS, and combination therapy groups, but significantly lower in the group that received 2 mg BUS. No safety signals were observed, and the patients' treatment acceptance was high (67%-85% of patients).

Conclusions: In a multicenter randomized trial, we found that the efficacy and safety of 4 mg BUS in treatment of active proctitis did not differ significantly from those of 1 g MES. Budesonide suppositories offer an alternative therapy to mesalamine for topical treatment of proctitis. Clinicaltrialsregister.eu no: 2012-003362-41.
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http://dx.doi.org/10.1016/j.cgh.2018.04.027DOI Listing
January 2019

Beneficial Effects of Education on Emotional Distress, Self-Management, and Coping in Patients with Inflammatory Bowel Disease: A Prospective Randomized Controlled Study.

Inflamm Intest Dis 2017 Apr 30;1(4):182-190. Epub 2016 Nov 30.

Department of Medical Psychology, Medical Sociology, and Rehabilitation Sciences, University of Würzburg, Würzburg, Germany.

Background: Patients with inflammatory bowel disease (IBD) suffer from various physical as well as psychological impairments, and patient education may help improve their well-being. Therefore, we developed a manualized education program for IBD patients addressing medical and psychological issues. This study aimed to evaluate it in a large controlled trial.

Methods: A total of 181 IBD outpatients participated in a prospective, randomized, waitlist-controlled trial; assessments were made before as well as 2 weeks and 3 months after intervention. Analysis of covariance was used to assess intervention effects on disease-related worries and concerns (primary outcome), fear of progression, coping with anxiety, health competencies, health-related quality of life (HRQoL), perceived disease activity, symptoms of depression and anxiety, disease-related knowledge, and coping strategies. Participants' satisfaction with the program was also evaluated.

Results: At 2 weeks and 3 months after intervention, we found significant large effects of our education program on skill and technique acquisition, knowledge, and coping with IBD. Moreover, we found significant medium effects on disease-related worries and concerns, fear of progression, coping with anxiety, constructive attitudes and approaches, as well as coping with disease-related negative emotions. The number of coping strategies used was significantly higher at 3 months. We did not find any effects on perceived disease activity, HRQoL, positive and active engagement in life, or symptoms of anxiety and depression. The program was rated very favorably by the attendees.

Conclusion: Our education program contributed to improvements in psychological distress, self-management skills, and coping and was appreciated by its attendees.
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http://dx.doi.org/10.1159/000452989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988160PMC
April 2017

Lifestyle and other risk factors for diverticulitis.

Minerva Gastroenterol Dietol 2017 Jun 1;63(2):110-118. Epub 2017 Feb 1.

Köln-Kalk Evangelical Hospital, Köln, Germany -

Diverticulosis is a very common condition. Around 20% of the carriers of diverticula are believed to suffer from diverticular disease during their lifetime. This makes diverticular disease one of the clinically and economically most significant diseases in gastroenterology. The etiopathogenesis of diverticulosis and diverticular disease is not well understood. Epidemiological studies allow defining risk factors for the development of diverticulitis and its complications. A comprehensive literature search was performed and the current knowledge about risk factors for diverticulitis and associated conditions reviewed. Besides non-controllable risk factors like age and sex, lifestyle factors like food, drinks and physical activity, drugs are described to increase or decrease the risk to develop diverticulitis or to suffer from complications. The recognition of risk factors for the development of diverticular disease or even complicated disease like lifestyle habits or medication is crucial for patient management.
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http://dx.doi.org/10.23736/S1121-421X.17.02371-6DOI Listing
June 2017

Promises and Dangers of Combination Therapy.

Dig Dis 2017 1;35(1-2):56-60. Epub 2017 Feb 1.

Evangelisches Krankenhaus Kalk, University of Cologne, Cologne, Germany.

The efficiency of the existing methods of treating inflammatory bowel disease (IBD) is limited. There are 2 ways to address this problem - either create new treatment modalities or optimize current therapies. Optimisation may be accomplished by using combinations of established therapeutic strategies. With regard to topically acting compounds such as 5-aminosalicylic acid, combining oral and rectal preparations is a commonly used method. Another commonly used combination is anti-tumor necrosis factor (TNF)-α antibody modalities together with immunosuppressants (thiopurines, methotrexate). Several aspects favour those combinations such as increased effectivity, prevention of immunogenicity and perhaps less adverse events. Currently, discussion on directly additive therapeutic effects is in progress, which have been demonstrated in some clinical trials. As on date, the combination of infliximab with azathioprine is most likely the most effective treatment of Crohn's disease. On the other hand, a combination therapy with both compounds affecting the immune system has, of course, risks. For sure, the frequency with which serious infectious complications are arising is increasing. Furthermore, the number of patients experiencing malignancies such as hepato-splenic lymphoma or melanoma is strongly suspected to be on the rise. In summary, combinations of current treatments for IBD are widely established. Various strategies have been studied and significant improvements of therapeutic effects have been demonstrated. Unfortunately, some of those proven combinations increase therapeutic risks, for example, increase the frequency of serious infections and also of some malignancies. Therefore, great caution has to be exercised when applying combination therapies.
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http://dx.doi.org/10.1159/000449084DOI Listing
February 2017

Development of an index to define overall disease severity in IBD.

Gut 2018 02 25;67(2):244-254. Epub 2016 Oct 25.

Medical University and General Hospital Vienna, Vienna, Austria.

Background And Aim: Disease activity for Crohn's disease (CD) and UC is typically defined based on symptoms at a moment in time, and ignores the long-term burden of disease. The aims of this study were to select the attributes determining overall disease severity, to rank the importance of and to score these individual attributes for both CD and UC.

Methods: Using a modified Delphi panel, 14 members of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) selected the most important attributes related to IBD. Eighteen IOIBD members then completed a statistical exercise (conjoint analysis) to create a relative ranking of these attributes. Adjusted utilities were developed by creating proportions for each level within an attribute.

Results: For CD, 15.8% of overall disease severity was attributed to the presence of mucosal lesions, 10.9% to history of a fistula, 9.7% to history of abscess and 7.4% to history of intestinal resection. For UC, 18.1% of overall disease severity was attributed to mucosal lesions, followed by 14.0% for impact on daily activities, 11.2% C reactive protein and 10.1% for prior experience with biologics. Overall disease severity indices were created on a 100-point scale by applying each attribute's average importance to the adjusted utilities.

Conclusions: Based on specialist opinion, overall CD severity was associated more with intestinal damage, in contrast to overall UC disease severity, which was more dependent on symptoms and impact on daily life. Once validated, disease severity indices may provide a useful tool for consistent assessment of overall disease severity in patients with IBD.
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http://dx.doi.org/10.1136/gutjnl-2016-312648DOI Listing
February 2018

German Guidelines.

J Clin Gastroenterol 2016 10;50 Suppl 1:S47-9

*Protestant Hospital, Kalk, Köln †University of Cologne, Cologne ‡St Lukas Hospital, Solingen, Solingen §St Bernwards Hospital, Hildesheim, Germany.

Because of its frequency, diverticular disease is a burden on health care systems. Only few formal guidelines covering all aspects of the disease exist. Here, some selected statements from the German guidelines are given. The guidelines include significant recommendations for the diagnosis and management of diverticular disease. Both diagnosis and management depend definitely on clear definitions of the situation of an individual patient. Therefore, a new classification is proposed that is based on earlier suggestions. An internationally established classification would not only enable better patient care but could also lead to studies with comparable results.
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http://dx.doi.org/10.1097/MCG.0000000000000632DOI Listing
October 2016

Iron Deficiency, Zinc, Magnesium, Vitamin Deficiencies in Crohn's Disease: Substitute or Not?

Dig Dis 2016 16;34(1-2):105-11. Epub 2016 Mar 16.

Evangelisches Krankenhaus Kalk, University of Cologne, Cologne, Germany.

Inflammatory bowel disease (IBD) is characterized by inflammatory reactions, complications, extraintestinal manifestations and a loss of intestinal functions, for example, failures of absorption and secretion. According to intestinal dysfunction, a wide array of pathogenetic pathways is existing leading to iron deficiency and numerous vitamins as well as trace element deficiencies. Complications, symptoms and signs of those deficiencies are common in IBD with varying degrees of clinical significance. This review focuses on selected micronutrients including iron, zinc, magnesium and some vitamins. Epidemiology with respect to IBD, pathophysiology, diagnosis and clinical aspects are addressed. Finally, some suggestions for treatment of deficient situations are discussed. In conclusion, some micronutrients have significant impact on complications and quality of life in IBD. Deficiencies may even influence the course of the disease. Those deficiencies should be thoroughly supplemented.
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http://dx.doi.org/10.1159/000443012DOI Listing
December 2016

[Inflammatory Bowel Disease Competence Network].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2016 Apr;59(4):465-74

Gastroenterologische Gemeinschaftspraxis Minden, Minden, Deutschland.

The Inflammatory Bowel Disease Competence Network is a network of more than 500 physicians and scientists from university clinics, hospitals and gastroenterology practices. The focus extends from the two major forms of inflammatory bowel diseases, Crohn's disease and ulcerative colitis, into other chronic inflammatory conditions affecting the intestine, including coeliac disease and microscopic colitis. The network translates basic science discoveries (in particular in the molecular epidemiology research) into innovative diagnostics and therapy. Through its strong networking structures it supports a continuous process to improve quality and standardisation in patient care that is implemented in close interaction with European networks addressing this disease group.Optimisation of patient care based on scientifically proven evidence is a main focus of the network. Therefore, it supports and coordinates translational research and infrastructure projects that investigate aetiology, improvement of diagnostic methods, and development of new or improved use of established therapies. Members participate in various training projects, thus ensuring the rapid transfer of research results into clinical practice.The competence network cooperates with the main patient organisations to engage patients in all levels of activities. The network and the patient organisations have interest in promoting public awareness about the disease entities, because their importance and burden is underestimated in non-specialised medical fields and among the general public.
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http://dx.doi.org/10.1007/s00103-016-2317-8DOI Listing
April 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

[Diverticular disease - clinical patterns and treatment].

Dtsch Med Wochenschr 2015 Sep 11;140(18):1353-9. Epub 2015 Sep 11.

Klinik für Gastroenterologie, Pulmonologie und Allgemeine Innere Medizin, Köln.

Diverticulosis, diverticular disease and diverticulitis have come into focus again because new aspects concerning diagnosis, risk factors and treatment arose only recently which prompted a new Guideline released by the DGVS and DGAV summarising the current evidence. Along with the guideline's essentials for medical practice a diagnosis of diverticulitis is considered unsatisfactory unless a cross-sectional imaging method (either ultrasonography [US] or computed tomography [CT] ) has proven that the clinical findings and inflammation (CRP considered superior to WBC and temperature) are due to diverticular inflammation. For reasons of practicability and considering relevant legislation for radiation exposure protection, US is the primary - and usually effectual - diagnostic method of choice as it is equipotent to CT. While US offers better resolution and enables precise imaging exactly at the location of pain as well as reiterative application, the latter implies advantages in the case of a deep abscess or diverticulitis in difficult locations (e. g. the small pelvis). Clinical evidence and laboratory and imaging findings allow for distinguishing a large number of differential diagnoses and also form the basis of a new classification (classification of diverticular disease, CDD) which comprises all forms of diverticular disease, from diverticulosis to bleeding and to the different facettes of diverticulitis. This classification -which should be applied in any patient with the diagnosis of diverticular disease- is independent of specific diagnostic preferences and applicable both to conservative and operative treatment options. While the number of recurrent episodes is no longer a significant indicator for surgery in diverticulitis, severity and / or complications determine treatment options along with the patients preferences. According to first data, conservative treatment may waive antibiotics under certain circumstances, however they are indispensible in complicated disease or patients bearing risk factors. Spasmoanalgetics and supportive fluid supply are individually necessary, and avoidance of potentially aggravating medications (e. g. NSAIDS) appears advisable, but many suggestions (nil by mouth, bed rest, laxatives) come along without an adaequate body of evidence. Similarly medical advice concerning prevention and secondary prophylaxis relies mainly on epidemiological plausibility. Because minor perforations (CDD type 2 a) as well as recurrent episodes of uncomplicated diverticulitis and even some abscesses > 1 cm (CDD type 2 b) respond favourably to medical treatment, the timely indication for surgery in these cases requires precise classification along with a close surveillance in trustful cooperation between the gastroenterologist and the surgeon.
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http://dx.doi.org/10.1055/s-0041-102396DOI Listing
September 2015

Management of diverticular disease.

Nat Rev Gastroenterol Hepatol 2015 Nov 14;12(11):629-38. Epub 2015 Jul 14.

Department of Internal Medicine, Evangelisches Krankenhaus Kalk, University of Cologne, Buchforststrasse 2, 51103 Cologne, Germany.

Diverticular disease is a common condition in Western countries and the incidence and prevalence of the disease is increasing. The pathogenetic factors involved include structural changes in the gut that increase with age, a diet low in fibre and rich in meat, changes in intestinal motility, the concept of enteric neuropathy and an underlying genetic background. Current treatment strategies are hampered by insufficient options to stratify patients according to individual risk. One of the main reasons is the lack of an all-encompassing classification system of diverticular disease. In response, the German Society for Gastroenterology and Digestive Diseases (DGVS) has proposed a classification system as part of its new guideline for the diagnosis and management of diverticular disease. The classification system includes five main types of disease: asymptomatic diverticulosis, acute uncomplicated and complicated diverticulitis, as well as chronic diverticular disease and diverticular bleeding. Here, we review prevention and treatment strategies stratified by these five main types of disease, from prevention of the first attack of diverticulitis to the management of chronic complications and diverticular bleeding.
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http://dx.doi.org/10.1038/nrgastro.2015.115DOI Listing
November 2015

Granulocyte/Monocyte Adsorptive Apheresis in Moderate to Severe Ulcerative Colitis--Effective or Not?

Digestion 2015 20;92(1):39-44. Epub 2015 Jun 20.

Clinic for Gastroenterology, Pulmonology and General Internal Medicine, Evangelisches Krankenhaus Kalk, University of Cologne, Cologne, Germany.

Background And Aims: Adsorptive granulocyte/monocyte apheresis (GMA) has shown promising efficacy in the treatment of patients with ulcerative colitis (UC). But a sham-controlled study was negative. A post-hoc analysis of this trial may haul out patients responding to GMA.

Methods: A total of 168 UC patients with a disease activity (DAI) between 6 and 11 were enrolled in this study. Out of 168 patients, 112 received GMA and 56 sham apheresis. The basis for this post hoc analysis is the clinical study report issued by Otsuka America Pharmaceutical.

Results: Baseline histology was available for 165 patients. Only 38% (63 of 165) of patients showed microscopic erosion/ulceration (group P). The remaining 62% of patients did not show microscopic erosion/ulceration (group A). The patients in group P showed significantly higher DAI, flexible proctosigmoidoscopy score and neutrophil infiltration into the colonic mucosa than those in group A (p = 0.0132, p = 0.0243 and p < 0.0001, respectively). Likewise, group P patients had a significantly (p = 0.0275) higher remission rate (11 of 46; 23.9%) when treated with GMA than with sham procedure (0 of 17; 0%).

Conclusions: Patients in group P who had more active UC than those in group A showed clear clinical efficacy in response to GMA. We believe that true DAI should be specified for further randomized controlled trials.
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http://dx.doi.org/10.1159/000431149DOI Listing
April 2016
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