Publications by authors named "Britta Siegmund"

182 Publications

Critical Illness and Systemic Inflammation Are Key Risk Factors of Severe Acute Kidney Injury in Patients With COVID-19.

Kidney Int Rep 2021 Apr 2;6(4):905-915. Epub 2021 Feb 2.

Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Introduction: Acute kidney injury (AKI) is an important complication in COVID-19, but its precise etiology has not fully been elucidated. Insights into AKI mechanisms may be provided by analyzing the temporal associations of clinical parameters reflecting disease processes and AKI development.

Methods: We performed an observational cohort study of 223 consecutive COVID-19 patients treated at 3 sites of a tertiary care referral center to describe the evolvement of severe AKI (Kidney Disease: Improving Global Outcomes stage 3) and identify conditions promoting its development. Descriptive statistics and explanatory multivariable Cox regression modeling with clinical parameters as time-varying covariates were used to identify risk factors of severe AKI.

Results: Severe AKI developed in 70 of 223 patients (31%) with COVID-19, of which 95.7% required kidney replacement therapy. Patients with severe AKI were older, predominantly male, had more comorbidities, and displayed excess mortality. Severe AKI occurred exclusively in intensive care unit patients, and 97.3% of the patients developing severe AKI had respiratory failure. Mechanical ventilation, vasopressor therapy, and inflammatory markers (serum procalcitonin levels and leucocyte count) were independent time-varying risk factors of severe AKI. Increasing inflammatory markers displayed a close temporal association with the development of severe AKI. Sensitivity analysis on risk factors of AKI stage 2 and 3 combined confirmed these findings.

Conclusion: Severe AKI in COVID-19 was tightly coupled with critical illness and systemic inflammation and was not observed in milder disease courses. These findings suggest that traditional systemic AKI mechanisms rather than kidney-specific processes contribute to severe AKI in COVID-19.
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http://dx.doi.org/10.1016/j.ekir.2021.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007085PMC
April 2021

Validation of the "Inflammatory Bowel Disease - Distribution, Chronicity, Activity (IBD-DCA) Score" for Ulcerative Colitis and Crohn´s disease.

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

Institute of Pathology, Klinikum Bayreuth GmbH, Bayreuth, Germany.

Background And Aims: Histological scoring plays a key role in the assessment of disease activity in ulcerative colitis (UC) and is also important in Crohn´s disease (CD). Currently, there is no common scoring available for UC and CD. We aimed to validate the Inflammatory Bowel Disease (IBD) - Distribution (D), Chronicity (C), Activity (A) score (IBD-DCA score) for histological disease activity assessment in IBD.

Methods: Inter- and intra-rater reliability were assessed by 16 observers on biopsy specimen from 59 patients with UC and 25 patients with CD. Construct validity and responsiveness to treatment were retrospectively evaluated on a second cohort of 30 patients.

Results: Inter-rater reliability was moderate to good for the UC cohort (intraclass correlation coefficients (ICCs) = 0.645, 0.623, 0.767 for D, C and A, respectively) and at best moderate for the CD cohort (ICC = 0.690, 0.303, 0.733 for D, C and A, respectively). Intra-rater agreement ranged from good to excellent in both cohorts. Correlation with the Nancy Histological Index (NHI) was moderate and strong with the Simplified Geboes Score (SGS) and a Visual Analog Scale (VAS). Large effect sizes (ES) were obtained for all three parameters. External responsiveness analysis revealed correlated changes between IBD-DCA score and NHI, SGS and VAS.

Conclusions: The IBD-DCA score is a simple histological activity score for UC and CD, agreed and validated by a large group of IBD specialists. It provides reliable information on treatment response. Therefore, it has potential value for use in routine diagnostics as well as clinical studies.
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http://dx.doi.org/10.1093/ecco-jcc/jjab055DOI Listing
March 2021

Location is important: differentiation between ileal and colonic Crohn's disease.

Nat Rev Gastroenterol Hepatol 2021 Mar 12. Epub 2021 Mar 12.

Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Crohn's disease can affect any part of the gastrointestinal tract; however, current European and national guidelines worldwide do not differentiate between small-intestinal and colonic Crohn's disease for medical treatment. Data from the past decade provide evidence that ileal Crohn's disease is distinct from colonic Crohn's disease in several intestinal layers. Remarkably, colonic Crohn's disease shows an overlap with regard to disease behaviour with ulcerative colitis, underlining the fact that there is more to inflammatory bowel disease than just Crohn's disease and ulcerative colitis, and that subtypes, possibly defined by location and shared pathophysiology, are also important. This Review provides a structured overview of the differentiation between ileal and colonic Crohn's disease using data in the context of epidemiology, genetics, macroscopic differences such as creeping fat and histological findings, as well as differences in regard to the intestinal barrier including gut microbiota, mucus layer, epithelial cells and infiltrating immune cell populations. We also discuss the translation of these basic findings to the clinic, emphasizing the important role of treatment decisions. Thus, this Review provides a conceptual outlook on a new mechanism-driven classification of Crohn's disease.
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http://dx.doi.org/10.1038/s41575-021-00424-6DOI Listing
March 2021

Recognition of food antigens by the mucosal and systemic immune system: Consequences for intestinal development and homeostasis.

Int J Med Microbiol 2021 Apr 25;311(3):151493. Epub 2021 Feb 25.

Institute for Medical Microbiology and Hygiene, Philipps University of Marburg, Marburg, Germany. Electronic address:

The impact of nutrition on systemic and intestinal immune responses remains controversially discussed and yet not fully understood. The majority of studies investigating the effects of dietary antigens focused to understand how local and systemic unresponsiveness is induced by innocuous food antigens. Moreover, it has been shown that both, microbial and dietary antigens are essential for the normal development of the mucosal immune system. Based on experimental findings from animals and IBD patients, we propose a model how the intestinal immune system performs the balancing act between recognition and tolerance of dietary antigens at the same time: In the healthy gut, repetitive uptake of dietary antigens by Peyer's patches leads to increasing activation of CD4 T cells till hyper-activated lymphocytes undergo apoptosis. In contrast to healthy controls, this mechanism was disturbed in Crohn's disease patients. This observation might help to better understand beneficial effects of dietary intervention therapy.
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http://dx.doi.org/10.1016/j.ijmm.2021.151493DOI Listing
April 2021

COVID-19-from mucosal immunology to IBD patients.

Mucosal Immunol 2021 Feb 19. Epub 2021 Feb 19.

Department for Medicine (Gastroenterology, Infectious diseases, Rheumatology), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Campus Benjamin Franklin, Berlin, Germany.

Viral infections with SARS-CoV-2 can cause a multi-facetted disease, which is not only characterized by pneumonia and overwhelming systemic inflammatory immune responses, but which can also directly affect the digestive system and infect intestinal epithelial cells. Here, we review the current understanding of intestinal tropism of SARS-CoV-2 infection, its impact on mucosal function and immunology and summarize the effect of immune-suppression in patients with inflammatory bowel disease (IBD) on disease outcome of COVID-19 and discuss IBD-relevant implications for the clinical management of SARS-CoV-2 infected individuals.
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http://dx.doi.org/10.1038/s41385-021-00384-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893623PMC
February 2021

International Perspectives on Management of Inflammatory Bowel Disease: Opinion Differences and Similarities Between Patients and Physicians From the IBD GAPPS Survey.

Inflamm Bowel Dis 2021 Jan 29. Epub 2021 Jan 29.

The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.

Background: Inflammatory bowel diseases (IBD), including Crohn disease (CD) and ulcerative colitis (UC), are complex disorders with multiple comorbidities. We conducted international patient and physician surveys to evaluate current experiences and perceptions of patients with CD or UC and physicians who treat IBD.

Methods: The IBD Global Assessment of Patient and Physician Unmet Need Surveys comprised a patient survey and a physician survey, fielded in North America and Europe between August 16, 2019, and November 10, 2019. Adults with CD or UC (targeted 1:1 ratio) were recruited from physicians, patient advocacy groups, and recruitment panels; physicians were recruited by recruitment agencies and panels.

Results: In total, 2398 patients with IBD (1368 CD, 1030 UC) and 654 physicians completed surveys. Anxiety and depression were the most common comorbidities among patients with IBD. Patients and physicians were generally aligned on treatment goals and patient-physician communication. Patients with IBD reported high quality-of-life impact by rectal urgency and need to use the toilet, which were rated as lower-impact by physicians. Patients defined remission based on symptoms; physicians defined remission based primarily on clinical tests. Patients expected current treatments to control their disease for a longer duration than did physicians. Patients expressed more concern about corticosteroid use compared with physicians; many physicians reported prescribing corticosteroids for more than 4 months per year in some patients.

Conclusions: Patients could benefit from education about disease remission and expectations for current therapies. High corticosteroid use is concerning to patients, and physicians should minimize the use of corticosteroids for extended periods of time.
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http://dx.doi.org/10.1093/ibd/izab006DOI Listing
January 2021

Aktualisierung der Colitis-ulcerosa-Leitlinie 2020.

Z Gastroenterol 2020 12 8;58(12):1208. Epub 2020 Dec 8.

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http://dx.doi.org/10.1055/a-1304-5038DOI Listing
December 2020

The impact of extra-musculoskeletal manifestations on disease activity, functional status, and treatment patterns in patients with axial spondyloarthritis: results from a nationwide population-based study.

Ther Adv Musculoskelet Dis 2020 21;12:1759720X20972610. Epub 2020 Nov 21.

Epidemiology Unit, German Rheumatism Research Centre, Berlin, Germany.

Objective: The aim of this study was to investigate the association of extra-musculoskeletal manifestations (EMMs) with disease activity, functional status, and treatment patterns in a large population-based cohort of patients with axial spondyloarthritis (axSpA).

Methods: A stratified random sample of patients with axSpA, drawn from health insurance data, received a survey on disease-related characteristics including history (ever presence) of the following EMMs: inflammatory bowel disease (IBD), psoriasis (PSO), and anterior uveitis (AU). Survey data were linked to health insurance data, gathering additional information on current occurrence (within one year) of EMMs and drug prescriptions. Separate multivariable linear regression models were calculated to determine the association of EMMs with disease activity (Bath Ankylosing Spondylitis Disease Activity Index), and functional status (Bath Ankylosing Spondylitis Functional Index) after adjustment for relevant parameters, including treatment.

Results: A total of 1729 patients with axSpA were included in the analyses (response: 47%; mean age: 56 years; 46% female) of whom 6% (9%) had current (ever) IBD, 10% (15%) had current (ever) PSO, and 9% (27%) had current (ever) AU. Ever presence of IBD and history of PSO were significantly associated with higher level of disease activity. Ever presence of PSO was also associated with higher level of functional impairment, whereas current AU was significantly associated with lower disease activity. Patients with current IBD or PSO received more frequently biological and conventional synthetic disease-modifying anti-rheumatic drugs as well as systemic steroids. AU was associated with a higher use of conventional synthetic disease-modifying anti-rheumatic drugs only.

Conclusion: Disease activity is higher in patients with axSpA with history of IBD or history of PSO. Functional impairment is also higher in patients with axSpA with history of PSO. The presence of different EMMs was associated with different treatment patterns in axSpA.
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http://dx.doi.org/10.1177/1759720X20972610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682214PMC
November 2020

Aktualisierung der Colitis ulcerosa Leitlinie 2020.

Z Gastroenterol 2020 12 1;58(12):1209-1232. Epub 2020 Dec 1.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Berlin, Germany.

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http://dx.doi.org/10.1055/a-1296-3494DOI Listing
December 2020

Aktualisierte S3-Leitlinie Colitis ulcerosa – Living Guideline.

Z Gastroenterol 2020 12 1;58(12):e241-e326. Epub 2020 Dec 1.

Medizinische Klinik I, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Deutschland.

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http://dx.doi.org/10.1055/a-1296-3444DOI Listing
December 2020

Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19.

Nat Neurosci 2021 02 30;24(2):168-175. Epub 2020 Nov 30.

Department of Neuropathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.

The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease. Moreover, thromboembolic events throughout the body, including in the CNS, have been described. Given the neurological symptoms observed in a large majority of individuals with COVID-19, SARS-CoV-2 penetrance of the CNS is likely. By various means, we demonstrate the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. Furthermore, we describe the morphological changes associated with infection such as thromboembolic ischemic infarction of the CNS and present evidence of SARS-CoV-2 neurotropism. SARS-CoV-2 can enter the nervous system by crossing the neural-mucosal interface in olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue, including delicate olfactory and sensory nerve endings. Subsequently, SARS-CoV-2 appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control center in the medulla oblongata.
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http://dx.doi.org/10.1038/s41593-020-00758-5DOI Listing
February 2021

A 39-Year-Old Man With Crohn's Disease and a Unclear Rash on His Left Cheek.

Am J Gastroenterol 2020 Oct 12. Epub 2020 Oct 12.

Interdisciplinary Clinic for Chronic Inflammatory Diseases, Campus Benjamin Franklin, Charité-University Medicine Berlin, Berlin, Germany.

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http://dx.doi.org/10.14309/ajg.0000000000000996DOI Listing
October 2020

Personalizing Treatment in IBD: Hype or Reality in 2020? Can We Predict Response to Anti-TNF?

Front Med (Lausanne) 2020 2;7:517. Epub 2020 Sep 2.

The Transregio 241 IBDome Consortium, Berlin, Germany.

The advent of anti-TNF agents as the first approved targeted therapy in the treatment of inflammatory bowel disease (IBD) patients has made a major impact on our existing therapeutic algorithms. They have not only been approved for induction and maintenance treatment in IBD patients, but have also enabled us to define and achieve novel therapeutic outcomes, such as combination of clinical symptom control and endoscopic remission, as well as mucosal healing. Nevertheless, approximately one third of treated patients do not respond to initiated anti-TNF therapy and these treatments are associated with sometimes severe systemic side-effects. There is therefore the currently unmet clinical need do establish predictive markers of response to identify the subgroup of IBD patients, that have a heightened probability of response. There have so far been approaches from different fields of IBD research, to descry markers that would empower us to apply TNF-inhibitors in a more rational manner. These markers encompass findings from disease-related and clinical factors, pharmacokinetics, biochemical markers, blood and stool derived parameters, pharmacogenomics, microbial species, metabolic compounds, and mucosal factors. Furthermore, changes in the intestinal immune cell composition in response to therapeutic pressure of anti-TNF treatment have recently been implicated in the process of molecular resistance to these drugs. Insights into factors that determine resistance to anti-TNF therapy give reasonable hope, that a more targeted approach can then be utilized in these non-responders. Here, IL-23 could be identified as one of the key factors determining resistance to TNF-inhibitors. Growing insights into the molecular mechanism of action of TNF-inhibitors might also enable us to derive critical molecular markers that not only mediate the clinical effects of anti-TNF therapy, but which level of expression might also correlate with its therapeutic efficacy. In this narrative review, we present an overview of currently identified possible predictive markers for successful anti-TNF therapy and discuss identified molecular pathways that drive resistance to these substances. We will also point out the necessity and difficulty of developing and validating a diagnostic marker concerning clinically relevant outcome parameters, before they can finally enter daily clinical practice and enable a more personalized therapeutic approach.
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http://dx.doi.org/10.3389/fmed.2020.00517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492550PMC
September 2020

Ulcerative colitis.

Nat Rev Dis Primers 2020 09 10;6(1):74. Epub 2020 Sep 10.

Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown aetiology affecting the colon and rectum. Multiple factors, such as genetic background, environmental and luminal factors, and mucosal immune dysregulation, have been suggested to contribute to UC pathogenesis. UC has evolved into a global burden given its high incidence in developed countries and the substantial increase in incidence in developing countries. An improved understanding of the mechanisms underlying UC has led to the emergence of new treatments. Since the early 2000s, anti-tumour necrosis factor (TNF) treatment has significantly improved treatment outcomes. Advances in medical treatments have enabled a paradigm shift in treatment goals from symptomatic relief to endoscopic and histological healing to achieve better long-term outcomes and, consequently, diagnostic modalities have also been improved to monitor disease activity more tightly. Despite these improvements in patient care, a substantial proportion of patients, for example, those who are refractory to medical treatment or those who develop colitis-associated colorectal dysplasia or cancer, still require restorative proctocolectomy. The development of novel drugs and improvement of the treatment strategy by implementing personalized medicine are warranted to achieve optimal disease control. However, delineating the aetiology of UC is necessary to ultimately achieve disease cure.
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http://dx.doi.org/10.1038/s41572-020-0205-xDOI Listing
September 2020

[Limits of the G-DRG system to reflect Complexity in German University Hospitals].

Z Gastroenterol 2020 Aug 22;58(8):747-753. Epub 2020 Jul 22.

Innere Medizin II, Universitätsklinikum des Saarlandes, Homburg, Germany.

Since the introduction of the G-DRG-system in Germany for the reimbursement of in-hospital patients in 2003 the Institute for the Hospital Remuneration System (InEK) annually determines case reimbursements for currently 1300 individual diagnosis-related groups (DRGs). These are based on the cost documentation of 200 representative hospitals, coopted by InEK (§ 21-KHEntG-dataset). Since DRGs represent cost averages, one half of German hospitals would be expected to report an annual income surplus, the other half a deficit. In spite of sustained cost reductions two thirds of public University Hospitals, but only 29 % of non-University hospitals, report annual deficits. The German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS) has obtained the § 21-cost-dataset from 74 InEK-hospitals and 7 Mio anonymized cases since 2012 in order to appeal for individual DRG-corrections to InEK. In the current project this database was used to investigate whether the cost of care at University Hospitals is appropriately reflected in three representative DRGs and OPS codes (operation and procedure codes): Liver cirrhosis with hepatic encephalopathy, endoscopic procedure-tiers, and an endoscopic intervention after patient transfer from one hospital to another. The analysis reveals that the higher patient complexity, severity and cost at University Hospitals cannot be corrected by modification or further differentiation of individual DRGs within the existing G-DRG-system. Even in DRGs for which a differentiation would be possible and economically appropriate it is often not permitted. A further rise of the systematic deficit of German University Hospitals (currently 300 Mio. Euro annually) can only be prevented by introducing either a case-based DRG-System-Surcharge for University Hospitals or by separation of a University Hospital U-DRG-System from the general G-DRG-System.
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http://dx.doi.org/10.1055/a-1219-8245DOI Listing
August 2020

Pro-inflammatory TNF-α and IFN-γ Promote Tumor Growth and Metastasis via Induction of MACC1.

Front Immunol 2020 27;11:980. Epub 2020 May 27.

Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Early stage CRC patients have a good prognosis. If distant metastasis occurs, the 5-year survival drops below 10%. Despite treatment success over the last decades, treatment options for metastatic disease are still limited. Therefore, novel targets are needed to foster therapy of advanced stage CRC patients and hinder progression of early stage patients into metastasis. A novel target is the crucial oncogene Metastasis-Associated in Colon Cancer 1 (MACC1) involved in molecular pathogenesis of CRC metastasis. MACC1 induces cell proliferation and motility, supports cellular survival and rewires metabolism resulting in increased metastasis . MACC1 is a prognostic biomarker not only for CRC but for more than 20 solid cancer entities. Inflammation plays a pivotal role in tumorigenesis, tumor progression and metastasis. For CRC, inflammatory bowel disease and ulcerative colitis are important inflammation associated risk factors. Certain cytokines, such as TNF-α and IFN-γ, are key factors in determining the contribution of the inflammatory process to CRC. Knowledge of the connection between inflammation and MACC1 driven tumors remains unclear. Gene expression analysis of CRC cells after cytokine stimulation was analyzed by qRT-PCR and Western blot. Cellular motility was assessed by Boyden chamber assays. MACC1 promoter activity after stimulation with pro-inflammatory cytokines was measured using promoter-luciferase constructs. To investigate signal transduction from receptor to effector molecules, blocking experiments using neutralizing antibodies and knockdown experiments were performed. Following TNF-α stimulation, MACC1 and c-Jun expression were significantly increased at the mRNA and protein level. Knockdown of c-Jun reduced MACC1 inducibility following TNF-α stimulation. TNF-α promoted MACC1-induced cell migration that was reverted following MACC1 knockdown. Moreover, MACC1 and c-Jun expression were downregulated by blocking TNFR1, but not TNFR2. Knock down of the NF-κB subunit, p65, reduced basal MACC1 and c-Jun mRNA expression levels. Adalimumab, a clinically approved monoclonal anti-TNF-α antibody, hindered MACC1 induction. The present study highlights that TNF-α regulates the induction of MACC1 via the NF-κB subunit p65 and the transcription factor c-Jun in CRC cells. This finding unravels a novel signaling pathway upstream of MACC1 and provides a potential therapeutic target for the treatment of CRC patients with an associated inflammation.
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http://dx.doi.org/10.3389/fimmu.2020.00980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326113PMC
April 2021

["Choosing wisely" - mission and aims].

Z Gastroenterol 2020 Jul 13;58(7):642-644. Epub 2020 Jul 13.

Medicine I, Charité, CBF, Berlin, Germany.

"Klug entscheiden" addresses the problem of over- and undersupply in medicine. Following the American model "Choosing wisely" an interdisciplinary team of all internal medicine societies develops evidence-based recommendations to improve the quality of indications. In contrast to guidelines, the initiative does not provide comprehensive medical recommendations, but focuses on problems that are particularly relevant to health care. In addition, it is intended to promote communication between doctors and patients, but also the national debate on the responsible and sensible use of medical resources.
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http://dx.doi.org/10.1055/a-1133-4540DOI Listing
July 2020

Emerging Treatment Options in Inflammatory Bowel Disease: Janus Kinases, Stem Cells, and More.

Digestion 2020 22;101 Suppl 1:69-82. Epub 2020 Jun 22.

Department of Gastroenterology and Hepatology, Kantonsspital St. Gallen, St. Gallen, Switzerland.

Background: Treatment of inflammatory bowel diseases (IBD) has tremendously improved during the last 20 years; however, a substantial fraction of patients does not respond to available therapies or lose response, and new strategies are needed.

Summary: Two pharmacological principles have been successfully used for IBD treatment: inhibition of cellular signaling and interference with leukocyte trafficking. Besides tumor necrosis factor, interleukin (IL)-23 is a promising drug target, and antibodies for the combined inhibition of IL-23 and IL-12 (ustekinumab and briakinumab) or selective IL-23 inhibition (brazikumab, risankizumab, and mirikizumab) seem to be effective in Crohn's disease (CD) with emerging evidence also for ulcerative colitis (UC). Janus kinase (JAK) mediates intracellular signaling of a large number of cytokines. Tofacitinib is the first JAK inhibitor approved for UC, and the JAK inhibitors filgotinib and upadacitinib showed potential in CD. Leukocyte trafficking can be inhibited by interference with lymphocyte integrin-α4β7 or endothelial MadCAM-1. The α4β7 integrin inhibitor vedolizumab is an established treatment in IBD, and long-term data of pivotal studies are now available. Additional molecules with therapeutic potential are α4β7-specific abrilumab, β7-specific etrolizumab, and the α4-specific small molecule AJM300. PF-00547659, an antibody against endothelial MadCAM-1, also showed therapeutic potential in UC. Modulation of sphingosine-1-phosphate receptor (S1PR) activity is necessary for the egress of lymphocytes into the circulation, and S1PR modulation results in lymphocyte trapping in lymphatic organs. Ozanimod, an S1PR1 and S1PR5 inhibitor, has been successfully tested in initial studies in UC. Mesenchymal stem cell therapy has been approved for the treatment of complex, active CD fistula, and mesenchymal stem cell therapy might be a paradigm shift for this condition. Autologous stem cell transplantation (ASCT) has been successfully used in CD case series; however, in a randomized trial, a highly stringent endpoint was not met. However, considering positive effects in secondary endpoints, ASCT might be a future treatment of last resort in severe, refractory CD cases, provided that safer protocols can be provided. Key messages: New IBD treatments are successful for a significant fraction of patients. However, new strategies for patient selection, treatment combinations, and/or additional therapies must be developed to serve the need of all IBD patients.
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http://dx.doi.org/10.1159/000507782DOI Listing
June 2020

Studying the pathophysiology of coronavirus disease 2019: a protocol for the Berlin prospective COVID-19 patient cohort (Pa-COVID-19).

Infection 2020 Aug 13;48(4):619-626. Epub 2020 Jun 13.

Department of Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Campus Virchow Klinikum, Augustenburgerplatz 1, 13353, Berlin, Germany.

Purpose: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide causing a global health emergency. Pa-COVID-19 aims to provide comprehensive data on clinical course, pathophysiology, immunology and outcome of COVID-19, to identify prognostic biomarkers, clinical scores, and therapeutic targets for improved clinical management and preventive interventions.

Methods: Pa-COVID-19 is a prospective observational cohort study of patients with confirmed SARS-CoV-2 infection treated at Charité - Universitätsmedizin Berlin. We collect data on epidemiology, demography, medical history, symptoms, clinical course, and pathogen testing and treatment. Systematic, serial blood sampling will allow deep molecular and immunological phenotyping, transcriptomic profiling, and comprehensive biobanking. Longitudinal data and sample collection during hospitalization will be supplemented by long-term follow-up.

Results: Outcome measures include the WHO clinical ordinal scale on day 15 and clinical, functional, and health-related quality-of-life assessments at discharge and during follow-up. We developed a scalable dataset to (i) suit national standards of care, (ii) facilitate comprehensive data collection in medical care facilities with varying resources, and (iii) allow for rapid implementation of interventional trials based on the standardized study design and data collection. We propose this scalable protocol as blueprint for harmonized data collection and deep phenotyping in COVID-19 in Germany.

Conclusion: We established a basic platform for harmonized, scalable data collection, pathophysiological analysis, and deep phenotyping of COVID-19, which enables rapid generation of evidence for improved medical care and identification of candidate therapeutic and preventive strategies. The electronic database accredited for interventional trials allows fast trial implementation for candidate therapeutic agents.

Trial Registration: Registered at the German registry for clinical studies (DRKS00021688).
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http://dx.doi.org/10.1007/s15010-020-01464-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293426PMC
August 2020

Level of Tumor Necrosis Factor Production by Stimulated Blood Mononuclear Cells Can Be Used to Predict Response of Patients With Inflammatory Bowel Diseases to Infliximab.

Clin Gastroenterol Hepatol 2021 Apr 6;19(4):721-731.e1. Epub 2020 Apr 6.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, Department for Medicine (Gastroenterology, Infectious diseases, Rheumatology), Berlin, Germany.

Background & Aims: A substantial proportion patients with inflammatory bowel disease (IBD) have a primary non-response to infliximab; markers are needed to identify patients most likely to respond to treatment. We investigated whether production of tumor necrosis factor (TNF) by peripheral blood mononuclear cells (PBMCs) can be used as a marker to predict response.

Methods: We performed a prospective study of 41 adults with IBD (mean age, 38 years; 21 male; 21 with Crohn's disease and 20 with ulcerative colitis) not treated with a biologic agent within the past 6 months; patients were given their first infusion of infliximab at a hospital or clinic in Berlin, Germany. We collected data on clinical scores, levels of C-reactive protein, and ultrasound results (Limberg scores) at baseline (before the first infusion) and after 6 weeks (3 infliximab infusion). PMBCs were obtained from patients at baseline and 10 healthy individuals (controls) and incubated with lipopolysaccharide. We measured production of cytokines (TNF, interleukin 1 [IL1], IL6, IL8, IL10, IL12p70, and IL22) by ELISA and performed cytometric bead array and flow cytometry analyses. The primary endpoint was clinical response (decrease in Harvey Bradshaw Index scores of 2 or more or decrease in partial Mayo scores of 3 or more at week 6) in patients with PBMCs that produced high vs low levels of TNF.

Results: Responders had a shorter median disease duration (P = .018) and higher median Limberg score (P = .021), than nonresponders. Baseline PBMCs from responders produced significantly more TNF (P = .049) and IL6 (P = .028) than from nonresponders; a level of 500 pg/ml TNF identified responders with 82% sensitivity and 78% specificity. In patients with Crohn's disease, this cutoff value (500 pg/ml TNF) identified responders with 100% sensitivity and 82% specificity; TNF levels above this level were independently associated with response to infliximab in multivariate analysis (odds ratio, 16.2; 95% CI, 1.8-148.7; P = .014). The percentage of TNF-positive cells was higher among CD14+ monocytes than lymphocytes after stimulation.

Conclusions: Production of a high level of TNF by PBMCs (specifically CD14+ cells) from patients with IBD can identify those most likely to have a clinical response to infliximab therapy. In patients with Crohn's disease, a cutoff value of 500 pg/ml TNF identified responders with 100% sensitivity and 82% specificity.
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http://dx.doi.org/10.1016/j.cgh.2020.03.066DOI Listing
April 2021

Use of microbiological and patient data for choice of empirical antibiotic therapy in acute cholangitis.

BMC Gastroenterol 2020 Mar 12;20(1):65. Epub 2020 Mar 12.

Charité - Universitätsmedizin Berlin, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Campus Benjamin Franklin, Berlin, Germany.

Background: Ineffective antibiotic therapy increases mortality of acute cholangitis. The choice of antibiotics should reflect local resistance patterns and avoid the overuse of broad-spectrum agents. In this study, we analysed how results of bile and blood cultures and patient data can be used for selection of empirical antibiotic therapy in acute cholangits.

Methods: Pathogen frequencies and susceptibility rates were determined in 423 positive bile duct cultures and 197 corresponding blood cultures obtained from 348 consecutive patients with acute cholangitis. Patient data were retrieved from the medical records. Associations of patient and microbiological data were assessed using the Chi-2 test and multivariate binary logistic regression.

Results: In bile cultures, enterobacterales and enterococci were isolated with equal frequencies of approximately 30% whereas in blood cultures, enterobacterales predominated (56% compared to 21% enterococci). Antibiotic resistance rates of enterobacterales were > 20% for fluorochinolones, cephalosporines and acylureidopenicillins but not for carbapenems (< 2%). The efficacy of empirical therapy was poor with a coverage of bacterial bile and blood culture isolates in 51 and 69%, respectively. By multivariate analysis, predictors for pathogen species, antibiotic susceptibility and expected antibiotic coverage were identified.

Conclusions: In unselected patients treated for acute cholangitis in a large tertiary refferential center, use of carbapenems seems necessary to achieve a high antibiotic coverage. However, by analysis of patient and microbiological data, subgroups for highly effective carbapenem-sparing therapy can be defined. For patients with community-acquired cholangitis without biliary prosthesis who do not need intensive care, piperacillin/tazobactam represents a regimen with an expected excellent antibiotic coverage.
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http://dx.doi.org/10.1186/s12876-020-01201-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066745PMC
March 2020

[August 2019 - AWMF-Registriernummer: 021-009].

Z Gastroenterol 2019 Nov 18;57(11):e1. Epub 2020 Feb 18.

Medizinische Klinik I, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Deutschland.

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http://dx.doi.org/10.1055/a-1108-3778DOI Listing
November 2019

Specific microbiota enhances intestinal IgA levels by inducing TGF-β in T follicular helper cells of Peyer's patches in mice.

Eur J Immunol 2020 06 27;50(6):783-794. Epub 2020 Feb 27.

Deutsches Rheuma-Forschungszentrum Berlin, a Leibniz Institute (DRFZ), Berlin, Germany.

In humans and mice, mucosal immune responses are dominated by IgA antibodies and the cytokine TGF-β, suppressing unwanted immune reactions but also targeting Ig class switching to IgA. It had been suggested that eosinophils promote the generation and maintenance of mucosal IgA-expressing plasma cells. Here, we demonstrate that not eosinophils, but specific bacteria determine mucosal IgA production. Co-housing of eosinophil-deficient mice with mice having high intestinal IgA levels, as well as the intentional microbiota transfer induces TGF-β expression in intestinal T follicular helper cells, thereby promoting IgA class switching in Peyer's patches, enhancing IgA plasma cell numbers in the small intestinal lamina propria and levels of mucosal IgA. We show that bacteria highly enriched for the genus Anaeroplasma are sufficient to induce these changes and enhance IgA levels when adoptively transferred. Thus, specific members of the intestinal microbiota and not the microbiota as such regulate gut homeostasis, by promoting the expression of immune-regulatory TGF-β and of mucosal IgA.
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http://dx.doi.org/10.1002/eji.201948474DOI Listing
June 2020

Are Serum-Based Markers Going to Replace Faecal Neutrophil Markers in Ulcerative Colitis?

Authors:
Britta Siegmund

J Crohns Colitis 2020 02;14(2):151-152

Medizinische Klinik m. S. Gastroenterologie, Infektiologie und Rheumatologie, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

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http://dx.doi.org/10.1093/ecco-jcc/jjz138DOI Listing
February 2020

Janus Kinase inhibitors in the New Treatment Paradigms of Inflammatory Bowel Disease.

Authors:
Britta Siegmund

J Crohns Colitis 2020 Aug;14(Supplement_2):S761-S766

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, Department for Medicine (Gastroenterology, Infectious diseases, Rheumatology), Berlin, Germany.

This review provides guidance in the decision-making process regarding when to choose a janus kinase [JAK] inhibitor as medical treatment strategy. The focus will be on ulcerative colitis, because the only yet available JAK inhibitor, tofacitinib, has approval for use in ulcerative colitis. The guidance path will include consideration of disease activity, previous treatment, comorbidities, family planning, patient preferences, pharmacology as well as concurrent chronic inflammatory diseases or extraintestinal manifestations. The suggested guidance path illustrates our daily difficulties in the decision-making process regarding best choice for the individual patient. However if predictive biomarkers are lacking, the named criteria can be applied to any other strategy and hence provide support in daily practice.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395309PMC
August 2020

Multi-parameter immune profiling of peripheral blood mononuclear cells by multiplexed single-cell mass cytometry in patients with early multiple sclerosis.

Sci Rep 2019 12 19;9(1):19471. Epub 2019 Dec 19.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). Studies in rodent models demonstrated an association of CNS-infiltrating monocyte-derived macrophages with disease severity. However, little is known about humans. Here, we performed an exploratory analysis of peripheral blood mononuclear cells (PBMCs) isolated from healthy controls and drug-naïve patients with early MS using multiplexed single-cell mass cytometry and algorithm-based data analysis. Two antibody panels comprising a total of 64 antibodies were designed to comprehensively analyse diverse immune cell populations, with particular emphasis on monocytes. PBMC composition and marker expression were overall similar between the groups. However, an increased abundance of CCR7 and IL-6 T cells was detected in early MS-PBMCs, whereas NFAT1T-betCD4 T cells were decreased. Similarly, we detected changes in the subset composition of the CCR7 and MIPβ HLA-DR lymphocyte compartment. Only mild alterations were detected in monocytes/myeloid cells of patients with early MS, namely a decreased abundance of CD141IRF8CXCR3CD68 dendritic cells. Unlike in Crohn's disease, no significant differences were found in the monocyte fraction of patients with early MS compared to healthy controls. This study provides a valuable resource for future studies designed to characterise and target diverse PBMC subsets in MS.
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http://dx.doi.org/10.1038/s41598-019-55852-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923404PMC
December 2019

Metabolic Control of Epigenetics and Its Role in CD8 T Cell Differentiation and Function.

Front Immunol 2019 26;10:2718. Epub 2019 Nov 26.

Division of Gastroenterology, Infectiology and Rheumatology, Medical Department, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Epigenetic programs that control posttranslational modifications of histone proteins and DNA itself tightly regulate transcriptional networks determining the identity and function of CD8 T cells. Chromatin-modifying enzymes such as histone acetyltransferases and deacetylases, represent key molecular determinants of the epigenetic imprinting of CD8 T cells. The functions of these enzymes highly depend on the availability of key products of cellular metabolism pathways such as acetyl-CoA, NAD (Nicotinamide adenine dinucleotide) and SEM (S-adenosylmethionine), suggesting that there is a close crosstalk between the metabolic and the epigenetic regulation of CD8 T cells. In this review, we will discuss the metabolic regulation of CD8 T cell epigenetics during activation and differentiation. We will furthermore summarize how metabolic signals from the tumor microenvironment (TME) shape the epigenetic landscape of CD8 T cells to better understand the mechanism underlying CD8 T cell exhaustion in anti-tumor and anti-viral immunity, which might help to overcome limitations of current CD8 T cell-based therapies.
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http://dx.doi.org/10.3389/fimmu.2019.02718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901948PMC
November 2020

Leptin induces TNFα-dependent inflammation in acquired generalized lipodystrophy and combined Crohn's disease.

Nat Commun 2019 12 10;10(1):5629. Epub 2019 Dec 10.

Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.

Leptin has been shown to modulate intestinal inflammation in mice. However, clinical evidence regarding its immune-stimulatory potential in human Crohn's disease remains sparse. We here describe a patient with the unique combination of acquired generalized lipodystrophy and Crohn's disease (AGLCD) featuring a lack of adipose tissue, leptin deficiency and intestinal inflammation. Using mass and flow cytometry, immunohistochemistry and functional metabolic analyses, the AGLCD patient was compared to healthy individuals and Crohn's disease patients regarding immune cell composition, function and metabolism and the effects of recombinant N-methionylleptin (rLeptin) were evaluated. We provide evidence that rLeptin exerts diverse pro-inflammatory effects on immune cell differentiation and function, including the metabolic reprogramming of immune cells and the induction of TNFα, ultimately aggravating Crohn's disease in the AGLCD patient, which can be reversed by anti-TNFα therapy. Our results indicate that leptin is required for human immune homeostasis and contributes to autoimmunity in a TNFα-dependent manner.
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http://dx.doi.org/10.1038/s41467-019-13559-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904732PMC
December 2019