Therapie der extraintestinalen CED-Manifestationen: Eine schwierige Herausforderung

Zusammenfassung: Morbus Crohn und Colitis ulcerosa sind chronisch-entzündliche Darmerkrankungen (CED), die nicht auf das Gastrointestinalsystem beschränkt sind. Zusätzlich können diverse Organsysteme mit betroffen sein, was die CED zu einer Systemerkrankung macht. Die häufigsten extraintestinalen Manifestationen beinhalten muskuloskelettale, ophthalmologische, dermatologische und hepatobiliäre Erkrankungen, obwohl prinzipiell jedes Organsystem betroffen sein kann. Sie können signifikant zur Morbidität von CED-Patienten beitragen und die Lebensqualität deutlich einschränken. Die Betreuung sollte aufgrund der Vielfalt der betroffenen Organsysteme interdisziplinär durch ein in der CED-Behandlung geschultes medizinisches Personal erfolgen. Ein frühes Erkennen von extraintestinalen Manifestationen ermöglicht eine gezielte Therapie und verringert die Gesamtmorbidität der betroffenen Patienten. Insbesondere kann eine effektive Erhaltungstherapie das Auftreten von Manifestationen, die eng mit der Krankheitsaktivität der zugrunde liegenden CED verknüpft sind, vermeiden helfen. Neben spezifischen Interventionen, die nicht mit der Krankheitsaktivität der CED verknüpft sind, spielt eine antiinflammatorische oder immunmodulatorische Therapie eine entscheidende Rolle. Zudem gewinnt die Verwendung einer TNF-Hemmer-Therapie in der Behandlung von verschiedenen extraintestinalen Manifestationen zunehmend an Bedeutun

Diffuse Bauchschmerzen und Eosinophilie

Zusammenfassung: Die eosinophile Gastroenteritis ist eine relativ seltene Erkrankung unklarer Ätiologie mit einem heterogenen Krankheitsbild. Wichtige Differenzialdiagnosen stellen intestinale parasitäre Infektionen, das hypereosinophile Syndrom, Lymphome und andere maligne und allergische Erkrankungen dar. Die Diagnose kann meist mittels Anamnese und Standardlabor, zusammen mit den Ergebnissen von Biopsien oder Parazentese gestellt werden. Milde Formen mit lediglich Diarrhö als klinischer Manifestation können symptombezogen behandelt werden. Die Therapie bei schwereren Verläufen erfolgt initial mit Kortikosteroide

Expression Patterns of TNFα, MAdCAM1, and STAT3 in Intestinal and Skin Manifestations of Inflammatory Bowel Disease.

Pathogenesis of cutaneous extraintestinal manifestations [EIM] in inflammatory bowel disease [IBD] remains elusive. Efficacy of anti-TNF agents suggests TNF-dependent mechanisms. The role of other biologics, such as anti-integrins or JAK-inhibitors, is not yet clear. We performed immunohistochemistry for TNFα, NFκB, STAT1/STAT3, MAdCAM1, CD20/68, caspase 3/9, IFNγ, and Hsp-27/70 on 240 intestinal [55 controls, 185 IBD] and 64 skin biopsies [11 controls, 18 erythema nodosum [EN], 13 pyoderma gangenosum [PG], 22 psoriasis]. A semiquantitative score [0-100%] was used for evaluation. TNFα was upregulated in intestinal biopsies from active Crohn`s disease [CD] vs controls [36.2 vs 12.1, p < 0.001], but not ulcerative colitis [UC: 17.9]. NFκB, however, was upregulated in intestinal biopsies from both active CD and UC [43.2 and 34.5 vs 21.8, p < 0.001 and p = 0.017, respectively]. TNFα and NFκB were overexpressed in skin biopsies from EN, PG, and psoriasis. No MAdCAM1 overexpression was seen in skin tissues, whereas it was upregulated in active UC vs controls [57.5 vs 35.4, p = 0.003]. STAT3 was overexpressed in the intestinal mucosa of active and non-active IBD, and a similar upregulation was seen in skin biopsies from EN [84.7 vs 22.3, p < 0.001] and PG [60.5 vs 22.3, p = 0.011], but not in psoriasis. Caspase 3 and CD68 overexpression in skin biopsies distinguished EN/PG from psoriasis and controls. Upregulation of TNFα/NFκB in EN and PG is compatible with the efficacy of anti-TNF in EIM management. Data on overexpressed STAT3, but not MAdCAM1, support a rationale for JAK-inhibitors in EN and PG, while questioning the role of vedolizumab

Uveitis manifestations in patients of the Swiss Inflammatory Bowel Disease Cohort Study.

The knowledge about risk factors for the onset of uveitis manifestations in patients with inflammatory bowel disease (IBD) is still limited. Here, we aimed to provide an overview of the clinical factors associated with the onset of uveitis in the Swiss IBD Cohort Study (SIBDCS). We included epidemiological and clinical data from 1840 patients with Crohn's disease (CD) and 1426 patients with ulcerative colitis (UC) followed up in the SIBDCS between 2006 and 2018. Associations between disease characteristics and uveitis were assessed in univariate and multivariate analyses. Overall, we identified 285 patients with uveitis. Uveitis was more frequent in patients with CD (11.1%; 205 of 1635) than UC (5.6%; 80 of 1346; odds ratio 2.11, p < 0.001). The occurrence of uveitis manifestations in patients with UC and CD was significantly associated with the onset of other extraintestinal manifestations, also in multivariate analyses. The onset of uveitis was associated with the hallmark features of severe disease in both CD and UC, including a higher clinical disease activity index and the use of immunomodulators or calcineurin inhibitors. In CD, uveitis was more frequent in females and showed a positive correlation with a positive family history of IBD. Our data demonstrate that uveitis in IBD occurs more often in CD as well as in women and is associated with a more severe disease course. This might guide physicians' awareness in at-risk patients to the presence of uveitis extraintestinal manifestations and help to improve patient care

Prevalence and risk factors for therapy escalation in ulcerative colitis in the Swiss IBD Cohort Study

BACKGROUND: Physicians traditionally treat ulcerative colitis (UC) using a step-up approach. Given the paucity of data, we aimed to assess the cumulative probability of UC-related need for step-up therapy and to identify escalation-associated risk factors. METHODS: Patients with UC enrolled into the Swiss IBD Cohort Study were analyzed. The following steps from the bottom to the top of the therapeutic pyramid were examined: (1) 5-aminosalicylic acid and/or rectal corticosteroids, (2) systemic corticosteroids, (3) immunomodulators (IM) (azathioprine, 6-mercaptopurine, methotrexate), (4) TNF antagonists, (5) calcineurin inhibitors, and (6) colectomy. RESULTS: Data on 996 patients with UC with a median disease duration of 9 years were examined. The point estimates of cumulative use of different treatments at years 1, 5, 10, and 20 after UC diagnosis were 91%, 96%, 96%, and 97%, respectively, for 5-ASA and/or rectal corticosteroids, 63%, 69%, 72%, and 79%, respectively, for systemic corticosteroids, 43%, 57%, 59%, and 64%, respectively, for IM, 15%, 28%, and 35% (up to year 10 only), respectively, for TNF antagonists, 5%, 9%, 11%, and 12%, respectively, for calcineurin inhibitors, 1%, 5%, 9%, and 18%, respectively, for colectomy. The presence of extraintestinal manifestations and extended disease location (at least left-sided colitis) were identified as risk factors for step-up in therapy with systemic corticosteroids, IM, TNF antagonists, calcineurin inhibitors, and surgery. Cigarette smoking at diagnosis was protective against surgery. CONCLUSIONS: The presence of extraintestinal manifestations, left-sided colitis, and extensive colitis/pancolitis at the time of diagnosis were associated with use of systemic corticosteroids, IM, TNF antagonists, calcineurin inhibitors, and colectomy during the disease course

Genotype-Phenotype Associations of the CD-Associated Single Nucleotide Polymorphism within the Gene Locus Encoding Protein Tyrosine Phosphatase Non-Receptor Type 22 in Patients of the Swiss IBD Cohort.

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) plays an important role in immune cell function and intestinal homeostasis. The single nucleotide polymorphism (SNP) rs2476601 within the PTPN22 gene locus results in aberrant function of PTPN22 protein and protects from Crohn's disease (CD). Here, we investigated associations of PTPN22 SNP rs2476601 in inflammatory bowel disease (IBD) patients in the Swiss IBD Cohort Study (SIBDCS). 2'028 SIBDCS patients (1173 CD and 855 ulcerative colitis (UC) patients) were included. The clinical characteristics were analysed for an association with the presence of the PTPN22 SNP rs2476601 genotypes 'homozygous variant' (AA), 'heterozygous' (GA) and 'homozygous wild-type' (GG). 13 patients (0.6%) were homozygous variant (AA) for the PTPN22 polymorphism, 269 (13.3%) heterozygous variant (GA) and 1'746 (86.1%) homozygous wild-type (GG). In CD, AA and GA genotypes were associated with less use of steroids and antibiotics, and reduced prevalence of vitamin D and calcium deficiency. In UC the AA and GA genotype was associated with increased use of azathioprine and anti-TNF antibodies, but significantly less patients with the PTPN22 variant featured malabsorption syndrome (p = 0.026). Our study for the first time addressed how presence of SNP rs2476601 within the PTPN22 gene affects clinical characteristics in IBD-patients. Several factors that correlate with more severe disease were found to be less common in CD patients carrying the A-allele, pointing towards a protective role for this variant in affected CD patients. In UC patients however, we found the opposite trend, suggesting a disease-promoting effect of the A-allele

Impact of Overweight and Obesity on Disease Outcome in the Pediatric Swiss Inflammatory Bowel Disease Cohort.

Given the paucity of data, we aimed to assess the impact of obesity on disease activity, complications, and quality of life (QoL) in pediatric inflammatory bowel disease (IBD) patients. Prospective analysis of pediatric IBD patients. Patients were categorized into 4 groups according to the World Health Organization (WHO) child growth standards: obese, overweight, normal weight, and underweight. Three hundred twenty-seven pediatric patients were included (146 with Crohn's disease [CD], 181 with ulcerative colitis of whom 13 [4%] were underweight, 272 [83.2%] had normal weight, 22 [6.7%] were overweight, and 20 [6.1%] were obese). Compared with normal weight patients, obese ulcerative colitis had a significantly higher clinical but not biological disease activity nor severity. Compared with normal weight patients, overweight/obese CD patients did not have higher clinical or biological disease activity nor severity. Perianal abscesses and surgery for this purpose were more frequently observed in overweight/obese CD patients compared with normal weight controls. Overweight/obese IBD patients were similarly hospitalized in the last 12 months compared with normal weight controls. Prevalence of overweight/obesity was 12.8% in pediatric IBD patients. Obesity was not associated with a decrease in disease remission rates nor an increase in the risk of complicated disease progression in IBD pediatric patients, except for the occurrence of perianal abscesses and related surgery in CD patients

Alcohol and cannabis consumption in patients with inflammatory bowel disease: prevalence, pattern of consumption and impact on the disease.

There is little guidance regarding the impact of alcohol and cannabis on the clinical course of inflammatory bowel disease. The aim of this study was to assess the prevalence, sociodemographic characteristics and impact of alcohol and cannabis use on the clinical course of the disease. We performed an analysis of prospectively collected data within the Swiss Inflammatory Bowel Disease Cohort Study with yearly follow-ups and substance-specific questionnaires. We analyzed the prevalence of use, the profile of users at risk for addiction and the impact of alcohol and cannabis on the course of the disease. We collected data of 2828 patients included between 2006 and 2018 and analyzed it according to their completion of specific surveys on alcohol and cannabis use. The prevalence of patient-reported active use was 41.3% for alcohol and 6% for cannabis. Heavy drinkers were over-represented among retired, married smokers receiving mostly aminosalicylates and less immunosuppression. In ulcerative colitis patients, low-to-moderate drinking was associated with less extensive disease. Cannabis users were often students with ileal Crohn's disease. A significant proportion of patients with inflammatory bowel disease consume alcohol or cannabis. Heavy alcohol consumption is most likely in male smokers >50 years, whereas young men with ileal disease rather use cannabis

The ATLAS trigger system for LHC Run 3 and trigger performance in 2022

The ATLAS trigger system is a crucial component of the ATLAS experiment at the LHC. It is responsible for selecting events in line with the ATLAS physics programme. This paper presents an overview of the changes to the trigger and data acquisition system during the second long shutdown of the LHC, and shows the performance of the trigger system and its components in the proton-proton collisions during the 2022 commissioning period as well as its expected performance in proton-proton and heavy-ion collisions for the remainder of the third LHC data-taking period (2022–2025)

Measurement of vector boson production cross sections and their ratios using pp collisions at √s = 13.6 TeV with the ATLAS detector

Abstract available from publisher's website