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Background: Inflammation is characterized by a metabolic switch promoting glycolysis and lactate production. Hexokinases (HK) catalyze the first reaction of glycolysis and inhibition of epithelial HK2 protected from colitis in mice. HK2 expression has been described as elevated in patients with intestinal inflammation; however, there is conflicting data from few cohorts especially with severely inflamed individuals; thus, systematic studies linking disease activity with HK2 levels are needed. Methods: We examined the relationship between HK2 expression and inflammation severity using bulk transcriptome data derived from the mucosa of thoroughly phenotyped inflammatory bowel disease (IBD) patients of two independent cohorts including both subtypes Crohn's disease (CD) and ulcerative colitis (UC). Publicly available single-cell RNA sequencing data were analyzed, and immunofluorescence staining on colonic biopsies of unrelated patients with intestinal inflammation was performed to confirm the RNA-based findings on cellular and protein level. Results: HK2 expression gradually increased from mild to intermediate inflammation, yet strongly declined at high inflammation scores. Expression of epithelial marker genes also declined at high inflammation scores, whereas that of candidate immune marker genes increased, indicating a cellular remodeling of the mucosa during inflammation with an infiltration of HK2-negative immune cells and a loss of terminal differentiated epithelial cells in the apical epithelium—the main site of HK2 expression. Normalizing for the enterocyte loss clearly identified epithelial HK2 expression as gradually increasing with disease activity and remaining elevated at high inflammation scores. HK2 protein expression was mostly restricted to brush border enterocytes, and these cells along with HK2 levels vanished with increasing disease severity. Conclusions: Our findings clearly define dysregulated epithelial HK2 expression as an indicator of disease activity in intestinal inflammation and suggest targeted HK2-inhibition as a potential therapeutic avenue. [ABSTRACT FROM AUTHOR]

Periodontitis is associated with systemic chronic inflammatory diseases. There is limited evidence on the influence of anti-cytokine therapies on the periodontal condition and microbiome in the tooth pocket of such patients, so the aim of this study was to elucidate this issue. In this observational trial, the periodontal status and the gingival crevicular fluid of 13 patients with different chronic inflammatory diseases were obtained before the initiation of anti-cytokine treatment and 14 weeks after. Gingival crevicular fluid was collected for 16S rRNA gene sequencing from a clinically healthy tooth and the deepest measured pocket. The Shannon Diversity Index significantly increased in the deepest pockets of patients (p = 0.039). The data showed alterations in the diversity of the subgingival microbiome over the course of the study, implying a shift towards a healthier condition after starting anti-cytokine therapy. Additional investigations are needed to analyze whether the administration of selective biologicals can improve periodontal conditions in patients with or without chronic inflammatory diseases. [ABSTRACT FROM AUTHOR]

We identified and tested a novel aspect of human resilience: The daily pursuit of maintenance goals. Taking inspiration from archaeological records, which point at routinized cultural practices as a central resilience factor, we tested whether personal routine practices, governed by maintenance goals, serve a similar function to individuals as traditional practices do to societies. Namely, we hypothesized that maintenance striving increases individuals' resilient responses to stressful events. Confirming this prediction, a longitudinal Study 1 showed that maintenance striving but not avoidance striving, predicted subsequent increases in well‐being following the third wave of the COVID‐19 pandemic in Germany. Study 2 confirmed our predictions on trait resilience and maintenance versus avoidance motivations in the household and relationship life domains in cross‐sectional data. These studies contribute to the understanding of resilience by demonstrating the benefits of maintenance goals for both situational and trait‐level resilience. [ABSTRACT FROM AUTHOR]

Key Points: Question: Among patients with moderately to severely active ulcerative colitis, does risankizumab improve clinical remission rates compared with placebo when risankizumab is administered as an induction and a maintenance therapy? Findings: Among the 975 patients analyzed in the induction trial, 1200 mg of risankizumab significantly increased the rates of clinical remission at 12-week follow-up compared with placebo (20.3% vs 6.2%, respectively). Among 548 patients included in the primary efficacy analysis for the maintenance trial, 180 mg of risankizumab and 360 mg of risankizumab significantly increased the rates of clinical remission (40.2% and 37.6%, respectively) compared with placebo (25.1%). Meaning: Risankizumab improved the rates of clinical remission when used as an induction and a maintenance therapy for patients with moderately to severely active ulcerative colitis. Importance: The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown. Objective: To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis. Design, Setting, and Participants: Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab. Interventions: For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks. Main Outcomes and Measures: The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial. Results: Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P <.001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P <.001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P =.002). No new safety risks were detected in the treatment groups. Conclusion and Relevance: Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up. Trial Registration: ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135 These 2 randomized clinical trials compare the efficacy and safety of risankizumab vs placebo during an induction trial and a maintenance trial in patients with ulcerative colitis. [ABSTRACT FROM AUTHOR]

Copyright of Zeitschrift für Rheumatologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Summary: Background: Filgotinib, an oral, once‐daily, Janus kinase 1 preferential inhibitor, is an approved treatment for moderately to severely active ulcerative colitis. Aims: The aim of this study is to assess the safety and efficacy of continued filgotinib therapy over ~4 years in the long‐term extension of the phase 2b/3 SELECTION trial (SELECTIONLTE; NCT02914535). Methods: In this interim analysis of SELECTIONLTE, SELECTION completers (week 10 responders to filgotinib who completed the maintenance study) continued their assigned treatment (double‐blind filgotinib 200 mg [FIL200] or filgotinib 100 mg) and SELECTION week 10 non‐responders received open‐label FIL200. We assessed safety by adverse events (AEs), and efficacy by partial Mayo Clinic Score (pMCS), inflammatory biomarkers and health‐related quality of life (HRQoL). We compared safety and efficacy between achievers and non‐achievers of a multi‐component endpoint, comprehensive disease control (CDC), comprising symptomatic, endoscopic, inflammatory biomarker and HRQoL improvements. Results: Data for completers (n = 250) and non‐responders (n = 372) were reported for ≤202 weeks. AE occurrences were low and consistent with previous analyses. The as‐observed proportion of FIL200‐treated patients in pMCS, biomarker and HRQoL remission during SELECTIONLTE remained high among completers (week 144: 80.0%, 86.4% and 86.0%, respectively) and increased among non‐responders (week 192: 62.1%, 76.7% and 59.3%, respectively). Significantly higher proportions of CDC achievers at SELECTION week 58 achieved pMCS, IBDQ and corticosteroid‐free pMCS remission than non‐achievers, up to LTE week 96. Conclusions: Filgotinib induced and maintained symptomatic remission and improved HRQoL over 4 years. Safety results showed a proven long‐term benefit–risk profile. FIL200‐treated CDC achievers had better long‐term outcomes than non‐achievers. [ABSTRACT FROM AUTHOR]

Background: Crohn's disease (CD) significantly affects patients' health-related quality of life and well-being. Aims: Communicating Needs and Features of IBD Experiences (CONFIDE) survey explores the experience and impact of moderate-to-severe CD symptoms on patients' lives and identifies communication gaps between patients and health care professionals (HCPs). Methods: Online, quantitative, cross-sectional surveys of patients, and HCPs were conducted in the United States (US), Europe (France, Germany, Italy, Spain, United Kingdom), and Japan. Criteria based on previous treatment, steroid use, and/or hospitalization defined moderate-to-severe CD. US and Europe data are presented as descriptive statistics. Results: Surveys were completed by 215 US and 547 European patients and 200 US and 503 European HCPs. In both patient groups, top three symptoms currently (past month) experienced were diarrhea, bowel urgency, and increased stool frequency, with more than one-third patients wearing diaper/pad/protection at least once a week in past 3 months due to fear of bowel urgency-related accidents. HCPs ranked diarrhea, blood in stool, and increased stool frequency as the most common symptoms. Although 34.0% US and 27.2% European HCPs ranked bowel urgency among the top five symptoms affecting patient lives, only 12.0% US and 10.9% European HCPs ranked it among top three most impactful symptoms on treatment decisions. Conclusion: Bowel urgency is common and impactful among patients with CD in the US and Europe. Differences in patient and HCP perceptions of experiences and impacts of bowel urgency exist, with HCPs underestimating its burden. Proactive communication between HCPs and patients in clinical settings is crucial for improving health outcomes in patients with CD. [ABSTRACT FROM AUTHOR]

Blood-based biomarkers that reliably indicate disease activity in the intestinal tract are an important unmet need in the management of patients with IBD. Extracellular vesicles (EVs) are cell-derived membranous microparticles, which reflect the cellular and functional state of their site of site of origin. As ultrasound waves may lead to molecular shifts of EV contents, we hypothesized that application of ultrasound waves on inflamed intestinal tissue in IBD may amplify the inflammation-specific molecular shifts in EVs like altered EV-miRNA expression, which in turn can be detected in the peripheral blood. 26 patients with IBD were included in the prospective clinical study. Serum samples were collected before and 30 min after diagnostic transabdominal ultrasound. Differential miRNA expression was analyzed by sequencing. Candidate inducible EV-miRNAs were functionally assessed in vitro by transfection of miRNA mimics and qPCR of predicted target genes. Serum EV-miRNA concentration at baseline correlated with disease severity, as determined by clinical activity scores and sonographic findings. Three miRNAs (miR-942-5p, mir-5588, mir-3195) were significantly induced by sonography. Among the significantly regulated EV-miRNAs, miR-942-5p was strongly induced in higher grade intestinal inflammation and correlated with clinical activity in Crohn’s disease. Prediction of target regulation and transfection of miRNA mimics inferred a role of this EV-miRNA in regulating barrier function in inflammation. Induction of mir-5588 and mir-3195 did not correlate with inflammation grade. This proof-of-concept trial highlights the principle of induced molecular shifts in EVs from inflamed tissue through transabdominal ultrasound. These inducible EVs and their molecular cargo like miRNA could become novel biomarkers for intestinal inflammation in IBD. [ABSTRACT FROM AUTHOR]

Summary: Background: IBDBIO‐ASSIST was a randomised controlled trial assessing the efficacy of care provided by IBD nurse specialists in Germany in improving health‐related quality of life (QoL) in IBD patients on biologic therapy. Aim: To evaluate patient‐related outcomes and economic consequences associated with integrating IBD nurses into usual care. Methods: We randomly assigned 1086 patients with IBD on biologic therapy to a control group (CG) receiving usual care or an intervention group (IG) receiving additional care from an IBD nurse specialist. The primary outcome was disease‐specific QoL (sIBDQ) assessed at 6, 12 and 18 months. Results: At baseline, patients in both groups were highly satisfied with their treatment situation and had relatively high sIBDQ values (range: 1–7; CG: 5.12; IG: 4.92). In the intention‐to‐treat (ITT) analysis of the overall sample, there was no significant difference in sIBDQ between groups at the assessment time points. However, a per‐protocol analysis of patients with impaired QoL at baseline (EQ‐VAS < 75 [median]), showed improvement in sIBDQ over 6 months that became significant at month 12 and remained significant through month 18 (baseline: IG 4.24; CG 4.31; 18 months: IG 5.02; CG 4.76; p = 0.017). Conclusion: High baseline satisfaction of IBD patients with treatment and the relatively high baseline sIBDQ values may have contributed to the lack of significant difference in sIBDQ scores for the overall sample. However, patients with impaired QoL derived significant benefit from additional care provided by an IBD nurse specialist, leading to meaningful improvements in sIBDQ over the long term. [ABSTRACT FROM AUTHOR]

Etrasimod is an investigational, once‐daily, oral, selective sphingosine 1‐phosphate receptor 1,4,5 modulator in development for immune‐mediated inflammatory diseases (IMIDs). Here, we report the human safety, pharmacokinetics, and pharmacodynamics of etrasimod obtained from both a single ascending dose (SAD; 0.1‐5 mg) study and a multiple ascending dose (MAD; 0.35‐3 mg once daily) study. Overall, 99 healthy volunteers (SAD n = 40, MAD n = 59) completed the 2 studies. Evaluated single and multiple doses were well tolerated up to 3 mg without severe adverse events (AEs). Gastrointestinal disorders were the most common etrasimod‐related AEs. Over the evaluated single‐ and multiple‐dose ranges, dose‐proportional and marginally greater‐than‐dose‐proportional etrasimod plasma exposure were observed, respectively. At steady state, etrasimod oral clearance and half‐life mean values ranged from 1.0 to 1.2 L/h and 29.7 to 36.4 hours, respectively. Dose‐dependent total peripheral lymphocyte reductions occurred following etrasimod single and multiple dosing. Etrasimod multiple dosing resulted in reductions from baseline in total lymphocyte counts ranging from 41.1% to 68.8% after 21 days. Lymphocyte counts returned to normal range within 7 days following treatment discontinuation. Heart rate lowering from pretreatment baseline on etrasimod dosing was typically mild, with mean reductions seen after the first dose of up to 19.5 bpm (5 mg dose). The favorable safety, pharmacokinetic, and pharmacodynamic properties of etrasimod in humans supported its further development and warranted its investigation for treatment of IMIDs. [ABSTRACT FROM AUTHOR]

Olamkicept selectively inhibits the cytokine interleukin‐6 (IL‐6) trans‐signaling pathway without blocking the classic pathway and is a promising immunoregulatory therapy for inflammatory bowel disease (IBD). These first‐in‐human, randomized, placebo‐controlled, single‐ (SAD) and multiple‐ascending dose (MAD) trials evaluated olamkicept safety, tolerability, pharmacokinetic, and pharmacodynamic characteristics. Doses tested in the SAD trial included seven single intravenous doses (0.75, 7.5, 75, 150, 300, 600, and 750 mg) and one subcutaneous (SC) dose (60 mg) given to healthy subjects (N = 64), and three intravenous doses (75 mg, 300 mg, and 750 mg) given to patients with Crohn's disease (CD; N = 24). Doses tested in the MAD trial included multiple intravenous doses (75, 300, and 600 mg once weekly for 4 weeks) given to healthy subjects (N = 24). No severe or serious treatment‐emergent adverse events (TEAEs) were recorded. The most common TEAEs were headache, nasopharyngitis, and myalgia in the SAD trial, and diarrhea, headache, and cough in the MAD trial. Infusion‐related reactions occurred in one and two subjects in the SAD and MAD trial, respectively, leading to treatment discontinuation in the MAD trial. Olamkicept showed dose‐independent pharmacokinetics after single and multiple administrations, and there was no major difference in systemic exposure between healthy subjects and patients with CD. Complete target engagement (inhibition of phosphorylation of signal transducer and activator of transcription‐3) was achieved in blood around or above olamkicept serum concentrations of 1–5 μg/mL. Overall, these results suggest that olamkicept is safe and well‐tolerated in healthy subjects and patients with CD after single intravenous/SC and multiple intravenous administrations. [ABSTRACT FROM AUTHOR]

This article discusses a study that examined the immune response to SARS-CoV-2 infection and vaccination in patients receiving anti-TNF therapy. The study found that these patients may have lower levels of neutralizing antibodies against different Omicron variants, even after receiving a booster dose. The results suggest the need for improved vaccines and vaccination regimens for this patient population. It is important to note that the study did not examine cellular immunity or provide conclusive evidence on current humoral immunity to SARS-CoV-2. [Extracted from the article]

Purpose: We aimed to assess symptoms in patients after SARS-CoV-2 infection and to identify factors predicting prolonged time to symptom-free. Methods: COVIDOM/NAPKON-POP is a population-based prospective cohort of adults whose first on-site visits were scheduled ≥ 6 months after a positive SARS-CoV-2 PCR test. Retrospective data including self-reported symptoms and time to symptom-free were collected during the survey before a site visit. In the survival analyses, being symptom-free served as the event and time to be symptom-free as the time variable. Data were visualized with Kaplan–Meier curves, differences were tested with log-rank tests. A stratified Cox proportional hazard model was used to estimate adjusted hazard ratios (aHRs) of predictors, with aHR < 1 indicating a longer time to symptom-free. Results: Of 1175 symptomatic participants included in the present analysis, 636 (54.1%) reported persistent symptoms after 280 days (SD 68) post infection. 25% of participants were free from symptoms after 18 days [quartiles: 14, 21]. Factors associated with prolonged time to symptom-free were age 49–59 years compared to < 49 years (aHR 0.70, 95% CI 0.56–0.87), female sex (aHR 0.78, 95% CI 0.65–0.93), lower educational level (aHR 0.77, 95% CI 0.64–0.93), living with a partner (aHR 0.81, 95% CI 0.66–0.99), low resilience (aHR 0.65, 95% CI 0.47–0.90), steroid treatment (aHR 0.22, 95% CI 0.05–0.90) and no medication (aHR 0.74, 95% CI 0.62–0.89) during acute infection. Conclusion: In the studied population, COVID-19 symptoms had resolved in one-quarter of participants within 18 days, and in 34.5% within 28 days. Over half of the participants reported COVID-19-related symptoms 9 months after infection. Symptom persistence was predominantly determined by participant's characteristics that are difficult to modify. [ABSTRACT FROM AUTHOR]

Purposes: Despite reports of a declining incidence over the last decade, Clostridioides difficile infection (CDI) is still considered the most important healthcare-associated causes of diarrhea worldwide. In Germany, several measures have been taken to observe, report, and influence this development. This report aims to analyze the development of hospital coding for CDI in Germany over the last decade and to use it to estimate the public health burden caused by CDI. Methods: Reports from the Institute for Hospital Remuneration Systems, German Federal Statistical Office (DESTATIS), the Robert-Koch-Institute (RKI), Saxonian authorities and hospital quality reports during 2010–2021 were examined for CDI coding and assessed in a structured expert consultation. Analysis was performed using 2019 versions of Microsoft Excel® and Microsoft Access®. Results: Peaks of 32,203 cases with a primary diagnosis (PD) of CDI and 78,648 cases with a secondary diagnosis (SD) of CDI were observed in 2015. The number of cases had decreased to 15,412 PD cases (− 52.1%) and 40,188 SD cases (− 48.9%) by 2021. These results were paralleled by a similar decline in notifiable severe cases. However, average duration of hospitalization of the cases remained constant during this period. Conclusions: Hospital coding of CDI and notification to authorities has approximately halved from 2015 to 2021. Potential influential factors include hospital hygiene campaigns, implementation of antibiotic stewardship programs, social distancing due to the COVID-19 pandemic, and a decrease in more pathogenic subtypes of bacteria. Further research is necessary to validate the multiple possible drivers for this development. [ABSTRACT FROM AUTHOR]

Summary: Background: Filgotinib 200 mg (FIL200) is an approved treatment for adults with moderately to severely active ulcerative colitis (UC). Aim: To report integrated safety data from the phase 2b/3 SELECTION study (NCT02914522) and its ongoing long‐term extension study SELECTIONLTE (NCT02914535). Methods: Safety outcomes were analysed in adults with moderately to severely active UC who received FIL200, filgotinib 100 mg (FIL100) or placebo once daily throughout the 11‐week SELECTION induction study, the 47‐week SELECTION maintenance study (if applicable) and SELECTIONLTE (if applicable). Exposure‐adjusted incidence rates (EAIRs) per 100 censored patient‐years of exposure with 95% confidence intervals were reported for treatment‐emergent adverse events (AEs). Certain AE data were presented in subgroups, including age and prior biologic exposure status. Results: This interim analysis included 1348 patients representing 3326.2 patient‐years of exposure. Baseline characteristics of patients entering SELECTION were similar across treatment groups. EAIRs for serious infection, thromboembolic events and major adverse cardiovascular events (MACE) were consistently low across treatment groups. Most patients with MACE had cardiovascular risk factors. The EAIR for herpes zoster was numerically higher for FIL200 than for placebo. Infection incidences were numerically higher in biologic‐experienced than biologic‐naive patients. Higher incidences of certain AEs in patients 65 years of age or older were as expected. Four deaths occurred, including three cardiovascular deaths, none of which was considered related to filgotinib. Conclusion: FIL200 and FIL100 were well tolerated with no unexpected safety signals in patients with moderately to severely active UC, regardless of previous biologic exposure or age. ClinicalTrials.gov Identifiers (NCT numbers): NCT02914522, NCT02914535. [ABSTRACT FROM AUTHOR]

Summary: The syndrome of inappropriate ADH-secretion (SIADH) is a common cause of low sodium levels with diverse aetiology. Here, we report a case of a 41 years old male patient diagnosed with SIADH and a good response to Tolvaptan therapy. Of interest, as a potential unique cause, magnetic resonance imaging revealed a micronodular structure in the posterior pituitary, while no other common cause of SIADH could be identified. Hence, to the best of our knowledge, this is the first case of a Tolvaptan-responsive SIADH associated with a pituitary micronodular structure. [ABSTRACT FROM AUTHOR]

Summary: Background: This observational real‐world evidence (RWE) study is based on prospectively collected data from the VEDOIBD registry study. Aim: To compare the effectiveness of vedolizumab and anti‐TNF agents in biologic‐naïve patients with ulcerative colitis (UC) at the end of induction and during maintenance treatment. Methods: Between 2017 and 2020, we enrolled 512 patients with UC starting therapy with vedolizumab or an anti‐TNF agent in 45 IBD centres across Germany. We excluded biologic‐experienced patients and those with missing partial Mayo (pMayo) outcomes; this resulted in a final sample of 314 (182 on vedolizumab and 132 on an anti‐TNF agent). The primary outcome was clinical remission measured using pMayo score; any switch to a different biologic agent was considered an outcome failure (modified ITT analysis). We used propensity score adjustment with inverse probability of treatment weighting to correct for confounding. Results: During induction therapy, clinical remission was relatively low and similar in vedolizumab‐ and anti‐TNF‐treated patients (23% vs. 30.4%, p = 0.204). However, clinical remission rates after two years were significantly higher for vedolizumab‐treated patients than those treated with an anti‐TNF agent (43.2% vs. 25.8%, p < 0.011). Among patients treated with vedolzumab, 29% switched to other biologics, versus 54% who had received an anti‐TNF agent. Conclusion: After two years of treatment, vedolizumab resulted in higher remission rates than anti‐TNF agents. [ABSTRACT FROM AUTHOR]

Introduction: The present study aimed to prove the metyrapone short test in a day clinic to be suitable for examining the integrity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with suspected secondary and tertiary adrenal insufficiency and to identify novel effector molecules in acute stress response. Methods: 44 patients were prospectively enrolled. Based on stimulated 11-deoxycortisol levels, patients were divided into a physiological (11-deoxycortisol ≥70 μg/L) and a pathological (11-deoxycortisol <70 μg/L) response group. Clinical follow-up examination was performed for validation. Ultraperformance liquid chromatography tandem mass spectrometry and a Fourier-transform-ion-cyclotron-resonance-mass-spectrometry were used for targeted and untargeted steroid metabolomics. Results: At baseline, lower levels of cortisone (42 vs. 50 nmol/L, p = 0.048) and 17-OH-progesterone (0.6 vs. 1.2 nmol/L, p = 0.041) were noted in the pathological response group. After metyrapone administration, the pathological response group exhibited significantly lower 11-deoxycortisol (39.0 vs. 94.2 μg/L, p < 0.001) and ACTH (49 vs. 113 pg/mL, p < 0.001) concentrations as well as altered upstream metabolites. Untargeted metabolomics identified a total of 76 metabolites to be significantly up- or downregulated by metyrapone. A significant increase of the bile acid glycochenodeoxycholic acid (GCDC, p < 0.01) was detected in both groups with an even stronger increase in the physiological response group. After a mean follow-up of 17.2 months, an 11-deoxycortisol cut-off of 70 µg/L showed a high diagnostic performance (sensitivity 100%, specificity 96%). Conclusion: The metyrapone short test is safe and feasible in a day clinic setting. The alterations of the bile acid GCDC indicate that the liver might be involved in the acute stress response of the HPA axis. [ABSTRACT FROM AUTHOR]

Autoimmune pancreatitis responds well to corticosteroids in most instances. Additional immunosuppression or low-dose maintenance steroids may be necessary upon relapse. There is limited data on alternative strategies when these regiments fail or cause adverse reactions. We report a case of a middleaged woman with autoimmune pancreatitis in whom tapering of prednisolone below the dose of 25mg per day resulted in relapse of symptoms and long-term steroid use led to development of steroid induced hyperglycaemia. Induction and maintenance of steroid-free remission was ultimately successful under vedolizumab therapy. Remission has been stable for over one year with reduced need for antidiabetic intervention. This is the first reported case of treatment of refractory autoimmune pancreatitis with vedolizumab. It highlights the overlap of immunological mechanisms within inflammatory diseases of the digestive tract and how knowledge of biological data can inform treatment decisions for individual cases. The demonstrated efficacy of vedolizumab and low risk of severe side effects warrant further investigation into its use in autoimmune pancreatitis. [ABSTRACT FROM AUTHOR]

Summary: Objective: Under the assumption of irreversibility, the Montreal classification provides a unidirectional assessment of the complications and behaviour of Crohn's disease (CD) that does not allow for downstaging. We examined the use of a bidirectional Montreal classification system that can capture disease regression. Design: From the BioCrohn Registry, an inception cohort of patients with CD for ≤12 months duration was defined and followed up for 5‐years. Cumulative probabilities for developing complications were estimated using the Kaplan–Meier method. Potential associations of explanatory variables with disease progression were estimated with Cox regression. Results: Among 393 incident CD patients (of whom 255 completed the entire follow‐up), the 5‐year cumulative probability of developing complications was 41.5% (15.6% and 25.9% for stricturing and penetrating complications respectively). Perianal disease (hazard ratio [95% confidence interval]: 8.45 [4.74–15.07]) and surgical resection of the intestine (2.71 [1.50–4.92]) in the very early phase of the disease were associated with a higher risk of developing a penetrating complication within the 5‐year follow‐up. The use of a bidirectional Montreal classification system which can account for disease regression demonstrated that 90% of patients exhibited inflammatory disease behaviour at 5 years, in contrast to 58%, if the hierarchical, unidirectional Montreal classification system was used. Conclusion: An additional bidirectional disease behaviour assessment capturing reversed or fully controlled complications may provide a more realistic appraisal of the complexity and unmet needs of patients treated with advanced therapies. [ABSTRACT FROM AUTHOR]

Copyright of Medizinische Klinik: Intensivmedizin & Notfallmedizin is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background As a national effort to better understand the current pandemic, three cohorts collect sociodemographic and clinical data from coronavirus disease 2019 (COVID-19) patients from different target populations within the German National Pandemic Cohort Network (NAPKON). Furthermore, the German Corona Consensus Dataset (GECCO) was introduced as a harmonized basic information model for COVID-19 patients in clinical routine. To compare the cohort data with other GECCO-based studies, data items are mapped to GECCO. As mapping from one information model to another is complex, an additional consistency evaluation of the mapped items is recommended to detect possible mapping issues or source data inconsistencies. Objectives The goal of this work is to assure high consistency of research data mapped to the GECCO data model. In particular, it aims at identifying contradictions within interdependent GECCO data items of the German national COVID-19 cohorts to allow investigation of possible reasons for identified contradictions. We furthermore aim at enabling other researchers to easily perform data quality evaluation on GECCO-based datasets and adapt to similar data models. Methods All suitable data items from each of the three NAPKON cohorts are mapped to the GECCO items. A consistency assessment tool (dqGecco) is implemented, following the design of an existing quality assessment framework, retaining their defined consistency taxonomies, including logical and empirical contradictions. Results of the assessment are verified independently on the primary data source. Results Our consistency assessment tool helped in correcting the mapping procedure and reveals remaining contradictory value combinations within COVID-19 symptoms, vital signs, and COVID-19 severity. Consistency rates differ between the different indicators and cohorts ranging from 95.84% up to 100%. Conclusion An efficient and portable tool capable of discovering inconsistencies in the COVID-19 domain has been developed and applied to three different cohorts. As the GECCO dataset is employed in different platforms and studies, the tool can be directly applied there or adapted to similar information models. [ABSTRACT FROM AUTHOR]

Background As a national effort to better understand the current pandemic, three cohorts collect sociodemographic and clinical data from coronavirus disease 2019 (COVID-19) patients from different target populations within the German National Pandemic Cohort Network (NAPKON). Furthermore, the German Corona Consensus Dataset (GECCO) was introduced as a harmonized basic information model for COVID-19 patients in clinical routine. To compare the cohort data with other GECCO-based studies, data items are mapped to GECCO. As mapping from one information model to another is complex, an additional consistency evaluation of the mapped items is recommended to detect possible mapping issues or source data inconsistencies. Objectives The goal of this work is to assure high consistency of research data mapped to the GECCO data model. In particular, it aims at identifying contradictions within interdependent GECCO data items of the German national COVID-19 cohorts to allow investigation of possible reasons for identified contradictions. We furthermore aim at enabling other researchers to easily perform data quality evaluation on GECCO-based datasets and adapt to similar data models. Methods All suitable data items from each of the three NAPKON cohorts are mapped to the GECCO items. A consistency assessment tool (dqGecco) is implemented, following the design of an existing quality assessment framework, retaining their - defined consistency taxonomies, including logical and empirical contradictions. Results of the assessment are verified independently on the primary data source. Results Our consistency assessment tool helped in correcting the mapping procedure and reveals remaining contradictory value combinations within COVID-19 symptoms, vital signs, and COVID-19 severity. Consistency rates differ between the different indicators and cohorts ranging from 95.84% up to 100%. Conclusion An efficient and portable tool capable of discovering inconsistencies in the COVID-19 domain has been developed and applied to three different cohorts. As the GECCO dataset is employed in different platforms and studies, the tool can be directly applied there or adapted to similar information models. [ABSTRACT FROM AUTHOR]

Background/Aims: The clinical efficacy and safety of CT-P13 are comparable to originator infliximab for Crohn’s disease in CT-P13 3.4 study (NCT02096861). We performed a multivariate logistic analysis to demonstrate the association between early infliximab trough levels and treatment outcomes of CT-P13 and originator infliximab. Methods: Early serum infliximab trough levels and anti-drug antibody (ADA) levels were compared between CT-P13 (n=100) and originator infliximab (n=98) groups. Receiver operating characteristic (ROC) analysis and multivariate logistic analysis were conducted to identify optimal cutoffs of serum infliximab trough levels and predictive factors for clinical outcomes. Results: The median infliximab trough levels were not different between CT-P13 and originator infliximab groups at week 6, week 14, and in median ADA levels at week 14, respectively. ROC analysis found an infliximab concentration threshold of 4.5 μg/mL at week 6 and 4.0 μg/mL at week 14 as the cutoff value with the highest accuracy for the prediction of clinical outcomes. Serum infliximab trough levels at weeks 6 and 14 predicted clinical remission at weeks 30 and 54, and endoscopic remission at week 54. The combinations of clinical remission or C-reactive protein normalization with an early infliximab trough level improved the prediction of long-term clinical or endoscopic remission. Conclusions: A threshold in serum infliximab trough level at week 6 and week 14 was highly predictive for long-term clinical outcomes. There were no statistical differences in serum infliximab trough levels and ADA levels between CT-P13 and originator infliximab. [ABSTRACT FROM AUTHOR]

Background and Objective: Whether benefits and risks of intravenous (IV) infliximab combotherapy with immunosuppressants versus infliximab monotherapy apply to subcutaneous (SC) infliximab is unknown. This post hoc analysis of a pivotal randomised CT-P13 SC 1.6 trial aimed to compare SC infliximab monotherapy with combotherapy in inflammatory bowel disease (IBD). Methods: Biologic-naïve patients with active Crohn's disease or ulcerative colitis received CT-P13 IV 5 mg/kg at Week (W) 0 and 2 (dose-loading phase). At W6, patients were randomised (1:1) to receive CT-P13 SC 120 or 240 mg (patients < 80 or ≥ 80 kg) every 2 weeks until W54 (maintenance phase), or to continue CT-P13 IV every 8 weeks until switching to CT-P13 SC from W30. The primary endpoint—non-inferiority of trough serum concentrations—was assessed at W22. We report a post hoc analysis comparing pharmacokinetic, efficacy, safety and immunogenicity outcomes up to W54 for patients randomised to CT-P13 SC, stratified by concomitant immunosuppressant use. Results: Sixty-six patients were randomised to CT-P13 SC (37 monotherapy, 29 combotherapy). At W54, there were no significant differences in the proportions of patients achieving target exposure (5 µg/mL; 96.6% monotherapy vs 95.8% combotherapy; p > 0.999) or meeting efficacy or biomarker outcomes including clinical remission (62.9% vs 74.1%; p = 0.418). Monotherapy and combotherapy groups had comparable immunogenicity (anti-drug antibodies [ADAs]: 65.5% vs 48.0% [p = 0.271], neutralising antibodies [in ADA-positive patients]: 10.5% vs 16.7% [p = 0.630], respectively). Conclusions: Pharmacokinetics, efficacy and immunogenicity were potentially comparable between SC infliximab monotherapy and combotherapy in biologic-naïve IBD patients. Trial Registration: ClinicalTrials.gov: NCT02883452. [ABSTRACT FROM AUTHOR]

Background: The therapeutic goal of clinical remission in patients with moderate to severe ulcerative colitis (UC) is achieved after biological therapy only in 16–39%. Individualization of therapeutic intervention would benefit from prediction of early response. Study Objective: The primary objective of our study was to assess golimumab (GLM) trough serum level of ≥2.5 μg/mL in combination with a reduction of faecal calprotectin (FC) of ≥50% at week 6 compared to baseline to predict clinical response at week 26 after regular GLM intake. Methods: Patients with moderate to severe active UC and planned GLM treatment were recruited for a prospective, multicentre, observational study in Germany. Prediction of clinical response was assessed by FC and GLM trough level. Missing data were imputed as therapy failure according to the last observation carried forward method. Results: Fifty nine patients have been enrolled. 54% of patients were anti-TNF naïve. Clinical response at week 6 was a significant predictor for achieving clinical response at week 26 (odds ratio [OR] 10.97, confidence interval [CI], 2.96–40.68; p < 0.001). Moreover, patients with a GLM trough level of ≥2.5 μg/mL and a ≥50% reduction of FC at week 6 had an OR of 5.33 (95% CI, 0.59–47.84) to achieve clinical response at week 26. Conclusion: Clinical response at week 6 is the best predictive marker for achieving clinical response at week 26. Consideration of significant reduction of FC and trough GLM serum levels could improve prediction of response. [ABSTRACT FROM AUTHOR]