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Objective: The aim of this study was to assess the utilization of surgical interventions in patients diagnosed with superficial vein thrombosis (SVT) and its potential association with the occurrence of venous thromboembolism (VTE) and bleeding events., Methods: INSIGHTS-SVT, a prospective, non-interventional, multicenter study in Germany, investigated the management and outcomes of patients with acute SVT who received conservative and/or invasive treatments at the discretion of the treating physician., Results: Among the 872 patients with 12-month data, 657 had medical therapy only, and 215 patients underwent vascular surgery (70 within 3 months of SVT diagnosis, 136 between months 4 and 12, and nine had an intervention in both periods). The most commonly performed procedures included endovenous thermal ablation, ligation of the saphenofemoral or saphenopopliteal junction, and vein stripping. The primary outcome of symptomatic VTE was observed in 5.8% of conservatively treated patients and 6.3% of those who underwent surgical intervention. Additionally, the secondary outcome of recurrent or extended SVT was documented in 4.7% of conservatively treated patients and 5.3% of invasively treated patients. Bleeding events occurred in 1.4% of conservatively treated patients and 2.1% of surgically treated patients. These differences were statistically not significant. Furthermore, our analysis indicated a potential protective effect associated with surgical treatments, such as ligation of the saphenofemoral or saphenopopliteal junction, stripping and endovenous thermal ablation, concerning the endpoint of VTE for patients when applied after 3 months from the index SVT event., Conclusions: In line with previous research, our study suggests that surgical interventions are not frequently employed in the management of SVT, although they may be warranted in select cases. Nevertheless, additional research is essential to gain a deeper understanding of the indications, criteria, and benefit of surgical interventions in the treatment of SVT., Competing Interests: Disclosures E.R. has received honoraria for lectures and advisory boards from Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Leo Pharma, and Pfizer. R.B. has received research support from AFNET, CPC, and FADOI; and honoraria from Bayer, BMS, Leo, Pfizer, and Viatris. H.G. has received honoraria for lectures and advisory boards from Aspen, Mylan, Bayer, and Boehringer-Ingelheim. D.P. has received honoraria for consultancy, advisory boards, or lectures by Actelion, Bayer, Biogen, Aspen, Amgen, MSD, Boehringer Ingelheim, Novartis, Daiichi Sankyo, Genzyme, and Zambon. F.L. has received honoraria for lectures or consultancy from Aspen, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, LEO Pharma, Pfizer, Sanofi, and Viatris. U.H. has received research support and honoraria for lectures and advisory boards from Bayer HealthCare Pharmaceuticals, Bristol-Myers-Squibb, Pfizer, Boehringer Ingelheim, Daiichi Sankyo, Leo Pharma, and Aspen. T.N. has received honoraria for consultancy from Medi Bayreuth; and honoraria for presentations from Aspen, Bayer, Bristol-Myers Squibb, and Mylan. A.H. was, at the time of the study, a full-time employee of Aspen Pharma GmbH, Munich, and is now an employee of Amgen GmbH, Germany. A.S. is a full-time employee of Mylan Germany GmbH, Germany., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

With the new ICD-11 developed by the WHO and translated into German for use in Germany by the Federal Institute for Drugs and Medical Devices, the German healthcare system is facing a change that is more than a simple change of a medical coding system. The ICD-11 modernises the coding system, for example, by including new, separate health conditions such as sleep-wake disorders and conditions related to sexual health, thus making the corresponding diseases more visible. The ICD-11 is more precise than the ICD-10: it allows cross-referencing between diagnoses, symptoms, functionality and locations and partially abandons the strict hierarchy of the ICD-10. In addition, a greater number of rare diseases are represented with their own specific code than was previously possible with ICD-10. Finally, the ICD-11 is also significantly more "modern" than the ICD-10 (which dates back to pre-digital times) in that it enables new, digitally-supported processes, such as keywords flexibility and sustainability when updating the system as well as actual coding at the point of care. The switch to ICD-11 can be a great opportunity for the German healthcare system that should not be missed. It will benefit health service research, which at best will be able to work with much more detailed and correct data sets. But medical care will also benefit because the ICD-11 reflects current medical knowledge. In addition, certain illnesses will be removed from the psychiatric category, meaning that those affected will no longer be stigmatised by their classification in the ICD. The improved coding of diagnoses will ultimately also support guideline-based treatments. However, the changeover is only the first step. The challenges - also for health service research - include in particular the latency of introduction and uniform use as well as the necessary change in coding habits. For ICD-11 to be a success in Germany, authorities, the medical profession, payers and patients must work together on strategies to ensure not only a rapid but also a comprehensive implementation that maximises the potential of ICD-11., Competing Interests: KB: none. The role of BfArM in the context of ICD-11 introduction in Germany includes translation and provision of the ICD-11 as well as support for the changeover process. BfArM has been a WHO Collaborating Centre since 2003. JC: Institutional grants from AbbVie, AstraZeneca, BMS, GALAPAGOS, GSK, Medac, MSD, Pfizer, UCB, Sanofi-Aventis, Lilly and grants from Pfizer, Janssen-Cilag, Idorsia Pharmaceuticals outside the submitted work. PK is an employee of Idorsia Pharmaceuticals Germany GmbH. CK is an employee of the German Cancer Society. JM is an employee of the AOK Bundesverband. CM provides institutional grants (project funding) from the Federal Ministry of Health, Federal Ministry of Education and Research and G-BA (Innovationsfonds). CS declares that he has received institutional grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Idorsia Pharmaceuticals Ltd, Inspire Medical, JAZZ, Löwenstein Medical, Mementor, Nox medical, ResMed, Respicardia, Sleepiz outside the submitted work., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Memory B cells (mBCs) are characterized by their long-term stability, fast reactivation, and capability to rapidly differentiate into antibody-secreting cells (ASCs). However, the role of T cells in the differentiation of mBCs, in contrast to naive B cells, remains to be delineated. We study the role of T cells in mBC responses, using CD40L stimulation and autologous T-B co-cultures. Our results showed that increased CD40L levels led to a selective increased proliferation of IgM+ mBC, which did not class-switched, resulting in higher frequencies of IgM+ ASCs and a lower frequency of IgG+ ASCs. The IgG+/IgA+ mBCs were unaffected. We further compared the transcription of immune-related genes in IgM+ and IgG+ pre-plasmablasts cultured at high (500 ng/mL) and low (50 ng/mL) CD40L levels. In response to increased CD40L levels, both populations exhibited a core response to genes related to activation (TRAF1, AKT3, CD69, and CD80). However, they differed in genes related to cytokine/chemokine/homing interactions (CCL3/4/17, LTA, NKX2-3, BCL2 and IL21R) and cell-cell interactions (HLADR, CD40, and ICOSL), which were largely confined to IgG+ cells. Our findings revealed that in co-cultures with a high T-ratio, the response was similar to that found in cultures with high CD40L levels. These results suggest that IgG+ mBCs have a greater capacity for proliferation and T cell interaction, and weaker migration capabilities, leading to a preference for an IgG response over IgM in the short term. This adaptable response could fine-tune the memory repertoire with different functions of IgG versus IgM mBCs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rincon-Arevalo, Stefanski, Le, Cases, Wiedemann, Szelinski, Ritter, Dang, Lino, Dörner and Schrezenmeier.)

Bone marrow plasma cells (BMPC) are the correlate of humoral immunity, consistently releasing antibodies into the bloodstream. It remains unclear if BMPC reflect different activation environments or maturation of their precursors. Here we define human BMPC heterogeneity and track the recruitment of antibody-secreting cells (ASC) from SARS-CoV-2 vaccine immune reactions to the bone marrow (BM). Trajectories based on single-cell transcriptomes and repertoires of peripheral and BM ASC reveal sequential colonisation of BMPC compartments. In activated B cells, IL-21 suppresses CD19 expression, indicating that CD19 low -BMPC are derived from follicular, while CD19 high -BMPC originate from extrafollicular immune reactions. In primary immune reactions, both CD19 low - and CD19 high -BMPC compartments are populated. In secondary immune reactions, most BMPC are recruited to CD19 high -BMPC compartments, reflecting their origin from extrafollicular reactivations of memory B cells. A pattern also observable in vaccinated-convalescent individuals and upon diphtheria/tetanus/pertussis recall-vaccination. Thus, BMPC diversity reflects the evolution of a given humoral immune response., (© 2024. The Author(s).)

Background: Previous studies have shown that growing up with rheumatic conditions can fuel dissatisfaction and psychological distress, which in turn affects disease self-management and treatment adherence. Primary objective of this study was to estimate the prevalence of anxiety and depression symptoms in adolescents and young adults (AYA) with juvenile idiopathic arthritis (JIA) and to identify correlates of conspicuous screening results., Methods: Initiated as part of the COACH multicenter observational study, outpatients aged 12 to 21 years participating in the National Pediatric Rheumatological Database (NPRD) were prospectively screened for mental health using the Patient Health Questionnaire-9 (PHQ-9) and the Generalised Anxiety Disorder Scale-7 (GAD-7)., Results: Data from 1,150 adolescents with JIA (mean age 15.6 ± 2.2 years; mean disease duration 7.2 ± 4.9 years, 69% female, 43% oligoarthritis, 26% polyarthritis) were analysed. Overall, 32.7% (n = 316) of AYA showed conspicuous screening results, of whom 30.4% reported clinically relevant suicidal or self-harm thoughts. About 19% of screened patients showed moderate to severe depressive or anxious symptoms. AYA with conspicuous screening results were older (15.8 vs. 15.2 years; p < 0.0001), more often female (81% vs. 64%; p < 0.0001) and more often overweight (25% vs. 17%; p = 0.006). They had higher disease activity (physician global assessment on NRS 0-10; 1.7 vs. 1.2; p < 0.0001), more functional limitations (CHAQ; 0.44 vs. 0.14; <0.0001) and rated their health status worse (NRS 0-10; 3.5 vs. 1.8; p < 0.0001) than AYA with inconspicuous screening results. Females (OR 2.33 [CI 1.53-3.56]; p < 0.0001), older age (OR 1.09 [CI 1.01-1.18]; p = 0.026), patients with more functional limitations (OR 3.36 [CI 1.98-5.72]; p < 0.0001), and patients with worse subjective health status (OR 1.17 [CI 1.07-1.27]; p < 0.0001) were more likely to have a conspicuous screening result. Regular sports participation was associated with a lower likelihood of conspicuous screening result (OR 0.69 [CI 0.49-0.98]; p = 0.039)., Conclusions: A large-scale outpatient screening of AYA with JIA in Germany shows a high prevalence of anxiety and depression symptoms. The need for routine screening for early detection of mental health problems became apparent., (© 2024. The Author(s).)

Background: Physical active lifestyles are essential throughout growth and maturation and may offer potential preventive and therapeutic benefit in patients with juvenile idiopathic arthritis (JIA). Insufficient physical activity (PA), in contrast, can lead to aggravation of disease-related symptoms. This study aimed to i) examine PA levels in children and adolescents with JIA compared to general population controls and ii) investigate correlates of pronounced physical inactivity in order to identify risk groups for sedentary behaviour., Methods: Data from children and adolescents with JIA and population controls aged 3 to 17 years documented in the National Pediatric Rheumatologic Database (NPRD) and the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) were used. Self-reported PA was collected from parents/guardians of children up to 11 years of age or adolescents 12 years of age and older. To compare PA-related data, age- and sex-specific pairwise analyses were conducted considering NPRD/KiGGS participants' data from 2017. Correlates of physical inactivity among patients were identified using a linear regression model., Results: Data of 6,297 matched-pairs (mean age 11.2 ± 4.2 years, female 67%, patients' disease duration 4.5 ± 3.7 years, persistent oligoarthritis 43%) were available for evaluation. Almost 36% of patients aged 3-17 years (vs. 20% of controls) achieved the WHO recommended amount of PA, while PA steadily decreased with age (18% of patients aged ≥ 12 years) and varied between JIA categories. Female adolescents and patients with enthesitis-related arthritis were least likely to achieve the minimum recommended level of PA. Physical inactivity was associated with female sex, higher age at disease onset, longer disease duration, more functional disability (C-HAQ) and higher disease activity (cJADAS-10)., Conclusions: Depending on JIA category, children and adolescents with JIA were similarly or even more likely to achieve the WHO recommended minimum level of PA compared to general population controls. However, since a large proportion of young JIA patients appear to be insufficiently physically active, engagement in targeted efforts to promote PA is urgently needed., (© 2024. The Author(s).)

Monogenic mutations in laccase domain-containing 1 (LACC1) are associated with clinical pictures that mimic severe courses of polyarticular or systemic juvenile idiopathic arthritis. The diseases are characterized by an early onset during the first year of life, a familial clustering and a high inflammatory activity. The courses are mostly difficult to influence and often lead to sequelae. In this article four cases from two families are presented in which the homozygous mutation p.T276fs* in LACC1 was detected. The children initially suffered from polyarticular or systemic forms of juvenile arthritis. Of the patients two are currently being treated with tocilizumab and methotrexate and one female patient without a basis treatment is currently only receiving local repeated intra-articular steroids. A fourth female patient underwent an allogeneic bone marrow transplantation due to a relapse of an acute lymphatic leukemia. Since then, no further inflammatory symptoms have occurred. The cases presented are compared with the other 50 courses published to date. In addition, recent studies investigating the influence of LACC1 mutations, particularly on macrophage function, are summarized., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Introduction: Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory bone-disease of unknown origin. The National Pediatric Rheumatologic Database (NPRD) collects long-term data of children and adolescents with rheumatic diseases including CNO., Objective: To assess characteristics, courses, and outcomes of CNO with onset in childhood and adolescence and to identify outcome predictors., Methods: From 2015 to 2021 patients with a confirmed diagnosis of CNO, who were registered in the NPRD during their first year of disease and at least one follow-up visit, were included in this analysis and observed for up to 4 years., Results: Four hundred patients with recent diagnosis of CNO were enrolled in the NRPD during the study period. After 4 years, patient data documentation was sufficient to be analyzed in 81 patients. A significant decline of clinical and radiological lesions is reported: at inclusion in the registry, the mean number of clinical lesions was 2.0 and 3.0 MRI lesions per patient. A significant decrease of manifestations during 4 years of follow-up (mean clinical lesions 0.5, p < 0.001; mean MRI lesions 0.9 (p < 0.001)) was documented. A significant improvement of physician global disease activity (PGDA), patient-reported overall well-being, and childhood health assessment questionnaire (C-HAQ) was documented. Therapeutically, an increase of disease-modifying anti-rheumatic drugs over the years can be stated, while bisphosphonates rather seem to be considered as a therapeutic DMARD option in the first years of disease. Only 5-7% of the patients had a severe disease course as defined by a PGDA >  = 4. Predictors associated with a severe disease course include the site of inflammation (pelvis, lower extremity, clavicle), increased erythrocyte sedimentation rate, and multifocal disease at first documentation. The previously published composite PedCNO disease activity score was analyzed revealing a PedCNO70 in 55% of the patients at 4YFU., Conclusion: An improvement of physician global disease activity (PGDA), patient reported overall well-being and imaging-defined disease activity measures was documented, suggesting that inactivity of CNO disease can be reached. PedCNO score and especially PGDA, MRI-defined lesions and in a number of patients also the C-HAQ seem to be reliable parameters for describing disease activity. The identification of risk factors at the beginning of the disease might influence treatment decision in the future., (© 2023. The Author(s).)

Objective: Long term incidence of symptomatic venous thromboembolism (VTE) and bleeding events in patients with superficial vein thrombosis (SVT) was investigated., Methods: In this prospective, observational study, patients with acute SVT were treated at the discretion of the responsible physician. The primary efficacy outcome was symptomatic VTE including deep vein thrombosis (DVT), pulmonary embolism (PE), and recurrent or extending SVT. The primary safety outcome was clinically relevant bleeding, recorded at periodic clinic visits over a 12 month period., Results: The mean age of 872 patients with 12 month follow up was 60.6 ± 14.5 years, 64.5% were female, 80.1% had chronic venous disease (defined as chronic venous insufficiency and or varicose veins), and 41.9% had a history of VTE. They were receiving fondaparinux in 62.1% (mean duration 34.9 ± 15.7 days), low molecular weight heparin (LMWH) in 25.0% (mean duration 26.2 ± 23.2 days), any other anticoagulants in 6.2%, and no anticoagulant in 6.7%. At 12 months, 108 patients (14.3%) achieved the primary efficacy outcome. The most common VTE event was recurrent or extending SVT in 11.0%, followed by symptomatic DVT in 2.7%, symptomatic PE in 2.4%, hospitalisation due to VTE in 1.8%, and death in 1.1%. Clinically relevant bleeding events occurred in 2.1% of patients, and major bleedings in 0.3%. By drug, the rate of the primary efficacy outcome was highest in the LMWH group (22.4%) and lowest in the fondaparinux group (10.4%). In a multivariable model, patients with events between three months and 12 months were significantly more likely to have higher BMI (hazard ratio [HR] 1.06; p = .002), history of VTE (HR 2.89; p = .002), and severe systemic infections (HR 7.59; p = .006)., Conclusion: The risk of symptomatic VTE remained elevated over 12 months of follow up. Therefore, anticoagulation beyond 45 days may be considered in patients with risk factors. [ClinicalTrials.gov identifier: NCT02699151.]., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Helper T (T h ) cells play a decisive role in triggering and maintaining chronic rheumatic inflammation. Via secretion of proinflammatory cytokines and expression of costimulatory cell surface molecules, T h  lymphocytes coordinate the recruitment and activation of effector cells, which are ultimately responsible for the immunopathology and tissue destruction. However, therapeutic approaches aimed at eliminating T h  cells were unsuccessful due to their lack of selectivity. At the German Rheumatism Research Center (Deutsches Rheuma-Forschungszentrum, DRFZ), we are working to improve the understanding of the T h  cells involved in chronic inflammatory reactions. Based on this understanding, our aim is to develop novel treatment strategies that selectively target the pathogenic T h  lymphocytes causing rheumatic inflammation. The current article summarizes the DRFZ's research activities on this subject., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Various research groups at the German Rheumatism Research Center in Berlin, in close cooperation with the Department of Rheumatology and Clinical Immunology of the Medical Clinic at the Charité, have made important contributions to the significance of B cells and plasma cells in rheumatic diseases, which are relevant not only for rheumatology but for all clinical specialties in which antibody-mediated diseases play a role. In particular, the research addresses impaired B cell homeostasis, the importance of the IgM Fc receptor in the regulation of autoimmunity, the role of long-lived memory plasma cells in maintaining autoimmunity and ensuring its survival in specific niches organized by stromal cells in bone marrow and inflamed tissues. The research results have contributed to a better understanding of the immunological and molecular mechanisms in rheumatic diseases and their treatment. The identification of the long-lived memory plasma cell has led to promising treatment approaches with curative potential in autoimmune diseases., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Autoinflammatory diseases present as multisystemic inflammation and often manifest in early childhood. In contrast, in a few diseases, e.g., the recently described VEXAS (vacuoles, E1 enzyme, X‑linked, autoinflammatory, somatic) syndrome, the first symptoms occur exclusively in adulthood. This article describes how the phenotypic expression and severity of individual autoinflammatory diseases differ depending on age. Furthermore, differences in the development of organ damage in children and adults are pointed out. In addition to the hereditary periodic fever syndromes, the clinical picture of deficiency of adenosine deaminase 2, the interferonopathies, periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome as well as VEXAS and Schnitzler syndromes are highlighted., (© 2021. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Calcium is a universal second messenger present in all eukaryotic cells. The mobilization and storage of Ca 2+ ions drives a number of signaling-related processes, stress-responses, or metabolic changes, all of which are relevant for the development of immune cells and their adaption to pathogens. Here, we introduce the Förster resonance energy transfer (FRET)-reporter mouse YellowCaB expressing the genetically encoded calcium indicator TN-XXL in B lymphocytes. Calcium-induced conformation change of TN-XXL results in FRET-donor quenching measurable by two-photon fluorescence lifetime imaging. For the first time, using our novel numerical analysis, we extract absolute cytoplasmic calcium concentrations in activated B cells during affinity maturation in vivo. We show that calcium in activated B cells is highly dynamic and that activation introduces a persistent calcium heterogeneity to the lineage. A characterization of absolute calcium concentrations present at any time within the cytosol is therefore of great value for the understanding of long-lived beneficial immune responses and detrimental autoimmunity., Competing Interests: CU, RL, AR, LN, HR, RN, AH No competing interests declared, FK Reviewing editor, eLife, (© 2021, Ulbricht et al.)

In the journal Nature, under the headline "Retire statistical significance", Amrhein et al. called for the concept of statistical significance to be abolished. This appeal, which was signed by about 800 other researchers, triggered a controversial discussion. One reason for the deliberately provocative call is the scientific practice in which the concept of statistical significance is often applied in an incorrect way for yes/no decisions. The criticism is not new and has been repeatedly expressed over the last 50 years. We refer to current and previously published caveats, give an overview of different applications of the concept of statistical significance as well as possible alternatives. We agree in principle with the criticism of the concept expressed by Amrhein et al. but in the absence of agreed alternatives and insufficient consideration of the many different applications of the concept of statistical significance, we consider the demand for its abolition to be exaggerated. A more pragmatic approach to the problem, supported by targeted instructions for scientists and reviewers, seems to be a more appropriate way forward.

Background: The research consortium Neuroimmunology and Pain (Neuroimpa) explores the importance of the relationships between the immune system and the nervous system in musculoskeletal diseases for the generation of pain and for the course of fracture healing and arthritis., Material and Methods: The spectrum of methods includes analyses at the single cell level, in vivo models of arthritis and fracture healing, imaging studies on brain function in animals and humans and analysis of data from patients., Results: Proinflammatory cytokines significantly contribute to the generation of joint pain through neuronal cytokine receptors. Immune cells release opioid peptides which activate opioid receptors at peripheral nociceptors and thereby evoke hypoalgesia. The formation of new bone after fractures is significantly supported by the nervous system. The sympathetic nervous system promotes the development of immune-mediated arthritis. The studies show a significant analgesic potential of the neutralization of proinflammatory cytokines and of opioids which selectively inhibit peripheral neurons. Furthermore, they show that the modulation of neuronal mechanisms can beneficially influence the course of musculoskeletal diseases., Discussion: Interventions in the interactions between the immune system and the nervous system hold a great therapeutic potential for the treatment of musculoskeletal diseases and pain.

T helper cells contribute to the induction and maintenance of rheumatic inflammation through the secretion of cytokines. The analysis of Th1 cells expressing interferon-γ, Th17 cells expressing interleukin-17 and the newly described Th1+17 cells could give insight into the pathophysiological mechanisms of rheumatic diseases. This could lead to the development of novel, targeted therapeutic strategies.

The intestinal microbiota contributes to the regulation of the intestinal immune system and protection against intestinal infections. Recent studies revealed that the locally restricted intestinal microbiota affects systemic immunity and influences the induction of autoimmunity.