German Rheumatism Research Center Research Articles

Rheumatological care in Germany : Memorandum of the German Society for Rheumatology and Clinical Immunology 2024

Rheumatology in Germany is facing major challenges. The need for rheumatological care is increasing and can no longer be met in some regions for capacity reasons. Too many people with an inflammatory rheumatic disease (IRD) have to forego appropriate care or receive it too late. The 4thnew edition of the memorandum of the German Society for Rheumatology and Clinical Immunology (DGRh) provides information on rheumatological care in Germany. It was produced under the leadership of the DGRh together with the Professional Association of German Rheumatologists (BDRh), the Association of Acute Rheumatology Clinics (VRA), the German Rheumatism League (DRL) and the German Rheumatism Research Center (DRFZ). The memorandum describes the current state and development of the following areas: number of people with IRD, outpatient, inpatient and rehabilitative care structures, number of specialists in rheumatology, education and training, quality of care, health economic aspects and digital care concepts. Proposals for health policy measures to safeguard rheumatological care are presented. Prevalence: approximately 1.8million adults in Germany have an IRD. The prevalence is increasing, due to changes in the demographic structure of the population, improved diagnostics, treatment and longer survival. Care structures: outpatient specialist care (ASV) for rheumatic diseases is developing as across-sectoral care model for hospital outpatient clinics and rheumatology practices. Hospitals have been able to be certified as rheumatology centers since 2020, which enables structural developments. Specialists in rheumatology: as of 31December 2023, there were 1164 specialists in rheumatology working in Germany. This included 715 physicians accredited to work in practices for national health assurance patients, 39% of whom were employees. In hospitals, 39% of doctors worked part-time. At least 2rheumatology specialists per 100,000 adults are needed, i.e. around 1400, in order to provide adequate care. This means that there is ashortage of around 700 rheumatology specialists in the outpatient sector alone. Of all working specialists, 30% are currently aged60 years old and over. Medical training: only 10 out of38 (26%) state universities have an independent chair in rheumatology. In addition, 11rheumatology departments are subordinate to anonrheumatology chair. In the rheumatology-integration into student training (RISA)III study, only 16 out of 36faculties fulfilled the recommended minimum number of compulsory hours of student rheumatology teaching. Continuing education in rheumatology: the annual postgraduate training qualificationsdo not cover the demand for rheumatology specialists, which isadditionally increasing due to intensified workload, reduced capacities through retirement, and part-time work. Quality of care: since the introduction of highly effective medication patients with IRD have amuch better chance of achieving remission of their disease. With early initiation of targeted therapy, the lives of many patients are hardly restricted at all: however, waiting times for afirst rheumatological visit often last more than 3 months. Quality target is afirst consultation within the first 6 weeks after the onset of symptoms. Models for early consultation, delegation of medical services, structured patient training and digital care concepts have been positively evaluated but are not covered financially. the total annual costs for inflammatory joint diseases alone amount to around 3billion euros. The direct costs have significantly risen since the introduction of biologics, while the indirect costs for sick leave, disability and hospitalization have fallen. The core demands of this memorandum are asignificant and sustainable increase in the number of further training positions in the outpatient and inpatient sector, the creation of chairs or at least independent departments for rheumatology at all universities and the further implementation of new and cross-sectoral forms of care. This will ensure modern needs-based rheumatological care for all patients in the future.

With RheMIT rheumatology centers can participate in the German national database-Expansion of the long-term rheumatological documentation

The national database (NDB) of the German regional collaborative rheumatology centers was switched to the RheMIT documentation software last year. Rheumatology centers that already use RheMIT for care contracts or other research projects can therefore use the software to also participate in the NDB. Experiences from ahospital, amedical care center and aspecialist practice show how the changeover to RheMIT from an existing documentation system or anew participation in the NDB with RheMIT can be implemented. The NDB team at the German Rheumatism Research Center in Berlin (DRFZ) welcomes new participating rheumatology centers.

The DRFZ-apioneer in research on the interaction between immune and stromal cells during de- and regeneration of the musculoskeletal system

Rheumatoid arthritis and osteoarthritis are two related chronic diseases of the musculoskeletal system which are particularly pronounced in the region of joints and bones. Their pathogeneses are associated with chronic inflammation, which can disrupt homeostasis in bones and articular cartilage. Degradation products deriving from articular cartilage can contribute to the exacerbation of inflammation in the joint region. Mechanical stimuli and blood vessels also play acentral role in both the regulation of bone growth as well as in the regeneration of bone tissue. Not only chronic inflammatory processes but also hormonal changes after menopause or undesired effects of glucocorticoid therapy have an influence on the balance between bone resorption and deposition, by promoting the former and reducing the latter. This results in decreased bone quality and, in some cases, considerable loss of bone or osteoporosis. An in-depth understanding of these processes at the molecular, cellular, and tissue level, as well as of the changes present in chronic inflammatory diseases, has been the focus of research at the German Rheumatism Research Center (Deutsches Rheuma-Forschungszentrum, DRFZ) since its foundation. Based on an improved understanding of these mechanisms, the DRFZ aims to develop improved prevention and treatment strategies with effects even in early disease stages.

How T lymphocytes coordinate rheumatic inflammation

Helper T (Th) cells play a decisive role in triggering and maintaining chronic rheumatic inflammation. Via secretion of proinflammatory cytokines and expression of costimulatory cell surface molecules, Thlymphocytes coordinate the recruitment and activation of effector cells, which are ultimately responsible for the immunopathology and tissue destruction. However, therapeutic approaches aimed at eliminating Thcells 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 Thcells involved in chronic inflammatory reactions. Based on this understanding, our aim is to develop novel treatment strategies that selectively target the pathogenic Thlymphocytes causing rheumatic inflammation. The current article summarizes the DRFZ's research activities on this subject.

B lymphocytes and plasma cells as drivers of rheumatic diseases

Verschiedene Arbeitsgruppen am Deutschen Rheuma-Forschungszentrum Berlin haben in enger Zusammenarbeit mit der Medizinischen Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie an der Charité wichtige Beiträge zur Bedeutung der B‑Zellen und Plasmazellen bei rheumatischen Erkrankungen geleistet, die nicht nur für die Rheumatologie, sondern für alle klinischen Fachgebiete, in denen antikörpervermittelte Erkrankungen eine Rolle spielen, relevant sind. Insbesondere wird auf die gestörte B‑Zell-Homöostase, die Bedeutung des Immunglobulin M(IgM)-Fc-Rezeptors für die Regulation der Autoimmunität, die Rolle der langlebigen Gedächtnis-Plasmazelle bei der Aufrechterhaltung der Autoimmunität sowie die Sicherung ihres Überlebens in speziellen, von Stromazellen organisierten Nischen im Knochenmark und in entzündeten Geweben eingegangen. Die Forschungsergebnisse haben zu einem besseren Verständnis der immunologischen und molekularen Mechanismen bei rheumatischen Erkrankungen und ihrer Therapie beigetragen. Die Identifizierung der langlebigen Gedächtnis-Plasmazelle hat zu vielversprechenden therapeutischen Ansätzen mit kurativem Potenzial bei Autoimmunerkrankungen geführt.

Perspectives for rheumatological health services research at the German Rheumatism Research Center

In diesem Übersichtsartikel werden aktuelle Projekte und Perspektiven der rheumatologischen Versorgungsforschung am Programmbereich Epidemiologie des DRFZ (Deutsches Rheuma-Forschungszentrum) zusammengefasst. Versorgungsforschung wird mithilfe verschiedener Datenquellen betrieben. Neben den klassischen rheumatologischen Krankheitsregistern werden zunehmend auch Krankenkassendaten und bevölkerungsbezogene Kohorten für Analysen verwendet. Von der Datenerfassung über das Monitoring bis zu Analysealgorithmen verändern digitale Anwendungen die Versorgungsforschung der nächsten Jahre. Kollaborative Analysen mit nationalen und internationalen Kooperationspartnern unter Einbindung von Biomarkern komplettieren die Forschung am Programmbereich Epidemiologie. Die Digitalisierung der Forschungsprojekte ist ein zentraler Baustein, der die Versorgungsforschung im kommenden Jahrzehnt weiter verändern wird.

Translational healthcare research : Show what is-Angela Zink, the grande dame of public health research in rheumatology

As director of the program area epidemiology and health care research at the German Rheumatism Research Center, Angela Zink established the German National Database, anational register for the care of people with inflammatory rheumatic diseases and other important registers for public health research in rheumatology. This publication summarizes Angela Zink's life work and sheds light on the national significance of this extraordinary achievement from the background of the research results achieved. The available literature and personal memories of the author formed the basis of this summary. The German National Database, which regularly collects data from more than 15,000patients with inflammatory rheumatic diseases per year, shows that the prognosis has steadily improved in many areas, disease activity has decreased, the burden of illness due to pain or functional limitations has decreased, the incidence of incapacity for work and early retirement has decreased and those affected can nowadays participate to amuch greater extent in social and working life; however, the data also revealed existing shortcomings, regional differences and differences between treatment by specialists or general practitioners. This made the database acentral instrument of quality assurance. The biologics register RABBIT, in which side effects of biologics were registered and used for risk management, has also gained great importance. The registers which were set up and systematically developed in the program area epidemiology under the leadership of Angela Zink, are atreasure trove of national importance. Acontinuation, even after the retirement of Angela Zink from active professional life, seems urgently necessary if the healthcare research of German rheumatology does not want to lose the international connection.

RABBIT-SpA: anew disease register for axial spondyloarthritis and psoriatic arthritis

The treatment of axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) has changed enormously in recent years due to market authorization of anumber of new biologicals with different modes of action and the increasing use of biosimilars. Real-world data on long-term safety and efficacy under routine daily conditions is not yet sufficient. Therefore, the German Rheumatism Research Center has initiated anew cohort study covering axSpA and PsA. Presentation of initial results from the new register RABBIT-SpA, which was started in May 2017. This is a prospective longitudinal cohort study with asimilar study design to the German biologics register RABBIT. Patients can be included at the start of anew treatment either in the so-called index drug group or in the comparison group (conventional systemic treatment, including non-steroidal anti-inflammatory drugs, NSAID). Follow-up per patient should be at least 5years and preferably 10years. The RABBIT-SpA uses aweb-based documentation system. Up to mid-December 2018 a total of 514 axSpA patients had been documented in RABBIT-SpA, 410 with an index drug and 104 with conventional treatment. There are differences between these treatment groups, e. g. in the duration of the disease and in parameters of disease activity. It is also noticeable that in axSpA patients, approximately 5years lie between the onset of the symptoms and confirmation of the diagnosis. Of the 355 PsA patients, 265 were included with an index drug and 90 with conventional treatment. Of the PsA patients 86% have adominant peripheral manifestation. The average number of pressure tender joints is8 and the average number of swollen joints is4. The online register RABBIT-SpA is well-received by the participating rheumatological institutions. The electronic recording of patient data can be carried out in areasonable time. Participation in the RABBIT-SpA is open to new rheumatological institutions at any time.

CD49b regulates the establishment and maintenance of T helper cell memory

Event Abstract Back to Event CD49b regulates the establishment and maintenance of T helper cell memory Asami Hanazawa1* and Koji Tokoyoda1* 1 German Rheumatism Research Center Berlin, Germany We have demonstrated that professional memory CD4 T cells reside and rest in the bone marrow (BM) adhering to IL-7-expressing stromal niches. Their absence induces a defective generation of high-affinity long-lived plasma cells. However, the molecular mechanisms on their establishment and maintenance remain unclear. We here demonstrate the roles of CD49b, which is also called integrin alpha2 and is expressed on most memory CD4 T cells, in the establishment and maintenance of memory CD4 T cells in the BM. We first counted antigen-specific effector and memory CD4 T cells in immunized CD49b-deficient and wild-type mice. The number of CD49b-deficient memory CD4 T cells was significantly impaired compared to wild-type cells, while the number of effector cells in both mice was comparable. So, to clarify why CD49b-deficient memory CD4 T cells are not generated, we transferred CD49b-deficient effector CD4 T cells into naive mice and evaluated their migration ability into the BM. The loss of CD49b induced a defective migration of effector cells into the BM. Then, to examine a role of CD49b in the maintenance of memory CD4 T cells, we inhibited the integrin during memory phase with injection of Fab fragments of anti-CD49b neutralization antibodies. The inhibition of CD49b reduced the number of memory CD4 T cells in the BM. We suggest that CD49b regulates the establishment and maintenance of memory CD4 T cells controlling the immigration of memory cell precursors into the BM and also the persistence of memory CD4 T cells on their survival niches. Keywords: T helper cell memory, CD49b, Collagen, niche, Immunological memory, Bone Marrow Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Adaptive Immunity Citation: Hanazawa A and Tokoyoda K (2013). CD49b regulates the establishment and maintenance of T helper cell memory. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00827 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 21 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Asami Hanazawa, German Rheumatism Research Center Berlin, Berlin, Germany, ahanazawa@ciea.or.jp Dr. Koji Tokoyoda, German Rheumatism Research Center Berlin, Berlin, Germany, tokoyoda@tottori-u.ac.jp Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Asami Hanazawa Koji Tokoyoda Google Asami Hanazawa Koji Tokoyoda Google Scholar Asami Hanazawa Koji Tokoyoda PubMed Asami Hanazawa Koji Tokoyoda Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Female-biased incidence of experimental autoimmune encephalomyelitis reflects sexually dimorphic expression of surface CTLA-4 (CD152) on T lymphocytes

Autoimmune reactions occur naturally and in most cases are controlled by regulatory mechanisms. However, unwanted autoimmune responses still appear in 5% to 7% of the population, in strikingly greater frequencies in women compared with men. The chronic inflammation characteristic of autoimmune diseases is mainly initiated and maintained by autoreactive CD4(+) T lymphocytes. Costimu-lation is required for an optimal response of T lymphocytes: CD28 is a T-cell activator, whereas CTLA-4 (cytotoxic T-lymphocyte antigen 4, also known as CD152) downregulates T-cell activity. Together these costimulatory molecules provide a balance in T-cell immune response. The aim of this study was to elucidate the role of the inhibitory receptor CTLA-4 in the quality of sex-specific immune responses. At the German Rheumatism Research Center (DRFZ), Berlin, Germany, between 2006 and 2010, we tested mouse strains commonly used for the development of experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis (MS). The SJL mouse strain not only mimics MS pathogenesis, but also exhibits the female predominance that occurs in patients with MS. Cells derived from SJL females revealed increased proliferation and a doubled frequency of T-helper (Th)1- and Th2-like cytokines, compared with their male counterparts. Moreover, activated Th cells from male mice express significantly higher frequencies (61%) of CTLA-4 expressed at the cell surface in comparison with those of females (46%). Accordingly, close to 50% reduction of CTLA-4 expression occurred in cells of both sexes after the addition of estrogen. We observed that interferon (IFN)-γ(high) production in females occurred in a higher frequency in CD4(+) T cells cultured under neutral conditions (24.6% in females, 15.9% in males). Moreover, we observed that the IFN-yhigh producers were mainly present in females (4.5% vs 0.4% in males). Our results suggest that induction of CTLA-4 expression could serve as a target for an immunomodulatory strategy to downregulate immune responses in sexually dimorphic autoimmune diseases.