[Rheumatological care in Germany : Memorandum of the German Society for Rheumatology and Clinical Immunology 2024]. / Rheumatologische Versorgung in Deutschland : Memorandum der Deutschen Gesellschaft für Rheumatologie und Klinische Immunologie 2024.

BACKGROUND: 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 4th new 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). METHODS: 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. RESULTS: Prevalence: approximately 1.8 million 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 a cross-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 31 December 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 2 rheumatology specialists per 100,000 adults are needed, i.e. around 1400, in order to provide adequate care. This means that there is a shortage of around 700 rheumatology specialists in the outpatient sector alone. Of all working specialists, 30% are currently aged 60 years old and over. Medical training: only 10 out of 38 (26%) state universities have an independent chair in rheumatology. In addition, 11 rheumatology departments are subordinate to a nonrheumatology chair. In the rheumatology-integration into student training (RISA) III study, only 16 out of 36 faculties fulfilled the recommended minimum number of compulsory hours of student rheumatology teaching. Continuing education in rheumatology: the annual postgraduate training qualifications do not cover the demand for rheumatology specialists, which is additionally 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 a much 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 a first rheumatological visit often last more than 3 months. Quality target is a first 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. COSTS: the total annual costs for inflammatory joint diseases alone amount to around 3 billion euros. The direct costs have significantly risen since the introduction of biologics, while the indirect costs for sick leave, disability and hospitalization have fallen. CONCLUSION: The core demands of this memorandum are a significant 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.

[Development of quality standards for patients with rheumatoid arthritis for use in Germany]. / Entwicklung von Qualitätsstandards für die Versorgung von Patient*innen mit rheumatoider Arthritis zur Anwendung in Deutschland.

Despite a qualitatively and structurally good care of patients with rheumatoid arthritis (RA) in Germany, there are still potentially amendable deficits in the quality of care. For this reason, the German Society for Rheumatology (DGRh) has therefore decided to ask a group of experts including various stakeholders to develop quality standards (QS) for the care of patients with RA in order to improve the quality of care. The QS are used to determine and quantitatively measure the quality of care, subject to relevance and feasibility. The recently published NICE and ASAS standards and a systematic literature search were used as the basis for development. A total of 8 QS, now published for the first time, were approved with the intention to measure and further optimize the quality of care for patients with RA in Germany.

[Current state, goals and quality standards of outpatient care in rheumatology: position paper of the Professional Association of German Rheumatologists (BDRh)]. / Aktueller Stand, Ziele und Qualitätsstandards der ambulanten Versorgung in der Rheumatologie: Positionspapier des Berufsverbandes der deutschen Rheumatologen (BDRh).

Even in the era of modern guidelines, the treatment of rheumatic diseases is only as good as the framework of rheumatological care within which the treatment is carried out. The access to high-quality medical treatment for all patients is therefore essentially decisive for the prognosis of the patients. This article describes the current state of outpatient treatment in rheumatology and demonstrates which quality projects, such as treatment contracts, outpatient specialized medical treatment (ASV), digitalization and training as specialized rheumatological assistant (RFA), have been created in order to ensure the treatment of our patients. Furthermore, standards are defined that can guarantee a contemporary and guideline-conform treatment in outpatient rheumatological units. As an example it is an affirmation of the Professional Association of German Rheumatologists (BDRh) for ensuring optimal care for all rheumatology patients through early or emergency rheumatology clinics, treat to target, appropriate delegation of medical duties and diversification of treatment, thus an assurance of the quality and comprehensive treatment in rheumatology. The important topic of safeguarding the next generation of rheumatologists, which is indispensable for this, is also discussed.

[Special treatment in rheumatology-cross-sectoral quality-oriented selective contracts]. / Vertragsentwicklung der Selektivverträge in der Versorgungslandschaft Rheuma.

In the last 4 years selective contracts according to §140a of the German Social Code Book V (SGB V) with three different health insurers were signed by the Professional Association of German Rheumatologists (BDRh) and from the beginning of the year 2018 by the management company of the association. The contracts were rolled out in five regions of Germany (Bavaria, Hesse, Mecklenburg-Western Pomerania, North Rhine and Saxony). Up to the end of 2018, 12,000 patients with chronic inflammatory rheumatic diseases were treated within the managed care of these contracts. The interface and the treatment pathways were initially consented with the associations of rheumatologists and general practitioners. The aim of the managed care was to provide the optimal quality in diagnostics and treatment and to improve management of rheumatic diseases. Quality indicators, such as treat-to-target principles, tight control, delegation to specially trained assistance personnel, patient education in rheumatoid arthritis (StruPi) and early arthritis consultation, are part of the managed care and are successfully promoted with incentive payments. Thus approximately 20% of the patients were enrolled for the first time in rheumatological care. The BDRh wants to promote the nationwide roll-out of this managed care in Germany with more participating health insurance funds.

[Outpatient specialist medical treatment (ASV)-a new treatment level in rheumatology]. / Ambulante spezialfachärztliche Versorgung (ASV) ­ eine neue Versorgungsebene in der Rheumatologie.

Since April 2018, the new third level care model of outpatient specialist care (ASV) according to §116b of the Social Code Book V (SGBV) has been available for patients with chronic inflammatory rheumatic diseases in Germany. Not only is a multiprofessional cooperation between the disciplines involved in treating rheumatic diseases promoted but also the cooperation between specialized rheumatologists and other specialists in private practice and in hospitals is encouraged. As budget capping limiting services and number of cases do not apply in ASV, a significant improvement of patient care in rheumatology is expected due to an increase in provider capacity. At the end of May 2019, 72 rheumatologists in the first 9 newly approved ASV teams had qualified for this new care concept. Bureaucratic obstacles have so far delayed the implementation of ASV. Difficulties arose in building a team with different specialties, in the process of registration of the teams and the assessment of the registration by certain regional boards responsible for access control. The national associations of rheumatologists, the Professional Association of German Rheumatologists (BDRh), the VRA (Verband der Rheumatologischen Akutkliniken e. V.) and the German Society of Rheumatology (DGRh) campaign for an easier admission of providers to the ASV and for adequate financing of all specialties involved in the ASV. The aim is to realize the chance of the ASV for better rheumatological care nationwide with shorter waiting times for a medical appointment and a better cooperation between specialists.

Local irritation/corrosion testing strategies: extending a decision support system by applying self-learning classifiers.

Procedures have been established and tested for the extension of a decision support system (DSS) for the prediction of the local irritation/corrosion potential of chemicals by using self-learning classifiers. The different approaches (decision trees, distances examinations in a multidimensional space, k-nearest-neighbour method) have been implemented, tested and evaluated independently. A combination of all of the established extension approaches was also developed and tested. Self-learning classifiers are constructed "automatically" by a computer, i.e. they are not derived by a human expert, and thus they can be constructed with minimal effort. The classifiers presented here extend the existing DSS in a manner that increased significantly the predictive power of the extended system. However, automatically calculated results of self-learning classifiers are produced by a machine, and a machine is incapable of explaining the toxicological relevance of the results obtained. Thus, these results must be accepted, despite an inability to prove their reliability. Only the mathematical correctness of the method and the prediction rates for suitable test cases can lend some credibility to predictions produced by a computer calculating on a self-learning basis. This may not be adequate for regulatory hazard assessment purposes.

A Computer-Based Structure-Activity Relationship Method for Predicting the Toxic Effects of Organic Chemicals from Onedimensional Representations of their Molecular Structures.

A computer-based method is presented for the analysis and interpretation of structural formulae characterising chemical molecules. This method was developed to enable a computer to identify substructures of chemical molecules that are relevant in the context of specific toxicological questions. The new computer-based structure-examination method was used to develop the "structure" parts of several electronic structure-activity relationship models (SAR models) for analysing and interpreting the structural formula of a chemical from its one dimensional representation, by applying recursive principles and identifying partial isomorphic graphs. The structure-examination method is designed as part of an open-endpoint procedure to be used in expert systems, and could be applied in the construction of SAR models for almost all toxicological endpoints. The system was satisfactorily tested by identifying substructures relevant to severely damaging effects on skin and eyes.

Development of a decision support system for the introduction of alternative methods into local irritancy/corrosivity testing strategies. Creation of fundamental rules for a decision support system.

The notification procedure of the European Union (EU) for new chemicals requires the application of protocols on physicochemical and toxicological tests for the evaluation of physicochemical properties and probable toxic effects of each notified substance. A computerised database was developed from data sets and toxicological test protocols relating to substance properties responsible for skin and eye irritation/corrosion. To develop specific structure-activity relationship (SAR) models and to find rules for a decision support system (DSS) to predict local irritation/corrosion, physical property data, chemical structure data and toxicological data for approximately 1300 chemicals, each having a purity of 95% or more, were evaluated. The evaluation demonstrated that the lipid solubility and aqueous solubility of a chemical are relevant to, or - in some cases - responsible for, the observed local effects of a substance on the skins and eyes of rabbits. The octanol/water partition coefficient and the measured value of the surface tension of a saturated aqueous solution of the substance give additional information that permits the definition of detailed SAR algorithms that use measured solubility values. Data on melting points and vapour pressure can be used to assess the intensity and duration of local contact with a chemical. Considerations relating to the reactivity of a pure chemical can be based on molecular weight and the nature of the heteroatoms present. With respect to local lesions produced following contact with the skin and eyes of rabbits, the data evaluation revealed that no general "local irritation/corrosion potential" of a chemical can be defined. A variety of mechanisms are responsible for the formation of local lesions on the skin or in the eyes: serious lesions are produced by mechanisms different from those that cause moderate irritation in these organs. In order to develop a DSS that uses the information extracted from the database, chemical main groups were categorised on the basis of their empirical formulae, and rules were defined of the type IF (physicochemical property) A, THEN not (toxic) effect B, based on correlations between specific local effects and measured physicochemical values. Other rules of the type IF substructure A, THEN effect B were developed based on correlations between specific local effects and the submitted structural formulae. Reactive chemical substructures relevant to the formation of local lesions and rules for the prediction of the absence of any skin irritation potential were identified. Proposals are made relating to the development of alternatives to eye irritation testing with rabbits.

Local irritation/corrosion testing strategies: development of a decision support system for the introduction of alternative methods.

The notification procedure for new chemicals of the European Union (EU) requires protocols on physicochemical and toxicological tests for the evaluation of physicochemical properties and probable toxic effects of each notified substance. In order to reduce the amount of animal testing, alternative methods should be introduced into toxicity testing. Therefore, we have developed a rule-based decision support system (DSS) for the prediction of the local corrosive/irritant properties of new chemicals. To this end, data on more than 1000 substances were examined, which resulted in approximately 180 "exception-rules" of the kind IF (physicochemical property) A THEN not (toxic) Effect B. In addition, the structural formulae of the chemicals were analysed, which resulted in approximately 160 "structure-rules" of the kind IF Substructure A THEN Effect B. The DSS can predict (based on theoretical structure-activity relationships) whether a chemical produces: a) corrosive effects (i.e. no testing is necessary; b) might have corrosive effects (i.e. no animal testing, in vitro tests are suitable) ; and c) will produce no effects or only marginal effects (i.e. animal tests are necessary based on current EU legislation for hazard assessment purposes). In addition, the DSS provides reliable data for legal classification and labelling based on a specific result.

Hepatitis C virus-specific T cell responses against conserved regions in recovered patients.

For the design of peptide-based vaccines against the hepatitis C virus it is essential to acquire more information on frequently recognized epitopes in patients with successful immune control of HCV in the context of different HLA types. A matrix approach using 393 15mer peptides from conserved HCV regions overlapping by 13 amino acids was applied in 52 HCV-recovered individuals. Candidate peptides were further tested in two independent laboratories. 38 peptides induced IFN-gamma responses in ELISPOT assays including 15 previously unknown epitopes. There was no particular immune dominance as only five peptides were recognized by more than three individuals. Seven out of 14 peptides tested in more detail could be confirmed to be immunogenic using ELISPOT and cytotoxicity assays. While only 33% of HCV-recovered individuals recognized recombinant HCV proteins, 81% of individuals tested positive in the matrix approach (p<0.001). The strength, frequency and breadth of HCV-specific T cell responses were similar in spontaneously recovered patients than in interferon-recovered patients. In conclusion (i) we identified novel HCV epitopes in conserved regions, (ii) confirmed the inter-individual diversity of HCV-specific T cell responses and (iii) found no significant differences in HCV-specific T cell responses between spontaneously recovered and IFN-recovered patients.

[Chest pain, reduced physical activity, and polyserositis in a 35-year old patient with anticonvulsive medication]. / Leistungsknick, Thoraxschmerz und Polyserositis bei einem 35-jährigen Patienten mit antikonvulsiver Therapie.

We report on a rare case of a late-onset drug-induced lupus erythematosus. A 35 year old male patient complained about dyspnea, chest pain and reduced physical activity for three months. His medical history consisted of epilepsy treated with carbamazepine for 20 years. After diagnosis of a large pericardial effusion and percardiocentesis (1200 ml) the diagnosis of viral perimyocarditis was suspected. Under antiphlogistic treatment the symptoms vanished initially. Four weeks later the pericardial effusion recurred and a livedo reticularis became evident. A structural or infectious heart disease, in particular viral myocarditis, was ruled out invasively. Serologic testing revealed antinuclear antibodies and antibodies against histones without presence of antibody against ds-DNA, thereby confirming the diagnosis of carbamazepine-induced lupus erythematodes. After discontinuation of carbamazepine and immunosuppressive medication the patient recovered completely.

Alcoholism and carcinoma change the intracellular pH and activate platelet Na+/H+-exchange in men.

The occurrence of carcinoma in chronic alcoholics exceeds that of the general population. Cytoplasmic alkalinization, due to the influence of different factors on the transmembrane Na+/H+ exchange (NHE), has been put forward as a triggering event in cell growth and division. In accordance with these findings, the carcinogenic potential of NHE deficient cell types is reported to be diminished. The aim of this study was to investigate whether the intracellular pH and the NHE activity is altered in chronic alcoholics. Seventy-two Caucasian males were assigned to one of four groups: non-alcoholics without carcinoma, chronic alcoholics without carcinoma, non-alcoholics with carcinoma and chronic alcoholics with carcinoma. Alcoholism was diagnosed according to DSM-III-R. The groups did not differ in relation to basic patient characteristics, such as age and blood pressure. Intracellular calcium, pH and NHE in platelets were determined by spectrofluorometry before and after thrombin stimulation. In chronic alcoholics with carcinoma, the intracellular pH was significantly more alkaline and the NHE activity was elevated. In contrast, a decrease in intracellular pH associated with an increased activity of NHE and a more acidic set point was found in chronic alcoholics without carcinoma. Basal and thrombin stimulated intracellular Ca2+ did not differ between groups except in chronic alcoholics with carcinoma in whom a thrombin-induced increase of Ca2+ due to liberation of Ca2+ from intracellular stores was demonstrated. In chronic alcoholics with carcinoma, cytoplasmic alkalinization was observed and this may be an indication of an increase in cell proliferation. The possibility that the increased incidence of carcinomas in chronic alcoholics is related to the increased activity of NHE and whether this may be prevented by NHE inhibitors requires further investigation.