[Limits of outpatient rheumatology care]. / Grenzen der ambulanten Rheumatologie.

BACKGROUND: In recent years outpatient rheumatology has developed into one of the most important pillars of rheumatological care. The better diagnostic possibilities, the well-founded training of rheumatologists and the diverse guidelines have led to increasingly more patients being diagnosed as outpatients and can be treated by the most modern options as outpatients. Nevertheless, limits have also been set for outpatient rheumatology. OBJECTIVE: This article aims to highlight what the limits of outpatient rheumatology currently are and who sets the limits. The presentation of the limitations should help all participants in the healthcare system to avoid false expectations and frustration; however, limits can also be relocated or overcome by appropriate motivation. The long-term target should be a further improvement in the interaction between outpatient and inpatient rheumatology and therefore the rheumatological care of patients. RESULTS AND DISCUSSION: The medical limits of outpatient rheumatology are relatively clear and predominantly uncontroversial, the unjustified referral to the inpatient section is, for example, relatively rarely a problem. Some theoretically possible outpatient interventions are carried out in the inpatient sector more due to logistical problems. The healthcare political and legal limitations of outpatient rheumatological institutions are greater. Despite further limitations of outpatient rheumatology this discipline and the outpatient activity still represents an exciting, modern and last but not least a very satisfying activity, which is promoted here.

[Digitalization in rheumatological practice]. / Digitalisierung in der Rheumapraxis.

Digitalization in medicine is of major interest since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. This article tries to present the induced changes and technical solutions with respect to the different parts in the patient journey. Symptom checkers, new health applications, digital appointment management etc. are described. Apart from the technical and digital possibilities, the changes in the quality of communication additionally have to be mentioned. There is an urgent need for further technical standardization including the interfaces. In many cases further studies must confirm the equivalence of digital applications in comparison to analogue techniques.

[Telemedicine in rheumatology]. / Telemedizin in der Rheumatologie.

Due to the outbreak of the COVID-19 pandemic, in recent months we have experienced deep changes in our daily and professional lives. In the context of pandemic containment, routine rheumatological procedures have changed in many areas. To guarantee sufficient protection against the infection for patients and staff, telemedicine (especially telephone and video consultation) has increasingly been used. Due to the Digital Healthcare Act (DiGAV), whereby patients will have a legal claim to specific digital health applications in Germany, medical apps and wearables will offer new opportunities for telemedical monitoring. This article provides an overview of telemedical care options in the field of rheumatology. Furthermore, opportunities and limitations of telemedicine in rheumatology are reviewed.

[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.

[Statement of the German Society for Rheumatology (DGRh) on the use of video consultations in rheumatology]. / Stellungnahme der Deutschen Gesellschaft für Rheumatologie e. V. (DGRh) zur Anwendung der Videosprechstunde in der Rheumatologie.

For several years video consultations have been regarded as a new form of medical healthcare infrastructure, in addition to personal doctor-patient contacts and have also been partly promoted. The COVID-19 pandemic brought unexpected topicality and attention to the use of video consultations. The National Association of Statutory Health Insurance Physicians (Kassenärztliche Bundesvereinigung) decided on special regulations in the context of the COVID-19 pandemic, which reduce previous obstacles to the use of telemedicine and video consultations (and also partly of conventional telephony). The present statement of the German Society of Rheumatology (DGRh) on the use of video consultations is intended to give an overview of in which form and with which limitations video consultations can be used in rheumatology in Germany. It sketches an outlook on how video consultations can undertake which functions in rheumatological care in the future.

[Position paper of the commission on digital rheumatology of the German Society of Rheumatology: tasks, targets and perspectives for a modern rheumatology]. / Positionspapier der Kommission Digitale Rheumatologie der Deutschen Gesellschaft für Rheumatologie e. V.: Aufgaben, Ziele und Perspektiven für eine moderne Rheumatologie.

Digitalization in the healthcare system is a great challenge for rheumatology as for other medical disciplines. The German Society for Rheumatology (DGRh) wants to actively participate in this process and benefit from it. By founding the commission on digital rheumatology, the DGRh has created a committee that deals with the associated tasks, advises the DGRh on questions and positions associated with digital health. For the DGRh, this affects the most diverse areas of digitalization in medicine and rheumatology. This position paper presents the topics and developments currently handled by the commission and the tasks identified.

[Endocrinology and interdisciplinary consultation in internal medicine : Illustrated using the example of polyglandular autoimmune syndrome]. / Endokrinologie als Schnittstelle in der interdisziplinären Inneren Medizin : Veranschaulichung anhand des polyglandulären Autoimmunsyndroms.

Polyglandular autoimmune syndromes encompass several endocrine and nonendocrine autoimmune disorders with variable onset and phenotype. Rheumatoid and gastroenterological symptoms in patients with autoimmune polyglandular syndromes are suggestive of additional rheumatoid gastrointestinal and hepatological autoimmune diseases. Autoimmune gastritis, celiac disease, autoimmune hepatitis, rheumatoid arthritis, Sjögren syndrome, and systemic Lupus erythematodus are of particular clinical relevance. In addition, unspecific rheumatoid and gastrointestinal attendant symptoms of the existing autoimmune endocrinopathy must be considered. Furthermore, certain disorders of polyglandular autoimmune syndromes, e. g., type 1 diabetes are frequently associated with particular gastrointestinal diseases such as small bowel bacterial overgrowth. An optimal patient-centered care of subjects with autoimmune diseases requires a comprehensive differential diagnostic work up and emphasizes the importance of an interdisciplinary cooperation.

[Intracerebral lesions after TNF-alpha inhibitor therapy with pre-existing sarcoidosis and sacroiliitis]. / Zerebrale Rundherde unter TNF-α-Blocker-Therapie bei vorbestehender Sarkoidose und Sakroiliitis.

This article reports the case of a 55-year-old man who presented with aphasia caused by intracerebral lesions and had a history of pulmonary sarcoidosis. Due to nonsteroidal anti-inflammatory drug-resistant spondyloarthritis TNF-alpha inhibitor treatment was started after a negative tuberculosis screening. Subsequently the patient developed pulmonary tuberculosis and cerebral tuberculoma reactivated by the TNF-alpha inhibitor therapy accompanied by pulmonary sarcoidosis with sacroiliitis and oligoarthritis. This case report emphasises the risk of atypical tuberculosis infections under TNF-alpha inhibitors despite negative results of tuberculosis screening.

Rapid destruction of human Cdc25A in response to DNA damage.

To protect genome integrity and ensure survival, eukaryotic cells exposed to genotoxic stress cease proliferating to provide time for DNA repair. Human cells responded to ultraviolet light or ionizing radiation by rapid, ubiquitin- and proteasome-dependent protein degradation of Cdc25A, a phosphatase that is required for progression from G1 to S phase of the cell cycle. This response involved activated Chk1 protein kinase but not the p53 pathway, and the persisting inhibitory tyrosine phosphorylation of Cdk2 blocked entry into S phase and DNA replication. Overexpression of Cdc25A bypassed this mechanism, leading to enhanced DNA damage and decreased cell survival. These results identify specific degradation of Cdc25A as part of the DNA damage checkpoint mechanism and suggest how Cdc25A overexpression in human cancers might contribute to tumorigenesis.

p53 and SCFFbw7 cooperatively restrain cyclin E-associated genome instability.

Cancers often exhibit high levels of cyclin E expression, and aberrant cyclin E activity causes genomic instability and increased tumorigenesis. Two tumor suppressor pathways protect cells against cyclin E deregulation. The p53 pathway is induced by excess cyclin E in primary cells and opposes cyclin E activity through induction of p21Cip1. In contrast, the Fbw7 pathway targets cyclin E for degradation, and Fbw7 mutations occur commonly in cancers. We investigated the cooperativity of these two pathways in countering cyclin E-induced genomic instability in primary human cells. We find that loss of p53 and Fbw7 synergistically unmasks cyclin E-induced instability. In normal cells, impaired cyclin E degradation produces genome instability, but this is rapidly mitigated by induction of p53 and p21. In contrast, p53 loss allows the high level of cyclin E kinase activity that results from Fbw7 loss to persist and continuously drive genome instability. Moreover, p21 plays a critical role in suppressing cyclin E when Fbw7 is disabled, and in the absence of p21, sustained cyclin E activity induces rapid cell death via apoptosis. These data directly demonstrate the cooperative roles of these Fbw7 and p53 pathways in restraining cyclin E activity and its associated genome instability.

p21WAF1/CIP1 mutants deficient in inhibiting cyclin-dependent kinases (CDKs) can promote assembly of active cyclin D/CDK4(6) complexes in human tumor cells.

The cyclin-dependent kinase (CDK) inhibitor p21WAF1/CIP1 is a multidomain, multifunctional protein and a candidate tumor suppressor. Here, we show that, among rationally designed and tumor-associated mutants of human p21 ectopically expressed in U-2-OS cells, those that are selectively deficient in binding to either cyclin or CDK are partially impaired in inhibiting endogenous CDK activities but efficiently promote assembly of active cyclin D/CDK4(6) complexes. These results provide mechanistic insights into the p21-cyclin/CDK interplay in vivo and suggest a functional subclassification of tumor-specific aberrations of p21. Intriguingly, the subclass exemplified by the melanoma-derived N50S mutant may promote tumorigenesis, by both attenuating CDK-inhibitory function and concomitantly activating the proto-oncogenic cyclin D-dependent kinases.

Enhanced protein stability: a novel mechanism of D-type cyclin over-abundance identified in human sarcoma cells.

The mammalian D-type cyclins promote progression through a G1 checkpoint by phosphorylating the retinoblastoma protein (pRB), and can contribute to oncogenesis via their deregulated expression achieved through gene amplification, chromosomal rearrangement, or retroviral integration. We now report a novel mechanism of tumour-associated D-cyclin over-abundance, resulting from enhanced protein stability. In two human cell lines established from a single uterine sarcoma biopsy, pRB-positive SK-UT-1B and pRB-deficient SK-UT-1, aberrant accumulation of functional cyclins D1, and D2 and D3 occurred in the absence of gene amplification and/or elevated mRNA expression. The abundance of D-cyclin proteins remained elevated throughout the cell cycle, and pulse-chase experiments revealed six to 10-fold prolongation of their protein half-lives as compared with either diploid fibroblasts or control U-2-OS sarcoma cells. These results point to a critical regulatory role of D-type cyclin turnover, and contribute to refinement of current views of the role played by the cyclin D-CDK-p16-pRB pathway in cell cycle control and tumorigenesis.

Cyclin D2 is a moderately oscillating nucleoprotein required for G1 phase progression in specific cell types.

To explore regulation and function of cyclin D2, a candidate cell cycle-regulatory proto-oncogene, we examined subcellular localisation, cell type- and cell cycle-dependent expression, and requirement of cyclin D2 protein for G1 progression, in a panel of 40 human normal and cancer cell types. Except for lymphoid cells and sarcoma cell lines, expression of cyclin D2 was considerably more restricted than that of cyclin D1, whereas both D-type cyclin proteins were low or undetectable in cells lacking functional retinoblastoma gene product. In G1 cells, the cyclin D2 protein was more resistant to extraction and localised predominantly to nuclei, whereas it became more soluble and distributed in both nuclei and cytoplasm from G1/S transition onwards. Centrifugal elutriation and multiparameter flow cytometry analyses of several cell types showed moderate cell cycle oscillation with maximum levels of the cyclin D2 protein reached in late G1. Microinjection and/or electroporation of antibodies to cyclin D2 during G1 arrested the cyclin D2-expressing lymphocytes, breast myoepithelium, and U-2-OS sarcoma cells in G1 phase, whereas cyclin D2-negative cell types were unaffected by such treatment. Consistent with the putative proto-oncogenic role of cyclin D2 in specific cell types, our data show that this G1 cyclin has properties closely resembling those of cyclin D1, including the essential positive role in regulation of G1.

p21/WAF1/Cip1 expression in invasive ductal breast carcinoma: relationship to p53, proliferation rate, and survival at 5 years.

The p21/WAF1/Cipl antibody, DCS-60, was characterized by means of immunoblotting and immunofluorescence on a variety of human breast cancer cell lines. Heterogeneous staining of nuclei was observed with strong staining of cells in early G1. p21/WAF1/Cipl expression in invasive ductal, not otherwise specified breast carcinomas was determined using immunohistochemistry with this antibody and computerized image analysis. Two hundred and twenty-two tumors, including 130 from patients with no axillary node involvement, were examined. p21-positive tumor cell nuclei were found in 30% of the breast carcinomas. The percentage of tumor cell nuclei that were positive ranged from less than 1% to greater than 10%. In the whole cohort of patients, p21 expression was significantly associated with a low histological grade. In the node-negative group, there was a significant negative correlation between p21 positivity and a high (>10%) MIB-1 score. The mean MIB-1 score was significantly lower in p21-positive tumors in the whole cohort of patients (P=0.03) and in the nodenegative group (P=0.02). No association was found between p21 expression and overall survival at 5 years. With respect to p21/p53 phenotype, the significant difference in survival was noted only for the group of patients treated with adjuvant chemotherapy. The p21- p53+ phenotype had the worst survival (58% surviving 5 years), while the p21+ p53- phenotype had good survival (83% surviving 5 years; P<0.05). The results seem to suggest a correlation between p21/p53 phenotype and response to adjuvant chemotherapy.

Monoclonal antibody probes for p21WAF1/CIP1 and the INK4 family of cyclin-dependent kinase inhibitors.

Inhibition of cyclin dependent kinases (cdk) by proteins of two families of cdk inhibitors (CKIs) represents one of the key modes of cell-cycle control. Although not fully understood at present, the functions of the individual members of the Cip/Kip and INK4 families of CKIs have been implicated in fundamental biological processes as diverse as cellular proliferation, responses to genotoxic stress, regulation of cellular differentiation, and senescence. In addition, the seven currently known CKIs qualify as either established or candidate tumor suppressors whose loss or inactivation contribute to molecular pathogenesis of a wide range of tumor types. In this study, we report the isolation and characterization of a panel of 10 mouse monoclonal antibodies (MAbs) that specifically recognize p21WAF1/CIP1 (p21) or the individual members of the INK4 family of CKIs: p15INK4b (p15), p16INK4a (p16), p18INK4c (p18), or p19INK4d (p19). These antibodies are proving to be invaluable molecular probes for analyses of protein abundance, subcellular localization, interacting cellular proteins, and ultimately the function(s) of these cell cycle regulators. Epitopes targeted by the antibodies were mapped by peptide enzyme-linked immunoadsorbent assay (ELISA), and performance of the MAbs assessed in a range of immunochemical techniques. Individual MAbs of our series recognize distinct pools of the respective CKIs, a feature reflected by their differential applicability in immunoblotting, immunoprecipitation, and immunostaining including immunohistochemistry on archival paraffin-embedded tissue sections. Together, these antibodies represent useful reagents to study CKIs in cells and tissues, a set of tools that should help elucidate the physiological roles played by the individual CKIs, and better understand the molecular mechanisms of loss or inactivation of these (candidate) tumor suppressors in human malignancies.

[Immunologic therapy for glomerulonephritis with combined immunoadsorption and IVIG therapy]. / Therapie immunologisch bedingter Glomerulonephritiden mittels kombinierter Immunadsorption und IVIG-Therapie.

Immunoadsorption is an improvement of extracorporeal therapy which differs from plasmapheresis. After plasma perfusion on a special adsorption filter the patient's plasma is reinfused. Meanwhile more than 270 immunoadsorptions have been performed. 7 patients with SLE and glomerulonephritis as well as 3 patients suffering from Wegener's vasculitis and glomerulonephritis had been treated with combined immunoadsorption and IVIG therapy. After three sessions of immunoadsorption (2-3 1 plasma filtrate) the patients received 10 g 7S-immunoglobulin infusions on three consecutive days. Patients with SLE and end-stage kidney involvement (2 patients) did not show any benefit by the above mentioned treatment regimen. Patients with Wegener's vasculitis and glomerulonephritis showed no significant improvement, except in one of three patients who showed a remarkable decrease in proteinuria. On the other hand, patients with SLE and "moderate" kidney involvement (short course of disease, no fixed structural changes) showed improvement on combined immunoadsorption and IVIG therapy.

Digital gangrene: a rare skin symptom in systemic lupus erythematosus.

A case of digital gangrene in a patient with systemic lupus erythematosus without secondary anti-phospholipid syndrome is reported. The acute onset of the necrotizing acrovasculitis occurred without a history of Raynaud's phenomenon. Preceding symptoms of the systemic lupus erythematosus were arthritis, photosensitivity, alopecia and anorexia. Despite the seriousness of the acute episode the patient achieved an excellent outcome.

[Case report: treatment of anti-basement membrane glomerulonephritis with immunoadsorption]. / Kasuistik: Therapie der antibasalmembranglomerulonephritis mittels Immunadsorption.

Immunoadsorption (IMAD) is a particle extracorporeal therapy in treatment of various autoimmune diseases which differs from plasmapheresis. In the case presented here IMAD was helpful in the therapy of an acute renal failure due to an antiglomerular basement membrane disease. IMAD resulted in a quick recovery and stabilisation of the renal function. In addition to IMAD, the patient was treated with steroids, an immunosuppressive therapy was started immediately after IMAD. Considering the course of this patient's disease, we are convicted that IMAD was a major factor in the therapeutic success. IMAD was well tolerated by the patient, no side effects were seen.