Unauthorized change of immunosuppressants by patients with rheumatic diseases in the COVID-19 pandemic: a cross-sectional analysis of a patient survey.

This study provides insight in behavior and perspective of rheumatic patients during the first COVID-19 wave. Especially, we analyzed the patients' fear of COVID-19 and unauthorized change of immunosuppressive medication in consequence of their fear. We hereby provide data from 877 patients with valuable insights into the patients' point of view. We retrospectively interviewed patients of our rheumatic university outpatient clinic. This way, we collected information about the patients' personal point of view. Data like the rheumatic diagnosis and immunosuppressive medication was extracted from the health records. Statistical analysis was conducted using IBM® SPSS® Statistics (version 26). A total of 877 patients were included into our study. We could show that fear of COVID-19 was clearly present in rheumatic patients. Higher fear levels seem to be associated with comorbidity burden. Unauthorized change of immunosuppressive medication was rare in our study (5%). In our study we provide novel insight into patients' point of view and behavior of rheumatic patients. Unauthorized change of immunosuppressive medication was rare (5%) as seen in other studies. The low rate of unauthorized change and high rate of compliance is reassuring since good disease control appears to be prognostically important in the progression of COVID-19 disease. Therefore, as the pandemic continues, treatment decisions should be made in close consultation between patient and practitioner to improve adherence and reduce morbidity and mortality.

Erectile function and connective tissue diseases. Prevalence of erectile dysfunction in German men with systemic sclerosis compared to other connective tissue diseases and healthy subjects.

OBJECTIVES: Women are more frequently affected by connective tissue diseases like systemic sclerosis (SSc). Therefore, few studies exist on male-specific complaints. This study aimed to investigate the prevalence and associated factors of erectile dysfunction (ED) in SSc compared with other connective tissue diseases (CTD) and healthy controls. METHODS: 64 patients were analysed and compared with 123 age-matched HC. The 15-item International Index for Erectile Function (IIEF) questionnaire was used to assess sexual function. The prevalence of depression was quantified by using the validated Beck Depression Inventory (BDI). RESULTS: Mean age was 52.3 years (SD 10.75) for SSc, 52.9 years (SD 11.01) for patients with other CTD and 52.6 (SD 12.37) for HC. Mean IIEF-15 score was 13.6 for SSc, 11.7 for other CTD and 23.6 for HC. ED was significantly more frequent in patients with SSc (55.0%) and other CTD (54.4%) than in HC (12.7%) (p<0.001) and correlated with diseases severity. The mean BDI score was 10.8 for SSc/CTD and 5.4 for HC (p<0.001). With 36.6%, SSc patients suffered more often from a depression than patients with other CTD (17.4%) and HC (6.3%). We found a significant correlation between the IIEF-15 and depression classified by BDI (r= -0.527; p<0.001). CONCLUSIONS: This is the first study to show increased prevalence of ED, especially severe ED, in men with SSc compared to other CTD and age-matched HC. Physicians should be aware of this influence on sexual health and its correlation to depression and disease severity.

C-Cbl regulates c-MPL receptor trafficking and its internalization.

Thrombocyte formation from megakaryocyte and their progenitor cells is tightly regulated by thrombopoietin (TPO) and its receptor c-MPL, thereby maintaining physiological functionality and numbers of circulating platelets. In patients, dysfunction of this regulation could cause thrombocytopenia or myeloproliferative syndromes. Since regulation of this pathway is still not completely understood, we investigated the role of the ubiquitin ligase c-Cbl which was previously shown to negatively regulated c-MPL signalling. We developed a new conditional mouse model using c-Cblfl/fl Pf4Cre mice and demonstrated that platelet-specific knockout of c-Cbl led to severe microthrombocytosis and impaired uptake of TPO and c-MPL receptor internalization. Furthermore, we characterized a constitutive STAT5 activation c-Cbl KO platelets. This study identified c-Cbl as a potential player in causing megakaryocytic and thrombocytic disorders.

NFAT2 is a critical regulator of the anergic phenotype in chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is a clonal disorder of mature B cells. Most patients are characterised by an indolent disease course and an anergic phenotype of their leukaemia cells, which refers to a state of unresponsiveness to B cell receptor stimulation. Up to 10% of CLL patients transform from an indolent subtype to an aggressive form of B cell lymphoma over time (Richter´s syndrome) and show a significantly worse treatment outcome. Here we show that B cell-specific ablation of Nfat2 leads to the loss of the anergic phenotype culminating in a significantly compromised life expectancy and transformation to aggressive disease. We further define a gene expression signature of anergic CLL cells consisting of several NFAT2-dependent genes including Cbl-b, Grail, Egr2 and Lck. In summary, this study identifies NFAT2 as a crucial regulator of the anergic phenotype in CLL.NFAT2 is a transcription factor that has been linked with chronic lymphocytic leukaemia (CLL), but its functions in CLL manifestation are still unclear. Here the authors show, by analysing mouse CLL models and characterising biopsies from CLL patients, that NFAT2 is an important regulator for the anergic phenotype of CLL.

Ubiquitination and degradation of the thrombopoietin receptor c-Mpl.

Regulation of growth factor and cytokine signaling is essential for maintaining physiologic numbers of circulating hematopoietic cells. Thrombopoietin (Tpo), acting through its receptor c-Mpl, is required for hematopoietic stem cell maintenance and megakaryopoiesis. Therefore, the negative regulation of Tpo signaling is critical in many aspects of hematopoiesis. In this study, we determine the mechanisms of c-Mpl degradation in the negative regulation of Tpo signaling. We found that, after Tpo stimulation, c-Mpl is degraded by both the lysosomal and proteasomal pathways and c-Mpl is rapidly ubiquitinated. Using site-directed mutagenesis, we were able to determine that c-Mpl is ubiquitinated on both of its intracellular lysine (K) residues (K(553) and K(573)). By mutating these residues to arginine, ubiquitination and degradation were significantly reduced and caused hyperproliferation in cell lines expressing these mutated receptors. Using short interfering RNA and dominant negative overexpression, we also found that c-Cbl, which is activated by Tpo, acts as an E3 ubiquitin ligase in the ubiquitination of c-Mpl. Our findings identify a previously unknown negative regulatory pathway for Tpo signaling that may significantly impact our understanding of the mechanisms affecting the growth and differentiation of hematopoietic stem cells and megakaryocytes.