Urinary CD4 + T Cells Predict Renal Relapse in ANCA-Associated Vasculitis.

SIGNIFICANCE STATEMENT: Early identification of patients at risk of renal flares in ANCA vasculitis is crucial. However, current clinical parameters have limitations in predicting renal relapse accurately. This study investigated the use of urinary CD4 + T lymphocytes as a predictive biomarker for renal flares in ANCA vasculitis. This study, including urine samples from 102 patients, found that the presence of urinary CD4 + T cells was a robust predictor of renal relapse within a 6-month time frame, with a sensitivity of 60% and a specificity of 97.8%. The diagnostic accuracy of urinary CD4 + T cells exceeded that of ANCA titers, proteinuria, and hematuria. Monitoring urinary CD4 + T lymphocytes could help assess the risk of future renal relapse, enabling early preventive measures and tailored treatment strategies. BACKGROUND: In ANCA-associated vasculitis, there is a lack of biomarkers for predicting renal relapse. Urinary T cells have been shown to differentiate active GN from remission in ANCA-associated vasculitis, but their predictive value for renal flares remains unknown. METHODS: The PRE-FLARED study was a prospective multicenter biomarker study including 102 individuals with ANCA-associated vasculitis in remission aimed to predict renal relapse by quantifying urinary CD4 + T-cell subsets using flow cytometry at baseline and monitoring clinical outcomes over a 6-month follow-up. RESULTS: Among the participants, ten experienced renal relapses, two had non-renal flares, and 90 remained in stable remission. The median baseline urinary CD4 + T-cell count was significantly higher in patients who relapsed compared with those in remission. Receiver operating characteristic curve analysis of urinary CD4 + T-cell counts showed an area under the curve value of 0.88 for predicting renal flares, outperforming ANCA titers, hematuria, and proteinuria. Using a cutoff of 490 CD4 + T cells per 100 ml urine, the sensitivity and specificity in identifying patients with future renal flares were 60% and 97.8%, respectively. In a post hoc analysis, combining urinary CD4 + T-cell counts with proteinase-3 ANCA levels suggested improved predictive performance in the PR3 + subgroup. In addition, the number of urinary CD4 + T cells showed a limited correlation with a decline in GFR and an increase in proteinuria over the follow-up period. CONCLUSIONS: This study concluded that urinary CD4 + T-cell counts could identify patients with ANCA-associated vasculitis at a substantial risk of renal relapse within 6 months. Combining these counts with ANCA levels further improved the prediction of relapse. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Urinary T Lymphocytes Predict Renal Flares in Patients With Inactive ANCA-associated Glomerulonephritis (PRE-FLARED), NCT04428398 .

A Managed Care System with Telemedicine Support for Neurological Emergencies.

OBJECTIVES: Telemedicine is frequently used to provide remote neurological expertise for acute stroke workup and was associated with better functional outcomes when combined with a stroke unit system-of-care. We investigated whether such system-of-care yields additional benefits when implemented on top of neurological competence already available onsite. METHODS: Quality improvement measures were implemented within a "hub-and-spoke" teleneurology network in 11 hospitals already provided with onsite or telestroke expertise. Measures included dedicated units for neurological emergencies, standardization of procedures, multiprofessional training, and quality-of-care monitoring. Intervention effects were investigated in a controlled study enrolling patients insured at 3 participating statutory health insurances diagnosed with acute stroke or other neurological emergencies. Outcomes during the intervention period between November 2017 and February 2020 were compared with those pre-intervention between October 2014 and March 2017. To control for temporal trends, we compared outcomes of patients with respective diagnoses in 11 hospitals of the same region. Primary outcome was the composite of up-to-90-day death, new disability with the need of ambulatory or nursing home care, expressed by adjusted hazard ratio (aHR). RESULTS: We included 1,418 patients post-implementation (55% female, mean age 76.7 ± 12.8 year) and 2,306 patients pre-implementation (56%, 75.8 ± 13.0 year, respectively). The primary outcome occurred in 479/1,418 (33.8%) patients post-implementation and in 829/2,306 (35.9%) pre-implementation. The aHR for the primary outcome was 0.89 (95% confidence interval [CI]: 0.79-0.99, p = 0.04) with no improvement seen in non-participating hospitals between post- versus pre-implementation periods (aHR 1.04; 95% CI: 0.95-1.15). INTERPRETATION: Implementation of a multicomponent system-of-care was associated with a lower risk of poor outcomes. ANN NEUROL 2023;93:511-521.

Anti-Ku + myositis: an acquired inflammatory protein-aggregate myopathy.

Myositis with anti-Ku-autoantibodies is a rare inflammatory myopathy associated with various connective tissue diseases. Histopathological studies have identified inflammatory and necrotizing aspects, but a precise morphological analysis and pathomechanistic disease model are lacking. We therefore aimed to carry out an in-depth morpho-molecular analysis to uncover possible pathomechanisms. Muscle biopsy specimens from 26 patients with anti-Ku-antibodies and unequivocal myositis were analyzed by immunohistochemistry, immunofluorescence, transcriptomics, and proteomics and compared to biopsy specimens of non-disease controls, immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Clinical findings and laboratory parameters were evaluated retrospectively and correlated with morphological and molecular features. Patients were mainly female (92%) with a median age of 56.5 years. Isolated myositis and overlap with systemic sclerosis were reported in 31%, respectively. Isolated myositis presented with higher creatine kinase levels and cardiac involvement (83%), whereas systemic sclerosis-overlap patients often had interstitial lung disease (57%). Histopathology showed a wide spectrum from mild to pronounced myositis with diffuse sarcolemmal MHC-class I (100%) and -II (69%) immunoreactivity, myofiber necrosis (88%), endomysial inflammation (85%), thickened capillaries (84%), and vacuoles (60%). Conspicuous sarcoplasmic protein aggregates were p62, BAG3, myotilin, or immunoproteasomal beta5i-positive. Proteomic and transcriptomic analysis identified prominent up-regulation of autophagy, proteasome, and hnRNP-related cell stress. To conclude, Ku + myositis is morphologically characterized by myofiber necrosis, MHC-class I and II positivity, variable endomysial inflammation, and distinct protein aggregation varying from IBM and IMNM, and it can be placed in the spectrum of scleromyositis and overlap myositis. It features characteristic sarcoplasmic protein aggregation on an acquired basis being functionally associated with altered chaperone, proteasome, and autophagy function indicating that Ku + myositis exhibit aspects of an acquired inflammatory protein-aggregate myopathy.

[Autoantibody diagnostics in idiopathic inflammatory myopathy]. / Autoantikörperdiagnostik bei idiopathisch inflammatorischen Myopathien.

Idiopathic inflammatory myopathy (IIM) is a group of rare and heterogeneous systemic diseases that manifest not only in the muscles but also in the skin, joints, and lungs. Initial symptoms can be isolated and variable and thus the diagnosis poses challenges to various specialist groups. As autoantibodies are sometimes the only specific findings that lead to the diagnosis and appropriate treatment, basic knowledge of them is essential. This article explains the available test systems, names the clinical indications necessary for the initiation of autoantibody diagnostics, provides information on the etymology, antigens, synonyms, and first descriptors, describes indirect immunofluorescence on HEp­2 cells induced by myositis antibodies, and provides clinical-serological associations. The comparison of the autoantibody findings with the clinical symptoms and laboratory findings enables the identification of false positive or false negative laboratory findings in the sense of a plausibility check.

Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus.

Daratumumab, a human monoclonal antibody that targets CD38, depletes plasma cells and is approved for the treatment of multiple myeloma. Long-lived plasma cells are implicated in the pathogenesis of systemic lupus erythematosus because they secrete autoantibodies, but they are unresponsive to standard immunosuppression. We describe the use of daratumumab that induced substantial clinical responses in two patients with life-threatening lupus, with the clinical responses sustained by maintenance therapy with belimumab, an antibody to B-cell activating factor. Significant depletion of long-lived plasma cells, reduction of interferon type I activity, and down-regulation of T-cell transcripts associated with chronic inflammation were documented. (Supported by the Deutsche Forschungsgemeinschaft and others.).

Eosinophilic fasciitis (Shulman syndrome)-recognition of the histological spectrum allows for new insights into possible pathomechanisms.

OBJECTIVES: EF is a rare disease characterized by fibrosis and inflammation of the fascia, scleroderma-like skin indurations and optional blood eosinophilia. We aimed to expand the knowledge about its aetiology and pathogenesis. METHODS: Biopsy specimens from 16 EF patients were assessed by histology, immunohistochemistry and quantitative reverse transcription PCR in comparison with anti-Mi-2+ DM patients and non-disease controls. RESULTS: Histologically, EF shows mild to severe inflammation at the muscle-fascia interface, with frequent involvement of the underlying muscle tissue, though varying in degree. CD206+ macrophages predominate and eosinophils are detected within the fascia in the majority of cases, however in quite small numbers, and seen infrequently within the muscle. Activators of the so-called Th2-M2 pathway like STAT6 and IL-4 are upregulated leading to high expression levels of CD206. Activators of the so-called Th1-M1 pathway like STAT1 and IFN-γ (IFNG) are also upregulated, though not translating into a significant upregulation of the effector molecule COX2. Interestingly, activators or chemoattractants of eosinophils show no significant upregulation in EF compared with DM. EF shows features of perifascicular pathology comparable to DM, with upregulation of MHC class I and II; however, this is not accompanied by perifascicular atrophy or any signs of a type I IFN response or hypoxia-mediated processes. CONCLUSIONS: Our findings highlight a specific immune phenotype of leucocyte infiltrates in EF along features of perifascicular pathology similar to DM, while there is no evidence of hypoxia-mediated or type I IFN-associated processes with perifascicular fibre atrophy, indicating different pathomechanisms of muscle involvement.

Clinical manifestations and immunomodulatory treatment experiences in psychiatric patients with suspected autoimmune encephalitis: a case series of 91 patients from Germany.

Autoimmune encephalitis (AE) can rarely manifest as a predominantly psychiatric syndrome without overt neurological symptoms. This study's aim was to characterize psychiatric patients with AE; therefore, anonymized data on patients with suspected AE with predominantly or isolated psychiatric syndromes were retrospectively collected. Patients with readily detectable neurological symptoms suggestive of AE (e.g., epileptic seizures) were excluded. Patients were classified as "probable psychiatric AE (pAE)," if well-characterized neuronal IgG autoantibodies were detected or "possible pAE" (e.g., with detection of nonclassical neuronal autoantibodies or compatible cerebrospinal fluid (CSF) changes). Of the 91 patients included, 21 (23%) fulfilled our criteria for probable (autoantibody-defined) pAE and 70 (77%) those for possible pAE. Among patients with probable pAE, 90% had anti-NMDA receptor (NMDA-R) autoantibodies. Overall, most patients suffered from paranoid-hallucinatory syndromes (53%). Patients with probable pAE suffered more often from disorientation (p < 0.001) and impaired memory (p = 0.001) than patients with possible pAE. Immunotherapies were performed in 69% of all cases, mostly with high-dose corticosteroids. Altogether, 93% of the patients with probable pAE and 80% of patients with possible pAE reportedly benefited from immunotherapies (p = 0.251). In summary, this explorative, cross-sectional evaluation confirms that autoantibody-associated AE syndromes can predominantly manifest as psychiatric syndromes, especially in anti-NMDA-R encephalitis. However, in three out of four patients, diagnosis of possible pAE was based on nonspecific findings (e.g., slight CSF pleocytosis), and well-characterized neuronal autoantibodies were absent. As such, the spectrum of psychiatric syndromes potentially responding to immunotherapies seems not to be limited to currently known autoantibody-associated AE. Further trials are needed.

Measuring PROMIS pain interference in German patients with chronic conditions: calibration, validation, and cross-cultural use of item parameters.

PURPOSE: To calibrate the item parameters of the German PROMIS® Pain interference (PROMIS PI) items using an item-response theory (IRT) model and investigate psychometric properties of the item bank. METHODS: Forty items of the PROMIS PI item bank were collected in a convenience sample of 660 patients, which were recruited during inpatient rheumatological treatment or outpatient psychosomatic medicine visits in Germany. Unidimensionality, monotonicity, and local independence were tested as required for IRT analyses. Unidimensionality was examined using confirmatory factor analyses (CFA) and exploratory factor analysis (EFA). Unidimensional and bifactor graded-response IRT models were fitted to the data. Bifactor indices were used to investigate whether multidimensionality would lead to biased scores. To evaluate convergent and discriminant validity, the item bank was correlated with legacy pain instruments. Potential differential item functioning (DIF) was examined for gender, age, and subsample. To investigate whether U.S. item parameters may be used to derive T-scores in German patients, T-scores based on previously published U.S. and newly estimated German item parameters were compared with each other after adjusting for sample specific differences. RESULTS: All items were sufficiently unidimensional, locally independent, and monotonic. Whereas the fit of the unidimensional IRT model was not acceptable, a bifactor IRT model demonstrated acceptable fit. Explained common variance and Omega hierarchical suggested that using the unidimensional model would not lead to biased scores. One item demonstrated DIF between subsamples. High correlations with legacy pain instruments supported construct validity of the item bank. T-scores based on U.S. and German item parameters were similar suggesting that U.S. parameters could be used in German samples. CONCLUSION: The German PROMIS PI item bank proved to be a clinically valid and precise instrument for assessing pain interference in patients with chronic conditions.

Psychometric properties of the German Penn Alcohol Craving Scale.

Craving for alcohol is an important diagnostic criterion in alcohol use disorder (AUD) and an established predictor of future relapse. The 5-item Penn Alcohol Craving Scale (PACS) is one of the most widely used questionnaires to quantify craving and has been translated into different languages. It is assumed that the PACS constitutes one factor, although theoretical considerations suggest an additional second factor. We conducted stability and factor analyses (principal component and confirmatory factor analyses) of the German PACS (PACS-G) in samples of patients with AUD from the following three German study sites: Erlangen, N = 188 (mean age: 47.1 years, 43.5% female); Mannheim, N = 440 (45.5 years, 28.6% female); Hannover, N = 107 (48.1 years, 48.6% female). In our samples, the 2-factor solution of the PACS-G version is more stable than the internationally assumed 1-factor solution. The resulting two PACS-G subscores 'difficulty to resist' (items 4 and 5) and 'thoughts about alcohol' (items 1, 2, and 3) have an internal consistency (Cronbach's alpha) of 0.80 ≤ α ≤ 0.90, m = 0.86 and 0.86 ≤ α ≤ 0.91, m = 0.89 with an overlap of R2 = 62%. We found good convergent validity assessed via the Craving Automatized Scale-Alcohol and the Obsessive-Compulsive Drinking Scale, but also correlations with depression and anxiety assessed via the Beck's Depression and Anxiety Inventories. This study is the first to provide evidence for a 2-factor solution ('difficulty to resist' and 'thoughts about alcohol') underlying the PACS-G version.

[Five Key Questions for Health Services Research: are SHI Claims Data Suitable for Your Research Project?] / 5 Leitfragen für die Versorgungsforschung ­ Eignen sich GKV-Routinedaten für Ihr Forschungsvorhaben?

Health services research examines the structures and processes of health care under everyday conditions. Routine data of the statutory health insurance (SHI) - the so-called routine practice data - represent real health care and are therefore an important data source for health services research. This paper presents 5 key questions that researchers and data-holding institutions can use to assess the suitability of this data source for answering their health services research question. The aim of these guiding questions is to generate a common understanding between researchers and data-holding institutions of the research project, the research objective, and the feasibility of implementation in health services research. The five guiding questions cover the formulation of the research question, the planned method, the target population, the relevant study periods, and the required information from SHI data. These methodologically oriented guiding questions are supplemented by the question of how the results of the research project could improve care. Thus, for researchers, the five guiding questions provide an initial structuring for data requests; for data-holding institutions, they provide a framework for considering possible involvement in or support of a research idea in health services research.

Evaluation of the EMPAR study population on the basis of metabolic phenotypes of selected pharmacogenes.

The impact of genetic variability of pharmacogenes as a possible risk factor for adverse drug reactions is elucidated in the EMPAR (Einfluss metabolischer Profile auf die Arzneimitteltherapiesicherheit in der Routineversorgung/English: influence of metabolic profiles on the safety of drug therapy in routine care) study. EMPAR evaluates possible associations of pharmacogenetically predicted metabolic profiles relevant for the metabolism of frequently prescribed cardiovascular drugs. Based on a German study population of 10,748 participants providing access to healthcare claims data and DNA samples for pharmacogenetic assessment, first analyses were performed and evaluated. The aim of this first evaluation was the characterization of the study population with regard to general parameters such as age, gender, comorbidity, and polypharmacy at baseline (baseline year) as well as important combinations of cardiovascular drugs with relevant genetic variants and predicted metabolic phenotypes. The study was registered in the German Clinical Trials Register (DRKS) on July 6, 2018 (DRKS00013909).

CSF2-dependent monocyte education in the pathogenesis of ANCA-induced glomerulonephritis.

OBJECTIVES: Myeloid cell activation by antineutrophil cytoplasmic antibody (ANCA) is pivotal for necrotising vasculitis, including necrotising crescentic glomerulonephritis (NCGN). In contrast to neutrophils, the contribution of classical monocyte (CM) and non-classical monocyte (NCM) remains poorly defined. We tested the hypothesis that CMs contribute to antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and that colony-stimulating factor-2 (CSF2, granulocyte-macrophage colony-stimulating factor (GM-CSF)) is an important monocyte-directed disease modifier. METHODS: Myeloperoxidase (MPO)-immunised MPO-/- mice were transplanted with haematopoietic cells from wild-type (WT) mice, C-C chemokine receptor 2 (CCR2)-/- mice to abrogate CM, or transcription factor CCAAT-enhancer-binding protein beta (C/EBPß)-/- mice to reduce NCM, respectively. Monocytes were stimulated with CSF2, and CSF2 receptor subunit beta (CSF2rb)-deficient mice were used. Urinary monocytes and CSF2 were quantified and kidney Csf2 expression was analysed. CSF2-blocking antibody was used in the nephrotoxic nephritis (NTN) model. RESULTS: Compared with WT mice, CCR2-/- chimeric mice showed reduced circulating CM and were protected from NCGN. C/EBPß-/- chimeric mice lacked NCM but developed NCGN similar to WT chimeric mice. Kidney and urinary CSF2 were upregulated in AAV mice. CSF2 increased the ability of ANCA-stimulated monocytes to generate interleukin-1ß and to promote TH17 effector cell polarisation. CSF2rb-/- chimeric mice harboured reduced numbers of kidney TH17 cells and were protected from NCGN. CSF2 neutralisation reduced renal damage in the NTN model. Finally, patients with active AAV displayed increased urinary CM numbers, CSF2 levels and expression of GM-CSF in infiltrating renal cells. CONCLUSIONS: CMs but not NCMs are important for inducing kidney damage in AAV. CSF2 is a crucial pathological factor by modulating monocyte proinflammatory functions and thereby TH17 cell polarisation.

Successful plasmapheresis and immunoglobulin treatment for severe lipid storage myopathy: Doing the right thing for the wrong reason.

Three consecutive skeletal muscle biopsies during a several months time-frame, showing different degrees of neutral lipid storage. This is highlighted by Oil-red-O stains (D, E, F) and electron microscopy (G, H, I). Note the impact on mitochondrial morphology with so called 'parking lots (K, L). Zooming 'in and out' into the ultrastructure, using the nanotomy platform provides interesting detailled information (http://nanotomy.org). ​.

Evaluation of SIGLEC1 in the diagnosis of suspected systemic lupus erythematosus.

OBJECTIVES: To evaluate and compare the diagnostic accuracy of SIGLEC1, a surrogate marker of type I IFN, with established biomarkers in an inception cohort of systemic lupus erythematosus (SLE). METHODS: SIGLEC1 was analysed by flow cytometry in 232 patients referred to our institution with suspected SLE between October 2015 and September 2020. RESULTS: SLE was confirmed in 76 of 232 patients (32.8 %) according to the 2019 EULAR/ACR classification criteria and their SIGLEC1 values were significantly higher compared with patients without SLE (P <0.0001). A sensitivity of 98.7 %, a specificity of 82.1 %, a negative predictive value (NPV) of 99.2 % and a positive predictive value (PPV) of 72.8 % were calculated for SIGLEC1. Adjusted to the highest reported prevalence of SLE, the NPV and PPV were >99.9 % and 0.1 %, respectively. Using receiver operating characteristic (ROC) analysis and DeLong testing, the area under the curve (AUC) for SIGLEC1 (AUC = 0.95) was significantly higher than for ANA (AUC = 0.88, P = 0.031), C3 (AUC = 0.83, P = 0.001) and C4 (AUC = 0.83, P = 0.002) but not for anti-dsDNA antibodies (AUC = 0.90, P = 0.163). CONCLUSION: IFN-I pathway activation is detectable in almost all newly diagnosed SLE patients. Thus, a negative test result for SIGLEC1 is powerful to exclude SLE in suspected cases.

Identifying and Investigating Ambulatory Care Sequences Before Invasive Coronary Angiography.

BACKGROUND: The concept of care pathways is widely used to provide efficient, timely, and evidence-based medical care. Recently, the investigation of actual empirical patient pathways has gained attention. We demonstrate the usability of State Sequence Analysis (SSA), a data mining approach based on sequence clustering techniques, on comprehensive insurance claims data from Germany to identify empirical ambulatory care sequences. We investigate patients with coronary artery disease before invasive coronary angiography (CA) and compare identified patterns with guideline recommendations. This patient group is of particular interest due to high and regionally varying CA rates. METHODS: Events relevant for the care of coronary artery disease patients, namely physician consultations and medication prescriptions, are identified based on medical guidelines and combined to define states. State sequences are determined for 1.5 years before CA. Sequence similarity is defined for clustering, using optimal matching with theory-informed substitution costs. We visualize clusters, present descriptive statistics, and apply logistic regression to investigate the association of cluster membership with subsequent undesired care events. RESULTS: Five clusters are identified, the included patients differing with respect to morbidity, urbanity of residential area, and health care utilization. Clusters exhibit significant differences in the timing, structure, and extent of care before CA. When compared with guideline recommendations, 3 clusters show signs of care deficits. CONCLUSIONS: Our analyses demonstrate the potential of SSA for exploratory health care research. We show how SSA can be used on insurance claims data to identify, visualize, and investigate care patterns and their deviations from guideline recommendations.

Skeletal muscle provides the immunological micro-milieu for specific plasma cells in anti-synthetase syndrome-associated myositis.

Anti-synthetase syndrome (ASyS)-associated myositis is a major subgroup of the idiopathic inflammatory myopathies (IIM) and is characterized by disease chronicity with musculoskeletal, dermatological and pulmonary manifestations. One of eight autoantibodies against the aminoacyl-transferase RNA synthetases (ARS) is detectable in the serum of affected patients. However, disease-specific therapeutic approaches have not yet been established.To obtain a deeper understanding of the underlying pathogenesis and to identify putative therapeutic targets, we comparatively investigated the most common forms of ASyS associated with anti-PL-7, anti-PL-12 and anti-Jo-1. Our cohort consisted of 80 ASyS patients as well as healthy controls (n = 40), diseased controls (n = 40) and non-diseased controls (n = 20). We detected a reduced extent of necrosis and regeneration in muscle biopsies from PL-12+ patients compared to Jo-1+ patients, while PL-7+ patients had higher capillary dropout in biopsies of skeletal muscle. Aside from these subtle alterations, no significant differences between ASyS subgroups were observed. Interestingly, a tissue-specific subpopulation of CD138+ plasma cells and CXCL12+/CXCL13+CD20+ B cells common to ASyS myositis were identified. These cells were localized in the endomysium associated with alkaline phosphatase+ activated mesenchymal fibroblasts and CD68+MHC-II+CD169+ macrophages. An MHC-I+ and MHC-II+ MxA negative type II interferon-driven milieu of myofiber activation, topographically restricted to the perifascicular area and the adjacent perimysium, as well as perimysial clusters of T follicular helper cells defined an extra-medullary immunological niche for plasma cells and activated B cells. Consistent with this, proteomic analyses of muscle tissues from ASyS patients demonstrated alterations in antigen processing and presentation. In-depth immunological analyses of peripheral blood supported a B-cell/plasma-cell-driven pathology with a shift towards immature B cells, an increase of B-cell-related cytokines and chemokines, and activation of the complement system. We hypothesize that a B-cell-driven pathology with the presence and persistence of a specific subtype of plasma cells in the skeletal muscle is crucially involved in the self-perpetuating chronicity of ASyS myositis. This work provides the conceptual framework for the application of plasma-cell-targeting therapies in ASyS myositis.

Safety and survival of docetaxel and cabazitaxel in metastatic castration-resistant prostate cancer.

OBJECTIVES: To investigate real-world haematological toxicity, overall survival (OS) and the treatment characteristics of docetaxel and cabazitaxel chemotherapy in metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: This retrospective claims data study followed patients with mCRPC receiving cabazitaxel or docetaxel from their first chemotherapy infusion. Haematological toxicities were measured using treatment codes and inpatient diagnoses. OS was estimated using the Kaplan-Meier method. A multivariable Cox regression analysis was used to identify OS predictors. RESULTS: Data from 539 patients administered docetaxel and 240 administered cabazitaxel were analysed. Regarding adverse events, within 8 months of treatment initiation, some kind of treatment for haematological toxicity was documented in 31% of patients given docetaxel and in 61% of patients given cabazitaxel. In the same period, hospitalization associated with haematological toxicity was documented in 11% of the patients in the docetaxel cohort and in 15% of the patients in the cabazitaxel cohort. In the docetaxel cohort, 9.9% of patients required reverse isolation and 13% were diagnosed with sepsis during hospitalization. In the cabazitaxel cohort, the cumulative incidence was 7.9% and 15%, respectively. The median OS was reached at 21.9 months in the docetaxel cohort and, because of a later line of therapy, at 11.3 months in the cabazitaxel cohort. A multivariate Cox regression revealed that indicators of locally advanced and metastatic disease, severe comorbidities, and prior hormonal/cytotoxic therapies were independent predictors of early death. CONCLUSION: Cabazitaxel patients face an increased risk of haematological toxicities during treatment. Together with their short survival time, this calls for a strict indication when using cabazitaxel in patients with mCRPC.

Regional variation in coronary angiography rates: the association with supply factors and the role of indication: a spatial analysis.

BACKGROUND: Coronary angiographies (CAs) are among the most common diagnostic procedures carried out in German hospitals, and substantial regional differences in their frequency of use have been documented. Given the heterogeneity with regard to the expected benefits and the varying scope for discretion depending on the indication for the procedure, we hypothesized that the observed variation and the association of need and supply factors differs by indication for CA. METHODS: We investigated the correlation between supply factors and the regional rates of CAs in Germany while controlling for need using spatial-autoregressive error models (SARE) and spatial cross-regressive models with autoregressive errors (SCRARE). The overall rates of CAs and the rates in specific patient subgroups, namely, patients with and without myocardial infarction (MI), were calculated based on a comprehensive set of nationwide routine data from three statutory health insurances at the district level. RESULTS: Although little variation was found in cases with MI, considerable variation was seen in the overall cases and cases without MI. The SARE models revealed a positive association between the number of hospitals with a cardiac catheterization laboratory per 10,000 population and the rates of overall cases and cases without MI, whereas no such relationship existed in cases with MI. Additionally, an association between regional deprivation and the rates of CAs was found in cases with MI, but no such association was seen in cases without MI. CONCLUSIONS: The results supported the hypothesis that the relative association of need and supply factors differed by the indication for CA. Although the regional differences in the frequency of use of CAs can only be explained in part by the factors examined in our study, it offers insight into patient access to and the provision of CA services and can provide a platform for further local research.

[Weighing the benefits and harms of psychotropic and analgesic substances - A perspective of German addiction medicine experts]. / Abwägung von Nutzen und Schädlichkeit von berauschenden und schmerzlindernden Substanzen aus der Perspektive von deutschen Suchtmedizinern.

BACKGROUND: In Europe, there have been several addiction-expert rankings of harms related to the use of psychotropic substances in the last 15 years. Among them, only one expert ranking took into account the potential benefits of these drugs. Non-Opioidergic Analgesics (NOAs), such as gabapentinoids and NSAIDs, which have been increasingly the subject of abuse / misuse reports, have not been considered in such expert rankings. Likewise, there is currently no multi-substance comparison as to whether the valuation rank of the harmfulness of an illegal drug may change along with an imagined change in legal status in Germany. OBJECTIVES AND METHODS: Using a questionnaire, 101 experienced addiction physicians (first cohort) evaluated 33 psychoactive substances including analgesics with regard to their health and social harms as well as potential usefulness for the consumer and their environment / society ('others'). In addition, this cohort investigated whether the harmfulness assessment of an illegal substance changes if it would be legalized. In order to obtain the average overall harmfulness (overall risk) of a substance, the percentage contribution of each dimension to the overall harmfulness was determined in a second survey (second cohort, 36 experienced addiction medicine experts). Finally, the average benefit and overall risk ratings of each substance were related to each other. RESULTS: Prescription psychoactive substances such as analgesics, NOAs (including gabapentinoids) and opioidergic maintenance medications to treat opiate dependence were judged to have a favorable benefit-harm profile. Cannabis and ketamine were placed in the midfield of both, the harm and benefit rankings. Together with most illicit narcotic drugs, alcohol and nicotine, have been ranked among the most harmful and least useful substances, whereby alcohol was judged on average to be more harmful but also more useful than nicotine. In the event of potential legalization, the overall harm of the traditional illegal drugs methamphetamine, heroin, cocaine and cannabis was estimated to be reduced. This was mainly due to a more favorable valuation of the harm to others under these virtual conditions. CONCLUSION: Prescription substances including opioidergic and non-opioidergic analgesics as well as opioid maintenance therapy medications (methadone and buprenorphine) were assigned a favorable benefit-harm profile. Alcohol, nicotine and traditional illicit drugs (with the exception of cannabis and ketamine) were determined to have an unfavorable profile. The overall harm of traditional illicit drugs was assessed to decrease along with legalization, mainly by decreasing the harm to others in this virtual event.

Systemic sclerosis-associated myositis features minimal inflammation and characteristic capillary pathology.

Systemic sclerosis represents a chronic connective tissue disease featuring fibrosis, vasculopathy and autoimmunity, affecting skin, multiple internal organs, and skeletal muscles. The vasculopathy is considered obliterative, but its pathogenesis is still poorly understood. This may partially be due to limitations of conventional transmission electron microscopy previously being conducted only in single patients. The aim of our study was therefore to precisely characterize immune inflammatory features and capillary morphology of systemic sclerosis patients suffering from muscle weakness. In this study, we identified 18 individuals who underwent muscle biopsy because of muscle weakness and myalgia in a cohort of 367 systemic sclerosis patients. We performed detailed conventional and immunohistochemical analysis and large-scale electron microscopy by digitizing entire sections for in-depth ultrastructural analysis. Muscle biopsies of 12 of these 18 patients (67%) presented minimal features of myositis but clear capillary alteration, which we termed minimal myositis with capillary pathology (MMCP). Our study provides novel findings in systemic sclerosis-associated myositis. First, we identified a characteristic and specific morphological pattern termed MMCP in 67% of the cases, while the other 33% feature alterations characteristic of other overlap syndromes. This is also reflected by a relatively homogeneous clinical picture among MMCP patients. They have milder disease with little muscle weakness and a low prevalence of interstitial lung disease (20%) and diffuse skin involvement (10%) and no cases of either pulmonary arterial hypertension or renal crisis. Second, large-scale electron microscopy, introducing a new level of precision in ultrastructural analysis, revealed a characteristic capillary morphology with basement membrane thickening and reduplications, endothelial activation and pericyte proliferation. We provide open-access pan-and-zoom analysis to our datasets, enabling critical discussion and data mining. We clearly highlight characteristic capillary pathology in skeletal muscles of systemic sclerosis patients.