School Well-Being and Academic Performance of Children With Juvenile Idiopathic Arthritis: A National Register-Based Study.

OBJECTIVE: We aimed to investigate how school well-being (SWB) and academic performance of children with juvenile idiopathic arthritis (JIA) compare to their peers on a national level using the Danish national registers. Further, we investigated the potential influence of socioeconomic status (SES). METHODS: A population-wide, register-based, cross-sectional study was performed. We compared the results of children with and without JIA in the Danish National Well-Being Questionnaire (DNWQ), the National Danish School Testing (NDST), and their ninth grade (aged approximately 16 yrs) final school marks in Danish and mathematics. The results were analyzed using adjusted ordinal logistic regression (SWB) and linear regression (tests and marks). RESULTS: In separate cohorts, we included a total of 505,340 children answering the DNWQ, 812,461 children with NDST results, and the ninth-grade final marks of 581,804 children. Of these children, 1042, 1541, and 1410, respectively, fulfilled the criteria of JIA. Children with JIA reported SWB comparable to their peers, except for the question "Do you perform well in school?" (odds ratio 0.89, 95% CI 0.81-0.99). In the NDST, the children with JIA in general did just as well as their peers. We found no differences in the ninth-grade final marks in either Danish or mathematics. Stratifying the analyses on SES showed no significant differences in the associations. CONCLUSION: Overall, children with JIA report SWB comparable to that of children without JIA and perform equally well in school as children without JIA.

Toll-like receptor 2, hyaluronan, and neutrophils play a key role in plaque erosion: the OPTICO-ACS study.

BACKGROUND AND AIMS: In one-third of patients with acute coronary syndrome (ACS), thrombosis occurs despite an intact fibrous cap (IFC) (IFC-ACS, 'plaque erosion'). Recent studies emphasize neutrophils as the immediate inflammatory response in this pathology, but their exact molecular activation patterns are still poorly understood and may represent future therapeutic targets. METHODS AND RESULTS: Thirty-two patients with IFC-ACS and matched patients with ACS with ruptured fibrous cap (RFC) (RFC-ACS) from the OPTICO-ACS study were included, and blood samples were collected from the local site of the culprit lesion and the systemic circulation. Neutrophil surface marker expression was quantified by flow cytometry. Neutrophil cytotoxicity towards endothelial cells was examined in an ex vivo co-culture assay. Secretion of active matrix metalloproteinase 9 (MMP9) by neutrophils was evaluated using zymography in supernatants and in plasma samples. Optical coherence tomography (OCT)-embedded thrombi were used for immunofluorescence analysis. Toll-like receptor 2 (TLR2) expression was higher on neutrophils from IFC-ACS than RFC-ACS patients. TLR2 stimulation increased the release of active MMP9 from local IFC-ACS-derived neutrophils, which also aggravated endothelial cell death independently of TLR2. Thrombi of IFC-ACS patients exhibited more hyaluronidase 2 with concomitant increase in local plasma levels of the TLR2 ligand: hyaluronic acid. CONCLUSION: The current study provides first in-human evidence for distinct TLR2-mediated neutrophil activation in IFC-ACS, presumably triggered by elevated soluble hyaluronic acid. Together with disturbed flow conditions, neutrophil-released MMP9 might be promoting endothelial cell loss-triggered thrombosis and therefore providing a potential future target for a phenotype-specific secondary therapeutic approach in IFC-ACS.

Culprit plaque morphology determines inflammatory risk and clinical outcomes in acute coronary syndrome.

AIMS: Rupture of the fibrous cap (RFC) and erosion of an intact fibrous cap (IFC) are the two predominant mechanisms causing acute coronary syndromes (ACS). It is uncertain whether clinical outcomes are different following RFC-ACS vs. IFC-ACS and whether this is affected by a specific inflammatory response. The prospective, translational OPTIcal-COherence Tomography in Acute Coronary Syndrome study programme investigates the impact of the culprit lesion phenotype on inflammatory profiles and prognosis in ACS patients. METHODS AND RESULTS: This analysis included 398 consecutive ACS patients, of which 62% had RFC-ACS and 25% had IFC-ACS. The primary endpoint was a composite of cardiac death, recurrent ACS, hospitalization for unstable angina, and target vessel revascularization at 2 years [major adverse cardiovascular events (MACE+)]. Inflammatory profiling was performed at baseline and after 90 days. Patients with IFC-ACS had lower rates of MACE+ than those with RFC-ACS (14.3% vs. 26.7%, P = 0.02). In 368-plex proteomic analyses, patients with IFC-ACS showed lower inflammatory proteome expression compared with those with RFC-ACS, including interleukin-6 and proteins associated with the response to interleukin-1ß. Circulating plasma levels of interleukin-1ß decreased from baseline to 3 months following IFC-ACS (P < 0.001) but remained stable following RFC-ACS (P = 0.25). Interleukin-6 levels decreased in patients with RFC-ACS free of MACE+ (P = 0.01) but persisted high in those with MACE+. CONCLUSION: This study demonstrates a distinct inflammatory response and a lower risk of MACE+ following IFC-ACS. These findings advance our understanding of inflammatory cascades associated with different mechanisms of plaque disruption and provide hypothesis generating data for personalized anti-inflammatory therapeutic allocation to ACS patients, a strategy that merits evaluation in future clinical trials.

Improvement of humoral immunity by repeated dose-intensified COVID-19 vaccinations in primary non- to low-responders and B cell deficient rheumatic disease patients.

OBJECTIVE: To determine whether repeated, dose-intensified mRNA vaccinations against COVID-19 increase humoral immunity in previously low-responding patients with autoimmune rheumatic diseases (AIRD), including rituximab-treated and B cell depleted patients. METHODS: Of 308 AIRD patients receiving basic immunization, 98 had a low serological response against SARS-CoV-2 with a neutralizing capacity of < 70% using surrogate neutralization assay. 38 patients received a third vaccination with 30 µg BNT162b2 16 weeks after second vaccination. If neutralizing serum capacity was below 70% four weeks after the last vaccination, then the fourth vaccination (n = 19) and the fifth (n = 4) vaccination with 100 µg mRNA-1273 took place eight weeks after the last vaccination. RESULTS: Each of the three booster vaccinations resulted in a significant increase of mean serum neutralizing capacity (3rd: Δ = 42%, p < 0.001; 4th: Δ = 19%, p = 0.049 and 5th: Δ = 51%, p = 0.043) and produced a significant proportion of high-responders (3rd: 34%; 4th: 32% and 5th: 75%). Low B cell counts (p = 0.047), lower previous antibody response (p < 0.001) and rituximab therapy (p = 0.021) were negatively associated with successful response to the third but not to the fourth vaccination. Remarkably, substantial increases in neutralization capacity of up to 99% were observed after repeated vaccinations in B cell depleted patients. CONCLUSION: AIRD patients with low humoral response benefited from up to three repeated dose-intensified mRNA booster vaccinations - despite low B cell count and previous rituximab therapy. Each additional vaccination substantially reduced the number of low-responding, vulnerable patients.

Biologics with or without methotrexate in treatment of polyarticular juvenile idiopathic arthritis: effectiveness, safety and drug survival.

OBJECTIVE: To investigate the impact of additionally given MTX on biologic treatment of polyarticular JIA in terms of effectiveness, safety and drug survival. METHODS: Patients suffering from polyarticular JIA and treated with either monotherapy with a first biologic or a combination of a biologic and MTX were selected from the BIKER registry. The TNF-α inhibitors (TNFi) adalimumab, etanercept and golimumab and the IL-6 inhibitor tocilizumab were considered. Upon a non-randomized study design, we adjusted the different cohorts using propensity score matching to improve comparability. RESULTS: A total of 2148 patients entered the analysis, who were treated by either combination therapy (n = 1464) or monotherapy (n = 684). Disease activity declined significantly more in patients upon combination therapy than upon biologic monotherapy. Comparison of adjusted cohorts revealed that patients who received TNFi gained more benefit from additionally given MTX than patients treated with tocilizumab. Median survival time of therapy with biologics was significantly longer upon combination therapy (3.1 years) than with monotherapy (2.7 years), as demonstrated by a Kaplan-Meier analysis (log rank test: P = 0.002). The safety profile was moderately affected by additional MTX due to increased incidence of gastrointestinal and hepatic adverse events. Serious adverse events occurred at an equal rate of 3.6 events per 100 patient-years in both cohorts. CONCLUSION: Additionally given MTX improves the effectiveness of biologic treatment in polyarticular JIA without seriously compromising treatment safety. Especially TNFi benefit from combination, while no improvement in outcome has been observed by combining tocilizumab with MTX.

Determinants of Late Venous Thromboembolic Events After Acute Isolated Superficial Vein Thrombosis in Daily Practice: 12 Month Results of the INSIGHTS-SVT Study.

OBJECTIVE: Long term incidence of symptomatic venous thromboembolism (VTE) and bleeding events in patients with superficial vein thrombosis (SVT) was investigated. METHODS: In this prospective, observational study, patients with acute SVT were treated at the discretion of the responsible physician. The primary efficacy outcome was symptomatic VTE including deep vein thrombosis (DVT), pulmonary embolism (PE), and recurrent or extending SVT. The primary safety outcome was clinically relevant bleeding, recorded at periodic clinic visits over a 12 month period. RESULTS: The mean age of 872 patients with 12 month follow up was 60.6 ± 14.5 years, 64.5% were female, 80.1% had chronic venous disease (defined as chronic venous insufficiency and or varicose veins), and 41.9% had a history of VTE. They were receiving fondaparinux in 62.1% (mean duration 34.9 ± 15.7 days), low molecular weight heparin (LMWH) in 25.0% (mean duration 26.2 ± 23.2 days), any other anticoagulants in 6.2%, and no anticoagulant in 6.7%. At 12 months, 108 patients (14.3%) achieved the primary efficacy outcome. The most common VTE event was recurrent or extending SVT in 11.0%, followed by symptomatic DVT in 2.7%, symptomatic PE in 2.4%, hospitalisation due to VTE in 1.8%, and death in 1.1%. Clinically relevant bleeding events occurred in 2.1% of patients, and major bleedings in 0.3%. By drug, the rate of the primary efficacy outcome was highest in the LMWH group (22.4%) and lowest in the fondaparinux group (10.4%). In a multivariable model, patients with events between three months and 12 months were significantly more likely to have higher BMI (hazard ratio [HR] 1.06; p = .002), history of VTE (HR 2.89; p = .002), and severe systemic infections (HR 7.59; p = .006). CONCLUSION: The risk of symptomatic VTE remained elevated over 12 months of follow up. Therefore, anticoagulation beyond 45 days may be considered in patients with risk factors. [ClinicalTrials.gov identifier: NCT02699151.].

Investigating significant health trends in progressive fibrosing interstitial lung disease (INSIGHTS-ILD): rationale, aims and design of a nationwide prospective registry.

BACKGROUND: The progressive course of pulmonary fibrosis (PPF) is observed with variable prevalence in different entities of fibrosing interstitial lung disease (fILD). PPF is characterised by worsening respiratory symptoms, declining lung function and increasing extent of fibrosis on high-resolution computer tomography. In Germany, data are limited on the characteristics and management of such patients. METHODS/DESIGN: INSIGHTS-ILD is a prospective observational longitudinal registry designed to describe characteristics, management and course of newly diagnosed (incident) and prevalent patients with fILD on the long term. The registry uses a non-probability sampling approach to collect data on characteristics, therapeutic interventions, health-related quality of life and health economic parameters. It is planned to include 900 patients in ambulatory care in about 30 expert sites over three years. The study has been initiated in December 2021, and currently (January 2023) follows 360 patients. DISCUSSION: The registry is expected to provide much-needed data on the characteristics, management, and trajectories of patients fILD in Germany. The start of the study comes at a time when new treatment options are available for PPF. We hypothesize that PPF represents a broad clinical phenotype that is differentially influenced by inflammatory and fibrotic pathomechanisms that need to be treated with anti-inflammatory and/or anti-fibrotic treatment strategies. This registry will allow comparisons with other countries. Gap analyses based on current guidelines for management of these patients will be possible. Trial registration DRKS00027389 (registered on 7.12.2021), BfArM NIS 7562.

Fc N-glycosylation of autoreactive Aß antibodies as a blood-based biomarker for Alzheimer's disease.

INTRODUCTION: Naturally occurring autoantibodies (nAbs) against the pathologic isoform of amyloid beta (Aß42 ) were found in body fluids and indicate a systemic B cell response that may prevent Alzheimer's disease (AD) onset. N-glycans attached to immunoglobulin G-Fab/Fc fragments are features that influence their mechanism of action. The aim was to study the role of N-glycans in nAbs-Aß42 . METHODS: nAbs-Aß42 were isolated from AD patients and age-/sex-matched controls (n = 40) and immunoglobulin preparations. Glycosylated/deglycosylated nAbs-Aß42 were analyzed for their effect on Aß42 's aggregation, toxicity, and phagocytosis. Glycan structure was analyzed using matrix assisted laser desorption ionization time of flight mass spectrometry. RESULTS: Deglycosylation of nAbs-Aß42 had a major impact on Aß42 's aggregation/toxicity/phagocytosis. The glycan structure showed considerable differences between AD and controls. We were able to predict disease status with a sensitivity/specificity of 95% (confidence interval [CI]: 76.4-99.7%)/100% (CI: 83.9-100%). DISCUSSION: N-glycosylation has been identified as a critical attribute maintaining the beneficial effects of autoreactive Aß antibodies. These data have consequences for the development of monocloncal Aß antibodies and may open new avenues for diagnostics.

Characterizing the individual course of health-related quality of life after subarachnoid haemorrhage: Latent growth mixture modelling.

BACKGROUND: Survivors of aneurysmal subarachnoid haemorrhage (SAH) show heterogeneous profiles of health-related quality of life (HrQoL). The aim of this study was to characterize individual differences in the course of HrQoL following SAH using latent growth mixture modelling (LGMM). METHODS: A longitudinal study with 113 incident cases of aneurysmal SAH was performed in order to evaluate clinical outcome (Hunt and Hess scale, Barthel-Index, Beck Depression Inventory) and HrQoL data (EQ-5D) at baseline, 6 and 12 months. The heterogeneity in HrQoL courses after SAH was analysed using LGMM. RESULTS: Four subgroups (classes) of different patterns of HrQoL course after SAH were identified. Two of these classes (1 and 3) comprised patients with considerably reduced initial HrQoL, which was associated with more severe symptoms of SAH. Class 1 showing the worst EQ5D-index values during the entire study period. Class 3 experiencing a considerable improvement in HrQoL values. In comparison to classes 1 and 3, class 2 and 4 were characterized by less severe SAH and better functional outcome. An important difference in the disease course between classes 2 and 4 was a temporary increase in depression scores at the 6-month time point in class 4, which was associated with a considerable reduction in HrQoL.The specific clinical parameters characterizing differences between classes, such as severity of SAH, functional outcome, cognitive impairment and post-stroke depression, were identified and the influence of their potential improvement on HrQoL was estimated. CONCLUSION: By means of LGMM we could classify the course of HrQoL after SAH in four different patterns, which are relevant for the clinical decisions. Clinical parameters, which can be modified in order to improve the course of HrQoL were identified and could help to develop individual therapeutic strategies for the rehabilitation after SAH.

Pausing methotrexate improves immunogenicity of COVID-19 vaccination in elderly patients with rheumatic diseases.

OBJECTIVE: To study the effect of methotrexate (MTX) and its discontinuation on the humoral immune response after COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD). METHODS: In this retrospective study, neutralising SARS-CoV-2 antibodies were measured after second vaccination in 64 patients with AIRD on MTX therapy, 31 of whom temporarily paused medication without a fixed regimen. The control group consisted of 21 patients with AIRD without immunosuppressive medication. RESULTS: Patients on MTX showed a significantly lower mean antibody response compared with patients with AIRD without immunosuppressive therapy (71.8% vs 92.4%, p<0.001). For patients taking MTX, age correlated negatively with immune response (r=-0.49; p<0.001). All nine patients with antibody levels below the cut-off were older than 60 years. Patients who held MTX during at least one vaccination showed significantly higher mean neutralising antibody levels after second vaccination, compared with patients who continued MTX therapy during both vaccinations (83.1% vs 61.2%, p=0.001). This effect was particularly pronounced in patients older than 60 years (80.8% vs 51.9%, p=0.001). The impact of the time period after vaccination was greater than of the time before vaccination with the critical cut-off being 10 days. CONCLUSION: MTX reduces the immunogenicity of SARS-CoV-2 vaccination in an age-dependent manner. Our data further suggest that holding MTX for at least 10 days after vaccination significantly improves the antibody response in patients over 60 years of age.

Soluble interleukin-2 receptor serum levels facilitate prediction of relapses in subgroups of patients with juvenile idiopathic arthritis.

OBJECTIVES: JIA is characterised by a chronic disease course. Once patients achieve a state of inactive disease, there are no established biomarkers to predict the further course of inflammation for these patients. Therefore, the purpose of this study was to quantify serum biomarkers during quiescent disease to evaluate their use in identifying JIA patients at risk for future disease flare. METHODS: Patients with non-systemic JIA reaching inactive disease status were divided into two groups: 92 patients with future active disease after a median period of 6 months (range 3-9) and 80 patients with persistent inactive disease for the following period (median 11 months, range 7-16) according to the juvenile arthritis DAS (JADAS). Clinical parameters and serum levels of various biomarkers were measured in the state of inactive disease using immunoassays in both groups and were analysed for their potential to predict the further course of disease. RESULTS: Soluble interleukin-2 receptor (sIL-2R) serum levels were significantly higher in patients with future active disease (P = 0.021), which especially applied to patients with RF-negative polyarticular and extended oligoarticular JIA (P < 0.001). Higher sIL-2R serum levels during inactive disease were associated with a greater number of active joints at future active disease. CONCLUSION: Patients without clinical signs of disease activity already presented with increased sIL-2R serum levels several months before disease relapses, whereas conventional inflammation parameters were not elevated. Determination of sIL-2R serum levels during inactive disease may facilitate identifying patients with subclinical disease activity at risk for future active disease.

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.

Burden of comorbid conditions in children and young people with juvenile idiopathic arthritis: a collaborative analysis of 3 JIA registries.

OBJECTIVES: Burden of comorbidities are largely unknown in JIA. From 2000, national and international patient registries were established to monitor biologic treatment, disease activity and adverse events in patients with JIA. The aim of this analysis was to investigate in parallel, for the first time, three of the largest JIA registries in Europe/internationally-UK JIA Biologic Registers (BCRD/BSPAR-ETN), German biologic registers (BiKeR/JuMBO), multinational Pharmachild-to quantify the occurrence of selected comorbidities in patients with JIA. METHODS: Information on which data the registers collect were compared. Patient characteristics and levels of comorbidity were presented, focussing on four key conditions: uveitis, MAS, varicella, and history of tuberculosis. Incidence rates of these on MTX/biologic therapy were determined. RESULTS: 8066 patients were registered into the three JIA registers with similar history of the four comorbidities across the studies; however, varicella vaccination coverage was higher in Germany (56%) vs UK/Pharmachild (16%/13%). At final follow-up, prevalence of varicella infection was lower in Germany (15%) vs UK/Pharmachild (37%/50%). Prevalence of TB (0.1-1.8%) and uveitis (15-19%) was similar across all registers. The proportion of systemic-JIA patients who ever had MAS was lower in Germany (6%) vs UK (15%) and Pharmachild (17%). CONCLUSION: This analysis is the first and largest to investigate the occurrence of four important comorbidities in three JIA registries in Europe and the role of anti-rheumatic drugs. Combined, these three registries represent one of the biggest collection of cases of JIA worldwide and offer a unique setting for future JIA outcome studies.

Secukinumab in the treatment for patients with juvenile enthesitis related arthritis non-responsive to anti-TNF treatment according the Juvenile Spondyloarthritis Disease Activity Index.

OBJECTIVES: To review the effectiveness of secukinumab (SEC) in patients with juvenile idiopathic enthesitis related arthritis (ERA), who had partial or no response on anti-TNF therapy. METHODS: We conducted a retrospective monocentric chart review of patients with ERA, who were treated with SEC, until March 15th 2019. We used the JADAS10 and the Juvenile Spondyloarthritis Disease Activity Index (jspADA) to evaluate response. We analysed the onset of AE and SAE. RESULTS: We analysed 17 patients with ERA. The mean age at the start of the treatment was 19.5 years (SD 4.9, range 13-34 years, median 18.2). The mean disease duration was 6.3 years (SD 3.3, range 2-12 years). The patients received in average 1.9 (SD1.0) different anti-TNF'́s before switching to SEC. SEC was applied at the start of the treatment with 150 mg per dose (n=13, 76.5%) and 300 mg per dose (n=4, 23.5%). The dose of 150 mg was increased in 11 patients (85% of 13) after baseline. The mean follow-up of patients was 18.2 months (SD 7.2) accounting to 25.8 years under exposure to SEC. The jspADA (mean change of -1.3; p<0.001; 95%CI: -1.9 to -0.7) and JADAS10 (mean change of -2.4; p=0.021; 95%CI: -4.5 to -0.4) signi cantly improved between baseline and the 24-month follow-up. There was no serious adverse event observed. CONCLUSIONS: In our anti-TNF non-responder patients SEC showed good effectiveness. The 150 mg dose seems to be insufficient in anti-TNF non-responder patients and most patients had to be escalated to the 300 mg/dose.

Myositis-specific autoantibodies and their associated phenotypes in juvenile dermatomyositis: data from a German cohort.

OBJECTIVES: To describe a German cohort of patients with juvenile dermatomyositis (JDM) and to evaluate clinical manifestations, disease course and prognosis in JDM patients with a certain myositis-specific autoantibody. METHODS: Cross-sectional data on patients with JDM documented in the National Paediatric Rheumatologic Database in Germany between 2014 and 2016 were analysed. In a subgroup of the cohort, MSAs were determined with a commercial multiplex array, and a retrospective chart review was conducted to specify the clinical phenotype and patient outcome. RESULTS: The total cohort consisted of 196 patients with JDM (mean age 12.2±4.0 years, mean disease duration 5.1±3.8 years, 70% female). Apart from typical skin changes and muscle weakness, 41% of patients also had arthritis and/or contractures, 27% had calcinosis and approximately 10% had interstitial lung disease. Immunoblot testing was performed on the sera of 91 (46%) patients, detecting MSAs in 44% of patients. Patient groups with specific MSAs differed in clinical characteristics such as calcinosis, dysphagia, and lung and joint involvement. The extent of muscle weakness evaluated by the Childhood Myositis Assessment Scale was significantly associated with an increased level of creatine kinase. Patients with anti-MDA5 were particularly affected by polyarthritis of the small joints. After 5 years, 51 patients of the MSA cohort (56.0%) achieved an inactive disease state, 12/51 (23.5%) were off therapy. CONCLUSIONS: Patients with JDM in Germany show a broad spectrum of clinical manifestations that can be grouped into homogeneous groups using MSA, which also helps to predict the course and prognosis of the disease.

Novel Insights into the Management of Patients with Very High Cardiovascular Risk Eligible for PCSK9 Inhibitor Treatment: Baseline Findings from the PERI-DYS Study.

AIM: The PERI-DYS study aims to characterize two groups of patients with dyslipidaemia at very high CV risk: PCSK9i receivers and patients qualifying for but not receiving PCSK9i. METHODS: This is an observational study by office-based and clinic-based physicians, mainly cardiologists and other internists in Germany, with data extracted from patient charts. CLINICALTRIALS: gov identifier NCT03110432. RESULTS: A total of 1659 patients were enrolled across 70 sites. The majority of patients (91.0%) were reported as having mixed dyslipidaemia or non-familial or heterozygous familial hypercholesterolemia. At enrolment, 794 (47.9%) of patients were PCSK9i receivers (of these 65.9% ongoing, and 34.1% newly treated within 30 days before their baseline visit). Among PCSK9i receivers, the majority had evolocumab 140 mg (n = 632, 38.1% of total). PCSK9i receivers compared to non-receivers were about 2 years younger and had a lower proportion of males. In terms of comorbidities, they had (statistically significantly) more often CAD, and less often PAD, diabetes mellitus, arterial hypertension and chronic renal disease. The calculated untreated median LDL-C was 187 mg/dl (IQR 127; 270) in ongoing PCSK9i receivers, 212 mg/dl (IQR 132; 277) in newly treated PCSK9i receivers, and 179 mg/dl (IQR 129; 257) in non-receivers. Physician-reported statin intolerance was much more common in the two PCSK9i receiver groups as compared to non-receivers (67.3% versus 15.3%). Consequently, patients in the PCSK9i groups received fewer concomitant statins. Mean total cholesterol (143 vs. 172 mg/dl) and LDL-C (69 vs. 99 mg/dl) were considerably lower in ongoing PCSK9i receivers compared to non-receivers. CONCLUSIONS: PCSK9i receivers are characterized by higher baseline LDL-C and a higher portion of statin intolerance compared to those qualified for but not-receiving PCSK9i treatment. On-treatment, LDL-C was lower in PCSK9i receivers. Ongoing follow-up will determine the prognostic importance of these findings.

Selective depletion of plasma cells in vivo based on the specificity of their secreted antibodies.

Antibody-mediated diseases affect more than 10% of the human population. For most, no cure is available, particularly when the pathogenic antibodies are secreted by long-lived plasma cells resistant to conventional immunosuppressive therapies. Current therapeutic approaches target not only the plasma cells that secrete pathogenic antibodies, but also those providing protective antibodies. Here, in a murine model bearing long-lived plasma cells secreting anti-OVA and -chicken gamma globulin (CGG) antibodies, we describe the first-time use of an antigen-antibody (OVA/anti-CD138 antibody) conjugate for in vivo labeling and selective ablation of plasma cells that secrete antibodies specific for the antigen OVA. The selective depletion also led to a stable reduction of the corresponding serum anti-OVA antibody levels. In contrast, CGG-specific plasma cells and circulating anti-CGG antibody levels remained unchanged. The method described here should enable the development of unique causative treatment strategies for established antibody-mediated diseases sparing humoral immunity.

Management and Outcomes of Patients with Isolated Superficial Vein Thrombosis under Real Life Conditions (INSIGHTS-SVT).

OBJECTIVE: Management and outcomes of superficial vein thrombosis (SVT) are highly variable and not well described. Therefore, the INvestigating SIGnificant Health TrendS in the management of SVT (INSIGHTS-SVT) study collected prospective data under real life conditions. METHODS: Prospective observational study of objectively confirmed acute isolated SVT. The primary outcome was a composite of symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), and extension or recurrence of SVT at three months. The primary safety outcome was clinically relevant bleeding. RESULTS: A total of 1 150 patients were included (mean age 60.2 ± 14.7 years; 64.9% women; mean BMI 29.4 ± 6.3 kg/m2). SVT was below the knee in 54.5%, above the knee in 26.7%, above and below the knee in 18.8%. At baseline, 93.6% received pharmacological treatment (65.7% fondaparinux, 23.2% heparins, 4.3% direct oral anticoagulants [DOACs], 14.5% analgesics), 77.0% compression treatment, and 1.9% surgery; 6.4% did not receive any anticoagulation. The primary outcome occurred in 5.8%; 4.7% had recurrent or extended SVT, 1.7% DVT, and 0.8% PE. Clinically relevant non-major bleeding occurred in 1.2% and major bleeding in 0.3%. Complete clinical recovery of SVT was reported in 708 patients (62.4%). Primary outcome adjusted by propensity score and for treatment duration was lower with fondaparinux compared with low molecular weight heparin (4.4% vs. 9.6%; hazard ratio [HR] 0.51; 95% confidence interval [CI] 0.3 - 0.9; p = .017). On multivariable analysis, associated factors for primary outcome included another SVT prior to the present SVT event (HR 2.3), age per year (HR 0.97), duration of drug treatment per week (HR 0.92), and thrombus length (HR 1.03). CONCLUSION: At three month follow up, patients with isolated SVT are at risk of thromboembolic complications (mainly recurrent or extended SVT), despite anticoagulation. In this real life study, about one third had received either heparins, oral anticoagulants, or no anticoagulation.

Consumer perspective on healthcare services for juvenile idiopathic arthritis: results of a multicentre JIA inception cohort study.

OBJECTIVES: To evaluate healthcare services for patients with juvenile idiopathic arthritis (JIA) from the parent-proxy perspective and to identify factors associated with perceived deficits in care. METHODS: Patients with JIA from 11 paediatric rheumatology units were enrolled in an inception cohort within the first 12 months after diagnosis. Healthcare services were assessed using The Child Healthcare Questionnaire on satisfaction, utilisation and needs. Factors associated with deficits in care were identified by logistic regression analysis. RESULTS: Data from parents of 835 JIA-patients were included in the analysis. At the assessment (4.7 months after diagnosis), 85% of the patients received drug treatment, and 50% had received multi-professional care. The most frequently used services were physiotherapy (84%), occupational therapy (23%), and telephone counselling (17%). Almost one-third of families reported that they had not received the services that they needed, with health education being the most frequently reported need. Most parents (93%) were satisfied with the overall healthcare provided for their children, especially regarding doctors' behaviour. However, approximately 1 in 3 consumers were dissatisfied with the time to JIA diagnosis and the school services. The lower the child's quality of life, the higher the chance was that the child and the family received multi-professional care, perceived unmet needs, and were dissatisfied with care. CONCLUSIONS: According to parents' experience and satisfaction with their child's care, performance at the system level can be further improved by diagnosing JIA earlier, providing additional information at disease onset, and ensuring that the child's social environment is taken into account.

The spatiotemporal movement of patients in and out of a psychiatric hospital: an observational GPS study.

BACKGROUND: Movement is a basic component of health. Little is known about the spatiotemporal movement of patients with mental disorders. The aim of this study was to determine how spatiotemporal movement of patients related to their symptoms and wellbeing. METHOD: A total of 106 patients (inpatients (n = 69) and outpatients (n = 37)) treated for a wide range of mental disorders (transdiagnostic sample) carried a GPS-enabled smartphone for one week at the beginning of treatment. Algorithms were applied to establish spatiotemporal clusters and subsequently related to known characteristics of these groups (i.e., at the hospital, at home). Symptomatology, Wellbeing, and Psychological flexibility were also assessed. RESULTS: Spatiotemporal patterns of inpatients and outpatients showed differences consistent with predictions (e.g., outpatients showed higher active areas). These patterns were largely unassociated with symptoms (except for agoraphobic symptoms). Greater movement and variety of movement were more predictive of wellbeing, however, in both inpatients and outpatients. CONCLUSION: Measuring spatiotemporal patterns is feasible, predictive of wellbeing, and may be a marker of patient functioning. Ethical issues of collecting GPS data are discussed.