Citations

Abstract Objective To determine COVID-19 vaccine-related adverse events (AEs) in the seven-day post-vaccination period in patients with SLE vs autoimmune rheumatic diseases (AIRDs), non-rheumatic autoimmune diseases (nrAIDs), and healthy controls (HC). Methods Data were captured through the COVID-19 Vaccination in Autoimmune Diseases (COVAD) questionnaire (March–December 2021). Multivariable regression models accounted for age, gender, ethnicity, vaccine type and background treatment. Results Among 9462 complete respondents, 583 (6.2%) were SLE patients (mean age: 40.1 years; 94.5% females; 40.5% Asian; 42.9% Pfizer-recipients). Minor AEs were reported by 83.0% of SLE patients, major by 2.6%, hospitalization by 0.2%. AE and hospitalization frequencies were similar between patients with active and inactive SLE. Rashes were more frequent in SLE patients vs HC (OR; 95% CI: 1.2; 1.0, 1.5), chills less frequent in SLE vs AIRDs (0.6; 0.4, 0.8) and nrAIDs (0.5; 0.3, 0.8), and fatigue less frequent in SLE vs nrAIDs (0.6; 0.4, 0.9). Pfizer-recipients reported higher overall AE (2.2; 1.1, 4.2) and injection site pain (2.9; 1.6, 5.0) frequencies than recipients of other vaccines, Oxford/AstraZeneca-recipients more body ache, fever, chills (OR: 2.5, 3.0), Moderna-recipients more body ache, fever, chills, rashes (OR: 2.6, 4.3). Hospitalization frequencies were similar across vaccine types. AE frequencies were similar across treatment groups, although chills were less frequent in antimalarial users vs non-users (0.5; 0.3, 0.9). Conclusion While COVID-19 vaccination-related AEs were reported by four-fifths of SLE patients, those were mostly minor and comparable to AEs reported by healthy individuals, providing reassurance regarding COVID-19 vaccination safety in SLE.

Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC’s inaugural meetings are presented herein.

Abstract Objectives The COVID-19 vaccination in autoimmune diseases (COVAD) study aimed to assess short-term COVID-19 vaccination-related adverse events (AEs) in RA patients. Methods An online self-reported questionnaire (March–December 2021) was used to capture data related to COVID-19 vaccination-related AEs in RA, other autoimmune rheumatic diseases (AIRDs) (excluding RA and inflammatory myositis), non-rheumatic autoimmune diseases (nrAIDs) and healthy controls (HCs). Descriptive and multivariable regression analyses were performed. Results Of the 9462 complete respondents, 14.2% (n = 1347) had been diagnosed with RA; they had a mean (s.d.) age of 50.7 (13.7) years, 74.2% were women and 49.3% were Caucasian. In total, 76.9% and 4.2% of patients with RA reported minor and major AEs, respectively. Patients with active and inactive RA had similar AE and hospitalization frequencies. Overall, AEs were reported more frequently by BNT162b2 and mRNA-1273 recipients and less frequently by BBV152 recipients compared with the rest. Major AE and hospitalization frequencies were similar across recipients of different vaccines. Patients receiving methotrexate and hydroxychloroquine reported fewer minor AEs than those patients not on them. Compared with HCs and patients with other AIRDs, patients with RA reported similar total AEs, overall minor AEs, and hospitalizations. Compared with nrAIDs, patients with RA reported lower frequencies of overall AEs, minor AEs (both odds ratio [OR] = 0.7; 95% CI: 0.5, 0.9), and injection site pain (OR = 0.6; 95% CI: 0.5, 0.8) with similar major AE and hospitalization frequencies. Conclusion Despite the differences in AE frequency across different COVID-19 vaccines, all were well tolerated in patients with RA and were comparable to HCs, providing reassurance as to the safety of COVID-19 vaccination.

Abstract Background A genome-wide association study (GWAS) assessing change in left ventricular ejection fraction (LVEF) in dilated cardiomyopathy (DCM), a surrogate marker of morbidity and mortality in heart failure (HF), had not been performed previously and could provide insight into novel biological pathways that could lead to the development of new drugs that might target myocardial recovery. The presence and extent of cardiac fibrosis in DCM is independently associated with myocardial recovery and cardiovascular mortality. Purpose To identify the biological relevance of genetic targets that are associated with change in LVEF in patients with DCM. Methods A GWAS was performed using DNA from 686 patients with recent onset DCM who were on standard HF therapy using change in LVEF at a median of 6 months after initial diagnosis. Cultured human cardiac fibroblasts (HCFs) were used as an in vitro model to study the functional and biological relevance of the gene target identified in the GWAS. Specifically, HCFs were transfected with siRNA by using the Lipofectamine™ RNAiMAX Transfection Reagent for gene knockdown (KD). RNA-seq was performed using the Illumina TruSeq protocol with expression analysis conducted with the EdgeR package. Ingenuity Pathway Analysis was used. Results A single-nucleotide polymorphism, rs11105445(G>A), mapping to the neuron navigator 3 (NAV3) gene (rs11105445, p=2.37E-07; beta 2.74±0.53) was associated with improvement in LVEF. We performed a phenome-wide association study using data from the UK Biobank and demonstrated that genetic variation in NAV3 was significantly associated with HF mortality (p=3.2E-28), highlighting the potential importance of this gene in HF. Using GTEx data we demonstrated that in LV tissue the minor allele A was associated with ↓NAV3 expression (p=0.03) suggesting that ↓NAV3 expression might be associated with improvement in LVEF. We demonstrated that NAV3 KD significantly ↓TGF-β1 mediated HCF transdifferentiation into myofibroblasts, ↓α-smooth muscle actin (ACTA2) and ↓collagen I (COL1A1), therefore NAV3 KD was anti-fibrotic (see Figure 1), 1a. HCFs treated by vehicle/TGF-β1 after KD of NAV3/ctrl, and ACTA2 and COL1A1 were analyzed by qPCR; 1b. Representative immunofluorescence staining for α-SMA (in green), RNA-seq after NAV3 KD followed by pathway analysis suggested that NAV3 exerted its effect by regulating cell cycle related proteins (Figure 2), 2a. Volcano plot shows significant differentially expressed genes identified by RNA-seq analysis (down-regulated in blue, up-regulated in red); 2b. NAV3 KD significantly increased expression of cell cycle related proteins, which was validated by Western blot. Conclusions Decreased expression of NAV3 is associated with myocardial recovery in DCM, most likely due to its anti-fibrotic effect via direct regulation of cell cycle proteins. The role of NAV3 as a novel therapeutic target in DCM needs to be explored. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Mayo Clinic Center for Individualized MedicineMayo Clinic Department of Cardiovascular Medicine

Purpose This study aimed to compare accuracy and efficiency of a convolutional neural network (CNN)–enhanced workflow for pancreas segmentation versus radiologists in the context of interreader reliability. Methods Volumetric pancreas segmentations on a data set of 294 portal venous computed tomographies were performed by 3 radiologists (R1, R2, and R3) and by a CNN. Convolutional neural network segmentations were reviewed and, if needed, corrected (“corrected CNN [c-CNN]” segmentations) by radiologists. Ground truth was obtained from radiologists' manual segmentations using simultaneous truth and performance level estimation algorithm. Interreader reliability and model's accuracy were evaluated with Dice-Sorenson coefficient (DSC) and Jaccard coefficient (JC). Equivalence was determined using a two 1-sided test. Convolutional neural network segmentations below the 25th percentile DSC were reviewed to evaluate segmentation errors. Time for manual segmentation and c-CNN was compared. Results Pancreas volumes from 3 sets of segmentations (manual, CNN, and c-CNN) were noninferior to simultaneous truth and performance level estimation–derived volumes [76.6 cm3 (20.2 cm3), P < 0.05]. Interreader reliability was high (mean [SD] DSC between R2-R1, 0.87 [0.04]; R3-R1, 0.90 [0.05]; R2-R3, 0.87 [0.04]). Convolutional neural network segmentations were highly accurate (DSC, 0.88 [0.05]; JC, 0.79 [0.07]) and required minimal-to-no corrections (c-CNN: DSC, 0.89 [0.04]; JC, 0.81 [0.06]; equivalence, P < 0.05). Undersegmentation (n = 47 [64%]) was common in the 73 CNN segmentations below 25th percentile DSC, but there were no major errors. Total inference time (minutes) for CNN was 1.2 (0.3). Average time (minutes) taken by radiologists for c-CNN (0.6 [0.97]) was substantially lower compared with manual segmentation (3.37 [1.47]; savings of 77.9%–87% [P < 0.0001]). Conclusions Convolutional neural network–enhanced workflow provides high accuracy and efficiency for volumetric pancreas segmentation on computed tomography.

Importance In patients with severe aortic valve stenosis at intermediate surgical risk, transcatheter aortic valve replacement (TAVR) with a self-expanding supra-annular valve was noninferior to surgery for all-cause mortality or disabling stroke at 2 years. Comparisons of longer-term clinical and hemodynamic outcomes in these patients are limited. Objective To report prespecified secondary 5-year outcomes from the Symptomatic Aortic Stenosis in Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI) randomized clinical trial. Design, Setting, and Participants SURTAVI is a prospective randomized, unblinded clinical trial. Randomization was stratified by investigational site and need for revascularization determined by the local heart teams. Patients with severe aortic valve stenosis deemed to be at intermediate risk of 30-day surgical mortality were enrolled at 87 centers from June 19, 2012, to June 30, 2016, in Europe and North America. Analysis took place between August and October 2021. Intervention Patients were randomized to TAVR with a self-expanding, supra-annular transcatheter or a surgical bioprosthesis. Main Outcomes and Measures The prespecified secondary end points of death or disabling stroke and other adverse events and hemodynamic findings at 5 years. An independent clinical event committee adjudicated all serious adverse events and an independent echocardiographic core laboratory evaluated all echocardiograms at 5 years. Results A total of 1660 individuals underwent an attempted TAVR (n = 864) or surgical (n = 796) procedure. The mean (SD) age was 79.8 (6.2) years, 724 (43.6%) were female, and the mean (SD) Society of Thoracic Surgery Predicted Risk of Mortality score was 4.5% (1.6%). At 5 years, the rates of death or disabling stroke were similar (TAVR, 31.3% vs surgery, 30.8%; hazard ratio, 1.02 [95% CI, 0.85-1.22]; P = .85). Transprosthetic gradients remained lower (mean [SD], 8.6 [5.5] mm Hg vs 11.2 [6.0] mm Hg; P &amp;lt; .001) and aortic valve areas were higher (mean [SD], 2.2 [0.7] cm 2 vs 1.8 [0.6] cm 2 ; P &amp;lt; .001) with TAVR vs surgery. More patients had moderate/severe paravalvular leak with TAVR than surgery (11 [3.0%] vs 2 [0.7%]; risk difference, 2.37% [95% CI, 0.17%- 4.85%]; P = .05). New pacemaker implantation rates were higher for TAVR than surgery at 5 years (289 [39.1%] vs 94 [15.1%]; hazard ratio, 3.30 [95% CI, 2.61-4.17]; log-rank P &amp;lt; .001), as were valve reintervention rates (27 [3.5%] vs 11 [1.9%]; hazard ratio, 2.21 [95% CI, 1.10-4.45]; log-rank P = .02), although between 2 and 5 years only 6 patients who underwent TAVR and 7 who underwent surgery required a reintervention. Conclusions and Relevance Among intermediate-risk patients with symptomatic severe aortic stenosis, major clinical outcomes at 5 years were similar for TAVR and surgery. TAVR was associated with superior hemodynamic valve performance but also with more paravalvular leak and valve reinterventions.

AbstractObjectivesThe assessment of physical function is fundamental in the management of patients with idiopathic inflammatory myopathies (IIMs). We aimed to investigate the physical function of patients with IIMs compared with those with non-IIM autoimmune rheumatic diseases (AIRDs) utilizing Patient-Reported Outcome Measurement Information System (PROMIS) Physical Function (PF) data obtained in the COVAD study, an international self-reported e-survey assessing the safety of COVID-19 vaccines in AIRDs.MethodsDemographics, AIRD diagnosis, disease activity, and PROMIS PF short form-10a data were extracted from the COVAD database. PROMIS PF-10a scores were compared between disease categories and stratified by disease activity. Factors affecting PROMIS PF-10a scores other than disease activity were identified by multivariable regression analysis in patients with inactive disease.ResultsA total of 1057 IIM patients, 3635 non-IIM AIRD patients and 3981 healthy controls (HCs) responded to the COVAD e-survey from April to August 2021. Using a binomial regression model, the predicted mean of PROMIS PF-10a scores was significantly lower in IIM patients compared with non-IIM AIRD patients or HCs [36.3 (95% CI 35.5, 37.1) vs 41.3 (95% CI 40.2, 42.5) vs 46.2 (95% CI 45.8, 46.6), P &lt; 0.001], irrespective of disease activity. The independent factors for lower PROMIS PF-10a scores in patients with inactive disease were older age, female, longer disease duration, and a diagnosis of inclusion body myositis or polymyositis.ConclusionPhysical function is significantly impaired in IIMs compared with non-IIM AIRDs or HCs, even in patients with inactive disease. Our study highlights a critical need for better strategies to minimize functional disability in patients with IIMs.