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Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1*08:04 and HLA-DRB1*11:02 alleles were associated with overall SSc risk, and the HLA-DRB1*08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1*13:01 and HLA-DRB1*07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1*13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1*13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 × 10-6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/β allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.

The article focuses on the establishment of the Office of Autoimmune Disease Research (OADR) to advance autoimmune disease research. Topics include the prevalence and impact of autoimmune diseases; challenges in studying environmental exposures and their link to autoimmune conditions; and the strategic initiatives and funding priorities of the OADR to enhance research and address gaps in the field.

Racial differences exist in the severity of systemic sclerosis (SSc). To enhance our knowledge about SSc in African Americans, we established a comprehensive clinical database from the largest multicenter cohort of African American SSc patients assembled to date (the Genome Research in African American Scleroderma Patients (GRASP) cohort).African American SSc patients were enrolled retrospectively and prospectively over a 30-year period (1987-2016), from 18 academic centers throughout the United States. The cross-sectional prevalence of sociodemographic, clinical, and serological features was evaluated. Factors associated with clinically significant manifestations of SSc were assessed using multivariate logistic regression analyses.The study population included a total of 1009 African American SSc patients, comprised of 84% women. In total, 945 (94%) patients met the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for SSc, with the remaining 64 (6%) meeting the 1980 ACR or CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) criteria. While 43% were actively employed, 33% required disability support. The majority (57%) had the more severe diffuse subtype and a young age at symptom onset (39.1 ± 13.7 years), in marked contrast to that reported in cohorts of predominantly European ancestry. Also, 1 in 10 patients had a severe Medsger cardiac score of 4. Pulmonary fibrosis evident on computed tomography (CT) chest was present in 43% of patients and was significantly associated with anti-topoisomerase I positivity. 38% of patients with CT evidence of pulmonary fibrosis had a severe restrictive ventilator defect, forced vital capacity (FVC) ≤50% predicted. A significant association was noted between longer disease duration and higher odds of pulmonary hypertension, telangiectasia, and calcinosis. The prevalence of potentially fatal scleroderma renal crisis was 7%, 3.5 times higher than the 2% prevalence reported in the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) cohort.Our study emphasizes the unique and severe disease burden of SSc in African Americans compared to those of European ancestry.

Aim: Interstitial lung disease (ILD) is the leading cause of disease‐related death in systemic sclerosis (SSc). Here, we assess baseline characteristics of SSc subjects with and without restrictive lung disease (RLD) in a multi‐center, US‐based registry. Methods: SSc patients within 5 years of disease onset were enrolled in the Collaborative National Quality and Efficacy Registry (CONQUER), a multi‐center US‐based registry of SSc study participants (age ≥ 18 years) enrolled at 13 expert centers. All subjects met 2013 American College of Rheumatology / European League Against Rheumatism criteria. Subjects with a pulmonary function test (PFT) at baseline before April 1, 2020 were included. High‐resolution computed tomography scan of the chest was not available to characterize ILD for all subjects. RLD was defined as forced vital capacity (FVC) <80% or total lung capacity (TLC) <80% predicted. Results: There were 160 (45%) SSc subjects characterized as having RLD. There was no significant difference in age, gender or disease duration. RLD subjects had a mean disease duration from date of first non‐Raynaud's symptom of 2.6 years and a mean FVC% predicted of 67% at baseline. In multivariable analysis, non‐White race, higher physician global health assessment and modified Medical Research Council (mMRC) dyspnea scores, were independently associated with RLD. In the subgroup of RLD subjects with ILD, ILD had a negative correlation with RNA polymerase III antibody. Conclusion: CONQUER is the largest, multi‐center, prospective cohort of early SSc patients in the US. Non‐White race was independently associated with RLD. In addition, 45% of CONQUER subjects already had RLD, highlighting the importance of screening for SSc‐ILD at initial diagnosis. [ABSTRACT FROM AUTHOR]

Abstract Background The American Board of Internal Medicine Certification Examination (ABIM-CE) is one of several methods used to assess medical knowledge, an Accreditation Council for Graduate Medical Education (ACGME) core competency for graduating internal medicine residents. With recent changes in graduate medical education program directors and internal medicine residents are seeking evidence to guide decisions regarding residency elective choices. Prior studies have shown that formalized elective curricula improve subspecialty ABIM-CE scores. The primary aim of this study was to evaluate whether the number of subspecialty elective exposures or the specific subspecialties which residents complete electives in impact ABIM-CE scores. Methods ABIM-CE scores, elective exposures and demographic characteristics were collected for MedStar Georgetown University Hospital internal medicine residents who were first-time takers of the ABIM-CE in 2006–2010 (n=152). Elective exposures were defined as a two-week period assigned to the respective subspecialty. ABIM-CE score was analyzed using the difference between the ABIM-CE score and the standardized passing score (delta-SPS). Subspecialty scores were analyzed using percentage of correct responses. Data was analyzed using GraphPad Prism version 5.00 for Windows. Results Paired elective exposure and ABIM-CE scores were available in 131 residents. There was no linear correlation between ABIM-CE mean delta-SPS and the total number of electives or the number of unique elective exposures. Residents with ≤14 elective exposures had higher ABIM-CE mean delta-SPS than those with ≥15 elective exposures (143.4 compared to 129.7, p=0.051). Repeated electives in individual subspecialties were not associated with significant difference in mean ABIM-CE delta-SPS. Conclusions This study did not demonstrate significant positive associations between individual subspecialty elective exposures and ABIM-CE mean delta-SPS score. Residents with ≤14 elective exposures had higher ABIM-CE mean delta-SPS than those with ≥15 elective exposures suggesting there may be an “ideal” number of elective exposures that supports improved ABIM-CE performance. Repeated elective exposures in an individual specialty did not correlate with overall or subspecialty ABIM-CE performance.

Mass spectrometry imaging (MSI) is used increasingly to simultaneously detect a broad range of biomolecules while mapping their spatial distributions within biological tissue sections. Matrix‐assisted laser desorption ionization (MALDI) is recognized as the method‐of‐choice for MSI applications due in part to its broad molecular coverage. In spite of the remarkable advantages offered by MALDI, imaging of neutral lipids, such as triglycerides (TGs), from tissue has remained a significant challenge due to ion suppression of TGs by phospholipids, e.g. phosphatidylcholines (PCs). To help overcome this limitation, silicon nanopost array (NAPA) substrates were introduced to selectively ionize TGs from biological tissue sections. This matrix‐free laser desorption ionization (LDI) platform was previously shown to provide enhanced ionization of certain lipid classes, such as hexosylceramides (HexCers) and phosphatidylethanolamines (PEs) from mouse brain tissue. In this work, we present NAPA as an MSI platform offering enhanced ionization efficiency for TGs from biological tissues relative to MALDI, allowing it to serve as a complement to MALDI‐MSI. Analysis of a standard lipid mixture containing PC(18:1/18:1) and TG(16:0/16:0/16:0) by LDI from NAPA provided an ~49 and ~227‐fold higher signal for TG(16:0/16:0/16:0) relative to MALDI, when analyzed without and with the addition of a sodium acetate, respectively. In contrast, MALDI provided an ~757 and ~295‐fold higher signal for PC(18:1/18:1) compared with NAPA, without and with additional Na+. Averaged signal intensities for TGs from MSI of mouse lung and human skin tissues exhibited an ~105 and ~49‐fold increase, respectively, with LDI from NAPA compared with MALDI. With respect to PCs, MALDI provided an ~2 and ~19‐fold increase in signal intensity for mouse lung and human skin tissues, respectively, when compared with NAPA. The complementary coverage obtained by the two platforms demonstrates the utility of using both techniques to maximize the information obtained from lipid MS or MSI experiments. [ABSTRACT FROM AUTHOR]

Objectives: Determine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease.Methods: Skin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated.Results: SSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression.Conclusions: Skin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design. [ABSTRACT FROM AUTHOR]