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.

Genotype-phenotype correlation in French patients with myelin protein zero gene-related inherited neuropathy.

BACKGROUND AND PURPOSE: Preparations for clinical trials of unfolded protein response (UPR) inhibitors (such as Sephin1) that target the upregulated UPR in patients with Charcot-Marie-Tooth disease (CMT) carrying MPZ mutations are currently underway. The inclusion criteria for these trials are still being formulated. Our objective was to characterize the relation between genotypes and phenotypes in patients with CMT caused by MPZ mutations, and to refine the inclusion criteria for future trials. METHODS: Clinical and neurophysiological data of CMT patients with MPZ mutations were retrospectively collected at 11 French reference centers. RESULTS: Forty-four mutations in MPZ were identified in 91 patients from 61 families. There was considerable heterogeneity. The same mutation was found to cause either axonal or demyelinating neuropathy. Three groups were identified according to the age at disease onset. CMT Examination Score (CMTES) tended to be higher in the early (≤22 years) and adult (23-47 years) onset groups (mean CMTESv2 = 10.4 and 10.0, respectively) than in the late onset group (>47 years, mean CMTESv2 = 8.6, p = 0.47). There was a significant positive correlation between CMTESv2 and the age of patients in Groups I (p = 0.027) and II (p = 0.023), indicating that clinical severity progressed with age in these patients. CONCLUSIONS: To optimize the selection of CMT patients carrying MPZ mutations for the upcoming trials, inclusion criteria should take into account the pathophysiology of the disease (upregulated UPR). Recruited patients should have a mild to moderate disease severity and a disease onset at between 18 and 50 years, as these patients exhibit significant disease progression over time.

Improved Cardiac Outcomes by Early Treatment with Angiotensin-Converting Enzyme Inhibitors in Becker Muscular Dystrophy.

BACKGROUND: The latest practice guidelines from the American College of Cardiology/American Heart Association recommend the prescription of an ACE-i for patients presenting with non-ischemic cardiomyopathy when left ventricular ejection fraction (LVEF) falls below 40%. OBJECTIVE: To determine if the initiation of treatment with an angiotensin-converting enzyme inhibitor (ACE-i) earlier than recommended by practice guidelines issued by professional societies improves the long-term cardiac outcomes of patients presenting with Becker muscular dystrophy (MD) cardiomyopathy. METHODS: From a multicenter registry of Becker MD, we selected retrospectively patients presenting between January 1990 and April 2019 with a LVEF ≥40 and ≤49%. We used a propensity score analysis to compare the risk of a) hospitalization for management of heart failure (HF), and b) a decrease in LVEF to <35% in patients who received an ACE-i when LVEF fell below 40% (conventional treatment), versus below 50% (early treatment). RESULTS: From the 183 patients entered in our registry, we identified 85 whose LVEF was between 40 and 49%, 51 of whom received early and 34 received conventional ACE-i treatment. Among patients with early versus conventional treatments, 2 (3.9%) versus 4 (11.8%) were hospitalized for management of HF [hazard ratio (HR) 0.151; 95% confidence interval (CI) 0.028 to 0.822; p = 0.029], and 9 (17.6%) versus 10 (29.4%) had a decrease in LVEF below 35% (HR 0.290; 95% CI 0.121 to 0.694; p = 0.005). CONCLUSIONS: The long-term cardiac outcome of patients presenting with Becker MD was significantly better when treatment with ACE-i was introduced after a decrease in LVEF below 50%, instead of below 40% as recommended in the current practice guidelines issued by professional societies.

SARS-CoV-2 Seroprevalence Survey Among District Residents Presenting for Serologic Testing at Three Community Based Test Sites in Washington, DC, July to August, 2020

BackgroundThe District of Columbia (DC), a major metropolitan area, continues to see community transmission of SARS-CoV-2. While serologic testing does not indicate current SARS-CoV-2 infection, it can indicate prior infection and help inform local policy and health guidance. The DC Department of Health (DC Health) conducted a community-based survey to estimate DCs SARS-CoV-2 seroprevalence and identify seropositivity-associated factors. MethodsA mixed-methods cross-sectional serology survey was conducted among a convenience sample of DC residents during July 27-August 21, 2020. Free serology testing was offered at three public test sites. Participants completed an electronic questionnaire on household and demographic characteristics, COVID-like illness (CLI) since January 1, 2020, comorbidities, and SARS-CoV-2 exposures. Univariate and bivariate analyses were conducted to describe the sample population and assess factors associated with seropositivity. ResultsAmong a sample of 671 participants, 51 individuals were seropositive, yielding an estimated seroprevalence of 7.6%. More than half (56.9%) of the seropositive participants reported no prior CLI; nearly half (47.1%) had no prior SARS-CoV-2 testing. Race/ethnicity, prior SARS-CoV-2 testing, prior CLI, employment status, and contact with confirmed COVID-19 cases were associated with seropositivity (P<0.05). Among those reporting prior CLI, loss of taste or smell, duration of CLI, fewer days between CLI and serology test, or prior viral test were associated with seropositivity (P[≤]0.006). ConclusionsThese findings indicate many seropositive individuals reported no symptoms consistent with CLI since January or any prior SARS-CoV-2 testing. This underscores the potential for cases to go undetected in the community and suggests wider-spread transmission than previously reported in DC. What is already known on this subject?Traditional case-based detection and syndromic surveillance efforts might not identify mildly symptomatic or asymptomatic SARS-CoV-2 infections. This is particularly true among people in the general population who do not have increased risk of severe illness or might not be tested otherwise. Consequently, the true population prevalence of prior SARS-CoV-2 infections might not be known. What this study adds?A community-based seroprevalence survey conducted in Washington, DC, during July 27-August 21, 2020 estimated that 7.6% of the convenience sample had antibodies to SARS-CoV-2, indicating prior infection. At the time of this survey, most of the participants reported that they had not been previously infected with or tested for SARS-CoV-2. These findings highlight both the value of serologic surveillance in complementing other surveillance methods, and the importance of continued prevention and mitigation measures, such as maintaining physical distances of at least 6 feet, avoiding crowds and poorly ventilated spaces, practicing frequent hand hygiene, and wearing face masks properly and consistently around people who do not live with you.