Frederick W Miller's research while affiliated with National Institute of Environmental Health Sciences and other places

Publications (234)

Article
Objectives: The 2016 ACR-EULAR Response Criteria for juvenile dermatomyositis (JDM) was developed as a composite measure with differential weights of six core set measures (CSMs) to calculate a Total Improvement Score (TIS). We assessed the contribution of each CSM, representation of muscle-related and patient-reported CSMs towards improvement, an...
Article
Objective: The ACR-EULAR myositis response criteria (MRC) were developed as a composite measure using absolute percentage change in six core set measures (CSMs). We aimed to further validate the MRC by assessing the contribution of each CSM, frequency of strength versus extramuscular activity improvement, representation of patient-reported outcome...
Article
Autoimmunity is characterized by self-reactive immune components and autoimmune disease by autoimmunity plus pathology. Both autoimmunity and autoimmune diseases are dramatically increasing in many parts of the world, likely as a result of changes in our exposures to environmental factors. Current evidence implicates the momentous alterations in ou...
Article
Objectives The B cell depleting biologic, rituximab, is used to treat refractory autoimmune myositis. However, the beneficial effects of rituximab appear to outweigh the known contribution of B-cells in myositis. We aimed to elucidate how myositis patients respond differently to rituximab and possible alternative mechanisms of action. Methods Here...
Article
Background Concentrated animal feeding operations (CAFOs) are a source of environmental pollution and have been associated with a variety of health outcomes. Immune-mediated diseases (IMD) are characterized by dysregulation of the normal immune response and, while they may be affected by gene and environmental factors, their association with living...
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Background Environmental exposures have been associated with the juvenile idiopathic inflammatory myopathies (JIIM). We undertook a questionnaire-based study to evaluate patient-reported exposures as possible risk factors for JIIM. Findings One-hundred-seven patients with JIIM were enrolled in a myositis natural history protocol and completed envi...
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Objectives: The idiopathic inflammatory myopathies (IIM) are heterogeneous diseases, thought to be initiated by immune activation in genetically predisposed individuals. In this study we imputed variants from the Immunochip array using a large reference panel to fine-map associations and identify novel associations in IIM. Methods: We analysed 2...
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Objective To estimate the nationally representative prevalence of chronic axial pain, inflammatory back pain (IBP), axial spondyloarthritis (axSpA), and peripheral arthritis in persons diagnosed with inflammatory bowel disease (IBD). Patients and Methods US National Health and Nutrition Examination Survey (NHANES) data from the 1976-1980 and 2009-...
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Background Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterised by myositis-related autoantibodies plus infiltration of leucocytes into muscles and/or the skin, leading to the destruction of blood vessels and muscle fibres, chronic weakness and fatigue. While complement-mediated destruction of capillary endothel...
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Background Between 1988 and 2012, prevalence of antinuclear antibodies (ANA) increased in the U.S., especially in adolescents and non-Hispanic Whites. Female predominance of ANA suggests a role for hormonal factors, including xenobiotic exposures that may disrupt endocrine signaling. Benzophenone-3 (BP-3) is one such chemical with increasing exposu...
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Objective: Growing evidence suggests increasing frequencies of autoimmunity and autoimmune diseases, but findings are limited by the lack of systematic data and evolving approaches and definitions. This study was undertaken to investigate whether the prevalence of antinuclear antibodies (ANA), the most common biomarker of autoimmunity, changed ove...
Article
Objectives Four-and-a-half LIM domains 1 (FHL1) is a muscle-specific protein. Autoantibodies against FHL1 were recently discovered in adults with idiopathic inflammatory myopathies (IIM) and were found to be associated with clinical features and outcomes indicative of increased disease severity. Anti-FHL1 autoantibodies have not been described in c...
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The HLA-DRB1*03:01 allele is a major genetic risk factor in systemic lupus erythematosus (SLE), but the mechanistic basis of the association is unclear. Here we show that in the presence of interferon gamma (IFN-γ), a short DRB1*03:01-encoded allelic epitope activates a characteristic lupus transcriptome in mouse and human macrophages. It also trig...
Article
Background The prevalence of autoimmunity in the U.S. has increased recently for undetermined reasons. Little is known about associations between autoimmunity and environmental causes. Objectives In a large representative sample of the U.S. population, we expanded our prior exploratory study of how exposures to selected xenobiotics and dioxin-like...
Preprint
The HLA-DRB1*03:01 allele is a major genetic risk factor in systemic lupus erythematosus (SLE), but the mechanistic basis of the association is unclear. Here we show that in the presence of interferon gamma (IFN-γ), a short DRB1*03:01 -encoded allelic epitope activates a characteristic lupus transcriptome in mouse and human macrophages. It also tri...
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Objective To examine the frequency of, and risk factors for, disease flare following COVID-19 vaccination in patients with systemic rheumatic disease (SRD). Methods An international study was conducted from April 2 to August 16, 2021, using an online survey of 5619 adults with SRD for adverse events following COVID-19 vaccination, including flares...
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Background Little is known about the spatial distribution of idiopathic inflammatory myopathies (IIM) in the United States (U.S.), or their geospatial associations. Methods We studied a national myositis patient registry, with cases diagnosed in the contiguous U.S. from 1985–2011 and comprised of dermatomyositis (DM, n = 484), polymyositis (PM, n...
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Objective: We undertook this study to examine the X chromosome complement in participants with systemic sclerosis (SSc) as well as idiopathic inflammatory myopathies. Methods: The participants met classification criteria for the diseases. All participants underwent single-nucleotide polymorphism typing. We examined X and Y single-nucleotide poly...
Article
Objectives: Anti-synthetase syndrome (ASSD) is a heterogeneous autoimmune disease characterised by multi-system involvement with a wide variety of manifestations. Validated classification criteria are necessary to improve recognition and prevent misclassification, especially given the lack of reliable and standardised autoantibody testing. We syst...
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Objectives Juvenile dermatomyositis (JDM) is a rare, severe autoimmune disease and the most common idiopathic inflammatory myopathy (IIM) of children. JDM and adult-onset dermatomyositis (DM) have similar clinical, biological and serological features, although these features differ in prevalence between childhood-onset and adult-onset disease, sugg...
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Autoimmunity prevalence, as measured by antinuclear antibodies (ANA), is increasing in U.S. adolescents. Improved hygiene and cleaner environments in childhood may reduce exposure to infections and other immune challenges, resulting in improper immune responses to later-life exposures. We examined associations of hygiene hypothesis indicators, incl...
Article
Idiopathic inflammatory myopathies (IIM), also known as myositis, are a heterogeneous group of autoimmune disorders with varying clinical manifestations, treatment responses and prognoses. Muscle weakness is usually the classical clinical manifestation but other organs can be affected, including the skin, joints, lungs, heart and gastrointestinal t...
Article
Objective To compare muscle ultrasound (MUS) parameters in patients with juvenile dermatomyositis (JDM) and healthy controls, and examine their association with JDM disease activity measures and magnetic resonance imaging (MRI). Methods MUS of the right mid-rectus femoris was performed in 21 patients with JDM meeting probable or definite Bohan and...
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Objectives Juvenile dermatomyositis (JDM) is an inflammatory myopathy characterized by prominent vasculopathy. Anti-endothelial cell antibodies (AECA) are frequently detected in inflammatory and autoimmune diseases. We sought to determine whether AECA correlate with clinical features of JDM, and thus serve as biomarkers to guide therapy or predict...
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Cell‐free DNA circulates in plasma at low levels as a normal by‐product of cellular apoptosis. Multiple clinical pathologies, as well as environmental stressors can lead to increased circulating cell‐free DNA (ccfDNA) levels. Plasma DNA studies frequently employ targeted amplicon deep sequencing platforms due to limited concentrations (ng/ml) of cc...
Article
Objective To define the prevalence and clinical phenotype of anti-cortactin autoantibodies in adult and juvenile myositis. Methods In this longitudinal cohort study, anti-cortactin autoantibody titers were assessed by ELISA in 670 adults and 343 juvenile myositis patients as well as 202 adult and 90 juvenile healthy controls. The prevalence of ant...
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We analyzed the prevalence of anti-mitochondrial autoantibodies (AMA) in adult- and juvenile-onset myositis longitudinal cohorts and investigated phenotypic differences in myositis patients with AMA. We screened sera from myositis patients including 619 adult- and 371 juvenile-onset dermatomyositis (DM, JDM), polymyositis (PM, JPM), inclusion body...
Article
Myositis is a group of conditions that vary greatly in risk factors, clinical manifestations, laboratory markers, presumed pathogenetic mechanisms, treatment responses and prognoses. Approaches to divide myositis into mutually exclusive and stable phenotypes are being considered, but are we thinking comprehensively enough in our attempts at classif...
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Associations between particular human leukocyte antigen (HLA) alleles and susceptibility to—or protection from—autoimmune diseases have been long observed. Allele-specific antigen presentation (AP) has been widely proposed as a culprit, but it is unclear whether HLA molecules might also have non-AP, disease-modulating effects. Here we demonstrate d...
Article
Objective: Myositis-specific autoantibodies have defined distinct phenotypes of patients with juvenile myositis (JIIM). We assessed the frequency and clinical significance of anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody-associated JIIM in a North American registry. Methods: Retrospective examination of the characteristics...
Article
Objective A North American registry of JDM patients was examined for frequency of and factors associated with corticosteroid discontinuation, complete clinical response and remission. Methods We evaluated probability of achieving final corticosteroid discontinuation, complete clinical response and remission in 307 JDM patients by Weibull time-to-e...
Article
Objectives: The subsarcolemmal accumulation of p62 aggregates in myofibres has been proposed to be characteristic of sporadic inclusion body myositis (sIBM). The objective of this study was to analyse the patterns and prevalence of p62 immunostaining and to quantitate p62 gene expression in muscle biopsies from a large number of patients with diff...
Preprint
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Statistical associations between particular human leukocyte antigen (HLA) alleles and susceptibility to - or protection from - autoimmune diseases have been long observed. Allele-specific antigen presentation (AP) has been widely proposed as a culprit mechanism; however, direct evidence to substantiate that hypothesis is scant. Here we demonstrate...
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Objectives Myositis is a heterogeneous family of diseases that includes dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM), inclusion body myositis (IBM), polymyositis and overlap myositis. Additional subtypes of myositis can be defined by the presence of myositis-specific autoantibodies (MSAs). The purp...
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Background: Juvenile dermatomyositis (JDM) is a systemic autoimmune disease with a prominent interferon (IFN) signature, but the pathogenesis of JDM and the etiology of its IFN signature remain unknown. The Mendelian autoinflammatory interferonopathies, Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature (CANDLE) a...
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Objective Growing evidence suggests increasing frequencies of autoimmunity and certain autoimmune diseases, but findings are limited by the lack of systematic data and evolving approaches and definitions. We investigated whether the prevalence of antinuclear antibodies (ANA), the most common biomarker of autoimmunity, changed over a recent 25‐year...
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Type I interferon (IFN) drives pathology in systemic lupus erythematosus (SLE) and can be tracked via IFN-inducible transcripts in blood. Here, we examined whether measurement of circulating proteins, which enter the bloodstream from inflamed tissues, also offers insight into global IFN activity. Using a novel protocol we generated 1,132 aptamer-ba...
Article
Objectives: Idiopathic inflammatory myopathies (IIM) are characterized by muscle inflammation and weakness, myositis specific autoantibodies (MSAs) and extramuscular organ damage. The role of neutrophil dysregulation and neutrophil extracellular traps (NETs) in IIM is unclear. We assessed if pathogenic neutrophil subsets (low-density granulocytes,...
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Objective Based on US National Health and Nutrition Examination Survey (NHANES) data, we attempted to provide an unbiased, population-based estimate of autoantibody prevalence overall and by age and sex. Methods US autoantibody prevalence estimates for detectable rheumatoid factor, anti-thyroglobulin, anti-thyroperoxidase, anti-transglutaminase, a...
Chapter
Autoimmune diseases appear to be increasing throughout the world, yet their rarity, heterogeneity and complex etiologies have limited our understanding of their pathogeneses. While the precise mechanisms for the development of autoimmune diseases are not known, evidence from many complementary lines of research suggests that autoimmune diseases res...
Chapter
To understand the myositis syndromes, also called the idiopathic inflammatory myopathies (IIMs), one must first understand the terminology used to describe the entities within them and how those entities are defined. Although what we know now as the IIMs were recognized as early as 1863, defining them is difficult because their definitions have cha...
Article
Background: Because immune responses are sensitive to environmental changes that drive selection of genetic variants, we hypothesized that polymorphisms of some xenobiotic response and immune response genes may be associated with specific types of immune-mediated diseases (IMD), while others may be associated with IMD as a larger category regardle...
Article
Objective: Dermatomyositis (DM) has been associated with geospatial differences in ultraviolet (UV) radiation, but the role of individual determinants of UV exposure prior to diagnosis is unknown. Methods: We analyzed questionnaire data from 1350 adults in a U.S. national myositis registry (638 with DM, 422 polymyositis [PM], and 290 inclusion b...
Article
Objective: Activation of the type 1 interferon (IFN1) pathway is a prominent feature of dermatomyositis (DM) muscle and may play a role in the pathogenesis of this disease. However, the relevance of the IFN1 pathway in patients with other types of myositis such as the antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and i...
Article
Objective Circulating endothelial cells (CECs), von Willebrand Factor (VWF) antigen, P-selectin and thrombomodulin are released from damaged endothelium, while decreases in circulating endothelial progenitor cells (CEPCs) have been associated with poor vascular outcomes. We examined these markers in the peripheral blood of juvenile dermatomyositis...
Article
Objective: Juvenile idiopathic inflammatory myopathies (JIIM) are rare, chronic autoimmune muscle diseases of childhood, with the potential for significant morbidity. Data on long-term outcomes is limited. In this study we investigate correlations between clinical and demographic features with long-term outcomes in a referral population of adult p...
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Objectives Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to...
Article
Objectives Anti-Ro52 autoantibodies are associated with more severe interstitial lung disease (ILD) in adult myositis patients with antiaminoacyl transfer (t)RNA synthetase autoantibodies. However, few studies have examined anti-Ro52 autoantibodies in juvenile myositis. The purpose of this study was to define the prevalence and clinical features as...
Article
Background: Clinical reports link specific medications with the development of antinuclear antibodies (ANA), but population-based evidence is limited. Objective: The present study investigated associations between prescription medication use and ANA in a representative sample of the adult noninstitutionalized US population, first focusing on med...
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Autoimmune diseases develop as a result of chronic inflammation owing to interactions between genes and the environment. However, the mechanisms by which autoimmune diseases evolve remain poorly understood. Newly discovered risk factors and pathogenic processes in the various idiopathic inflammatory myopathy (IIM) phenotypes (known collectively as...
Article
Objective: Few controlled studies are available to guide treatment decisions in juvenile dermatomyositis (JDM). This study evaluated therapies received, changes of treatment over time, and factors associated with medication choices in JDM. Methods: We performed a retrospective analysis of the number and type of therapies and duration of treatmen...
Article
Objective Cigarette smoking is associated with immune-mediated disorders. We explored the contribution of smoking to polymyositis (PM) and dermatomyositis (DM) phenotypes and attempted to determine whether cigarette smoking effects differ by race and genotype. Methods Associations of tobacco smoking with disease features, autoantibodies, HLA types...
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Objectives Autoantibodies recognising cytosolic 5′-nucleotidase 1A (NT5C1A) are found in adult patients with myositis and other autoimmune diseases. They are especially prevalent in adults with inclusion body myositis (IBM), in which they are associated with more severe weakness and higher mortality. This study was undertaken to define the prevalen...
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Objective To describe the methodology used to develop new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIMs) and their major subgroups. Methods An international, multidisciplinary group of myositis experts produced a set of 93 potentially relevant variables to be tested for inclusion in the criteria. Rheumatol...
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Objective To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups. Methods Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology and paediatric c...
Article
Objective: To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups. Methods: Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology, and pediatr...
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Objective Recent studies suggest antinuclear antibodies (ANA) may be related to mortality risk, but evidence is sparse and inconclusive. Thus, we investigated ANA associations with all-cause and cause-specific mortality in U.S. adults. Methods Our sample included 3357 adults (ages ≥20 years) from the 1999–2004 National Health and Nutrition Examina...
Article
Objective: To investigate in a pilot study the safety and efficacy of infliximab in patients with refractory dermatomyositis (DM) and polymyositis (PM). Methods: A randomized, double-blind, placebo-controlled trial including subjects with active DM or PM. Participants had stable doses of immunosuppressive medication and prednisone (≤0.5mg/kg/day...
Article
Objective: The objective was to describe the methodology used to develop new response criteria for adult DM/PM and JDM. Methods: Patient profiles from prospective natural history data and clinical trials were rated by myositis specialists to develop consensus gold-standard ratings of minimal, moderate and major improvement. Experts completed a s...
Article
To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM). Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement i...
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To develop response criteria for juvenile dermatomyositis (DM). We analysed the performance of 312 definitions that used core set measures from either the International Myositis Assessment and Clinical Studies Group (IMACS) or the Paediatric Rheumatology International Trials Organisation (PRINTO) and were derived from natural history data and a con...
Article
Objective.: The aim was to assess environmental factors associated with disease flare in juvenile and adult dermatomyositis (DM). Methods.: An online survey of DM patients from the USA and Canada examined smoking, sun exposure, infections, medications, vaccines, stressful life events and physical activity during the 6 months before flares, or in...
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Objective: To develop response criteria for juvenile dermatomyositis (DM). Methods: We analyzed the performance of 312 definitions that used core set measures from either the International Myositis Assessment and Clinical Studies Group (IMACS) or the Paediatric Rheumatology International Trials Organisation (PRINTO) and were derived from natural...
Article
Objective: To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM). Methods: Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different...
Article
Objective: Autoantibodies recognizing 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) are associated with statin exposure, the HLA allele DRB1*11:01, and necrotizing muscle biopsies in adult myositis patients. The aim of this study was to characterize the features of pediatric anti-HMGCR-positive myositis patients. Methods: The sera of 4...
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Objective: Extensive studies on health-related quality of life (HRQOL) in idiopathic inflammatory myopathies (IIM) are lacking. Our objective was to document HRQOL and to identify factors associated with a reduced HRQOL in IIM patients. Methods: A total of 1,715 patients (median age 49.9, 70% female, 87% Caucasian) who met probable or definite B...
Article
Objective: The importance of hypomethylation in SLE is well recognized; however, the significance of hypermethylation has not been well characterized. We screened hypermethylated marks in SLE and investigated their possible implications. Methods: DNA methylation marks were screened in SLE whole-blood DNA by microarray, and two marks (CD3Z and VH...
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Objective: Little is known about arsenic and diabetes in youth. We examined the association of arsenic with type 1 and type 2 diabetes in the SEARCH for Diabetes in Youth Case-Control study. Because one-carbon metabolism can influence arsenic metabolism, we also evaluated the potential interaction of folate and vitamin B12 with arsenic metabolism...
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Objective: To identify muscle gene expression patterns that predict rituximab responses and assess the effects of rituximab on muscle gene expression in PM and DM. Methods: In an attempt to understand the molecular mechanism of response and non-response to rituximab therapy, we performed Affymetrix gene expression array analyses on muscle biopsy...
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Viral agents are of interest as possible autoimmune triggers due to prior reported associations and widely studied molecular mechanisms of antiviral immune responses in autoimmunity. Here we examined new viral candidates for the initiation and/or promotion of systemic autoimmune diseases (SAID), as well as possible related signaling pathways shared...
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Objective: Complement-mediated vasculopathy of muscle and skin are clinical features of juvenile dermatomyositis (JDM). We assess gene copy-number variations (CNVs) for complement C4 and its isotypes, C4A and C4B, in genetic risks and pathogenesis of JDM. Methods: The study population included 105 patients with JDM and 500 healthy European Ameri...