RESUMO
OBJECTIVE: Diagnostic muscle biopsies are routinely immunostained for major histocompatibility complex class I (MHC-I) protein. In this study we analysed the prevalence and patterns of MHC-I immunostaining in biopsies from patients with different types of myopathies and neurogenic disorders. METHODS: All 357 diagnostic muscle biopsies processed at the Johns Hopkins Neuromuscular Pathology Laboratory from August 2013 to January 2017 were immunostained for MHC-I. The prevalence and patterns of MHC-I immunostaining were compared between patients with histologically normal muscle biopsies (n = 31), idiopathic inflammatory myopathies (IIMs; n = 170), non-inflammatory myopathies (n = 60) and neurogenic disorders (n = 96). RESULTS: MHC-I immunostaining was abnormal in most patients with DM (98%), sporadic IBM (sIBM; 100%), immune-mediated necrotizing myopathy (IMNM; 100%) and polymyositis (77%). In contrast, MHC-I immunostaining was less frequently present in non-inflammatory myopathies (32%) or neurogenic disorders (30%). Overall, abnormal MHC-I immunostaining had a sensitivity of 0.95 and a specificity of 0.82 for diagnosing IIMs. A focal MHC-I staining pattern was associated with IMNM, whereas a global pattern was more prevalent in sIBM and a perifascicular pattern was significantly more common in dermatomyositis. Among 18 DM biopsies without perifascicular atrophy, 50% had a perifascicular MHC-I staining pattern. Sarcoplasmic upregulation staining was more common than sarcolemmal staining across all groups. CONCLUSION: MHC-I immunostaining was useful to distinguish IIMs from non-inflammatory myopathies or neurogenic disorders. Of note, a perifascicular MHC-I staining pattern was present only in those with DM, including half of those without perifascicular atrophy; many of these biopsies may not otherwise have been diagnostic for DM.
Assuntos
Doenças Musculares , Miosite , Humanos , Miosite/diagnóstico , Doenças Musculares/diagnóstico , Doenças Musculares/patologia , Antígenos de Histocompatibilidade Classe I , Biópsia , Músculos/química , Músculos/metabolismo , Músculos/patologia , Atrofia , Músculo Esquelético/patologiaRESUMO
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 different types of myopathic and neurogenic disorders. METHODS: For the p62 immunostaining analysis, all patients with a muscle biopsy immunostained for p62 at the Johns Hopkins Neuromuscular Pathology Laboratory from 2013 to 2017 were included (n=303). The prevalence and pattern of p62 immunostaining were compared between patients with histologically normal muscle (n=29), inflammatory myopathies (n=136), non-inflammatory myopathies (n=53), and neurogenic disorders (n=85). p62 expression levels were analysed using an existing RNAseq dataset including data from dermatomyositis (DM; n=39), immune-mediated necrotising myopathy (IMNM; n=49), antisynthetase syndrome (AS; n=18), and sIBM (n=23) patients as well as 20 histologically normal muscle biopsies. RESULTS: p62 staining was absent in normal biopsies, but present in biopsies from those with polymyositis (29%), non-inflammatory myopathies (all <31%), neurogenic disorders (31%), dermatomyositis (57%), sIBM (92%) and IMNM (87%). In all diseases studied, p62 accumulation was more prevalent in biopsies with more severe muscle damage. sIBM biopsies had decreased p62 expression levels compared to the other groups (corrected p<0.04). CONCLUSIONS: p62 accumulation is a general response to muscle injury and not a specific marker for sIBM. Also, in sIBM, p62 RNA levels are decreased, suggesting that, in this disease, p62 aggregation is not due to overexpression.
Assuntos
Doenças Autoimunes , Miosite de Corpos de Inclusão , Miosite , Polimiosite , Autofagossomos , Humanos , Músculo Esquelético , Miosite/epidemiologia , Miosite de Corpos de Inclusão/genéticaRESUMO
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 purpose of this study was to define unique gene expression profiles in muscle biopsies from patients with MSA-positive DM, AS and IMNM as well as IBM. METHODS: RNA-seq was performed on muscle biopsies from 119 myositis patients with IBM or defined MSAs and 20 controls. Machine learning algorithms were trained on transcriptomic data and recursive feature elimination was used to determine which genes were most useful for classifying muscle biopsies into each type and MSA-defined subtype of myositis. RESULTS: The support vector machine learning algorithm classified the muscle biopsies with >90% accuracy. Recursive feature elimination identified genes that are most useful to the machine learning algorithm and that are only overexpressed in one type of myositis. For example, CAMK1G (calcium/calmodulin-dependent protein kinase IG), EGR4 (early growth response protein 4) and CXCL8 (interleukin 8) are highly expressed in AS but not in DM or other types of myositis. Using the same computational approach, we also identified genes that are uniquely overexpressed in different MSA-defined subtypes. These included apolipoprotein A4 (APOA4), which is only expressed in anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) myopathy, and MADCAM1 (mucosal vascular addressin cell adhesion molecule 1), which is only expressed in anti-Mi2-positive DM. CONCLUSIONS: Unique gene expression profiles in muscle biopsies from patients with MSA-defined subtypes of myositis and IBM suggest that different pathological mechanisms underly muscle damage in each of these diseases.
Assuntos
Doenças Autoimunes/genética , Doenças Musculares/genética , Miosite de Corpos de Inclusão/genética , Miosite/genética , Adulto , Animais , Apolipoproteínas A/metabolismo , Biópsia , Proteína Quinase Tipo 1 Dependente de Cálcio-Calmodulina/metabolismo , Moléculas de Adesão Celular/metabolismo , Técnicas de Cultura de Células , Dermatomiosite/genética , Fatores de Transcrição de Resposta de Crescimento Precoce/metabolismo , Feminino , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Interleucina-8/metabolismo , Aprendizado de Máquina , Masculino , Camundongos , Mucoproteínas/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Miosite/patologia , Polimiosite/genética , TranscriptomaRESUMO
OBJECTIVES: To study muscle biopsy tissue from patients with juvenile dermatomyositis (JDM) in order to test the reliability of a score tool designed to quantify the severity of histological abnormalities when applied to biceps humeri in addition to quadriceps femoris. Additionally, to evaluate whether elements of the tool correlate with clinical measures of disease severity. METHODS: 55 patients with JDM with muscle biopsy tissue and clinical data available were included. Biopsy samples (33 quadriceps, 22 biceps) were prepared and stained using standardised protocols. A Latin square design was used by the International Juvenile Dermatomyositis Biopsy Consensus Group to score cases using our previously published score tool. Reliability was assessed by intraclass correlation coefficient (ICC) and scorer agreement (α) by assessing variation in scorers' ratings. Scores from the most reliable tool items correlated with clinical measures of disease activity at the time of biopsy. RESULTS: Inter- and intraobserver agreement was good or high for many tool items, including overall assessment of severity using a Visual Analogue Scale. The tool functioned equally well on biceps and quadriceps samples. A modified tool using the most reliable score items showed good correlation with measures of disease activity. CONCLUSIONS: The JDM biopsy score tool has high inter- and intraobserver agreement and can be used on both biceps and quadriceps muscle tissue. Importantly, the modified tool correlates well with clinical measures of disease activity. We propose that standardised assessment of muscle biopsy tissue should be considered in diagnostic investigation and clinical trials in JDM.
Assuntos
Dermatomiosite/patologia , Músculo Quadríceps/patologia , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Biópsia , Complexo CD3/metabolismo , Criança , Pré-Escolar , Dermatomiosite/metabolismo , Feminino , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Miosinas/metabolismo , Músculo Quadríceps/metabolismo , Reprodutibilidade dos Testes , Índice de Gravidade de DoençaRESUMO
Dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM) are four major types of idiopathic inflammatory myopathy (IIM). Muscle biopsies from each type of IIM have unique transcriptomic profiles. MicroRNAs (miRNAs) target messenger RNAs (mRNAs), thereby regulating their expression and modulating transcriptomic profiles. In this study, 18 DM, 12 IMNM, 6 AS, 6 IBM, and 6 histologically normal muscle biopsies underwent miRNA profiling using the NanoString nCounter system. Eleven miRNAs were exclusively differentially expressed in DM compared to controls, seven miRNAs were only differentially expressed in AS, and nine miRNAs were specifically upregulated in IBM. No differentially expressed miRNAs were identified in IMNM. We also analyzed miRNA-mRNA associations to identify putative targets of differentially expressed miRNAs. In DM and AS, these were predominantly related to inflammation and cell cycle progression. Moreover, our analysis showed an association between miR-30a-3p, miR-30e-3p, and miR-199b-5p downregulation in DM and the upregulation of target genes induced by type I interferon. In conclusion, we show that muscle biopsies from DM, AS, and IBM patients have unique miRNA signatures and that these miRNAs might play a role in regulating the expression of genes known to be involved in IIM pathogenesis.
Assuntos
Doenças Autoimunes , MicroRNAs , Miosite de Corpos de Inclusão , Miosite , Humanos , Miosite/genética , MicroRNAs/genética , RNA MensageiroRESUMO
INTRODUCTION: The diagnosis of amyloid myopathy is delayed when monoclonal gammopathies are not detected on initial testing and muscle biopsies are nondiagnostic, and the EMG and symptoms can mimic an inflammatory myopathy. METHODS: Case report of a patient presenting with severe progressive muscle weakness of unclear etiology despite an extensive workup including two nondiagnostic muscle biopsies. RESULTS: Directed by MRI, a third biopsy revealed amyloid angiopathy and noncongophilic kappa light chain deposition in scattered subsarcolemmal rings and perimysial regions. A serum free light chain (FLC) assay revealed a kappa monoclonal gammopathy, which was not detected by multiple immunofixations. CONCLUSIONS: The spectrum of immunoglobulin deposition in muscle is similar to other organs. It comprises a continuum that includes parenchymal amyloid deposition, amyloid angiopathy, and noncongophilic Light Chain Deposition Disease (LCDD). We recommend including the FLC assay in the routine investigation for monoclonal gammopathies. This case also highlights the value of MRI-guided muscle biopsy.
Assuntos
Cadeias Leves de Imunoglobulina/sangue , Músculo Esquelético/metabolismo , Paraproteinemias/sangue , Paraproteinemias/patologia , Adenosina Trifosfatases/metabolismo , Idoso , Amiloidose/sangue , Amiloidose/etiologia , Biópsia , Vermelho Congo , Humanos , Cadeias kappa de Imunoglobulina/metabolismo , Masculino , Músculo Esquelético/patologia , Paraproteinemias/complicaçõesRESUMO
Sporadic inclusion body myositis (IBM) is the most common acquired muscle disease in adults over age 50, yet it remains unclear whether the disease is primarily driven by T cellmediated autoimmunity. IBM muscle biopsies display nuclear clearance and cytoplasmic aggregation of TDP-43 in muscle cells, a pathologic finding observed initially in neurodegenerative diseases, where nuclear loss of TDP-43 in neurons causes aberrant RNA splicing. Here, we show that loss of TDP-43mediated splicing repression, as determined by inclusion of cryptic exons, occurs in skeletal muscle of subjects with IBM. Of 119 muscle biopsies tested, RT-PCRmediated detection of cryptic exon inclusion was able to diagnose IBM with 84% sensitivity and 99% specificity. To determine the role of T cells in pathogenesis, we generated a xenograft model by transplanting human IBM muscle into the hindlimb of immunodeficient mice. Xenografts from subjects with IBM displayed robust regeneration of human myofibers and recapitulated both inflammatory and degenerative features of the disease. Myofibers in IBM xenografts showed invasion by human, oligoclonal CD8+ T cells and exhibited MHC-I up-regulation, rimmed vacuoles, mitochondrial pathology, p62-positive inclusions, and nuclear clearance and cytoplasmic aggregation of TDP-43, associated with cryptic exon inclusion. Reduction of human T cells within IBM xenografts by treating mice intraperitoneally with anti-CD3 (OKT3) suppressed MHC-I up-regulation. However, rimmed vacuoles and loss of TDP-43 function persisted. These data suggest that T cell depletion does not alter muscle degenerative pathology in IBM.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Miosite de Corpos de Inclusão , Miosite , Animais , Linfócitos T CD8-Positivos , Proteínas de Ligação a DNA/genética , Xenoenxertos , Humanos , Camundongos , Músculo Esquelético/patologia , Miosite/diagnóstico , Miosite/patologia , Miosite de Corpos de Inclusão/diagnóstico , Miosite de Corpos de Inclusão/patologia , Vacúolos/patologiaRESUMO
OBJECTIVE: Myofiber necrosis without prominent inflammation is a nonspecific finding in patients with dystrophies and toxic or immune-mediated myopathies. However, the etiology of a necrotizing myopathy is often obscure, and the question of which patients would benefit from immunosuppression remains unanswered. The aim of this study was to identify novel autoantibodies in patients with necrotizing myopathy. METHODS: Muscle biopsy specimens and serum samples were available for 225 patients with myopathy. Antibody specificities were determined by performing immunoprecipitations from (35)S-methionine-labeled HeLa cell lysates. Selected biopsy specimens were stained for membrane attack complex, class I major histocompatibility complex (MHC), and endothelial cell marker CD31. RESULTS: Muscle biopsy specimens from 38 of 225 patients showed predominantly myofiber necrosis. Twelve of these patients had a known autoantibody association with or other etiology for their myopathy. Sixteen of the remaining 26 sera immunoprecipitated 200-kd and 100-kd proteins; this specificity was observed in only 1 of 187 patients without necrotizing myopathy. Patients with the anti-200/100 autoantibody specificity had proximal weakness (100%), high creatine kinase levels (mean maximum 10,333 IU/liter), and an irritable myopathy on electromyography (88%). Sixty-three percent of these patients had been exposed to statins prior to the onset of weakness. All patients responded to immunosuppressive therapy, and many experienced a relapse of weakness when the medication was tapered. Immunohistochemical studies showed membrane attack complex on small blood vessels in 6 of 8 patients and on the surface of non-necrotic myofibers in 4 of 8 patients. Five of 8 patients had abnormal capillary morphology, and 4 of 8 patients expressed class I MHC on the surface of non-necrotic myofibers. CONCLUSION: An anti-200/100-kd specificity defines a subgroup of patients with necrotizing myopathy who previously were considered to be autoantibody negative. We propose that these patients have an immune-mediated myopathy that is frequently associated with prior statin use and should be treated with immunosuppressive therapy.
Assuntos
Autoanticorpos/sangue , Proteínas Musculares/imunologia , Músculo Esquelético/patologia , Miosite/imunologia , Miosite/patologia , Idoso , Biomarcadores/metabolismo , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Células HeLa , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Técnicas Imunoenzimáticas , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Miosite/tratamento farmacológico , Necrose , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismoRESUMO
OBJECTIVE: Mitochondrial DNA mutations are associated with an increased risk of heart disease. Whether an increased prevalence of cardiovascular disease is present in patients presenting with mitochondrial abnormalities on skeletal muscle biopsy remains unknown. This study was designed to determine the prevalence of cardiac conduction disease and structural heart disease in patients presenting with mitochondrial abnormalities on skeletal muscle biopsy. METHODS: This is a retrospective cohort study of 103 patients with mitochondrial abnormalities on skeletal muscle biopsy who were referred for evaluation of muscle weakness at a single tertiary care referral center from 2012 to 2018. Of these patients, 59 (57.3%) had an electrocardiogram available and were evaluated for the presence of conduction disease. An echocardiogram was available in 43 patients (42%) who were evaluated for the presence of structural heart disease. The prevalence of cardiac disease was compared to control cohort populations (Framingham and the Atherosclerosis Risk in Communities, ARIC cohorts). RESULTS: Mitochondrial abnormalities associated with cardiac conduction disease (defined as QRS duration ≥ 120 msec) were present in 8.9%, versus 2.0% (p < 0.001) in the Framingham population and 2.6% (p = 0.003) in the ARIC cohort. LV systolic dysfunction (LVEF ≤ 50%) was present in 11.6%, versus 3.6% (p < 0.01) in the Framingham and 3% (p < 0.01) in the ARIC populations. Left ventricular hypertrophy was present in 28.6%, versus 13.6% (p < 0.02) in the Framingham and 10.4% (p < 0.001) in the ARIC populations. INTERPRETATION: Given the increased prevalence of cardiovascular disease, patients with mitochondrial abnormalities on skeletal muscle biopsy should undergo routine cardiac screening with physical exam, electrocardiography, and cardiac imaging.
Assuntos
DNA Mitocondrial/genética , Cardiopatias/diagnóstico , Cardiopatias/epidemiologia , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/epidemiologia , Músculo Esquelético/patologia , Biópsia , Comorbidade , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos RetrospectivosRESUMO
Rituximab is a chimeric monoclonal antibody that binds CD20 and causes the depletion of B-cell subsets. Although initially designed to treat lymphoma, it has found wide use in the management of various autoimmune conditions, including myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction. Treated myasthenia patients are often on an oral steroid-sparing agent. To determine the safety of stopping oral steroid-sparing agents at the initiation of rituximab therapy and its effectiveness we reviewed the records of 27 MG patients with rituximab, including 13 with anti-MuSK+ MG, 10 with anti-AChR+ MG, and 4 double seronegative MG patients. All patients that were on an oral steroid-sparing agent (21 of 27) were able to stop it, and they did not require re-introduction of the medication. Also, the daily prednisone dosage was significantly decreased in 20/24 patients across all three serotype groups. MGFA post intervention status analysis also showed 15/27 of all patients achieved minimal manifestation status or remission across all groups. Antibody titers decreased dramatically and promptly in anti-MuSK+ MG patients. Our data suggests that stopping oral steroid-sparing agents at initiation of rituximab therapy is safe. Also, our data indicates that rituximab is highly effective in the management of seropositive MG patients.
Assuntos
Imunossupressores/uso terapêutico , Miastenia Gravis/tratamento farmacológico , Rituximab/uso terapêutico , Esteroides/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios/uso terapêutico , Anticorpos/análise , Inibidores da Colinesterase/uso terapêutico , Estudos de Coortes , Feminino , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Colinérgicos/imunologia , Rituximab/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To define the clinical phenotype of patients with myositis with anti-U1-ribonucleoprotein (RNP) autoantibodies. METHODS: In this longitudinal cohort study, the prevalence and severity of clinical features at disease onset and during follow-up in patients with anti-U1-RNP-positive myositis were compared to those with dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM), and the antisynthetase syndrome (AS). RESULTS: Twenty anti-U1-RNP-positive patients, 178 patients with DM, 135 patients with IMNM, and 132 patients with AS were included. Anti-U1-RNP-positive patients were younger (â¼37 years) and more likely to be black (60%) than patients with AS, DM, or IMNM. Muscle weakness was a presenting feature in 15% of anti-U1-RNP-positive patients; 80% eventually developed weakness. Four of 7 anti-U1-RNP-positive patients had necrotizing muscle biopsies. Arthritis occurred in 60% of anti-U1-RNP-positive patients; this was increased compared to DM (18%) or IMNM (6%) (all p < 0.01). DM-specific skin features developed in 60% of anti-U1-RNP-positive patients. Interstitial lung disease (ILD) occurred in 45% of anti-U1-RNP-positive patients; fewer patients with DM (13%) and IMNM (6%) and more patients with AS (80%) developed ILD (all p < 0.01). Glomerulonephritis and pericarditis occurred in 25% and 40% of anti-U1-RNP-positive patients, respectively, but rarely in the other groups; these features occurred only in those with coexisting anti-Ro52 autoantibodies. No anti-U1-RNP patient had cancer-associated myositis or died during the study period. CONCLUSIONS: Patients with anti-U1-RNP myositis typically present with proximal weakness and necrotizing muscle biopsies. Arthritis, dermatitis, and ILD are the most common extramuscular clinical features. Pericarditis and glomerulonephritis are uniquely found in patients with anti-U1-RNP-positive myositis.
Assuntos
Artrite/fisiopatologia , Doenças Autoimunes/fisiopatologia , Glomerulonefrite/fisiopatologia , Debilidade Muscular/fisiopatologia , Miosite/fisiopatologia , Pericardite/fisiopatologia , Adulto , Negro ou Afro-Americano , Idade de Início , Idoso , Artrite/etiologia , Autoanticorpos/imunologia , Doenças Autoimunes/complicações , Doenças Autoimunes/etnologia , Estudos de Casos e Controles , Estudos de Coortes , Dermatomiosite/etnologia , Dermatomiosite/fisiopatologia , Feminino , Glomerulonefrite/etiologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Músculo Esquelético/patologia , Miosite/complicações , Miosite/etnologia , Miosite/imunologia , Necrose , Pericardite/etiologia , Ribonucleoproteína Nuclear Pequena U1/imunologia , População Branca , Adulto JovemRESUMO
OBJECTIVE: To define the clinical phenotype of dermatomyositis (DM) with anti-Mi2 autoantibodies. METHODS: In this longitudinal cohort study, the prevalence and severity of clinical features at disease onset and during follow-up in patients with anti-Mi2-positive DM were compared to patients with anti-Mi2-negative DM, antisynthetase syndrome (AS), and immune-mediated necrotizing myopathy (IMNM). Longitudinal anti-Mi2 autoantibody titers were assessed. RESULTS: A total of 58 patients with anti-Mi2-positive DM, 143 patients with anti-Mi2-negative DM, 162 patients with AS, and 170 patients with IMNM were included. Among patients with anti-Mi2-positive DM, muscle weakness was present in 60% at disease onset and occurred in 98% during longitudinal follow-up; fewer patients with anti-Mi2-negative DM developed weakness (85%; p = 0.008). Patients with anti-Mi2-positive DM were weaker and had higher creatine kinase (CK) levels than patients with anti-Mi2-negative DM or patients with AS. Muscle biopsies from patients with anti-Mi2-positive DM had prominent necrosis. Anti-Mi2 autoantibody levels correlated with CK levels and strength (p < 0.001). With treatment, most patients with anti-Mi2-positive DM had improved strength and CK levels; among 10 with multiple serum samples collected over 4 or more years, anti-Mi2 autoantibody titers declined in all and normalized in 3, 2 of whom stopped immunosuppressant treatment and never relapsed. Patients with anti-Mi2-positive DM had less calcinosis (9% vs 28%; p = 0.003), interstitial lung disease (5% vs 16%; p = 0.04), and fever (7% vs 21%; p = 0.02) than did patients with anti-Mi2-negative DM. CONCLUSIONS: Patients with anti-Mi2-positive DM have more severe muscle disease than patients with anti-Mi2-negative DM or patients with AS. Anti-Mi2 autoantibody levels correlate with disease severity and may normalize in patients who enter remission.
Assuntos
Autoanticorpos/imunologia , Calcinose/epidemiologia , Dermatomiosite/imunologia , Febre/epidemiologia , Doenças Pulmonares Intersticiais/epidemiologia , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/imunologia , Debilidade Muscular/epidemiologia , Adulto , Idoso , Calcinose/fisiopatologia , Estudos de Casos e Controles , Estudos de Coortes , Creatina Quinase/sangue , Dermatomiosite/sangue , Dermatomiosite/epidemiologia , Dermatomiosite/fisiopatologia , Feminino , Humanos , Estudos Longitudinais , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/fisiopatologia , Miosite/imunologia , Miosite/fisiopatologia , Necrose , Fenótipo , Prevalência , Índice de Gravidade de DoençaRESUMO
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 inclusion body myositis (IBM) is largely unknown. Moreover, the activation of the type 2 interferon (IFN2) pathway has not been comprehensively explored in myositis. In this cross-sectional study, our objective was to determine whether IFN1 and IFN2 pathways are differentially activated in different types of myositis by performing RNA sequencing on muscle biopsy samples from 119 patients with DM, IMNM, AS, or IBM and on 20 normal muscle biopsies. METHODS: The expression of IFN1- and IFN2-inducible genes was compared between the different groups. RESULTS: The expression of IFN1-inducible genes was high in DM, moderate in AS, and low in IMNM and IBM. In contrast, the expression of IFN2-inducible genes was high in DM, IBM, and AS but low in IMNM. The expression of IFN-inducible genes correlated with the expression of genes associated with inflammation and muscle regeneration. Of note, ISG15 expression levels alone performed as well as composite scores relying on multiple genes to monitor activation of the IFN1 pathway in myositis muscle biopsies. CONCLUSIONS: IFN1 and IFN2 pathways are differentially activated in different forms of myositis. This observation may have therapeutic implications because immunosuppressive medications may preferentially target each of these pathways.
Assuntos
Interferon Tipo I/genética , Interferon gama/genética , Músculo Esquelético/metabolismo , Miosite/genética , Miosite/metabolismo , Feminino , Expressão Gênica , Humanos , Interferon Tipo I/biossíntese , Interferon gama/biossíntese , Masculino , Músculo Esquelético/patologia , Miosite/patologiaRESUMO
OBJECTIVE: Although more than a dozen myositis-specific autoantibodies (MSAs) have been identified, most patients with myositis are positive for a single MSA. The specific overexpression of a given myositis autoantigen in myositis muscle has been proposed as initiating and/or propagating autoimmunity against that particular autoantigen. The present study was undertaken to test this hypothesis. METHODS: In order to quantify autoantigen RNA expression, RNA sequencing was performed on muscle biopsy samples from control subjects, MSA-positive patients with myositis, regenerating mouse muscles, and cultured human muscle cells. RESULTS: Muscle biopsy samples were available from 20 control subjects and 106 patients with autoantibodies recognizing hydroxymethylglutaryl-coenzyme A reductase (n = 40), signal recognition particles (n = 9), Jo-1 (n = 18), nuclear matrix protein 2 (n = 12), Mi-2 (n = 11), transcription intermediary factor 1γ (n = 11), or melanoma differentiation-associated protein 5 (n = 5). The increased expression of a given autoantigen in myositis muscle was not associated with autoantibodies recognizing that autoantigen (all q > 0.05). In biopsy specimens from both myositis muscle and regenerating mouse muscles, autoantigen expression correlated directly with the expression of muscle regeneration markers and correlated inversely with the expression of genes encoding mature muscle proteins. Myositis autoantigens were also expressed at high levels in cultured human muscle cells. CONCLUSION: Most myositis autoantigens are highly expressed during muscle regeneration, which may relate to the propagation of autoimmunity. However, factors other than overexpression of specific autoantigens are likely to govern the development of unique autoantibodies in individual patients with myositis.
Assuntos
Autoanticorpos/imunologia , Autoantígenos/metabolismo , Músculo Esquelético/imunologia , Miosite/imunologia , Regeneração/imunologia , Animais , Autoantígenos/imunologia , Biópsia , Células Cultivadas , Humanos , Camundongos , Mioblastos/imunologia , Mioblastos/metabolismo , Miosite/fisiopatologia , RNA/imunologia , RNA/metabolismoRESUMO
OBJECTIVE: In the context of clinical evaluations performed on our prospective myositis cohort, we noted a striking association of severe cardiac disease in myositis patients with anti-mitochondrial antibodies. We sought to review all cases of anti-mitochondrial antibody (AMA) associated myositis in our cohort to describe the clinical features of this disease subset. METHODS: We identified 7 patients with confirmed anti-mitochondrial antibodies who presented as an inflammatory myopathy. A retrospective chart review was completed to assess their clinical presentation, laboratory, imaging, electrophysiologic, and histopathologic features. RESULTS: One patient presented with dermatomyositis and 6 were classified as polymyositis using Bohan and Peter criteria. In all but one patient, a chronic course of muscle involvement was appreciated with an average of 6.5 years of weakness prior to presentation. Muscle atrophy was often noted, as well as atypical findings of scapular winging in 2 of the patients. Muscle biopsies were consistent with immune-mediated necrotizing myopathy in 4 patients, dermatomyositis in 1, polymyositis in 1 and nonspecific or granulomatous myositis in 1 patient. Changes pointing to mitochondrial alterations were seen in 2 of the 7 patients. Cardiac involvement (including myocarditis, atrial and ventricular arrhythmias, and cardiomyopathy), was seen in 5 out of 7 (71%) of the patients, and usually preceded the muscle involvement. Coexisting autoimmune conditions were seen in 3/7of the patients and included primary biliary cirrhosis, autoimmune hepatitis, psoriasis, and Hashimoto's thyroiditis. CONCLUSIONS: Anti-mitochondrial antibodies identify a distinct inflammatory myopathy phenotype that is frequently associated with chronic skeletal muscle disease and severe cardiac involvement. Early recognition of this rare entity as an immune-mediated process is important due to implications for treatment. We propose that anti-mitochondrial antibody status should be determined in patients with a compatible clinical picture.
Assuntos
Autoanticorpos/imunologia , Mitocôndrias/imunologia , Miocárdio/imunologia , Miosite/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos RetrospectivosRESUMO
OBJECTIVE: To define the clinical features of myositis patients with anti-PM/Scl-75 and/or anti-PM/Scl-100 autoantibodies at disease onset and during the course of disease and compare them to patients with other forms of myositis. METHODS: In this longitudinal cohort study, the prevalence and severity of clinical features at disease onset and during follow-up were compared between anti-PM/Scl-positive patients and those with the antisynthetase syndrome (AS), dermatomyositis (DM), and immune-mediated necrotizing myopathy (IMNM). RESULTS: Forty-one anti-PM/Scl-positive, 132 AS, 178 DM, and 135 IMNM patients were included. Although muscle weakness was a presenting feature in just 37% of anti-PM/Scl-positive patients, 93% eventually developed weakness. Unlike the other groups, anti-PM-Scl-positive patients had more severe weakness in arm abductors than hip flexors. Interstitial lung disease was a presenting feature in just 10% of anti-PM/Scl-positive patients, but occurred in 61% during follow-up; fewer patients with DM (13%, p < 0.001) and IMNM (6%, p < 0.001) and more patients with AS (80%, p < 0.05) developed interstitial lung disease during the course of disease. Mechanic's hands (80%), Raynaud syndrome (78%), sclerodactyly (66%), telangiectasias (66%), esophageal reflux disease (61%), subcutaneous edema (46%), puffy hands (39%), and calcinosis (39%) occurred more frequently in anti-PM/Scl-positive patients than in the other groups. Although 30% of anti-PM/Scl-positive patients met criteria for systemic sclerosis, less than 5% had renal crisis or finger ulcerations. No differences were found between patients with only anti-PM/Scl-100 or only anti-PM/Scl-75 autoantibodies. CONCLUSIONS: Unlike patients with DM, AS, or IMNM, anti-PM/Scl-positive patients have weaker arm abductors than hip flexors. Anti-PM/Scl-positive patients also have the most extensive extramuscular features.
Assuntos
Autoanticorpos/sangue , Doenças Autoimunes/sangue , Dermatomiosite/sangue , Complexo Multienzimático de Ribonucleases do Exossomo/imunologia , Músculo Esquelético/patologia , Miosite/sangue , Adulto , Idoso , Doenças Autoimunes/diagnóstico por imagem , Doenças Autoimunes/terapia , Estudos de Coortes , Creatina Quinase/sangue , Dermatomiosite/diagnóstico por imagem , Dermatomiosite/terapia , Eletromiografia , Feminino , Humanos , Estimativa de Kaplan-Meier , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/fisiopatologia , Miosite/diagnóstico por imagem , Miosite/terapia , Análise de Regressão , Testes de Função RespiratóriaRESUMO
OBJECTIVE: To determine if a unique subtype of scleroderma muscle disease exists by comparing the clinical features of systemic sclerosis (SSc; scleroderma) patients with predominant fibrosis on muscle biopsy to those with inflammatory muscle histopathology. METHODS: This retrospective, cross-sectional study included SSc patients with muscle weakness and an available muscle biopsy. Biopsies with fibrosis but without inflammation/necrosis were designated as "fibrosing myopathy," and those with inflammation and/or necrosis were assigned a category of "inflammatory myopathy." Clinical data, including features of SSc, serum creatine kinase (CK) levels, electromyography, autoantibody profile, and survival, were compared between the 2 groups. RESULTS: The study population consisted of 37 weak SSc patients, 8 with fibrosing myopathy and 29 with inflammatory myopathy. Compared to those with inflammatory myopathy, patients with fibrosing myopathy were more likely to have diffuse SSc skin subtype (87% versus 62%; P = 0.18), African American race (62.5% versus 37.9%; P = 0.20), and a lower mean ± SD forced vital capacity (55.5 ± 31.9 versus 66.4 ± 17.6; P = 0.23). They also had lower mean ± SD CK values (516 ± 391 versus 2,477 ± 3,511 IU/liter; P = 0.007) and lower aldolase values (13.8 ± 4.7 versus 27.3 ± 4.7; P = 0.01). Patients with fibrosing myopathy had a significantly higher mortality (5 of 8 [62.5%] versus 4 of 29 [14.3%]; P = 0.005). CONCLUSION: Fibrosing myopathy is a unique histologic subtype of muscle disease among weak patients with SSc and is associated with significantly worse mortality compared to those with inflammation and/or necrosis on muscle biopsy.
Assuntos
Músculo Esquelético/patologia , Doenças Musculares/diagnóstico , Doenças Musculares/mortalidade , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/mortalidade , Adulto , Estudos de Coortes , Estudos Transversais , Feminino , Fibrose/diagnóstico , Fibrose/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Estudos RetrospectivosRESUMO
Sporadic inclusion body myositis (IBM) is the most common primary myopathy in the elderly, but its pathoetiology is still unclear. Perturbed myocellular calcium (Ca2+) homeostasis can exacerbate many of the factors proposed to mediate muscle degeneration in IBM, such as mitochondrial dysfunction, protein aggregation, and endoplasmic reticulum stress. Ca2+ dysregulation may plausibly be initiated in IBM by immune-mediated membrane damage and/or abnormally accumulating proteins, but no studies to date have investigated Ca2+ regulation in IBM patients. We first investigated protein expression via immunoblot in muscle biopsies from IBM, dermatomyositis, and non-myositis control patients, identifying several differentially expressed Ca2+-regulatory proteins in IBM. Next, we investigated the Ca2+-signaling transcriptome by RNA-seq, finding 54 of 183 (29.5%) genes from an unbiased list differentially expressed in IBM vs. controls. Using an established statistical approach to relate genes with causal transcription networks, Ca2+ abundance was considered a significant upstream regulator of observed whole-transcriptome changes. Post-hoc analyses of Ca2+-regulatory mRNA and protein data indicated a lower protein to transcript ratio in IBM vs. controls, which we hypothesized may relate to increased Ca2+-dependent proteolysis and decreased protein translation. Supporting this hypothesis, we observed robust (4-fold) elevation in the autolytic activation of a Ca2+-activated protease, calpain-1, as well as increased signaling for translational attenuation (eIF2a phosphorylation) downstream of the unfolded protein response. Finally, in IBM samples we observed mRNA and protein under-expression of calpain-3, the skeletal muscle-specific calpain, which broadly supports proper Ca2+ homeostasis. Together, these data provide novel insight into mechanisms by which intracellular Ca2+ regulation is perturbed in IBM and offer evidence of pathological downstream effects.
Assuntos
Cálcio/metabolismo , Calpaína/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Proteínas Musculares/metabolismo , Miosite de Corpos de Inclusão/metabolismo , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Biossíntese de Proteínas , RNA Mensageiro/metabolismo , Transcriptoma , Resposta a Proteínas não DobradasRESUMO
A slowly progressive hemiparesis beginning in a single limb with evolution to the ipsilateral limb was originally described in 8 patients in 1906 by Mills. We present 5 cases of progressive hemiparetic corticospinal tract degeneration, identified by the clinical presentation and the exclusion of other etiologies using serological, imaging, and electrodiagnostic studies.
RESUMO
OBJECTIVE: Individual dermatomyositis (DM)-associated autoantibodies are associated with distinct clinical phenotypes. This study was undertaken to explore the association of these autoantibodies with specific muscle biopsy features. METHODS: DM subjects with a muscle biopsy reviewed at Johns Hopkins had sera screened for autoantibodies recognizing Mi-2, transcriptional intermediary factor 1-γ (TIF1-γ), NXP2, MDA5, Ro52, PM-Scl, and Jo1. We also included anti-Jo1positive patients with polymyositis (PM) who had a biopsy read at Johns Hopkins. Analyzed histological features included perifascicular atrophy, perivascular inflammation, mitochondrial dysfunction, primary inflammation, and myofiber necrosis. Duration of disease, biopsy location, and treatment at biopsy were also analyzed. RESULTS: We studied 91 DM and 7 anti-Jo1positive patients with PM. In univariate analyses, TIF1-γ+ patients had more mitochondrial dysfunction (47% vs 18%; p = 0.05), NXP2+ patients had less primary inflammation (0% vs 28%; p = 0.01), Mi-2+ patients had more primary inflammation (50% vs 19%; p = 0.03), and PM-Scl+ patients had more primary inflammation (67% vs 18%; p = 0.004) than those who were negative for each autoantibody. Although reliability was limited because of small sample numbers, multivariate analysis confirmed that TIF1-γ+ patients had more mitochondrial dysfunction [prevalence ratio (PR) 2.6, 95% CI 1.06.5, p = 0.05] and PM-Scl+ patients had more primary inflammation (PR 5.2, 95% CI 2.013.4; p = 0.001) independent of disease duration at biopsy, biopsy site, and treatment at biopsy. No differences in muscle biopsy features were noted between anti-Jo1positive patients diagnosed with DM and PM. CONCLUSION: The prevalence of different histological features varies according to autoantibody status in DM. Muscle biopsy features are similar in anti-Jo1 patients with and without a rash.