Tubular aggregate myopathy causing progressive fatiguable weakness.

Tubular aggregate myopathies comprise a rare group of disorders with characteristic pathological findings and heterogeneous phenotypes, including myasthenic syndrome. We describe a patient with tubular aggregate myopathy who presented with fatiguable weakness improving with pyridostigmine, respiratory involvement and possible cardiac manifestations. We highlight the utility of muscle biopsy in atypical myasthenic syndrome.

The pattern of MHC class I expression in muscle biopsies from patients with myositis and other neuromuscular disorders.

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.

Accumulation of autophagosome cargo protein p62 is common in idiopathic inflammatory myopathies.

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.

Machine learning algorithms reveal unique gene expression profiles in muscle biopsies from patients with different types of myositis.

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.

Clinical features of LRP4/agrin-antibody-positive myasthenia gravis: A multicenter study.

INTRODUCTION: Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin-antibody-positive double-seronegative myasthenia gravis (DNMG). METHODS: DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected. RESULTS: Of 181 DNMG patients, 27 (14.9%) were positive for either low-density lipoprotein receptor-related protein 4 (LRP4) or agrin antibodies. Twenty-three DNMG patients (12.7%) were positive for both antibodies. More antibody-positive patients presented with generalized symptoms (69%) compared with antibody-negative patients (43%) (P ≤ .02). Antibody-positive patients' maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody-negative patients (P ≤ .005). Seventy percent of antibody-positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody-negative patients. Most LRP4- and agrin-antibody-positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow-up of 11 years. DISCUSSION: Antibody-positive patients had more severe clinical disease than antibody-negative patients. Most DNMG patients responded to standard therapy regardless of antibody status.

Validation of a score tool for measurement of histological severity in juvenile dermatomyositis and association with clinical severity of disease.

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.

The composition of cellular infiltrates in anti-HMG-CoA reductase-associated myopathy.

INTRODUCTION: To characterize cellular infiltrates in muscle biopsies from patients with anti-3-hydroxy-3-methyl-gulatryl-CoA reductase (HMGCR)-associated myopathy. METHODS: Biopsies from 18 anti-HMGCR myopathy and 7 control dermatomyositis patients were analyzed. RESULTS: CD4+ and CD8+ T-cells were scattered within the endomysium in 50% of anti-HMGCR biopsies. All anti-HMGCR biopsies included increased endomysial and/or perivascular CD163+ M2 macrophages; CD11c+ M1 macrophages were present in 18.8%. CD123+ plasmacytoid dendritic (PD) cells were observed within the endomysium and perivascular spaces in 62.5% of anti-HMGCR biopsies. Membrane attack complex was deposited on endothelial cells in 50% and on the sarcolemma of nonnecrotic muscle fibers in 85.7% of anti-HMGCR cases. Major histocompatibility complex class I antigen was up-regulated in 87.5% of the anti-HMGCR cases. CONCLUSIONS: In addition to necrosis, scattered CD4+, CD8+, and PD cells are characteristic of anti-HMGCR myopathy. Predominant M2 polarization suggests infiltrating macrophages are more likely to be involved with tissue repair than destruction.

A Heterozygous Mutation in MFF Associated with a Mild Mitochondrial Phenotype.

BACKGROUND: The number of mutations in nuclear encoded genes causing mitochondrial disease is ever increasing. Identification of these mutations is particularly important in the diagnosis of neuromuscular disorders as their presentation may mimic other acquired disorders.We present a novel heterozygous variant in mitochondrial fission factor (MFF) which mimics myasthenia gravis. OBJECTIVE: To determine if the MFF c.937G>A, p.E313K variant causes a mild mitochondrial phenotype. METHODS: We used whole exome sequencing (WES) to identify a novel heterozygous variant in MFF in a patient with ptosis, fatigue and muscle weakness. Using patient derived fibroblasts, we performed assays to evaluate mitochondrial and peroxisome dynamics. RESULTS: We show that fibroblasts derived from this patient are defective in mitochondrial fission, despite normal recruitment of Drp1 to the mitochondria. CONCLUSIONS: The MFF c.937G>A, p.E313K variant leads to a mild mitochondrial phenotype and is associated with defective mitochondrial fission in patient-derived fibroblasts.

Coordinated local RNA overexpression of complement induced by interferon gamma in myositis.

Complement proteins are deposited in the muscles of patients with myositis. However, the local expression and regulation of complement genes within myositis muscle have not been well characterized. In this study, bulk RNA sequencing (RNAseq) analyses of muscle biopsy specimens revealed that complement genes are locally overexpressed and correlate with markers of myositis disease activity, including the expression of interferon-gamma (IFNγ)-induced genes. Single cell and single nuclei RNAseq analyses showed that most local expression of complement genes occurs in macrophages, fibroblasts, and satellite cells, with each cell type expressing different sets of complement genes. Biopsies from immune-mediated necrotizing myopathy patients, who have the lowest levels of IFNγ-induced genes, also had the lowest complement gene expression levels. Furthermore, data from cultured human cells showed that IFNγ upregulates complement expression in macrophages, fibroblasts, and muscle cells. Taken together, our results suggest that in myositis muscle, IFNγ coordinates the local overexpression of complement genes that occurs in several cell types.

Identification of Unique microRNA Profiles in Different Types of Idiopathic Inflammatory Myopathy.

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.

Expanding the spectrum of monoclonal light chain deposition disease in muscle.

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.

Clinical and histopathological features of myositis in systemic lupus erythematosus.

OBJECTIVE: The objectives of this study were to compare the clinical features of patients with SLE with and without myopathy and to describe the muscle biopsy features of patients with SLE myopathy. METHODS: This nested case-control study included all subjects enrolled in the Hopkins Lupus Cohort database from May 1987 to June 2016. Subjects with elevated creatine kinase along with evidence of muscle oedema on MRI, myopathic electromyography and/or myopathic muscle biopsy features were defined as having SLE myopathy. Demographic, serological and clinical features were compared between patients with SLE with and without myopathy. Muscle biopsies were histologically classified as polymyositis, dermatomyositis, necrotising myopathy or non-specific myositis. RESULTS: From among 2437 patients with SLE, 179 (7.3%) had myopathy. African American patients were more likely to develop myositis than Caucasian patients (p<0.0001). Compared with those without myopathy, patients with SLE myopathy were more likely to have malar rash (OR 1.67, 1.22-2.29), photosensitivity (OR 1.43, 1.04-1.96), arthritis (OR 1.81, 1.21-2.69), pleurisy (OR 1.77, 1.3-2.42), pericarditis (OR 1.49, 1.06-2.08), acute confusional state (OR 2.07, 1.09-3.94), lymphopaenia (OR 1.64, 1.2-2.24), anti-double-stranded DNA antibodies (OR 1.52, 1.09-2.13), lupus anticoagulant (OR 1.42, 1-2), cognitive impairment (OR 1.87, 1.12-3.13), cataract (OR 1.5, 1.04-2.18), pulmonary hypertension (OR 1.98, 1.13-3.47), pleural fibrosis (OR 2.01, 1.27-3.18), premature gonadal failure (OR 1.9, 1.05-3.43), diabetes (OR 1.92, 1.22-3.02) or hypertension (OR 1.45, 1.06-2). Among 16 muscle biopsies available for review, the most common histological classifications were necrotising myositis (50%) and dermatomyositis (38%). CONCLUSIONS: Patients with SLE myopathy have a higher prevalence of numerous SLE disease manifestations. Necrotising myopathy and dermatomyositis are the most prevalent histopathological features in SLE myopathy.

Loss of TDP-43 function and rimmed vacuoles persist after T cell depletion in a xenograft model of sporadic inclusion body myositis.

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.

Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy.

Unique autoantibody specificities are strongly associated with distinct clinical phenotypes, making autoantibodies useful for diagnosis and prognosis. To investigate the mechanisms underlying this striking association, we examined autoantigen expression in normal muscle and in muscle from patients with autoimmune myositis. Although myositis autoantigens are expressed at very low levels in control muscle, they are found at high levels in myositis muscle. Furthermore, increased autoantigen expression correlates with differentiation state, such that myositis autoantigen expression is increased in cells that have features of regenerating muscle cells. Consistent with this, we found that cultured myoblasts express high levels of autoantigens, which are strikingly down-regulated as cells differentiate into myotubes in vitro. These data strongly implicate regenerating muscle cells rather than mature myotubes as the source of ongoing antigen supply in autoimmune myositis. Myositis autoantigen expression is also markedly increased in several cancers known to be associated with autoimmune myositis, but not in their related normal tissues, demonstrating that tumor cells and undifferentiated myoblasts are antigenically similar. We propose that in cancer-associated myositis, an autoimmune response directed against cancer cross-reacts with regenerating muscle cells, enabling a feed-forward loop of tissue damage and antigen selection. Regulating pathways of antigen expression may provide unrecognized therapeutic opportunities in autoimmune diseases.

A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy.

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.

Prevalence of heart disease in patients with mitochondrial abnormalities on skeletal muscle biopsy.

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.

Epidemiological evidence for a hereditary contribution to myasthenia gravis: a retrospective cohort study of patients from North America.

OBJECTIVES: To approximate the rate of familial myasthenia gravis and the coexistence of other autoimmune disorders in the patients and their families. DESIGN: Retrospective cohort study. SETTING: Clinics across North America. PARTICIPANTS: The study included 1032 patients diagnosed with acetylcholine receptor antibody (AChR)-positive myasthenia gravis. METHODS: Phenotype information of 1032 patients diagnosed with AChR-positive myasthenia gravis was obtained from clinics at 14 centres across North America between January 2010 and January 2011. A critical review of the epidemiological literature on the familial rate of myasthenia gravis was also performed. RESULTS: Among 1032 patients, 58 (5.6%) reported a family history of myasthenia gravis. A history of autoimmune diseases was present in 26.6% of patients and in 28.4% of their family members. DISCUSSION: The familial rate of myasthenia gravis was higher than would be expected for a sporadic disease. Furthermore, a high proportion of patients had a personal or family history of autoimmune disease. Taken together, these findings suggest a genetic contribution to the pathogenesis of myasthenia gravis.

Stopping oral steroid-sparing agents at initiation of rituximab in myasthenia gravis.

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.

Muscular and extramuscular features of myositis patients with anti-U1-RNP autoantibodies.

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 (∼37 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.