Publications by authors named "Iago Pinal-Fernandez"

83 Publications

Anti-mitochondrial autoantibodies are associated with cardiomyopathy, dysphagia, and features of more severe disease in adult-onset myositis.

Clin Rheumatol 2021 Apr 13. Epub 2021 Apr 13.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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 myositis (IBM), or amyopathic DM patients and from healthy controls, including 164 adults and 92 children, for AMA by ELISA. Clinical characteristics were compared between myositis patients with and without AMA. AMA were present in 5% of adult myositis patients (16 of 216 DM, 10 of 222 PM, 4 of 140 IBM, 1 of 19 amyopathic DM), 1% of juvenile myositis patients (3 of 302 JDM, 1 of 25 JPM), and 1% of both adult and juvenile healthy controls. In patients with adult-onset myositis, AMA were associated with persistent muscle weakness, Raynaud's phenomenon, dysphagia, and cardiomyopathy. Adult myositis patients with AMA may have more severe or treatment refractory disease, as they more frequently received glucocorticoids and intravenous immunoglobulin. In juvenile myositis, children with AMA often had falling episodes and dysphagia, but no other clinical features or medications were significantly associated with AMA. AMA are present in 5% of adult myositis patients and associated with cardiomyopathy, dysphagia, and other signs of severe disease. The prevalence of AMA is not increased in patients with juvenile myositis compared to age-matched healthy controls. Our data suggest that the presence of AMA in adult myositis patients should prompt screening for cardiac and swallowing involvement. Key Points • Approximately 5% of a large North American cohort of adult myositis patients have anti-mitochondrial autoantibodies. • Adults with anti-mitochondrial autoantibodies often have chronic weakness, Raynaud's, dysphagia, cardiomyopathy, and more severe disease. • Anti-mitochondrial autoantibodies are rare in juvenile myositis and not associated with a specific clinical phenotype.
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http://dx.doi.org/10.1007/s10067-021-05730-7DOI Listing
April 2021

Myositis-specific autoantibodies as relevant adjusting variables in myositis research.

Arthritis Rheumatol 2021 Mar 1. Epub 2021 Mar 1.

Muscle Disease Unit, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.

We have read with great interest the article of Dr. Hou et al.(1) in which muscle ISG15 expression was shown to be strongly associated with the diagnosis of juvenile dermatomyositis. Moreover, they found that anti-MDA5 juvenile dermatomyositis patients have a higher expression of ISG15 than other subgroups. This confirms previous studies, both in adults and in children, emphasizing the relevance of the interferon pathway in patients with dermatomyositis.(2-6).
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http://dx.doi.org/10.1002/art.41705DOI Listing
March 2021

Response to Treatment in IgG4-Related Disease Assessed by Quantitative PET/CT Scan.

Clin Nucl Med 2021 06;46(6):e307-e311

From the Division of Systemic Autoimmune Diseases, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Barcelona, Spain.

Objective: The aim of this study was to assess disease activity by different PET/CT measurements in IgG4-related disease (IgG4-RD) flares and their correlation with the IgG4-RD responder index (IgG4-RI).

Patients And Methods: Patients were retrospectively recruited from a single center in Barcelona, Spain. They all had IgG4-RD flares with an 18F-FDG PET/CT examination performed within the 2 first weeks of the flare onset and another one after at least 3 months of treatment between 2012 and 2018. Epidemiologic, clinical, laboratory, and therapeutic data were collected at baseline and at follow-up. Semiquantitative and volumetric measurements from PET/CT explorations were recorded. In addition, a 5-point visual scale was (adapted Deauville score) trialed. The IgG4-RI was used as the criterion standard to assess response before and after treatment.

Results: Eighteen patients with a total of 23 flares were included. The median time to second PET/CT examination was 7 months. Remission (complete and partial) according to IgG4-RI was observed in 20 flares (87%). All PET/CT measurements (SUVmax and SUVmean, total lesion glycolysis, MTV, and adapted Deauville score) were statistically significantly lower on the follow-up evaluation, except for the size of the lesion. The correlation of all these parameters with the IgG4-RI was positive except for SUVmean and the size of the lesion.

Conclusions: Semiquantitative, volumetric, and visual parameters in PET/CT scans correlated with response to treatment assessed by IgG4-RI. Volumetric and visual items are less subject to variations and could be used to improve activity scores and treatment strategies.
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http://dx.doi.org/10.1097/RLU.0000000000003537DOI Listing
June 2021

Response to: 'Correspondence on 'Machine learning algorithms reveal unique gene expression profiles in muscle biopsies from patients with different types of myositis'' by Takanashi .

Ann Rheum Dis 2021 Jan 13. Epub 2021 Jan 13.

Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA

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http://dx.doi.org/10.1136/annrheumdis-2020-219767DOI Listing
January 2021

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

Clin Exp Rheumatol 2021 Mar-Apr;39(2):351-356. Epub 2020 Sep 1.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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.
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April 2021

The indirect immunofluorescence assay autoantibody profiles of myositis patients without known myositis-specific autoantibodies.

Clin Exp Rheumatol 2021 May-Jun;39(3):519-524. Epub 2020 Sep 3.

National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, and Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Objectives: The indirect immunofluorescence assay (IIFA) is used to screen for the presence of autoantibodies. Our objective was to determine the prevalence and clinical features of IIFA positive myositis patients without known myositis-specific autoantibodies (MSA).

Methods: Sera from healthy comparators (HC) and patients with dermatomyositis (DM), inclusion body myositis (IBM), and polymyositis (PM) with no detectable MSA were tested by IIFA on HEp-2 cells. The pattern of positivity was classified according to the International Consensus on Antinuclear Antibody Patterns. The prevalence and frequency of each IIFA pattern were compared between the different groups.

Results: Sera from 100 HC, 71 DM, 53 IBM, and 69 PM subjects were included in the study. The IIFA was positive in 35% HC compared to 66% DM (p<0.001), 49% IBM, and 64% (p<0.001) PM sera. Among IIFA positive sera, the staining was moderate or intense in 43% HC compared to 79% DM (p<0.001) but just 54% IBM, and 52% PM sera. IIFA positivity was predominantly nuclear in all groups (all >69%). The most common pattern in myositis patients was fine speckled with no differences between groups. In general, IIFA positive and negative DM patients showed similar clinical features and disease activity.

Conclusions: Half of MSA-negative DM patients have moderate/strong IIFA positivity, predominantly with a fine speckled pattern. In contrast, MSA-negative PM, IBM, and healthy comparators are more often weakly positive for IIFA. These findings suggest that unidentified autoantibodies are more likely to exist in DM patients than in the other myositis groups.
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May 2021

Ultra-efficient sequencing of T Cell receptor repertoires reveals shared responses in muscle from patients with Myositis.

EBioMedicine 2020 Sep 3;59:102972. Epub 2020 Sep 3.

Division of Immunology, Pathology Department, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Background: Myositis, or idiopathic inflammatory myopathy (IIM), is a group disorders of unknown etiology characterized by the inflammation of skeletal muscle. The role of T cells and their antigenic targets in IIM initiation and progression is poorly understood. T cell receptor (TCR) repertoire sequencing is a powerful approach for characterizing complex T cell responses. However, current TCR sequencing methodologies are complex, expensive, or both, greatly limiting the scale of feasible studies.

Methods: Here we present Framework Region 3 AmplifiKation sequencing ("FR3AK-seq"), a simplified multiplex PCR-based approach for the ultra-efficient and quantitative analysis of TCR complementarity determining region 3 (CDR3) repertoires. By using minimal primer sets targeting a conserved region immediately upstream of CDR3, undistorted amplicons are analyzed via short read, single-end sequencing. We also introduce the novel algorithm Inferring Sequences via Efficiency Projection and Primer Incorporation ("ISEPPI") for linking CDR3s to their associated variable genes.

Findings: We find that FR3AK-seq is sensitive and quantitative, performing comparably to two different industry standards. FR3AK-seq and ISEPPI were used to efficiently and inexpensively characterize the T cell infiltrates of surgical muscle biopsies obtained from 145 patients with IIM and controls. A cluster of closely related TCRs was identified in samples from patients with sporadic inclusion body myositis (IBM).

Interpretation: The ease and minimal cost of FR3AK-seq removes critical barriers to routine, large-scale TCR CDR3 repertoire analyses, thereby democratizing the quantitative assessment of human TCR repertoires in disease-relevant target tissues. Importantly, discovery of closely related TCRs in muscle from patients with IBM provides evidence for a shared antigen-driven T cell response in this disease of unknown pathogenesis.

Funding: This work was supported by NIH grant U24AI118633 and a Prostate Cancer Foundation Young Investigator Award.
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http://dx.doi.org/10.1016/j.ebiom.2020.102972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484536PMC
September 2020

Risk factors associated with Pneumocystis jirovecii pneumonia in juvenile myositis in North America.

Rheumatology (Oxford) 2021 02;60(2):829-836

Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.

Objectives: Pneumocystis jirovecii pneumonia (PJP) is associated with significant morbidity and mortality in adult myositis patients; however, there are few studies examining PJP in juvenile myositis [juvenile idiopathic inflammatory myopathy (JIIM)]. The purpose of this study was to determine the risk factors and clinical phenotypes associated with PJP in JIIM.

Methods: An research electronic data capture (REDCap) questionnaire regarding myositis features, disease course, medications and PJP infection characteristics was completed by treating physicians for 13 JIIM patients who developed PJP (PJP+) from the USA and Canada. Myositis features and medications were compared with 147 JIIM patients without PJP (PJP-) from similar geographic regions who enrolled in National Institutes of Health natural history studies.

Results: PJP+ patients were more often of Asian ancestry than PJP- patients [odds ratio (OR) 8.7; 95% CI 1.3, 57.9]. Anti- melanoma differentiation associated protein 5 (MDA5) autoantibodies (OR 12.5; 95% CI 3.0, 52.4), digital infarcts (OR 43.8; 95% CI 4.2, 460.2), skin ulcerations (OR 12.0; 95% CI 3.5, 41.2) and interstitial lung disease (OR 10.6; 95% CI 2.1, 53.9) were more frequent in PJP+ patients. Before PJP diagnosis, patients more frequently received pulse steroids, rituximab and more immunosuppressive therapy compared with PJP- patients. Seven PJP+ patients were admitted to the intensive care unit and four patients died due to PJP or its complications.

Conclusions: PJP is a severe infection in JIIM that can be associated with mortality. Having PJP was associated with more immunosuppressive therapy, anti-MDA5 autoantibodies, Asian race and certain clinical features, including digital infarcts, cutaneous ulcerations and interstitial lung disease. Prophylaxis for PJP should be considered in juvenile myositis patients with these features.
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http://dx.doi.org/10.1093/rheumatology/keaa436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850515PMC
February 2021

Performance of the 2019 ACR/EULAR classification criteria for IgG4-related disease and clinical phenotypes in a Spanish multicentre registry (REERIGG4).

Rheumatology (Oxford) 2021 01;60(1):217-223

Internal Medicine Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain.

Objectives: Several IgG4-related disease (IgG4-RD) phenotypes have been proposed and the first set of classification criteria have been recently created. Our objectives were to assess the phenotype distribution and the performance of the classification criteria in Spanish patients as genetic and geographical differences may exist.

Methods: We performed a cross-sectional multicentre study (Registro Español de Enfermedad Relacionada con la IgG4, REERIGG4) with nine participating centres from Spain. Patients were recruited from November 2013 to December 2018. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria (AECC) were used.

Results: We included 105 patients; 88% had Caucasian ethnicity. On diagnosis, 86% met the international pathology consensus while 92% met the Japanese comprehensive criteria. The phenotype distribution was head and neck 25%, Mikulicz and systemic (MS) 20%, pancreato-hepato-biliary (PHB) 13%, retroperitoneal and aorta (RA) 26%. Sixteen per cent had an undefined phenotype. Seventy-seven per cent of the cases met the AECC. From the 24 patients not meeting the AECC, 33% met exclusion criteria, and 67% did not get a score ≥20 points. Incomplete pathology reports were associated to failure to meet the AECC.

Conclusions: The PHB phenotype was rare among Spanish IgG4-RD patients. The MS phenotype was less frequent and the RA phenotype was more prevalent than in other, Asian patient series. An undefined phenotype should be considered as some patients do not fall into any of the categories. Three quarters of the cases met the 2019 AECC. Incomplete pathology reports were the leading causes of failure to meet the criteria.
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http://dx.doi.org/10.1093/rheumatology/keaa247DOI Listing
January 2021

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

Ann Rheum Dis 2020 09 16;79(9):1234-1242. Epub 2020 Jun 16.

Muscle Disease Unit, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Insititutes of Health, Bethesda, Maryland, USA

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.
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http://dx.doi.org/10.1136/annrheumdis-2019-216599DOI Listing
September 2020

Neutrophil dysregulation is pathogenic in idiopathic inflammatory myopathies.

JCI Insight 2020 02 13;5(3). Epub 2020 Feb 13.

Systemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, Maryland, USA.

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 whether pathogenic neutrophil subsets (low-density granulocytes [LDGs]) and NETs were elevated in IIM, associated with clinical presentation and MSAs, and their effect on skeletal myoblasts and myotubes. Circulating NETs and LDGs were quantified and correlated with clinical measures. Specific MSAs were tested for their ability to induce NETs. NETs and neutrophil gene expression were measured in IIM biopsies. Whether NETs damage skeletal myoblasts and myotubes was tested. Circulating LDGs and NETs were increased in IIM. IIM LDGs had an enhanced ability to form NETs. LDGs and NETs correlated with IIM disease activity and muscle damage. The serum MSA anti-MDA5 correlated with circulating and tissue NETs and directly enhanced NET formation. An enhanced neutrophil gene signature was present in IIM muscle and associated with muscle injury and tissue IFN gene signatures. IIM NETs decreased the viability of myotubes in a citrullinated histone-dependent manner. Dysregulated neutrophil pathways may play pathogenic roles in IIM through their ability to directly injure muscle cells and other affected tissues.
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http://dx.doi.org/10.1172/jci.insight.134189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098779PMC
February 2020

Trim33 (Tif1γ) is not required for skeletal muscle development or regeneration but suppresses cholecystokinin expression.

Sci Rep 2019 12 6;9(1):18507. Epub 2019 Dec 6.

National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.

The expression of Trim33 (Tif1γ) increases in skeletal muscles during regeneration and decreases upon maturation. Although Trim33 is required for the normal development of other tissues, its role in skeletal muscle is unknown. The current study aimed to define the role of Trim33 in muscle development and regeneration. We generated mice with muscle-specific conditional knockout of Trim33 by combining floxed Trim33 and Cre recombinase under the Pax7 promoter. Muscle regeneration was induced by injuring mouse muscles with cardiotoxin. We studied the consequences of Trim33 knockdown on viability, body weight, skeletal muscle histology, muscle regeneration, and gene expression. We also studied the effect of Trim33 silencing in satellite cells and the C2C12 mouse muscle cell line. Although Trim33 knockdown mice weighed less than control mice, their skeletal muscles were histologically unremarkable and regenerated normally following injury. Unexpectedly, RNAseq analysis revealed dramatically increased expression of cholecystokinin (CCK) in regenerating muscle from Trim33 knockout mice, satellite cells from Trim33 knockout mice, and C2C12 cells treated with Trim33 siRNA. Trim33 knockdown had no demonstrable effect on muscle differentiation or regeneration. However, Trim33 knockdown induced CCK expression in muscle, suggesting that suppression of CCK expression requires Trim33.
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http://dx.doi.org/10.1038/s41598-019-54651-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898130PMC
December 2019

PET Scan: Nuclear Medicine Imaging in Myositis.

Curr Rheumatol Rep 2019 11 21;21(11):64. Epub 2019 Nov 21.

National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Johns Hopkins University School of Medicine, Baltimore, USA.

Purpose Of Review: Positron emission tomography (PET) combined with computed tomography (CT) has proven useful as a cancer screening technique in patients with inflammatory myopathy, mainly dermatomyositis. In this review, we focus on advances in this direction and other potential applications of PET/CT in patients with inflammatory myopathy.

Recent Findings: Cancer screening by PET/CT seems suitable and cost-effective in patients with myositis. It has also shown value as a hybrid technique for diagnosing myositis versus controls and could be of interest for differentiating between polymyositis and sporadic inclusion body myositis. Quantification of muscle activity by PET/CT seems reliable. Preliminary data suggest that it could also be used to diagnose and measure the activity of the disease in the lung. PET/CT should be in the toolbox of physicians managing patients with myositis. The multiple applications of PET/CT include its value for cancer screening, measuring the activity of the disease in muscle, and helping to differentiate between myositis phenotypes. The possibility to diagnose and monitor inflammatory lung activity remains to be demonstrated in well-designed studies.
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http://dx.doi.org/10.1007/s11926-019-0864-3DOI Listing
November 2019

Validation of anti-Mi2 autoantibody testing by line blot.

Autoimmun Rev 2020 Jan 14;19(1):102425. Epub 2019 Nov 14.

Muscle Disease Unit, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, United States of America; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. Electronic address:

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http://dx.doi.org/10.1016/j.autrev.2019.102425DOI Listing
January 2020

Case 22-2019: A 65-Year-Old Woman with Myopathy.

N Engl J Med 2019 10;381(17):1693-1694

National Institutes of Health, Bethesda, MD

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http://dx.doi.org/10.1056/NEJMc1911058DOI Listing
October 2019

Malignancy and myositis, from molecular mimicry to tumor infiltrating lymphocytes.

Neuromuscul Disord 2019 11 26;29(11):819-825. Epub 2019 Sep 26.

National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Johns Hopkins University School of Medicine, Baltimore, United States.

Cancer-associated dermatomyositis provides a unique opportunity to explore the relationship between autoimmunity and cancer. In this review, we describe the related epidemiological issues, considering the various currently accepted myositis phenotypes, their link with cancer, and the possible mechanisms leading to this relationship. We discuss current evidence regarding the role of molecular mimicry, somatic DNA tumor mutations, and the PD-1/PD-L1 pathway in the association between cancer and myositis. We also review tumor-infiltrating lymphocytes as a relevant factor to be evaluated in cancer-associated myositis, their interaction with tumor neoantigens, and the tumor mutational burden, all of which have implications for the treatment of these patients with immunotherapy. Finally, we discuss clinical scenarios related to the relationship between cancer and myositis, delineating a comprehensive theory linking autoimmunity and cancer.
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http://dx.doi.org/10.1016/j.nmd.2019.09.014DOI Listing
November 2019

More prominent muscle involvement in patients with dermatomyositis with anti-Mi2 autoantibodies.

Neurology 2019 11 8;93(19):e1768-e1777. Epub 2019 Oct 8.

From the Muscle Disease Unit, Laboratory of Muscle Stem Cells and Gene Regulation (I.P.-F., M.C.-D., K.P., Y.H., W.H., A.L.M.), National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda; Departments of Neurology (I.P.-F., M.C.-D., A.M.C., L.C.-S., A.L.M.) and Medicine (C.A.M., J.A., E.T., J.J.P., S.K.D., L.C.-S., A.L.M.), Johns Hopkins University School of Medicine, Baltimore, MD; Faculty of Health Sciences (I.P.-F.), Universitat Oberta de Catalunya, Barcelona, Spain; Department of Medicine (J.H.), Medstar Georgetown University Hospital, Washington, DC; and Department of Medicine (C.J.), Hospital of the University of Pennsylvania, Philadelphia.

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%; = 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 ( < 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%; = 0.003), interstitial lung disease (5% vs 16%; = 0.04), and fever (7% vs 21%; = 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.
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http://dx.doi.org/10.1212/WNL.0000000000008443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946486PMC
November 2019

Identification of distinctive interferon gene signatures in different types of myositis.

Neurology 2019 09 21;93(12):e1193-e1204. Epub 2019 Aug 21.

From the National Institute of Arthritis and Musculoskeletal and Skin Diseases (I.P.-F, M.C.-D, A.D., K.P., P.P., F.W.M., A.L.M.), NIH, Bethesda; Johns Hopkins University School of Medicine (I.P.-F., M.C.-D., J.P., J.A., L.C.-S., T.E.L., A.M.C., A.L.M.), Baltimore, MD; Clinic Hospital and the University of Barcelona (J.C.M., J.M.G.-J.); Vall d'Hebron Hospital and Autonomous University of Barcelona (A.S.-O.); and Faculty of Health Sciences (I.P.-F.), Universitat Oberta de Catalunya, Barcelona, Spain.

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, 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.
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http://dx.doi.org/10.1212/WNL.0000000000008128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6808530PMC
September 2019

Sporadic inclusion body myositis: Diagnostic value of p62 immunostaining.

Med Clin (Barc) 2019 12 26;153(11):437-440. Epub 2019 Jun 26.

Muscle Research Unit, Internal Medicine Service, Hospital Clínic de Barcelona, Universidad de Barcelona and Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain.

Background And Objectives: Sporadic inclusion body myositis (sIBM) diagnosis is frequently delayed or confused with another class of disorders, and misdiagnosis is common. Sometimes, we have problems diagnosing an sIBM in the early stages or predicting when a PM is going to become an sIBM. In this sense, we believe that p62 immunostaining could help clinicians.

Case Report: We report the case of a 61-year-old patient with sIBM who six years earlier had been diagnosed with polymyositis (PM). After muscle biopsies analyses, we showed the natural history of sIBM by p62 expression.

Results: When we looked for p62 aggregates retrospectively we could see small dotted p62 aggregates in the muscle fibres of the first muscle biopsy. Six years later, the patient presented with the typical clinical picture of sIBM, also the muscle biopsy was characteristic, with large p62 aggregates.

Conclusions: Probably p62 immunostaining could help to distinguish PM patients that are going to become sIBM, but to date there has been no systematic study to clarify p62 utility in myositis.
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http://dx.doi.org/10.1016/j.medcli.2019.04.022DOI Listing
December 2019

Long-Term Treatment With Azathioprine and Mycophenolate Mofetil for Myositis-Related Interstitial Lung Disease.

Chest 2019 11 22;156(5):896-906. Epub 2019 Jun 22.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD. Electronic address:

Background: The efficacy of azathioprine (AZA) and mycophenolate mofetil (MMF) for interstitial lung disease (ILD) has been described, but mainly in connective tissue disease-associated ILD. The objective of this study was to evaluate the effect of AZA and MMF on lung function and prednisone dose in myositis-related ILD (M-ILD).

Methods: In this retrospective study, patients with M-ILD seen at Johns Hopkins and treated with AZA or MMF and no other steroid-sparing agents were included. Linear mixed-effects models adjusted for sex, age, antisynthetase antibody, and smoking status were used to compare the change in FVC % predicted, diffusing capacity of the lungs for carbon monoxide (Dlco) % predicted, and prednisone dose.

Results: Sixty-six patients with M-ILD were treated with AZA and 44 with MMF. At treatment initiation, mean FVC % predicted and Dlco % predicted were significantly lower in the AZA group than in the MMF group. In both groups, FVC % predicted improved and the prednisone dose was reduced over 2 to 5 years; however, for Dlco % predicted, only the AZA group improved. The adjusted model showed no significant difference in posttreatment FVC % predicted or Dlco % predicted between groups (mean difference of 1.9 and -8.2, respectively), but a 6.6-mg lower dose of prednisone at 36 months in the AZA group. Adverse events were more frequent with AZA than MMF (33.3% vs 13.6%; P = .04).

Conclusions: In M-ILD, AZA treatment was associated with improved FVC % predicted and Dlco % predicted, and lower prednisone dose. Patients treated with MMF had improved FVC % predicted and lower prednisone dose. After 36 months, patients treated with AZA received a lower prednisone dose than those treated with MMF.
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http://dx.doi.org/10.1016/j.chest.2019.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945652PMC
November 2019

On using machine learning algorithms to define clinically meaningful patient subgroups.

Ann Rheum Dis 2020 10 21;79(10):e128. Epub 2019 Jun 21.

Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Laboratory of Muscle Stem Cells and Gene Expression, Bethesda, Maryland, USA

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http://dx.doi.org/10.1136/annrheumdis-2019-215852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509515PMC
October 2020

Response to: 'Comment on: 'Anti-Ro52 autoantibodies are associated with interstitial lung disease and more severe disease in patients with juvenile myositis' by Sabbagh S by Yang .

Ann Rheum Dis 2020 08 17;79(8):e97. Epub 2019 Jun 17.

Muscle Disease Unit, Laboratory of Muscle Stem Cells and Gene Expression, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA

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http://dx.doi.org/10.1136/annrheumdis-2019-215693DOI Listing
August 2020

Efficacy and adverse effects of methotrexate compared with azathioprine in the antisynthetase syndrome.

Clin Exp Rheumatol 2019 Sep-Oct;37(5):858-861. Epub 2019 Apr 29.

Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Objectives: To study the efficacy in terms of muscle strength, and corticosteroid tapering as well as the prevalence of adverse effects in patients with the antisynthetase syndrome (ASyS) treated with azathioprine (AZA) compared to those treated with methotrexate (MTX).

Methods: We compared the clinical outcomes in ASyS patients treated with AZA versus MTX including change in corticosteroid dose, strength, and creatine kinase (CK) as well as the prevalence of adverse effects.

Results: Among 169 patients with ASyS, 102 were treated at some point exclusively with either AZA or MTX (± corticosteroids). There were no significant differences in the rate of muscle strength recovery, CK decrease or corticosteroid tapering between those ASyS patients treated with MTX versus AZA. The prevalence of adverse events in patients treated with AZA and MTX was similar (29% vs. 25%, p>0.05); elevated liver enzymes (17% AZA vs. 12% MTX) and gastrointestinal involvement (10% AZA vs. 8% MTX) were the most common adverse events. While no patients treated with AZA developed lung complications, two of the patients treated with MTX experienced reversible pneumonitis with MTX cessation.

Conclusions: AZA and MTX showed similar efficacy and adverse events in patients with ASyS. Pneumonitis is a rare but important event in patients receiving MTX.
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October 2019

Amyloid-PET: a new tool for diagnosing IBM?

Nat Rev Rheumatol 2019 06;15(6):321-322

Muscle Disease Unit, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.1038/s41584-019-0223-9DOI Listing
June 2019

Anti-Ro52 autoantibodies are associated with interstitial lung disease and more severe disease in patients with juvenile myositis.

Ann Rheum Dis 2019 07 24;78(7):988-995. Epub 2019 Apr 24.

Environmental Autoimmunity Group, National Institute of EnvironmentalHealth Sciences, National Institutes of Health (NIH), Bethesda, MD, United States.

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 associated with anti-Ro52 autoantibodies in a large cohort of patients with juvenile myositis.

Methods: We screened sera from 302 patients with juvenile dermatomyositis (JDM), 25 patients with juvenile polymyositis (JPM) and 44 patients with juvenile connective tissue disease-myositis overlap (JCTM) for anti-Ro52 autoantibodies by ELISA. Clinical characteristics were compared between myositis patients with and without anti-Ro52 autoantibodies.

Results: Anti-Ro52 autoantibodies were found in 14% patients with JDM, 12% with JPM and 18% with JCTM. Anti-Ro52 autoantibodies were more frequent in patients with antiaminoacyl tRNA synthetase (64%, p<0.001) and anti-MDA5 (31%, p<0.05) autoantibodies. After controlling for the presence of myositis-specific autoantibodies, anti-Ro52 autoantibodies were associated with the presence of ILD (36% vs 4%, p<0.001). Disease course was more frequently chronic, remission was less common, and an increased number of medications was received in anti-Ro52 positive patients.

Conclusions: Anti-Ro52 autoantibodies are present in 14% of patients with juvenile myositis and are strongly associated with anti-MDA5 and antiaminoacyl tRNA synthetase autoantibodies. In all patients with juvenile myositis, those with anti-Ro52 autoantibodies were more likely to have ILD. Furthermore, patients with anti-Ro52 autoantibodies have more severe disease and a poorer prognosis.
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http://dx.doi.org/10.1136/annrheumdis-2018-215004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570952PMC
July 2019

The ILD-GAP risk prediction model performs poorly in myositis-associated interstitial lung disease.

Respir Med 2019 04 21;150:63-65. Epub 2019 Feb 21.

Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 500, Baltimore, MD, 21224, USA. Electronic address:

Purpose: Myositis-associated interstitial lung disease (MA-ILD) is associated with increased mortality, but no prognostic model exists in this population. The ILD-GAP index was developed to predict mortality risk across all subtypes of chronic ILD. The purpose of this study was to validate the ILD-GAP risk prediction model in patients with MA-ILD.

Procedures: We completed a retrospective cross-sectional study of patients enrolled in the Johns Hopkins Myositis Center database between 2006 and 2017. Cumulative mortality rates were estimated using the Kaplan-Meier test. Model calibration was determined by using standardized mortality ratios of observed versus expected deaths.

Main Findings: 179 participants with MA-ILD were included. The mean baseline percent predicted forced vital capacity was 65.2 ± 20.6%, forced expiratory volume in the first second 65.4 ± 20.4%, and carbon monoxide diffusing capacity 61.6 ± 20.0%. Thirty-two participants died (17.9%). The ILD-GAP model had poor discriminative performance and calibration.

Conclusions: The ILD-GAP risk prediction model is a poor predictor of mortality among individuals with MA-ILD. The identification of a better predictive model for MA-ILD is needed to help guide care in this patient population.
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http://dx.doi.org/10.1016/j.rmed.2019.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461370PMC
April 2019

Myositis Autoantigen Expression Correlates With Muscle Regeneration but Not Autoantibody Specificity.

Arthritis Rheumatol 2019 08 18;71(8):1371-1376. Epub 2019 Jun 18.

National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, and Johns Hopkins University School of Medicine, Baltimore, Maryland.

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.
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http://dx.doi.org/10.1002/art.40883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663619PMC
August 2019

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

Neurology 2019 03 1;92(13):e1416-e1426. Epub 2019 Mar 1.

From the Muscle Disease Unit (M.C.-D., I.P.-F., A.L.M.), Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda; Departments of Neurology (M.C.-D., I.P.-F., A.M.C., L.C.-S., A.L.M.) and Medicine (J.P., J.A., L.C.-R., C.J., S.K.D., L.C.-S., E.T., A.L.M.), Johns Hopkins University School of Medicine, Baltimore, MD; and Faculty of Health Sciences (J.P.-F.), Universitat Oberta de Catalunya, Barcelona, Spain.

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 < 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 < 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.
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http://dx.doi.org/10.1212/WNL.0000000000007188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453768PMC
March 2019

Successful treatment of refractory mechanic's hands with ustekinumab in a patient with the antisynthetase syndrome.

Rheumatology (Oxford) 2019 07;58(7):1307-1308

Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda.

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http://dx.doi.org/10.1093/rheumatology/kez020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821353PMC
July 2019